Vonoprazan fumarate, intragastric retention tablet thereof and application of vonoprazan fumarate in gastrointestinal tract

Abstract

The invention discloses vonoprazan fumarate, intragastric retention tablets of the vonoprazan fumarate and application of the vonoprazan fumarate to gastrointestinal tracts, and relates to the technical field of medicines.The vonoprazan fumarate is prepared through a synthesis method comprising the following steps that in the presence of an organic solvent and alkali, 5-(2-fluorophenyl) pyrrole-3-formaldehyde and pyridine-3-sulfonyl chloride are subjected to a reaction, and the vonoprazan fumarate is obtained. Hydroxypropyl-beta-cyclodextrin is added into a reaction system, and a compound WNLZ-1 is generated; reacting the compound WNLZ-1 with methylamine, and then reducing to obtain a compound WNLZ-3; the compound WNLZ-3 and fumaric acid are subjected to a salt forming reaction, and vonoprazan fumarate is obtained. According to the preparation method, hydroxypropyl-beta-cyclodextrin is introduced as a reaction accelerant in the synthesis step, the yield and purity of an intermediate are improved, meanwhile, hydroxypropyl-beta-cyclodextrin and xanthan gum are jointly used in the preparation, and the whole process optimization from raw material medicine synthesis to preparation performance is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to vonoprazan fumarate, its gastric retention tablets, and its application in the gastrointestinal tract. Background Technology

[0002] Vonoprazan fumarate (trade name Takecab) is a novel oral anti-acid drug jointly developed by Takeda Pharmaceutical and Otsuka Pharmaceutical. It belongs to the potassium-competitive acid blocker (P-CAB) class and is a reversible proton pump inhibitor. Vonoprazan fumarate is an effective potassium-competitive acid blocker used to treat gastrointestinal disorders associated with stomach acid. In existing technologies, its synthesis typically involves multiple chemical reactions. However, in the preparation step of the key intermediate WNLZ-1, there are technical challenges in improving the reaction yield and chemical purity of the product, which affects the production efficiency and economics of the final active pharmaceutical ingredient.

[0003] Furthermore, to improve the duration of local action and efficacy of drugs in the stomach, they are often formulated as gastric retention tablets. However, existing gastric retention tablets generally suffer from unstable buoyancy and uncontrollable drug release behavior in the complex dynamic environment of the stomach, making it difficult to balance long-term buoyancy with stable release, thus affecting the reliability of drug administration and therapeutic effect. Summary of the Invention

[0004] This application provides vonoprazan fumarate, its gastric retention tablets, and their application in the gastrointestinal tract. It addresses the technical problems of low synthetic yield and purity of vonoprazan fumarate in the prior art, as well as the difficulty in simultaneously achieving good floating performance and drug release behavior in its gastric retention tablets. By introducing hydroxypropyl-β-cyclodextrin as a reaction promoter in the synthesis step, the yield and purity of the intermediate are improved. Simultaneously, the combined use of hydroxypropyl-β-cyclodextrin and xanthan gum in the formulation utilizes their synergistic effect to construct a gel matrix system that ensures rapid tablet floating and long-lasting retention while achieving stable and complete drug release. This achieves full-process optimization from API synthesis to formulation performance.

[0005] This application provides a vonoprazan fumarate, which is prepared by a synthetic method including the following steps: (1) In the presence of an organic solvent and a base, 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde is reacted with pyridine-3-sulfonyl chloride, and hydroxypropyl-β-cyclodextrin is added to the reaction system to generate compound WNLZ-1. (2) Compound WNLZ-1 was reacted with methylamine and then reduced to obtain compound WNLZ-3; (3) Compound WNLZ-3 was reacted with fumaric acid to form a salt, yielding vonorazan fumaric acid.

[0006] Furthermore, in step (1), the amount of hydroxypropyl-β-cyclodextrin added is 8% to 12% of the mass of 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde.

[0007] Furthermore, in step (1), the hydroxypropyl-β-cyclodextrin has a particle size d90 of less than 50 μm and a degree of substitution of 0.6 to 0.75.

[0008] Furthermore, this includes the use of vonoprazan fumarate in the preparation of medicaments for the treatment of gastrointestinal diseases.

