Gastro-retentive sustained release formulations of amoxicillin

Abstract

The present application relates to a kind of amoxicillin gastric retention sustained-release preparation, which contains amoxicillin, sustained-release material, swelling agent and other pharmaceutical adjuvant, preferably also contains stabilizer or ion regulator.The combination of the above-mentioned adjuvant can be retained in the stomach for up to 24 hours, the complete release time is 10-24h, which can significantly prolong the retention time of amoxicillin in the stomach, has the advantages of fast floating, high effective concentration of drug in the stomach, long stable concentration time, and is beneficial to reduce the frequency of drug administration of patients;Further preferably, it is made into a double-layer tablet containing immediate-release layer, which can quickly reach effective concentration and also can be released slowly and continuously, maintaining effective concentration for a long time;When combined with proton pump inhibitors such as vonolabian, etc., combination kit or compound, only 1-2 times per day is needed, which can further improve the therapeutic effect and patient compliance.

Description

Technical Field

[0001] This invention relates to a gastric retention sustained-release formulation with amoxicillin as the main drug and its preparation method, belonging to the field of pharmaceutical preparations. Background Technology

[0002] Helicobacter pylori (Hp) is a Gram-negative spiral-shaped bacterium. Hp infection is associated with many upper gastrointestinal diseases such as atrophic gastritis and peptic ulcers. Evidence suggests that patients infected with Hp are more likely to develop gastric cancer and mucosa-associated lymphoid lymphoma (MALT). Eradication of Hp can prevent these diseases and halt their progression.

[0003] Amoxicillin is an antibiotic, also known as amoxicillin, belonging to the aminopenicillin class of the penicillin family. It is a major type of second-generation penicillin, a broad-spectrum semi-synthetic antibiotic that inhibits bacterial cell wall synthesis, has highly effective broad-spectrum antibacterial activity, and has few toxic side effects.

[0004] Amoxicillin has little post-antibiotic effect against Helicobacter pylori (HP) and is a basic antibiotic in HP eradication programs. Its bactericidal efficacy depends on the time the concentration exceeds the minimum inhibitory concentration (MIC), which is low (MIC: 0.03 mg / L). Therefore, the antibacterial effect of amoxicillin against Helicobacter pylori is time-dependent; that is, the longer amoxicillin acts on the bacteria, the better its antibacterial effect.

[0005] Amoxicillin is a time-dependent antibiotic with a short half-life (less than 1.5 hours), rapid absorption, and excretion in urine within 6-8 hours. Its concentration above the minimum inhibitory concentration (MIC) is maintained for a relatively short period. The longer the concentration exceeds the MIC, the greater its effectiveness. Because Helicobacter pylori resides in the gastric mucosa of the stomach wall, conventional oral antibiotic treatment requires the antibiotic to be absorbed into the bloodstream through the intestines and then transported to the gastric mucosa via blood circulation. The actual effective concentration at the lesion site is relatively low. To maintain an effective inhibitory concentration, large doses of antibiotics are needed, or multiple doses per day. Therefore, in clinical practice, when used to eradicate H. pylori, the dosage of amoxicillin is often 3g / day (0.75g*4 times / day or 1.0g*3 times / day), a high dose taken 3-4 times daily, leading to increased side effects and poor patient compliance due to the need for frequent dosing.

[0006] Currently, amoxicillin preparations available on the market include capsules, tablets, and granules. Since the lesions of acute and chronic gastritis and peptic ulcers are primarily located in the stomach, specifically the gastric mucosa, amoxicillin's mechanism of action in treating these diseases mainly involves directly killing Helicobacter pylori in the gastric mucosa, thereby protecting the gastric mucosa and preventing ulcers. However, currently available amoxicillin capsules, tablets, and granules have a short residence time in the stomach, generally 0.5 to 2 hours. Therefore, increasing the dosage and frequency of amoxicillin administration is necessary to increase the contact time between amoxicillin and the gastric mucosa, maintain an effective drug concentration in the blood, and thus improve the bactericidal effect against Helicobacter pylori, thereby increasing the success rate of treatment. However, the short residence time of existing amoxicillin preparations in the stomach means that most of the drug is excreted into the small intestine before it can reach the lesions in the stomach, resulting in a lack of sustained efficacy and potential systemic side effects. If amoxicillin is formulated into a gastric retention drug system, the active ingredient can be retained in the stomach for a long time and released slowly, acting on the lesion site in the stomach for a long time, usually for more than 8 hours, thus significantly prolonging the drug's efficacy.

[0007] Amoxicillin is mainly absorbed in the upper part of the small intestine. If amoxicillin is formulated into a gastric retention sustained-release preparation, it can prolong its residence time in the stomach, allowing it to gradually release amoxicillin and have sufficient contact with Helicobacter pylori for a longer period of time, thus killing it. On the other hand, it can also be gradually transported to the duodenum and jejunum to achieve full absorption, improve bioavailability, reduce the frequency of medication, and improve clinical compliance.

[0008] Amoxicillin can be formulated as a gastric retention preparation in the following ways: 1. Gastric floating type: A formulation with a density less than the stomach contents. After entering the stomach, it floats on the surface of the gastric juice, prolonging the drug's residence time in the stomach. This is generally achieved by adding low-density excipients, such as fatty acids, fatty alcohols, waxes, and other hydrophobic materials, to reduce the overall density of the formulation. For example, some gastric floating tablets float on the gastric juice like small boats, slowly releasing the drug.

[0009] 2. Gastric expansion type: The preparation expands after entering the stomach, increasing in volume and making it difficult to pass through the pylorus, thus remaining in the stomach. This type mainly utilizes water-absorbing and swelling materials, such as crospovidone and sodium carboxymethyl cellulose. The drug is encapsulated in these materials, and upon entering the stomach, the materials absorb water, causing the preparation to expand and prolonging its retention time in the stomach.

[0010] 3. Bioadhesive type: This type utilizes bioadhesive materials to allow the formulation to adhere to the surface of the gastric mucosa or epithelial cells. These materials contain groups that can interact with the gastric mucosal surface, such as polymers with carboxyl or hydroxyl groups, like carbomer and chitosan. Through the interaction between these groups and gastric mucosal glycoproteins, the drug formulation adheres to the stomach for a long time.

[0011] 4. Effervescent formulation: This type of formulation contains effervescent disintegrants, typically organic acids (such as citric acid) and bicarbonates (such as sodium bicarbonate). Upon contact with water, the acid and carbonate react to produce a large amount of carbon dioxide gas. This carbon dioxide gas causes the formulation to expand, and since its density is less than that of gastric juice, it floats on the surface of the stomach. This prolongs the drug's residence time in the stomach, achieving a slow release and increased drug absorption.

[0012] For example, Chinese patent CN200710304012.3 (CN101467957A) relates to a method for preparing amoxicillin gastric floating tablet and its application. This novel dosage form is characterized by the gastric floating tablet comprising a hydrophilic gel material hydroxypropyl methylcellulose, an auxiliary floating material cetyl alcohol or stearic acid, a foaming agent sodium bicarbonate or magnesium carbonate, and a release regulator polyethylene glycol. Due to the presence of multiple hydrophilic polymers, upon contact with gastric juice, the surface hydrates into a gel, causing volume expansion. Combined with the gas produced by the reaction of the foaming agent with gastric acid, the tablet's weight is less than the buoyancy of the gastric juice, allowing the tablet to float on top and prolonging its residence time in the stomach. The problems with this tablet are: the foaming agent requires a certain amount of time to take effect and cannot achieve rapid floating; during the floating process, the formulation is easily damaged by food pressure and may even be expelled from the stomach, resulting in a short gastric residence time; furthermore, the foaming agent's mechanism of action is to produce gas, which may cause discomfort symptoms such as bloating and belching.

