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CN-121974887-A - Vonoprazan fumarate, gastric retention tablet thereof and application of Vonoprazan fumarate in gastrointestinal tract

CN121974887ACN 121974887 ACN121974887 ACN 121974887ACN-121974887-A

Abstract

The application discloses vonoprazan fumarate, a gastric retention tablet and application thereof on gastrointestinal tracts, and relates to the technical field of medicines, wherein the vonoprazan fumarate is prepared by a synthesis method comprising the following steps of reacting 5- (2-fluorophenyl) pyrrole-3-formaldehyde with pyridine-3-sulfonyl chloride in the presence of an organic solvent and alkali, and adding hydroxypropyl-beta-cyclodextrin into a reaction system to generate a compound WNLZ-1; reacting WNLZ-1 with methylamine, then reducing to obtain WNLZ-3, and salifying WNLZ-3 with fumaric acid to obtain Vonoprazan fumarate. By introducing hydroxypropyl-beta-cyclodextrin as a reaction accelerator in the synthesis step, the yield and purity of the intermediate are improved, and simultaneously, the hydroxypropyl-beta-cyclodextrin and the xanthan gum are used in combination in the preparation, so that the whole process optimization from the synthesis of raw materials to the preparation performance is realized.

Inventors

  • LU CHENGXIAN
  • XIE LUJIE
  • LU XIN

Assignees

  • 峨眉山鸿森生物医药股份有限公司

Dates

Publication Date
20260505
Application Date
20251212

Claims (8)

  1. 1. Vonoprazan fumarate, characterized in that said vonoprazan fumarate is prepared by a synthetic method comprising the steps of: (1) reacting 5- (2-fluorophenyl) pyrrole-3-formaldehyde with pyridine-3-sulfonyl chloride in the presence of an organic solvent and alkali, adding hydroxypropyl-beta-cyclodextrin into the reaction system to form a compound WNLZ-1, (2) reacting the compound WNLZ-1 with methylamine, and then reducing to obtain a compound WNLZ-3, (3) salifying the compound WNLZ-3 with fumaric acid to obtain voronoi pranoprazan fumarate.
  2. 2. Vonoprazan fumarate according to claim 1, wherein in step (1), said hydroxypropyl- β -cyclodextrin is added in an amount of 8% to 12% by mass of 5- (2-fluorophenyl) pyrrole-3-carbaldehyde.
  3. 3. Vonoprazan fumarate according to claim 1, wherein in step (1), the particle diameter d90 of said hydroxypropyl- β -cyclodextrin is less than 50 μm and the degree of substitution is 0.6 to 0.75.
  4. 4. Use of voronoi fumarate in the manufacture of a medicament for the treatment of gastrointestinal disorders.
  5. 5. The use of claim 4, wherein the medicament is a gastroretentive tablet.
  6. 6. An intragastric retention tablet for the treatment of gastrointestinal disorders, characterized by comprising voronoi fumarates as an active ingredient according to any one of claims 1 to 3, and pharmaceutically acceptable excipients comprising hydroxypropyl- β -cyclodextrin and xanthan gum.
  7. 7. The gastroretentive tablet of claim 6, wherein each thousand pieces contains 20.0g of vorofacian fumarate, 2.5-4.5g of hydroxypropyl-beta-cyclodextrin, and 2.0-4.0g of xanthan gum.
  8. 8. The gastro-retentive tablet of claim 6, wherein the hydroxypropyl- β -cyclodextrin comprises hydroxypropyl- β -cyclodextrin component a and hydroxypropyl- β -cyclodextrin component B, wherein the substitution degree of component a is 0.60 to 0.75, the particle diameter d50 is 40 to 60 μm, d90≤90 μm, the substitution degree of component B is 0.40 to 0.55, the particle diameter d50 is 70 to 90 μm, d90≤130 μm, and the mass ratio of component a to component B is 65:35 to 75:25.