[0009] Furthermore, the drug is a gastric retention tablet.

[0010] Furthermore, it comprises vonoprazan fumarate obtained by the above-described synthetic method as the active ingredient, and pharmaceutically acceptable excipients, said excipients comprising hydroxypropyl-β-cyclodextrin and xanthan gum.

[0011] Furthermore, per thousand tablets, it contains: 20.0g vonoprazan fumarate, 2.5-4.5g hydroxypropyl-β-cyclodextrin, and 2.0-4.0g xanthan gum.

[0012] Furthermore, the hydroxypropyl-β-cyclodextrin comprises hydroxypropyl-β-cyclodextrin component A and hydroxypropyl-β-cyclodextrin component B, wherein component A has a degree of substitution of 0.60-0.75, a particle size d50 of 40-60 μm, and d90 ≤ 90 μm, component B has a degree of substitution of 0.40-0.55, a particle size d50 of 70-90 μm, and d90 ≤ 130 μm, and the mass ratio of component A to component B is 65:35 to 75:25.

[0013] One or more technical solutions provided in the embodiments of this application have at least the following technical effects or advantages: The synthesis of vonoprazan fumarate involves three consecutive chemical reactions to construct the chemical structure of the target molecule: First, under low-temperature alkaline conditions, a five-membered heterocyclic aldehyde undergoes a nucleophilic substitution reaction with sulfonyl chloride to form the key intermediate WNLZ-1; then, a methylamine group is introduced through a reductive amination reaction to obtain intermediate WNLZ-3; finally, a salt-forming reaction is carried out with fumaric acid to obtain the final product.

[0014] By introducing hydroxypropyl-β-cyclodextrin as a reaction promoter into the original synthesis process, the quality and efficiency of the active pharmaceutical ingredient were effectively improved. Furthermore, in the formulation design, hydroxypropyl-β-cyclodextrin was used in combination with xanthan gum. Xanthan gum constructed a physical framework that maintains long-term floating, while hydroxypropyl-β-cyclodextrin performed a release regulation function within this framework. Through molecular and macroscopic synergy, the two jointly solved the core technical problem of unstable performance of gastric retention tablets in the dynamic gastric environment, and successfully prepared vonoprazan fumarate gastric retention tablets with excellent performance of rapid floating, long-term retention and stable release.

[0015] By introducing a composite system composed of HP-β-CD with different particle sizes and degrees of substitution, a multidimensional synergy is achieved with the gel framework constructed from xanthan gum. The two-component HP-β-CD achieves temporal regulation of release behavior in the time series, while xanthan gum provides a stable long-lasting floating platform in space. The two work together to successfully prepare vonoprazan fumarate gastric retention tablets with a more ideal release curve and higher clinical consistency. Detailed Implementation

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; the terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to limit the invention; the term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0017] Example 1: A synthetic process for vonoprazan fumarate, specifically including the following steps: Step 1: Preparation of compound WNLZ-1 ; Add 500 kg of tetrahydrofuran to a reaction vessel, and cool to 0-5 °C under nitrogen protection; add 50 kg of potassium tert-butoxide and 26 kg of 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde sequentially; add 2.6 kg of hydroxypropyl-β-cyclodextrin (HP-β-CD) (particle size d90 < 50 μm, degree of substitution 0.6-0.75); slowly add 100 kg of anhydrous tetrahydrofuran solution of pyridine-3-sulfonyl chloride, controlling the addition temperature at 0-5 °C; keep the reaction stirred at this temperature for 3-4 hours, and monitor the reaction endpoint by TLC; quench the reaction with water, allow it to stand and separate into layers, wash the organic layer with saturated sodium chloride solution; dry with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness; recrystallize the residue with methanol, filter, and dry under vacuum at 50 °C to obtain compound WNLZ-1; Step 2: Preparation of compound WNLZ-3 ; Add WNLZ-1, 2000 kg of methanol, and 100 kg of 30% methylamine methanol solution to a reaction vessel; stir the reaction at 30-40℃ for 2-3 hours, and monitor the reaction completion by TLC; cool to 0-5℃ and add 100 kg of sodium borohydride in batches; heat to 20-30℃ and stir for 1 hour; quench the reaction with water, concentrate under reduced pressure to half the original volume; adjust the pH to 10 with ammonia, and extract with ethyl acetate; wash the organic phase with water until neutral, add ethyl acetate:ethanol (1:1) mixed solvent; add hydrochloric acid ethyl acetate solution, heat and stir to form salt, filter to obtain crude product; recrystallize the crude product with methanol:water, and dry at 50-60℃ to obtain compound WNLZ-3; Step 3: Preparation of Vonolazine Fumarate ; Dissolve WNLZ-3 in water, add ammonia to adjust pH to 12; extract with ethyl acetate, wash the organic phase with water until neutral; add a mixed solution of ethyl acetate and DMF, add 200 kg of fumaric acid; stir the reaction at 20-40℃, filter; heat the filter cake with a methanol:water (1:1) mixed solution to reflux; cool and recrystallize, filter, dry to obtain vonoprazan fumarate raw material.