[0013] Chinese patent CN201410116Y discloses an amoxicillin-sulbactam-pivoxil dual-release capsule, comprising a capsule shell and two types of micro-tablets filled within the capsule shell. The two types of micro-tablets are sulbactam-pivoxil immediate-release micro-tablets and amoxicillin gastric-floating sustained-release micro-tablets. The amoxicillin gastric-floating sustained-release micro-tablets are composed of: amoxicillin 125mg, hydroxypropyl methylcellulose (HPMC) 60mg, cetyl alcohol 60mg, crospovidone 12mg, magnesium stearate 2mg, and mannitol 6mg. The problem with this tablet is that the micro-tablets themselves cannot float; their flocculation relies mainly on the capsule. However, the capsule quickly becomes completely wetted and softened, making it more susceptible to compression and shell breakage, leading to easier expulsion from the stomach. This shortens the contact time with the stomach and reduces the bactericidal effect. Summary of the Invention

[0014] The gastric retention mechanism of amoxicillin sustained-release formulations in existing technologies CN200710304012.3 and CN201410116Y is gastric floating. The hydrophilic polymers such as hydroxypropyl cellulose in these formulations require a certain amount of time to absorb water and swell in the stomach, potentially resulting in a significant delay in the floating time. Furthermore, when hydroxypropyl methylcellulose is used as the gel backbone, the sample strength is low, and it may be prematurely expelled from the stomach due to gastric peristalsis, leading to a short effective gastric retention time. Additionally, the backbone structure formed by cetyl alcohol in the later stages of drug release is relatively dense, preventing complete release of some drug and reducing bioavailability.

[0015] To address the shortcomings of existing technologies, the inventors have conducted in-depth research and provided an amoxicillin sustained-release formulation that can achieve gastric retention. This sustained-release formulation has the following characteristics: (1) The amoxicillin gastric retention sustained-release formulation of the present invention has a gastric retention time of more than 8 hours, and up to 24 hours. It also has a certain rigidity during the gastric retention period, which can prevent gastric peristalsis from causing the formulation to be expelled from the body too early.

[0016] (2) The amoxicillin in the gastric retention sustained-release formulation of the present invention is usually completely dissolved and released within 10 to 12 hours, maintaining a high effective concentration of amoxicillin in the stomach for a long period of time. It can be taken twice a day, which reduces the number of times it can be taken compared with existing amoxicillin formulations and improves patient compliance.

[0017] (3) The present invention also provides a long-release amoxicillin gastric retention sustained-release formulation, which can continuously dissolve and release amoxicillin for up to 20-24 hours, and maintain the effect for a longer period of time, so that it can be taken only once a day.

[0018] (3) The preparation process of the present invention is simple and easy to implement.

[0019] (4) The strength of a single gastric retention sustained-release formulation is 250-750 mg (calculated as amoxicillin), wherein the preferred strength of a gastric retention sustained-release formulation with a complete release time of 10-12 h is 250-500 mg, such as 250 mg, 375 mg, 500 mg; and the strength of a gastric retention sustained-release formulation with a complete release time of 20-24 h is 500-750 mg.

[0020] To achieve the above-mentioned objectives, the present invention provides the following technical solution: (i) The first technical solution of the present invention provides an amoxicillin sustained-release formulation with a complete release time of 10-12 hours, comprising amoxicillin, sustained-release material, swelling agent and other pharmaceutical excipients. The formulation is available in strengths of 250-500 mg, such as 250 mg, 375 mg, and 500 mg, preferably 375 mg.

[0021] The sustained-release material in the aforementioned amoxicillin sustained-release formulation can alter (e.g., slow down) the drug's release characteristics.

[0022] The sustained-release material is selected from polyethylene glycol, povidone, polyvinyl acetate, carbomer, chitosan, sodium alginate, and hydroxypropyl methylcellulose, etc. These sustained-release materials can be used alone or in combination of two or more. Among them, a commercially available mixture of polyvinyl acetate and povidone in a weight ratio of 80 / 20 is preferred.

[0023] The gastric floating sustained-release formulation of the present invention has a total weight of sustained-release material of 5% to 70% of the formulation weight and a release time of 10-12 hours. The preferred dosage is 10% to 50% of the formulation weight, and the optimal dosage is 20% to 45% of the formulation weight.

[0024] In the aforementioned amoxicillin sustained-release formulation, the swelling agent can absorb water from gastric juice, thereby expanding the size of the solid formulation, and can also affect the drug release rate by, for example, creating channels or forming hydrophilic colloids. The swelling agent may be water-soluble or water-insoluble. The swelling agent of the present invention may be selected from one or more of crospovidone, crospovidone, sodium carboxymethyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0025] The sustained-release formulation of the present invention is a gastric floating sustained-release formulation in which the swelling agent is 10% to 70% of the formulation weight and the release time is 10-12 hours. The preferred dosage is 20% to 50% of the formulation weight, and the optimal dosage is 35% to 45% of the formulation weight.

[0026] In the aforementioned amoxicillin sustained-release formulation, the other pharmaceutical excipients are lubricants and fillers.

[0027] The lubricant of the present invention has excellent lubrication properties, significantly reducing friction between particles and between particles and the die, resulting in a smooth tablet surface that is easy to eject from the die. The lubricant of the present invention is magnesium stearate, used in tablets at a dosage of 0.25% to 5%.

[0028] The filler in this invention primarily functions to increase the weight and volume of the tablets, thereby reducing major dosage deviations. The filler in this invention is selected from one or more combinations of lactose, sucrose, D-mannitol, calcium hydrogen phosphate, calcium sulfate, sorbitol, xylitol, and microcrystalline cellulose, and is used in the formulation at a dosage of 0% to 15%.

[0029] The sustained-release formulation of the present invention is suitable for oral administration, such as in the form of solid medicines like tablets or capsules, with tablets being preferred.

[0030] Amoxicillin exhibits poor stability in both acidic and alkaline environments. As a β-lactam antibiotic, its β-lactam ring is easily destroyed by acids and alkalis. For example, under acidic conditions in the stomach, the β-lactam ring may undergo a ring-opening reaction, leading to structural damage and loss of antibacterial activity. To prevent degradation of amoxicillin in acidic environments, it is preferable to add stabilizers to the formulation to maintain a near-neutral pH. When used in combination with proton pump inhibitors such as omeprazole or vonoprazan, or in combination formulations, the proton pump inhibitors can inhibit gastric acid secretion, raising the gastric pH to above 4.0. In such cases, stabilizers may be unnecessary or minimally added.

[0031] The stabilizer described in this invention is an alkaline compound or an alkaline buffer system, which needs to be added to adjust the pH of the formulation's microenvironment to be neutral. The alkaline compound includes: alkaline salts, oxides, and hydroxides, such as sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium oxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, sodium citrate, etc.; the alkaline buffer system includes phosphate buffer systems and bicarbonate buffer systems, such as a buffer pair composed of dihydrogen phosphate and hydrogen phosphate, or a buffer pair composed of carbonic acid (H₂CO₃) and bicarbonate ions (HCO₃⁻). The stabilizer dosage is 0% to 20% of the formulation dosage, and the sum of all components is 100%.