[0018] The preparation of gastric retention tablets using vonoprazan fumarate as an active pharmaceutical ingredient includes the following steps: (1) Raw material pretreatment; The vonoprazan fumarate raw material was pulverized to d90 < 180 μm and passed through an 80-mesh sieve. Xanthan gum passed through a 60-mesh sieve, with a particle size d90 < 120 μm; Hydroxypropyl methylcellulose K4M and K100M passed through a 60-mesh sieve respectively; Other excipients (sodium bicarbonate, polyethylene glycol 6000, carnauba wax, mannitol, magnesium stearate) passed through a 60-mesh sieve; (2) The excipients are mixed according to the following prescription amounts (per 1000 tablets): Vonorazan fumarate 20.0g; HP-β-CD 3.0-4.0g; Xanthan gum 2.5-3.5g; Hydroxypropyl methylcellulose K4M 40-50g; Hydroxypropyl methylcellulose K100M 40-50g; 20-30g of sodium bicarbonate; Polyethylene glycol 6000 8-12g; 10-15g of carnauba wax; Magnesium stearate 1.5-2.5g; Adjust the total weight with mannitol to 200g; Mixing process: Add the active ingredients, HP-β-CD, xanthan gum, HPMC, sodium bicarbonate, carnauba wax, polyethylene glycol 6000, and mannitol to a hopper mixer; mix at 20 rpm for 10-15 minutes; add magnesium stearate and continue mixing at 20 rpm for 2-3 minutes. (3) Tableting: A rotary tablet press with a shallow concave punch of φ8.0mm is used; the tablet hardness is controlled at 30-50N; the tablet weight is 200mg±3%; the tableting environment is controlled as follows: temperature 25±2℃, relative humidity ≤45%; (4) Packaging: Aluminum-plastic packaging, with the humidity of the packaging environment controlled at ≤45%.

[0019] The following experiments were conducted to verify the effects of HP-β-CD and xanthan gum on the synthesis of vonoprazan fumarate and the performance of the gastric retention tablets. I. Experimental Objective; The effect of adding HP-β-CD during the synthesis stage on improving reaction yield and product purity was verified.

[0020] To verify the effects of HP-β-CD and xanthan gum, alone and in combination, on the floating properties and drug release behavior of gastric retention tablets during the formulation stage.

[0021] II. Experimental Grouping and Parameter Design; A. Synthesis experimental grouping (for step 1: preparation of WNLZ-1); All groups used the basic feed amounts (potassium tert-butoxide 50 kg, 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde 26 kg, etc.) as described in the technical disclosure document. The only difference was the addition of HP-β-CD. The experimental groups are shown in Table 1 below. Table 1

[0022] B. Grouping of formulation experiments; Vonoprazan fumarate, composed of A3 components, was used as the uniform active pharmaceutical ingredient. The formulation was modified based on Example 1 of the prior art document, with the total tablet weight controlled at 200 mg / tablet. Grouping is shown in Table 2 below; Table 2

[0023] The dosage of other excipients is fixed (20g vonoprazan fumarate, 30g sodium bicarbonate, 10g polyethylene glycol 6000, 10g carnauba wax, 2g magnesium stearate, and mannitol to make up to 200g).

[0024] III. Experimental Procedures and Operating Parameters; Synthesis steps (preparation of WNLZ-1): For group A1, the step of adding HP-β-CD is omitted. For groups A2 and A3, the corresponding amount of HP-β-CD is added together with the reactants.

[0025] Key parameters: dropping temperature 0-5℃, reaction time 3 hours, quenching water temperature 10-15℃, recrystallization solvent is methanol.

[0026] Detection: After the reaction was completed, the yield of WNLZ-1 was calculated and its chemical purity was determined by HPLC.

[0027] Formulation steps (preparation of gastric retention tablets): All groups used the same mixing sequence, mixing time (12 min for main mixing, 2 min for lubricant), and tableting parameters.

[0028] Key parameters: tablet hardness controlled at 40±5N, and ambient humidity controlled at ≤45%.

[0029] IV. Performance Testing and Methods; Floating time: The time required from the tablet contacting the liquid surface to the tablet starting to float in 37℃ and 0.1M HCl (simulated gastric juice, pH~1.2).

[0030] Sustained floating time: The total duration for which a tablet remains floating under the same conditions (records its state after 12 hours).

[0031] Drug release rate: The slurry method according to the Chinese Pharmacopoeia was used. The drug was released in 900 mL of 0.1 M HCl at a speed of 50 / 75 rpm and a temperature of 37 °C. Samples were taken at 1, 2, 4, 6, 8, and 12 hours, and the cumulative percentage of drug release was determined by HPLC.

[0032] Observation of floating state: Visually observe the morphological changes of the tablets during the floating process, such as expansion, disintegration, and sinking.

[0033] The results of the synthesis and formulation experiments are shown in Tables 3 and 4 below: Table 3

[0034] It is evident that the addition of HP-β-CD can significantly improve the synthesis yield and product purity.

[0035] Table 4

[0036] The results of this experiment show that during the synthesis stage, the addition of HP-β-CD (8-12%) significantly improved the yield (from 85% to 92%) and purity of WNLZ-1 through molecular inclusion. In the formulation stage, while HP-β-CD alone improved drug release (85% release rate at 12 hours), its floating persistence was insufficient (10 hours); while xanthan gum alone ensured long-lasting floating (>12 hours), drug release was incomplete (82%). The combined effect of both: the strong gel framework constructed by xanthan gum ensured rapid initiation (15 seconds) and sustained floating, while HP-β-CD ensured stable and complete release (92%) by regulating drug release behavior. The combined formulation was significantly superior to the individual use of each component and the blank control, effectively balancing buoyancy and release.

[0037] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages: This approach aims to overcome the technical bottlenecks in the existing synthesis process of vonoprazan fumarate, such as the need to improve reaction yield and purity, as well as the unstable floating performance and uncontrollable drug release behavior of its gastric retention tablets in the complex gastric environment. By introducing hydroxypropyl-β-cyclodextrin and xanthan gum at the synthesis and formulation stages respectively, and utilizing their synergistic effect, the entire process from API synthesis to formulation performance has been optimized.

[0038] The synthesis of vonoprazan fumarate involves three consecutive chemical reactions to construct the chemical structure of the target molecule: First, under low-temperature alkaline conditions, a five-membered heterocyclic aldehyde undergoes a nucleophilic substitution reaction with sulfonyl chloride to form the key intermediate WNLZ-1; then, a methylamine group is introduced through a reductive amination reaction to obtain intermediate WNLZ-3; finally, a salt-forming reaction is carried out with fumaric acid to obtain the final product.

[0039] In the first step of this synthetic process, hydroxypropyl-β-cyclodextrin is introduced. This molecule, with its unique hydrophobic cavity, encapsulates the hydrophobic groups in the reactants. This supramolecular interaction achieves multiple effects: firstly, it improves the apparent solubility and dispersion uniformity of the reactants in the reaction system; secondly, it pre-organizes the reactant molecules through steric confinement, allowing their reactive centers to be more fully exposed to favorable reaction conformations; and thirdly, it provides a unique hydrophobic microenvironment for the reaction, contributing to the stability of the reaction transition state. This significantly improves the selectivity and rate of the main reaction, macroscopically manifested in a significant increase in the yield and chemical purity of the key intermediate WNLZ-1.