[0032] In summary, the first technical solution of the present invention provides an amoxicillin sustained-release formulation with a complete release time of 10-12 hours, which comprises amoxicillin, sustained-release material, swelling agent and other pharmaceutical excipients, including lubricant and filler. Besides the active pharmaceutical ingredient amoxicillin, the sustained-release material comprises 5%–70%, the swelling agent 10%–70%, the lubricant 0.25%–5%, and the filler 0%–15%, with the total amount of all components being 100%. Preferably, besides the active pharmaceutical ingredient amoxicillin, the sustained-release material comprises 20%–50%, the swelling agent 20%–50%, the lubricant 0.25%–5%, and the filler 0%–15%, with the total amount of all components being 100%. Most preferably, besides the active pharmaceutical ingredient amoxicillin, the sustained-release material comprises 20%–45%, the swelling agent 35%–45%, the lubricant 0.25%–5%, and the filler 0%–15%, with the total amount of all components being 100%. Further preferably, it also contains the aforementioned stabilizer, at an amount of 0%–20% of the formulation weight, with the total amount of all components being 100%.

[0033] Another object of the present invention is to provide a method for preparing an amoxicillin sustained-release formulation.

[0034] To prepare pharmaceutical products, a hopper mixer is typically used to dry-mix the components of a drug composition, followed by compaction of the resulting mixture in a tableting machine to produce individual dosage forms (tablets). To improve product homogeneity, components may be combined and mixed in stages. For example, APIs may be granulated with one or more components using fluidized bed or extrusion granulation, and then mixed with the remaining components. Similarly, APIs may first be dry-mixed with one or more matrix-forming agents, and then subsequently mixed with swelling agents, fillers, lubricants, etc., in one or more mixing operations. If necessary, the size of one or more components may be controlled prior to mixing by sieving or grinding, or both. Further processing, such as polishing and coating, may be performed on the compressed dosage form to prepare the final drug product.

[0035] The amoxicillin sustained-release formulation composition of the present invention can be prepared according to the following method: (1) Mix amoxicillin with the sustained-release material, swelling agent and filler, and stabilizer (if any) using a hopper mixer until homogeneous; (2) Add lubricant to the well-mixed (1) and mix thoroughly; (3) Compress the mixed (2) into tablets using a tablet press.

[0036] (4) The amoxicillin sustained-release formulation of the present invention can also be coated with a film coating material to improve the appearance of the tablet and further improve the stability of the tablet.

[0037] (ii) The second technical solution of the present invention provides an amoxicillin gastric retention bilayer sustained-release formulation comprising an amoxicillin immediate-release layer and a sustained-release layer.

[0038] When amoxicillin preparations are used to kill Helicobacter pylori, it is preferable to have a high release rate in the early stage of release in the stomach, so that amoxicillin can be rapidly released to reach a high effective concentration in a short time. After administration, it can quickly play a role in treating Helicobacter pylori. Then, in the subsequent time, amoxicillin is released continuously and stably to maintain the effective concentration of amoxicillin for a longer period of time.

[0039] To achieve the above objectives, the present invention also provides an amoxicillin gastric retention bilayer sustained-release formulation, which is a bilayer tablet comprising an immediate-release layer and a sustained-release layer. An immediate-release layer is added to the aforementioned sustained-release tablet layer. Upon entering the stomach, the immediate-release layer is rapidly released, quickly reaching the effective concentration of amoxicillin in the stomach. Subsequently, the sustained-release layer sustainably and stably maintains the effective concentration of amoxicillin. This characteristic is not possessed by the single-layer gastric floating sustained-release tablet of the prior art (CN200710304012.3).

[0040] The immediate-release layer of the aforementioned amoxicillin gastric retention bilayer sustained-release formulation comprises amoxicillin, filler, disintegrant, and lubricant.

[0041] The filler for the immediate-release layer described in this invention is selected from one or a combination of lactose, sucrose, D-mannitol, sorbitol, xylitol, and microcrystalline cellulose.

[0042] The disintegrant of the immediate-release layer described in this invention is selected from one or more of the following: dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and crospovidone carboxymethyl cellulose.

[0043] The lubricant in the quick-release layer of this invention is magnesium stearate.

[0044] The amoxicillin gastric retention bilayer sustained-release formulation of the present invention comprises amoxicillin accounting for approximately 20% to 40% of the weight of the immediate-release layer, a filler accounting for approximately 20% to 80%, a disintegrant accounting for approximately 1% to 15%, and a lubricant accounting for approximately 0.5% to 5%, with the sum of all the above components being 100%.

[0045] The amoxicillin gastric retention bilayer sustained-release formulation of the present invention has the same sustained-release layer formulation composition as the amoxicillin gastric retention sustained-release formulation with a release time of 10-12h in the first technical solution of the present invention (I) mentioned above.

[0046] The amoxicillin gastric retention bilayer sustained-release formulation of the present invention has an amoxicillin weight ratio of 20-40:60-80 in the immediate-release layer and 20:60:80 in the sustained-release layer, for example, 20:80, 25:75, 30:70, 35:65, or 40:60. After conversion, the amoxicillin in the immediate-release layer accounts for 20%-40% of the total weight of amoxicillin.

[0047] The amoxicillin gastric retention sustained-release formulation of the present invention allows amoxicillin to be completely dissolved after 10-12 hours. When used in combination with vonoprazan in the treatment of Helicobacter pylori, the dosage is the same as vonoprazan, and they can be taken simultaneously twice a day to improve patient compliance.

[0048] The amoxicillin gastric retention sustained-release formulation of the present invention will not be used in combination with formulations such as vonoprazan when treating various infectious diseases such as respiratory tract infections, genitourinary infections, and skin and soft tissue infections. In order to avoid gastric acid causing amoxicillin degradation, a stabilizer is preferably added to the formulation. The type of stabilizer is the same as the stabilizer in the first technical solution of the present invention (I) mentioned above.

[0049] (iii) The third technical solution of the present invention provides a combination of amoxicillin gastric retention sustained-release formulation and proton pump inhibitor, specifically including combination kits or compound formulations.

[0050] As a preferred embodiment, a combination pillbox is provided. The amoxicillin gastric retention sustained-release formulation of the present invention can completely dissolve amoxicillin after 10-12 hours. Therefore, it can be combined with a proton pump inhibitor, preferably vonoprazan, to form a combination pillbox. That is, the amoxicillin gastric retention sustained-release formulation and vonoprazan tablets are packaged in one medicine package for simultaneous administration, twice a day, further improving patient compliance.

[0051] As another preferred option, a compound amoxicillin gastric retention sustained-release formulation is provided, wherein the formulation contains, in addition to the amoxicillin gastric retention sustained-release portion, a proton pump inhibitor, preferably vonoprazan or its pharmaceutical salt.

[0052] Amoxicillin belongs to the β-lactam antibiotic class, and its β-lactam ring is easily destroyed by acids and alkalis. For example, under acidic conditions in the stomach, the β-lactam ring may undergo a ring-opening reaction, leading to the destruction of the drug's structure and loss of antibacterial activity. Therefore, amoxicillin is used in combination with proton pump inhibitors (PPIs) to treat Helicobacter pylori, such as omeprazole, lansoprazole, pantoprazole, and rabeprazole. PPIs inhibit gastric acid secretion, preventing amoxicillin from being destroyed under acidic conditions. Vonoprazan is a novel potassium-competitive acid blocker that inhibits gastric acid secretion by competitively inhibiting potassium ions on gastric parietal cells.