[0040] In gastric retention tablets, hydroxypropyl-β-cyclodextrin and xanthan gum are co-introduced into the formulation. The residual or added portion of hydroxypropyl-β-cyclodextrin in the formulation can form inclusion complexes with drug molecules and act as a hydrophilic porogen, precisely controlling the pathways of water penetration and drug diffusion by regulating its own dissolution rate. Xanthan gum rapidly hydrates upon contact with water, and its rigid helical molecular chains entangle to form a three-dimensional gel network framework with high yield stress. This framework effectively encapsulates the gas generated by sodium bicarbonate in acidic conditions and provides the tablet as a whole with excellent mechanical strength to resist the shear forces of gastric peristalsis.

[0041] The synergy between the two is based on their intermolecular physicochemical interactions and functional complementarity. Hydroxypropyl-β-cyclodextrin, as a functional molecular regulatory unit, can form a broad hydrogen bond network with the hydroxyl groups and carboxyl groups on the xanthan gum molecular chain through its outer hydroxyl groups. This anchors hydroxypropyl-β-cyclodextrin within the three-dimensional hydration gel framework constructed by xanthan gum at the microscale. This combination prevents hydroxypropyl-β-cyclodextrin from existing as an isolated phase in the gel system, avoiding competition for hydration sites with hydrophilic gel materials and thus eliminating the potential risk of gel structure weakening. At the macroscale, xanthan gum, with its rigid chain structure and high pseudoplasticity, constitutes the main gel framework that maintains tablet shape, encapsulates gas, and provides shear resistance. The hydroxypropyl-β-cyclodextrin integrated and fixed within this framework continues to function as a nanoscale drug release regulation unit: on the one hand, its cavity provides additional diffusion barriers through its inclusion of drug molecules; on the other hand, its own solubility properties can form regular micropores in the gel, guiding water to permeate in a more controllable manner.

[0042] Therefore, the two work synergistically to construct a dual regulatory system of rigid framework and dynamic diffusion. Xanthan gum is mainly responsible for maintaining the integrity of the macroscopic structure to ensure long-term buoyancy, while hydroxypropyl-β-cyclodextrin, within the stabilized gel environment, finely regulates the dissolution and diffusion kinetics of the drug. This synergistic effect is initiated simultaneously upon the formulation's contact with gastric juice, jointly determining the morphology of the drug release profile and achieving simultaneous optimization of buoyancy performance and release behavior.

[0043] Example 2: The above examples effectively improved the quality and efficiency of the active pharmaceutical ingredient by introducing hydroxypropyl-β-cyclodextrin as a reaction promoter into the original synthesis process. Furthermore, in the formulation design, hydroxypropyl-β-cyclodextrin was used in combination with xanthan gum. Xanthan gum constructed the physical framework that maintains long-lasting buoyancy, while hydroxypropyl-β-cyclodextrin performs release regulation within this framework. Through synergy at both the molecular and macroscopic levels, the core technical challenge of unstable performance of gastric retention tablets in the dynamic gastric environment was solved, successfully preparing vonoprazan fumarate gastric retention tablets with excellent performance of rapid buoyancy, long-lasting retention, and stable release. Further improvements were made based on Example 1 to further enhance its overall performance.

[0044] In the preparation of the gastric retention tablet, HP-β-CD contains HP-β-CD component A and HP-β-CD component B; The degree of substitution (DS) of HP-β-CD component A ranges from 0.60 to 0.75, and the particle size distribution is d50 = 40-60 μm, d90 ≤ 90 μm. The degree of substitution (DS) of HP-β-CD component B ranges from 0.40 to 0.55, and the particle size distribution is d50 = 70-90 μm, d90 ≤ 130 μm. The mass ratio of HP-β-CD component A to HP-β-CD component B is 65:35 to 75:25, with a preferred ratio of 70:30.

[0045] Experiments were conducted on the technical solution of this embodiment to verify the optimization effect of using HP-β-CD combinations (component A and component B) with different particle sizes and degrees of substitution in the formulation on the floating performance and drug release behavior of vonoprazan fumarate gastric retention tablets compared to a single specification of HP-β-CD. I. Experimental Grouping and Parameter Design; Active pharmaceutical ingredient: Vonolazan fumarate prepared using the synthesis process described in this embodiment (with the addition of synthesis-specific HP-β-CD, d90<50μm).