[0053] Currently, the dual-dose regimen of vonoprazan plus high-dose amoxicillin is used to treat Helicobacter pylori. After multiple clinical studies, its efficacy and safety have been clearly demonstrated, leading to its consistent recommendation in domestic and international guidelines. However, this dual-dose regimen requires amoxicillin at 3g / day (0.75g x 4 times / day or 1.0g x 3 times / day) and vonoprazan at 20mg x 2 times / day. The frequent dosing and inconsistent dosing frequencies of the two drugs make it inconvenient and prone to errors for patients.

[0054] Therefore, the present invention also provides a compound amoxicillin gastric retention sustained-release formulation, wherein the formulation contains, in addition to the amoxicillin gastric retention sustained-release portion, a proton pump inhibitor, preferably vonoprazan or its pharmaceutical salt. This compound formulation, on the one hand, can effectively treat Helicobacter pylori, and on the other hand, reduces the number of doses required, making it more convenient for patients and improving patient compliance.

[0055] The above-mentioned compound amoxicillin gastric retention sustained-release preparation is preferably a bilayer tablet. The first layer contains amoxicillin, and the prescription composition is the same as that of the amoxicillin gastric retention sustained-release preparation with a release time of 10-12h in the first technical solution of the present invention (I) above. The second layer contains vonoprazan or its pharmaceutical salt, and the prescription composition includes vonoprazan fumarate, filler, disintegrant, binder and lubricant.

[0056] In the above-mentioned amoxicillin sustained-release formulation, the filler in the second layer (containing vonoprazan or its pharmaceutical salt) is selected from one or more of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, sorbitol, and sucrose. The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. The binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and povidone.

[0057] The lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, micronized silica gel, and talc.

[0058] The second layer of the above-mentioned amoxicillin sustained-release formulation (containing vonoprazan or its pharmaceutical salt) has the following proportions of each component in the second layer: vonoprazan fumarate 5%~15%, filler 60%~80%, disintegrant 0%~10%, binder 1%~5%, lubricant 0.5%~5%, and the sum of all the above components is 100%.

[0059] The compound amoxicillin gastric retention sustained-release formulation of the present invention, wherein the amoxicillin portion can be completely dissolved after 10-12 hours, is taken twice a day, and the method of administration is the same as that of single-agent vonoprazan, ensuring clinical efficacy and facilitating improved patient compliance.

[0060] (iv) The fourth technical solution of the present invention provides a compound amoxicillin gastric retention sustained-release formulation. This compound formulation contains, in addition to the amoxicillin gastric retention sustained-release portion, amoxicillin immediate-release portion and a proton pump inhibitor, preferably vonoprazan or its pharmaceutical salt. In this compound formulation, vonoprazan can be rapidly released and maintain the gastric pH between 4.5 and 7.0. Simultaneously, amoxicillin has a high release rate in the early stage of release, quickly reaching an effective concentration. The sustained-release layer stably and continuously maintains the effective concentration of amoxicillin.

[0061] The above-mentioned compound amoxicillin preparation is a bilayer tablet. The sustained-release layer has the same formulation as the sustained-release preparation with a release time of 10-12h in the first technical solution of the present invention (I) mentioned above. The immediate-release layer has a formulation including amoxicillin, vonoprazan, filler, disintegrant and lubricant.

[0062] The filler for the immediate-release layer described in this invention is selected from one or a combination of lactose, sucrose, D-mannitol, sorbitol, xylitol, and microcrystalline cellulose.

[0063] The disintegrant of the immediate-release layer described in this invention is selected from one or more of the following: dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and crospovidone carboxymethyl cellulose.

[0064] The lubricant in the quick-release layer of this invention is magnesium stearate.

[0065] The amoxicillin gastric retention bilayer sustained-release formulation of the present invention comprises amoxicillin accounting for approximately 20% to 40% of the weight of the immediate-release layer, vonoprazan accounting for approximately 0.5% to 1%, filler accounting for approximately 20% to 80%, disintegrant accounting for approximately 1% to 15%, and lubricant accounting for approximately 0.5% to 5%, with the sum of all the above components being 100%.

[0066] The compound amoxicillin formulation of the present invention comprises an immediate-release layer in which amoxicillin is rapidly released to reach an effective concentration and has a fast onset of action; and a sustained-release layer in which amoxicillin maintains a high effective concentration for a long time. At the same time, vonoprazan or its pharmaceutical salt can regulate the pH in the stomach, prevent the degradation of amoxicillin, improve the bioavailability of amoxicillin, and enhance the therapeutic effect.

[0067] The methods for determining the dissolution profile, floating characteristics, and swelling properties of the amoxicillin gastric retention sustained-release formulation in this invention are as follows: 1. Medium pH The amoxicillin sustained-release formulation of the present invention is used in combination with vonoprazan in the treatment of Helicobacter pylori. Because vonoprazan can maintain the pH in the stomach between 4.0 and 7.5 for a long time after administration, the pH of the amoxicillin sustained-release formulation in the stomach environment is consistent with the pH maintained by vonoprazan.

[0068] The inventors investigated the liquid stability of amoxicillin in media at pH 4.5, pH 6.0, and pH 6.8. The degradation of amoxicillin in these media at pH 4.5, 6.0, and 6.8 was less than 3% after 8 hours. The above three media had a relatively small impact on the liquid stability of amoxicillin. Therefore, the release curve, floating characteristics, and swelling properties of the amoxicillin formulation of this invention were investigated in a medium at pH 4.5.

[0069] Meanwhile, when amoxicillin sustained-release formulations are used alone to treat infections of the respiratory tract, skin, and genitourinary tract, they are affected by gastric juice. Therefore, the release curve, floating characteristics, and swelling curve need to be investigated in 0.06 mol / L hydrochloric acid solution (approximately pH 1.2, which is close to the pH of gastric juice).

[0070] 2. Release curve determination method: According to Method II of the 2020 edition of the Chinese Pharmacopoeia, the release medium is 900 ml of degassed pH 4.5 medium or 0.06 mol / L hydrochloric acid solution, the rotation speed is 50 rpm, and the temperature is 37℃±5℃. At 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, and 24h, 10 ml of the release medium is taken, and an equal volume of fresh medium at the same temperature is added simultaneously. The mixture is filtered through a 0.45 μm PES microporous membrane, and 100 μl of the filtrate is injected into the high-performance liquid chromatograph. The peak area is measured at 254 nm. In addition, an appropriate amount of reference standard is accurately weighed and determined using the same method. The cumulative release percentage is calculated and should meet the requirements.

[0071] 3. Floating characteristics and swelling determination methods: The floating behavior of the drug in acidic medium was determined using the second method of dissolution determination in the 2020 edition of the Chinese Pharmacopoeia. The medium volume was 900 ml, the medium temperature was 37 ± 0.5℃, and the stirring speed was 50 rpm. The floating behavior of the drug after being added to the dissolution vessel was recorded. The size of the drug will increase over time. Drug samples were periodically removed from the dissolution medium, and their diameter was measured using a measuring instrument.

[0072] 4. Methods for detecting the retention of drugs in the stomach: Adding an X-ray-impermeable substance, such as barium sulfate, to tablets allows for observation of the tablet's position and morphology in the stomach over time using X-rays, recording the duration of the tablet's intact structure within the stomach. This method provides a direct visual representation of the tablet's position within the stomach.

[0073] (V) The fifth technical solution of the present invention provides an amoxicillin gastric retention sustained-release formulation with a complete release time of 20-24 hours, comprising amoxicillin, a sustained-release material, a swelling agent, and other pharmaceutical excipients. The preferred specification of this technical solution is 500mg-750mg. The sustained-release material is hydroxypropyl methylcellulose; the total amount of the sustained-release material is 5%-50% of the formulation weight, preferably 8%-40% of the formulation weight, optimally 10%-30% of the formulation weight, and the optimal value is 15%. The swelling agent is selected from crospovidone, polyoxyethylene, and sodium alginate; the total amount of the swelling agent is 10%-50% of the formulation weight, preferably 20%-48% of the formulation weight, optimally 25%-45% of the formulation weight, and the optimal value is 40%.

[0074] In the aforementioned amoxicillin sustained-release formulation, the other pharmaceutical excipients are ion modifiers, flow aids, and lubricants. The flow aid is selected from silica, the lubricant from magnesium stearate, and the ion modifier from calcium hydrogen phosphate; the total amount of lubricant is 0.5% to 5% of the formulation weight, the total amount of flow aid is 0.2% to 5% of the formulation weight, and the total amount of ion modifier is 0.5% to 5% of the formulation weight.

[0075] The sum of all the above components is 100%.

[0076] Therefore, the present invention provides an amoxicillin gastric retention sustained-release formulation with a complete release time of 20-24 hours, comprising amoxicillin, a sustained-release material, a swelling agent, and other pharmaceutical excipients, wherein the other pharmaceutical excipients are ion modifiers, flow aids, and lubricants; apart from amoxicillin, the composition, by weight, comprises: lubricant 0.5%~5%, flow aid 0.2%~5%, ion modifier 0.5%~5%, sustained-release material 6%~48%, and swelling agent 10%~50%, wherein a further preferred proportion is 7%~35%, swelling agent 20%~48%, most preferred proportion is 10%~30%, with an optimal value of 15%, and swelling agent 25%~45%, with an optimal value of 40%, and the sum of all the above components is 100%.

[0077] Another objective of this invention is to provide a method for preparing an amoxicillin sustained-release formulation with a complete release time of 20-24 hours. The method includes premixing, total mixing, tableting, and coating processes, with each process operated as follows: The materials, except for magnesium stearate, are premixed using a mixer. Then, magnesium stearate is added to the premix to obtain a total powder. This powder is then compacted using a tablet press to obtain unmixed tablets. The unmixed tablets are then coated to obtain coated tablets. If necessary, the size of one or more components can be controlled before mixing by sieving, grinding, or both.

[0078] The amoxicillin sustained-release formulation composition of the present invention, with a complete release time of 20-24 hours, can be prepared according to the following method: (1) Mix amoxicillin with sustained-release material, swelling agent, ion regulator and flow aid evenly using a mixer; (2) Add lubricant to the well-mixed (1) and mix thoroughly; (3) Compress the mixed (2) into tablets using a tablet press; (4) Coat the pressed (3) with a film coating material.

[0079] (vi) The sixth technical solution of the present invention provides a combination of amoxicillin gastric retention monolayer sustained-release formulation with a complete release time of 20-24h and a proton pump inhibitor, particularly a combination drug box.

[0080] This invention provides an amoxicillin gastric retention sustained-release formulation with a complete release time of 20-24 hours, allowing for sustained amoxicillin release for up to 24 hours. When used in combination with vonoprazan in the treatment of Helicobacter pylori, it can be taken concurrently, once or twice daily, improving patient compliance. Compared to other smaller formulations with shorter release times, this further avoids the problems of frequent dosing and a higher number of tablets required.

[0081] As a preferred option, amoxicillin gastric retention sustained-release formulations with a complete release time of 20-24 hours can be packaged with vonoprazan formulations in a combination pack. This means that amoxicillin gastric retention sustained-release formulations and vonoprazan tablets are packaged together in one medicine package for simultaneous administration, twice a day, or amoxicillin gastric retention sustained-release formulations can be taken once a day, further improving patient compliance.

[0082] The amoxicillin sustained-release formulation of the present invention will not be used in combination with formulations such as vonoprazan when treating various infectious diseases such as respiratory tract infections, genitourinary infections, skin and soft tissue infections. In order to avoid the degradation of amoxicillin caused by gastric acid, it is preferable to add a stabilizer to the formulation. The type of stabilizer is the same as the stabilizer in the first technical solution of the present invention (I) mentioned above.

[0083] The method for determining the dissolution profile of amoxicillin gastric retention sustained-release formulations with a complete release time of 20-24 hours is as follows: Amoxicillin gastric retention sustained-release formulations with a complete release time of 20-24 hours require a long time to determine the release curve. Considering that in the paddle method, the tablets float on the liquid surface for a long time and one side cannot fully contact the medium, which cannot truly reflect its situation in the body, the basket method was chosen for dissolution testing.

[0084] According to Method I of the 2020 edition of the Chinese Pharmacopoeia, the release medium is 1000 ml of degassed pH 4.5 medium or 0.06 mol / L hydrochloric acid solution, the rotation speed is 100 rpm, and the temperature is 37℃±5℃. At 4h, 6h, 8h, 12h, 16h, 20h, and 24h, 10 ml of the release medium is taken, and an equal volume of fresh medium at the same temperature is added simultaneously. The medium is filtered through a 0.45 μm PES microporous membrane, and 100 μl of the filtrate is injected into a high-performance liquid chromatograph. The peak area is measured at 254 nm. In addition, an appropriate amount of reference standard is accurately weighed and measured using the same method. The cumulative release percentage is calculated and should meet the requirements. Through testing and comparison, the amoxicillin gastric retention sustained-release formulation of the present invention has the following advantages:

[0085] (1) The production process of this invention is simple and easy to operate.

[0086] (2) Amoxicillin gastric retention sustained-release formulation has strong buoyancy in slightly acidic media and floats immediately after being added to the dissolution vessel. It can float for 24 hours and maintains good tablet shape, and the expansion size also meets the condition of being larger than the pylorus, so it will not be excreted from the body prematurely.

[0087] (3) The amoxicillin gastric retention sustained-release formulation (double-layer tablet) of the present invention can rapidly release amoxicillin after entering the stomach, reaching an effective concentration for treating Helicobacter pylori. Subsequently, amoxicillin can be released continuously and stably to maintain the effective concentration of amoxicillin.

[0088] (4) The amoxicillin gastric retention sustained-release formulation of the present invention allows amoxicillin to be completely dissolved in 10-12 hours. When used in combination with the proton pump inhibitor vonoprazan in the treatment of Helicobacter pylori, the method of administration is the same as that of vonoprazan, and they can be taken at the same time, twice a day, which facilitates the improvement of patient compliance.

[0089] (5) The compound amoxicillin gastric retention sustained-release preparation of the present invention contains amoxicillin gastric retention sustained-release fraction and proton pump inhibitor vonoprazan. On the one hand, it can effectively treat Helicobacter pylori, and on the other hand, it reduces the amount of preparation to be taken, which is convenient for patients and improves patient compliance.

[0090] (6) Compared with the prior art CN200710304012.3 (CN101467957A) and CN201410116Y, the present invention has the following advantages: The gastric retention sustained-release tablets of the present invention can float in a short time and can float in the stomach for more than 24 hours; they have a good swelling effect, and the swelling size is larger than the average diameter of the human pylorus by 13mm, making them difficult to be discharged from the stomach, thereby prolonging their residence time in the stomach, allowing the active ingredients to be retained in the stomach for a long time and released slowly, and having long and sufficient contact with pathogens, thus improving the killing effect and significantly prolonging the efficacy.

[0091] (7) For amoxicillin gastric retention sustained-release formulations with a complete release time of 20-24 hours, after testing and comparison, the following advantages were found: (1) The production process of this invention is simple and easy to operate.