[0046] Basic prescription (per 1000 tablets): Vonolazan fumarate 20.0g, xanthan gum 3.0g, HPMC (K4M / K100M 1:1) 80g, sodium bicarbonate 25g, polyethylene glycol 6000 10g, carnauba wax 12g, magnesium stearate 2g, mannitol to make up to 200g.

[0047] Variables: The composition of HP-β-CD, with a fixed total addition of 3.5 g / 1000 tablets. Experimental groups are shown in Table 5 below; Table 5

[0048] Preparation of HP-β-CD premix: Place component A and component B HP-β-CD in a V-type mixer according to the proportions in the table above, mix at 20 rpm for 10 minutes, and pass through a 60-mesh sieve for later use. II. Experimental Procedures and Operating Parameters; Tablet preparation: Add the corresponding HP-β-CD premix and excipients such as xanthan gum to the total mixture. Key parameters: Total mixing time 12 minutes (20 rpm), then mix for 2 minutes after adding magnesium stearate. Tableting hardness should be controlled at 40 ± 3 N.

[0049] Performance testing: The method is the same as in Example 1: the floating time and continuous floating time were measured at 37℃ and 0.1M HCl, and the cumulative drug release was measured at 1, 2, 4, 6, 8, and 12 hours.

[0050] New detection points: Record the 4-hour release rate (D4h) and 8-hour release rate (D8h) to more precisely assess the stability of the mid-range of the release curve. The experimental results are shown in Table 6 below; Table 6

[0051] The results of this experiment show that tablets using only component A (HP-β-CD, C1) exhibit rapid onset and complete release, but with a slightly faster initial release; while tablets using only component B (HP-β-CD, C2) show slow onset and incomplete release in the later stages. The combination of components A and B combines the advantages of both. Among these, C4 (A:B=70:30) demonstrates the best overall performance: rapid onset (15 seconds), achieving the most stable release curve (gradual change in release rate from 4h to 8h), and ultimately complete release. Component A (HP-β-CD) is responsible for rapid onset and maintaining the later release momentum, while component B (HP-β-CD), through its slow dissolution characteristic, effectively slows down the release rate in the middle stages.

[0052] The technical solutions described in the embodiments of this application have at least the following technical effects or advantages: This embodiment aims to further optimize the drug release kinetics of vonoprazan fumarate gastric retention tablets, addressing the issues of unstable release profiles and significant inter-individual variability in the complex gastric environment. By introducing a two-component HP-β-CD system with different particle sizes and degrees of substitution into the formulation system, and synergistically interacting with xanthan gum, more precise and sustained temporal regulation of drug release behavior is achieved.

[0053] A composite functional system was constructed using two hydroxypropyl-β-cyclodextrins with different physicochemical properties. HP-β-CD component A, with a high degree of substitution and small particle size, exhibits rapid hydration and dissolution, enabling it to quickly encapsulate drug molecules and rapidly establish initial channels and energy barriers for drug diffusion in the early stages of gel formation. HP-β-CD component B, with a low degree of substitution and large particle size, exhibits relatively slow hydration and dissolution rates. It serves as a long-lasting release regulator in the gel system, continuously providing encapsulation and maintaining the stability of the gel network structure in the mid-to-late stages of drug release.

[0054] This two-component HP-β-CD system is based on the differentiated dissolution and diffusion behaviors of its two components within a hydrophilic gel framework. Component A ensures timely initiation of drug release and achievement of effective therapeutic concentrations in the initial stages, avoiding delayed onset of action. Component B, through its slow and continuous dissolution characteristics, effectively slows the drug diffusion rate in the later stages of release, preventing potential runaway release or premature termination due to the functional decay of a single component. The two components complement each other over time, jointly shaping a more stable, near-zero-order ideal drug release curve.