[0092] (2) Amoxicillin gastric retention sustained-release formulation has strong buoyancy in slightly acidic media and floats immediately after being added to the dissolution vessel. It can float for 24 hours and maintains good tablet shape, and the expansion size also meets the condition of being larger than the pylorus, so it will not be excreted from the body prematurely.

[0093] (3) The amoxicillin gastric retention sustained-release formulation of the present invention provides sustained release of amoxicillin for 24 hours. When used in combination with the proton pump inhibitor vonoprazan in the treatment of Helicobacter pylori, the method of administration is the same as that of vonoprazan, and they can be taken at the same time, twice a day. Compared with other formulations with shorter release times, fewer tablets are required, which helps to improve patient compliance.

[0094] Attached image description.

[0095] Figure 1 Dissolution curve of amoxicillin sustained-release formulation in Example 1 Figure 2 Dissolution curve of amoxicillin sustained-release formulation in Example 2 Figure 3 Dissolution curve of amoxicillin sustained-release formulation in Example 3 Figure 4Dissolution curve of amoxicillin sustained-release formulation in Example 4 Figure 5 Dissolution curve of amoxicillin sustained-release formulation in Example 5 Figure 6 Dissolution curve of amoxicillin sustained-release formulation in Example 6 Figure 7 Dissolution curve of amoxicillin sustained-release formulation in Example 7 Figure 8 Dissolution curve of amoxicillin sustained-release formulation in Example 8 Figure 9 Dissolution curve of amoxicillin sustained-release formulation in Example 9 Figure 10 Dissolution curve of amoxicillin sustained-release formulation in Example 12 Figure 11 Dissolution curve of amoxicillin sustained-release formulation in Example 13 Figure 12 Dissolution curve of amoxicillin sustained-release formulation in Example 14 Figure 13 The dissolution curve of the amoxicillin sustained-release formulation in 0.06 mol / L hydrochloric acid solution is shown in Example 15. Figure 14 Dissolution curve of amoxicillin sustained-release formulation in Example 18 Figure 15 Dissolution curve of amoxicillin sustained-release formulation in Example 19 Figure 16 Dissolution curve of amoxicillin sustained-release formulation in Example 20 Figure 17 Dissolution curve of amoxicillin sustained-release formulation in Example 21 Figure 18 Dissolution curve of amoxicillin sustained-release formulation in Example 22 Figure 19 Dissolution curve of amoxicillin sustained-release formulation in Example 23 Figure 20 Dissolution curve of amoxicillin sustained-release formulation in Example 24 Detailed Implementation

[0096] The invention will be described in more detail with the application of the following embodiments. However, the following embodiments are provided for illustrative purposes only and are not intended to limit the invention.

[0097] Example 1

[0098] Preparation process of Examples 1-11: (1) Take amoxicillin of appropriate particle size and other excipients except magnesium stearate, and mix them evenly in a hopper mixer.

[0099] (2) Add the prescribed amount of magnesium stearate to the well mixed (1) and mix thoroughly.

[0100] (3) Use a tablet press to compress the total mixed granules into tablets. The punch size is (seed-shaped, 22*10.8mm), and the tablet hardness is 160N~210N.

[0101] The amoxicillin sustained-release formulation prepared in this invention is used in combination with vonoprazan for the eradication of Helicobacter pylori. Vonoprazan is a novel potassium-competitive acid blocker that inhibits gastric acid secretion by competitively inhibiting potassium ions on gastric parietal cells, thus maintaining the gastric pH between 4.0 and 7.5. The release rate, buoyancy, and swelling of the formulations prepared according to Examples 1-17 were tested in a pH 4.5 medium.

[0102] Methods for detecting the release rate of amoxicillin extended-release formulations: According to Method II of the 2020 edition of the Chinese Pharmacopoeia, the release medium was 900 ml of degassed pH 4.5 medium, the rotation speed was 50 rpm, and the temperature was 37℃±5℃. At 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, and 24h, 10 ml of the release medium was taken, and an equal volume of fresh medium at the same temperature was added simultaneously. The mixture was filtered through a 0.45 μm PES microporous membrane, and 100 μl of the filtrate was injected into a high-performance liquid chromatograph. The peak area was measured at 254 nm. Separately, an appropriate amount of reference standard was accurately weighed and measured using the same method to calculate the cumulative release percentage.

[0103] The release rate of the amoxicillin sustained-release formulation in Example 1 is shown in the figure. Figure 1 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 151 mg polyvinyl acetate and polyvinylpyrrolidone mixture, 56 mg carbomer, 225 mg polyoxyethylene, 281 mg crospovidone, 100 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0104] Example 2

[0105] The release rate of the amoxicillin sustained-release formulation in Example 2 is shown in [reference needed]. Figure 2 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 56 mg polyvinyl acetate and polyvinylpyrrolidone mixture, 151 mg sodium alginate, 225 mg polyoxyethylene, 281 mg crospovidone, 100 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0106] Example 3

[0107] The release rate of the amoxicillin sustained-release formulation in Example 3 is shown in [reference needed]. Figure 3 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 56 mg carbomer, 151 mg hydroxypropyl methylcellulose, 225 mg polyoxyethylene, 281 mg crospovidone, 100 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0108] Example 4

[0109] The release rate of the amoxicillin sustained-release formulation in Example 4 is shown in [reference needed]. Figure 4 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 290 mg sodium alginate, 182 mg polyoxyethylene, 200 mg crospovidone, 60 mg dicalcium phosphate, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0110] Example 5

[0111] The release rate of the amoxicillin sustained-release formulation in Example 5 is shown in [reference needed]. Figure 5 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 207 mg hydroxypropyl methylcellulose, 225 mg polyoxyethylene, 281 mg crospovidone, 100 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0112] Example 6

[0113] The release rate of the amoxicillin sustained-release formulation in Example 6 is shown in [reference needed]. Figure 6 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 56 mg carbomer, 201 mg sodium alginate, 225 mg sodium carboxymethyl cellulose, 281 mg crospovidone, 50 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0114] Example 7

[0115] The release rate of the amoxicillin extended-release formulation in Example 7 is shown in [reference needed]. Figure 7 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 151 mg polyvinyl acetate and polyvinylpyrrolidone mixture, 56 mg sodium alginate, 275 mg sodium carboxymethyl cellulose, 281 mg crospovidone, 50 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0116] Example 8

[0117] The release rate of the amoxicillin extended-release formulation in Example 8 is shown in [example description]. Figure 8 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 151 mg hydroxypropyl methylcellulose, 352 mg polyoxyethylene, 260 mg crospovidone, 50 mg lactose, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0118] Example 9

[0119] The release rate of the amoxicillin sustained-release formulation in Example 9 is shown in [reference needed]. Figure 9 This indicates that the sustained-release formulation containing 375 mg amoxicillin, 284 mg sodium alginate, 70 mg dicalcium phosphate, 142 mg polyoxyethylene, 284 mg crospovidone, and 11 mg magnesium stearate per tablet has a good sustained-release effect.

[0120] Floating properties and swelling The amoxicillin sustained-release formulations prepared in Examples 1-9 were tested according to Method II (paddle method) of the Dissolution Test in Part II of the 2020 Chinese Pharmacopoeia. The test medium was pH 4.5 acetate buffer, with a medium volume of 900 ml, a rotation speed of 50 rpm, and a medium temperature of 37℃±5℃. Timing began as soon as the amoxicillin sustained-release formulation was added to the medium. The floating characteristics and the initial and final data of the length, width, and height of the formulation at 12 hours are shown in the table below.

[0121] Table 1. Floating characteristics of amoxicillin sustained-release formulations

[0122] Table 2. Swelling properties (length, width, height) of amoxicillin sustained-release formulations

[0123] Example 10

[0124] Example 11

[0125] In Examples 10 and 11, stabilizers such as magnesium hydroxide and sodium citrate were added to the sustained-release formulation. The release of amoxicillin in 0.06 mol / L hydrochloric acid solution was tested, as in Example 9. The release results showed that adding stabilizers to the formulation can effectively reduce the degradation of amoxicillin in 0.06 mol / L hydrochloric acid solution.

[0126] Table 3 Release rates of Examples 9, 10, and 11 in 0.06 mol / L hydrochloric acid

[0127] Example 12 Double-layer sheet Sustained-release layer

[0128] Immediate-release layer:

[0129] Preparation process of Examples 12-15: (1) Weigh amoxicillin of appropriate particle size and other excipients except magnesium stearate according to the formula of immediate-release layer and sustained-release layer, and mix them evenly in a hopper mixer.

[0130] (2) Add the prescribed amount of magnesium stearate to the well mixed (1) and mix thoroughly.

[0131] (3) Use a tablet press to compress the total mixture of immediate-release and sustained-release granules into tablets. The punch size is (seed-shaped, 22*10.8mm), and the tablet hardness is 160N~210N.

[0132] The release rate of the amoxicillin sustained-release formulation in Example 12 is shown in [the figure]. Figure 10 This indicates that the formulation with an amoxicillin weight ratio of 20:80 in the immediate-release layer and the sustained-release layer has a good sustained-release effect and a high release rate in the early stage of release.

[0133] Example 13 Double-layer sheet Sustained-release layer

[0134] Immediate-release layer:

[0135] The release rate of the amoxicillin sustained-release formulation in Example 13 is shown in [the figure]. Figure 11 This indicates that the formulation with an amoxicillin weight ratio of 30:70 in the immediate-release layer and the sustained-release layer has a good sustained-release effect and a high release rate in the early stage of release.

[0136] Example 13 Double-layer sheet Sustained-release layer

[0137] Immediate-release layer:

[0138] The release rate of the amoxicillin sustained-release formulation in Example 13 is shown in [the figure]. Figure 11 This indicates that the formulation with an amoxicillin weight ratio of 30:70 in the immediate-release layer and the sustained-release layer has a good sustained-release effect and a high release rate in the early stage of release.

[0139] Example 15: Double-layer sheet Sustained-release layer

[0140] Immediate-release layer:

[0141] The dissolution curve of the amoxicillin sustained-release formulation in 0.06 mol / L hydrochloric acid solution in Example 15 is shown below. Figure 13 Adding magnesium hydroxide as a stabilizer to the sustained-release formulation can increase the amoxicillin release rate to over 90% in about 12 hours.

[0142] Example 16: A compound preparation containing vonoprazan fumarate First layer:

[0143] Second layer:

[0144] Preparation method of Example 16: (1) First layer (containing amoxicillin): Take amoxicillin of appropriate particle size and mix it evenly with the excipients except magnesium stearate, then add magnesium stearate and mix evenly.

[0145] (2) Second layer (containing vonoprazan): Vonoprazan fumarate, stabilizer, filler and disintegrant are mixed evenly to obtain drug powder; the drug powder is granulated with an aqueous solution containing binder to make drug granules.

[0146] (3) The granules obtained in (1) and (2) are compressed into tablets using a tablet press.

[0147] In Example 16, after being introduced into a hydrochloric acid medium at 37°C and pH 1.2, the following phenomena were observed: the second layer (containing vonoprazan) completely disintegrated within 30 minutes, while the first layer (containing amoxicillin) absorbed water, swelled, and continued to float, releasing amoxicillin.

[0148] Example 17: Immediate-release layer containing a compound preparation of vonoprazan fumarate and amoxicillin Sustained-release layer

[0149] Immediate-release layer:

[0150] In Example 17, after being introduced into a hydrochloric acid medium at 37°C and pH 1.2, the following phenomena were observed: the second layer (containing vonoprazan fumarate and amoxicillin) completely disintegrated within 30 minutes, while the first layer (containing amoxicillin) absorbed water, swelled, and continued to float, releasing amoxicillin.

[0151] Example 18

[0152] Example 18, with an increased strength of 500mg, further reduced the dosage. The release rate of the amoxicillin extended-release formulation is shown in [reference needed]. Figure 14 A sustained-release formulation containing 500mg amoxicillin, 575mg hydroxypropyl methylcellulose, 20mg sodium alginate, 40mg polyoxyethylene, 60mg crospovidone, and 11mg magnesium stearate exhibits good sustained-release effects.

[0153] Example 19

[0154] Example 19, based on Example 18, adds dicalcium phosphate and silica to stabilize the system and improve flowability. The release rate of the amoxicillin sustained-release formulation is shown in [reference needed]. Figure 15 A sustained-release formulation containing 500mg amoxicillin, 80mg hydroxypropyl methylcellulose, 100mg sodium alginate, 100mg polyoxyethylene, 410mg crospovidone, 10mg dicalcium phosphate, 10mg silica, and 11mg magnesium stearate has a good sustained-release effect.

[0155] Example 20

[0156] The release rate of the amoxicillin extended-release formulation in Example 20 is shown in [reference needed]. Figure 16 This indicates that the sustained-release formulation containing 500mg amoxicillin, 420mg hydroxypropyl methylcellulose, 40mg sodium alginate, 80mg polyoxyethylene, 120mg crospovidone, 20mg dicalcium phosphate, 10mg silica, and 11mg magnesium stearate per tablet has a good sustained-release effect.

[0157] Example 21

[0158] The release rate of the amoxicillin extended-release formulation in Example 21 is shown in [the figure]. Figure 17 This indicates that the sustained-release formulation containing 500mg amoxicillin, 90mg hydroxypropyl methylcellulose, 82mg sodium alginate, 100mg polyoxyethylene, 400mg crospovidone, 20mg dicalcium phosphate, 10mg silica, and 11mg magnesium stearate per tablet has a good sustained-release effect.

[0159] Example 22

[0160] The release rate of the amoxicillin extended-release formulation in Example 22 is shown in [the figure]. Figure 18This indicates that the sustained-release formulation containing 500mg amoxicillin, 360mg hydroxypropyl methylcellulose, 60mg sodium alginate, 100mg polyoxyethylene, 140mg crospovidone, 20mg dicalcium phosphate, 10mg silica, and 11mg magnesium stearate per tablet has a good sustained-release effect.

[0161] Example 23

[0162] The release rate of the amoxicillin extended-release formulation in Example 23 is shown in [the figure]. Figure 19 This indicates that the sustained-release formulation containing 500mg amoxicillin, 120mg hydroxypropyl methylcellulose, 70mg sodium alginate, 100mg polyoxyethylene, 370mg crospovidone, 20mg dicalcium phosphate, 10mg silica, and 11mg magnesium stearate per tablet has a good sustained-release effect.

[0163] Example 24

[0164] The release rate of the amoxicillin extended-release formulation in Example 24 is shown in [reference needed]. Figure 20 This indicates that the sustained-release formulation containing 500mg amoxicillin, 180mg hydroxypropyl methylcellulose, 40mg sodium alginate, 100mg polyoxyethylene, 340mg crospovidone, 20mg dicalcium phosphate, 10mg silica, and 11mg magnesium stearate per tablet has a good sustained-release effect.