[0055] The synergistic effect of the two-component HP-β-CD system and xanthan gum is based on intermolecular interactions and macroscopic functional complementarity. Upon contact with water, xanthan gum rapidly forms a robust three-dimensional gel network framework through its rigid molecular chains. This framework provides the tablet with the mechanical strength required to resist gastric peristalsis shearing, forming the physical basis for maintaining long-term buoyancy. HP-β-CD component A dissolves rapidly in the early stages of hydration, and its molecules quickly combine with xanthan gum molecular chains through hydrogen bonding. This immediate integration behavior, on the one hand, acts as a physical cross-linking point, enhancing the strength of the initial gel network and facilitating rapid tablet buoyancy; on the other hand, its cavities rapidly encapsulate drug molecules, primarily establishing the diffusion kinetics mode in the early stages of drug release. HP-β-CD component B exhibits delayed and sustained action characteristics. Its slower dissolution rate allows it to gradually integrate into the xanthan gum network only in the middle and later stages of gel hydration. This slow integration process produces a sustained reinforcing effect on the gel framework, improving the network's stability against long-term erosion. Simultaneously, throughout the entire release process, especially in the middle and later stages, it provides continuous and stable drug encapsulation and release inhibition, effectively preventing the late-stage decay of the release rate.

[0056] The resulting synergistic effects are: the tablets not only maintain the excellent performance of rapid initiation and ultra-long-term floating, but more importantly, they achieve optimization of drug release kinetics, resulting in a more stable release curve and a significant reduction in inter-individual release differences, thereby improving the predictability of drug administration and the consistency of therapeutic effects.

[0057] This embodiment introduces a composite system composed of HP-β-CD with different particle sizes and degrees of substitution, which produces multidimensional synergy with the gel framework constructed by xanthan gum. The two-component HP-β-CD achieves temporal regulation of release behavior in the time series, while xanthan gum provides a stable long-lasting floating platform in space. The two work together to successfully prepare vonoprazan fumarate gastric retention tablets with a more ideal release curve and higher clinical consistency.

[0058] The technical solutions described in the above embodiments of this application have at least the following technical effects or advantages: The above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A vonoprazan fumarate, characterized in that, The vonoprazan fumarate is prepared by a synthetic method comprising the following steps: (1) In the presence of an organic solvent and a base, 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde was reacted with pyridine-3-sulfonyl chloride, and hydroxypropyl-β-cyclodextrin was added to the reaction system to generate compound WNLZ-1; (2) compound WNLZ-1 was reacted with methylamine, and then reduced to obtain compound WNLZ-3. (3) Compound WNLZ-3 was reacted with fumaric acid to form a salt, yielding vonorazan fumaric acid.

2. The vonoprazan fumarate as described in claim 1, characterized in that, In step (1), the amount of hydroxypropyl-β-cyclodextrin added is 8% to 12% of the mass of 5-(2-fluorophenyl)pyrrole-3-carboxaldehyde.

3. The vonoprazan fumarate as described in claim 1, characterized in that, In step (1), the hydroxypropyl-β-cyclodextrin has a particle size d90 of less than 50 μm and a degree of substitution of 0.6 to 0.

75.

4. The use of vonoprazan fumarate in the preparation of a drug for treating gastrointestinal diseases.

5. The application as described in claim 4, characterized in that, The medication in question is a gastric retention tablet.

6. A gastric retention tablet for treating gastrointestinal diseases, characterized in that, It comprises vonoprazan fumarate as an active ingredient as described in any one of claims 1 to 3, and pharmaceutically acceptable excipients comprising hydroxypropyl-β-cyclodextrin and xanthan gum.

7. The gastric retention tablet as described in claim 6, characterized in that, Each thousand tablets contains: 20.0g vonoprazan fumarate, 2.5-4.5g hydroxypropyl-β-cyclodextrin, and 2.0-4.0g xanthan gum.

8. The gastric retention tablet as described in claim 6, characterized in that, The hydroxypropyl-β-cyclodextrin comprises hydroxypropyl-β-cyclodextrin component A and hydroxypropyl-β-cyclodextrin component B, wherein component A has a degree of substitution of 0.60-0.75, a particle size d50 of 40-60 μm, and d90 ≤ 90 μm, and component B has a degree of substitution of 0.40-0.55, a particle size d50 of 70-90 μm, and d90 ≤ 130 μm, and the mass ratio of component A to component B is 65:35 to 75:25.

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