[0165] The preparation process for Examples 18-24 is as follows: (1) Weigh out each material according to the prescription and set aside; (2) Place all materials except magnesium stearate in a mixer and mix them evenly; (3) Add the prescribed amount of magnesium stearate to the well mixed (2) and mix thoroughly.

[0166] (4) Use a tablet press to compress the total powder into tablets. The punch size is (seed-shaped, 22*10.8mm), and the tablet hardness is 160N~220N.

[0167] The floating properties and swelling results of Examples 18-24 are as follows: All embodiments were continuously floated for 24 hours, and the swelling properties were studied as follows: Table 4. Swelling properties (length, width, height) of formulations in Examples 18-25

[0168] Comparative Example 1 Chinese Patent CN200710304012.3 (CN101467957A) relates to a method for preparing amoxicillin gastric floating tablets and its application. Comparative Example 1 describes a formulation preparation based on the patent content. The formulation is as follows:

[0169] When one tablet from the comparative example was placed in 0.06 mol / L hydrochloric acid, the floating speed was slow, and the floating time was greater than 30 minutes. A small number of bubbles were generated during the floating process. The slow floating speed means that the formulation is easily damaged by food compression and may even be expelled from the stomach. The short gastric retention time and the fact that the foaming agent works by generating gas may cause discomfort such as bloating and belching.

[0170] Comparative Example 2

[0171] Chinese Patent CN201410116Y provides a dual-release capsule of amoxicillin-sulbactam-pidil, prepared according to Comparative Example 2, which describes the preparation of amoxicillin microplates based on the patent. The prescription is as follows: The microplates from Comparative Example 2 were loaded into capsules and then placed in 0.06 mol / L hydrochloric acid. The capsules immediately began to float and were completely wetted after about 1 hour. After being wetted, the capsules became soft and were easily damaged by compression.

[0172] When the micro-flakes of Comparative Example 2 were placed in 0.06 mol / L hydrochloric acid, the floating speed was slow, the floating time was greater than 30 minutes, and the swelling effect was mediocre. The original diameter of the micro-flakes was 6 mm, and after swelling, it was about 8 mm, indicating a poor swelling effect. The volume was smaller than the average pyloric diameter of the human body (13 mm). In summary, this indicates that the floating effect of Comparative Example 2 mainly relies on the capsule. Once the capsule is fully wetted, it is more susceptible to compression and breakage, making it easier to be expelled from the stomach, thus shortening its contact time with the stomach and reducing its bactericidal effect.

Claims

1. An amoxicillin gastric retention sustained-release formulation, characterized in that, The complete release time is 10-12 hours, and the components include amoxicillin, sustained-release material, swelling agent and other pharmaceutical excipients.

2. The amoxicillin gastric retention sustained-release formulation according to claim 1, characterized in that, The sustained-release material is selected from one or more of polyethylene glycol, povidone, polyvinyl acetate, carbomer, chitosan, sodium alginate, hydroxypropyl methylcellulose, etc.; the total amount of sustained-release material is 5% to 60% of the weight of the formulation, the preferred amount is 10% to 50% of the weight of the formulation, and the optimal amount is 20% to 45% of the weight of the formulation.

3. The amoxicillin gastric retention sustained-release formulation according to claim 1, characterized in that, The swelling agent is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the total amount of swelling agent is 10% to 70% of the weight of the preparation, the preferred amount is 20% to 50% of the weight of the preparation, and the optimal amount is 35% to 45% of the weight of the preparation.

4. An amoxicillin gastric retention sustained-release formulation, characterized in that, The sustained-release formulation is a bilayer tablet, comprising a sustained-release layer and an immediate-release layer. The formulation components of the sustained-release layer are the same as those of the amoxicillin gastric retention sustained-release formulation described in claims 1-3. The weight ratio of amoxicillin in the immediate-release layer to that in the sustained-release layer is 20-40:60-80, and the amoxicillin in the immediate-release layer accounts for 20%-40% of the total weight of amoxicillin.

5. The amoxicillin gastric retention sustained-release formulation according to claim 4, characterized in that, The immediate-release layer formulation includes amoxicillin, fillers, disintegrants, and lubricants.

6. The amoxicillin gastric retention sustained-release formulation according to claim 5, characterized in that... The filler in the immediate-release layer formulation is selected from one or more combinations of lactose, sucrose, D-mannitol, sorbitol, xylitol, and microcrystalline cellulose.

7. The amoxicillin gastric retention sustained-release formulation according to claim 5, characterized in that... The disintegrant in the immediate-release layer formulation is selected from one or more of the following: dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and sodium crospovidone carboxymethyl cellulose.

8. The amoxicillin gastric retention sustained-release formulation according to claim 5, characterized in that... The immediate-release layer formulation contains approximately 20% to 40% amoxicillin, approximately 20% to 80% filler, approximately 1% to 15% disintegrant, and approximately 0.5% to 5% lubricant.

9. A compound gastric retention sustained-release formulation containing amoxicillin, characterized in that... This sustained-release formulation is a bilayer tablet, with the first layer containing amoxicillin gastric retention sustained-release layer and the second layer containing vonoprazan or its pharmaceutical salt.

10. The compound amoxicillin gastric retention sustained-release formulation according to claim 9, characterized in that... The second layer of the formulation containing vonoprazan or its pharmaceutical salt includes vonoprazan fumarate, fillers, disintegrants, binders, and lubricants. The fillers are selected from one or more of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, sorbitol, and sucrose. The disintegrants are selected from one or more of dry starch, croscarmellose sodium, bipovidone, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. The binders are selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and povidone. Preferably, the proportions of each component in the second layer are: vonoprazan fumarate 5%–15%, fillers 60%–80%, disintegrants 0%–10%, binders 1%–5%, and lubricants 0.5%–5%. The sum of all the above components is 100%.

11. A compound amoxicillin gastric retention sustained-release formulation, characterized in that... The sustained-release formulation is a bilayer tablet. The first layer is a gastric retention sustained-release layer containing amoxicillin, with the formulation components as described in claims 1-3. The second layer is an immediate-release layer containing vonoprazan fumarate and amoxicillin. The formulation components of the second layer include amoxicillin, vonoprazan fumarate, fillers, disintegrants, binders, and lubricants. The fillers are selected from one or more combinations of lactose, sucrose, D-mannitol, sorbitol, xylitol, and microcrystalline cellulose. The disintegrants are selected from one or more combinations of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and crospovidone carboxymethyl cellulose. The binders are selected from one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and povidone. The lubricants are selected from one or more combinations of magnesium stearate, sodium stearate fumarate, micronized silica, and talc.

12. An amoxicillin gastric retention sustained-release formulation, characterized in that, The complete release time is 20-24 hours. The components include amoxicillin, sustained-release material, swelling agent, and other pharmaceutical excipients. The sustained-release material is selected from hydroxypropyl methylcellulose; the total amount of sustained-release material is 6%-48% of the formulation weight, preferably 7%-35%, and optimally 10%-30%. The swelling agent is selected from crospovidone, polyoxyethylene, and sodium alginate; the total amount of swelling agent is 10%-50% of the formulation weight, preferably 20%-48%, and optimally 25%-45%. The other pharmaceutical excipients include flow aids, lubricants, and ion modifiers. The flow aid is selected from silica, the lubricant from magnesium stearate, and the ion modifier from calcium hydrogen phosphate; the total amount of lubricant is 0.5%-5% of the formulation weight, the total amount of flow aid is 0.2%-5% of the formulation weight, and the total amount of ion modifier is 0.5%-5% of the formulation weight.

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