Description

Vonoprazan fumarate, gastric retention tablet thereof and application of Vonoprazan fumarate in gastrointestinal tract Technical Field The invention relates to the technical field of medicines, in particular to vonoprazan fumarate, a gastric retention tablet thereof and application thereof in gastrointestinal tracts. Background Vonoprazan fumarate (Vonoprazan fumarate, trade name Takecab) is a novel oral gastric resistant drug developed by the combination of martial arts and tsukamurella, belongs to a potassium ion competitive acid blocker (P-CAB), and is a reversible nature daughter pump inhibitor. Vonoprazan fumarate is an effective potassium competitive acid blocker for the treatment of gastric acid related gastrointestinal disorders. In the prior art, the synthesis usually involves multi-step chemical reactions, but in the preparation step of key intermediate WNLZ-1, there is a technical problem that the reaction yield and the chemical purity of the product are to be improved, which affects the production efficiency and the economy of the final raw material drug. In addition, in order to improve the local action time and curative effect of the medicine in the stomach, the medicine is often prepared into a gastric retention tablet. However, the existing gastric retention tablet has the common problems of unstable floating performance and uncontrollable drug release behavior in a complex dynamic environment in the stomach, and is difficult to combine long-acting floating and stable release, so that the administration reliability and the treatment effect are affected. Disclosure of Invention The embodiment of the application solves the technical problems that the synthesis yield and purity of the voronoi fumarate are low and the floating performance and drug release behavior of the voronoi fumarate are difficult to consider in the prior art by providing the voronoi fumarate and the gastric retention tablet and the application thereof on the gastrointestinal tract, improves the yield and purity of an intermediate by introducing hydroxypropyl-beta-cyclodextrin as a reaction accelerator in a synthesis step, and simultaneously, jointly uses the hydroxypropyl-beta-cyclodextrin and the xanthan gum in a preparation, and jointly constructs a gel skeleton system capable of ensuring the rapid bleaching and long-acting retention of the tablet and realizing the stable and complete release of the drug by utilizing the synergistic effect of the hydroxypropyl-beta-cyclodextrin and the xanthan gum, thereby realizing the full-flow optimization from the synthesis of raw materials to the preparation performance. The embodiment of the application provides vonoprazan fumarate, which is prepared by a synthesis method comprising the following steps of: (1) Reacting 5- (2-fluorophenyl) pyrrole-3-formaldehyde with pyridine-3-sulfonyl chloride in the presence of an organic solvent and alkali, wherein hydroxypropyl-beta-cyclodextrin is added into a reaction system to generate a compound WNLZ-1; (2) Reacting compound WNLZ-1 with methylamine followed by reduction to give compound WNLZ-3; (3) Salifying compound WNLZ-3 with fumaric acid to obtain Vonoprazan fumarate. Further, in the step (1), the addition amount of the hydroxypropyl-beta-cyclodextrin is 8 to 12% of the mass of the 5- (2-fluorophenyl) pyrrole-3-formaldehyde. Further, in the step (1), the particle diameter d90 of the hydroxypropyl-beta-cyclodextrin is less than 50 μm, and the substitution degree is 0.6 to 0.75. Further, the application of Vonoprazan fumarate in preparing medicines for treating gastrointestinal diseases is included. Further, the medicine is a gastric retention tablet. Further, the voronoi fumarate prepared by the synthesis method is used as an active ingredient, and pharmaceutically acceptable auxiliary materials comprise hydroxypropyl-beta-cyclodextrin and xanthan gum. Further, the composition comprises 20.0g of vorofan fumarate, 2.5-4.5g of hydroxypropyl-beta-cyclodextrin and 2.0-4.0g of xanthan gum per thousand tablets. Further, the hydroxypropyl-beta-cyclodextrin comprises a hydroxypropyl-beta-cyclodextrin component A and a hydroxypropyl-beta-cyclodextrin component B, wherein the substitution degree of the component A is 0.60-0.75, the particle diameter d50 is 40-60 mu m, d90 is less than or equal to 90 mu m, the substitution degree of the component B is 0.40-0.55, the particle diameter d50 is 70-90 mu m, d90 is less than or equal to 130 mu m, and the mass ratio of the component A to the component B is 65:35-75:25. One or more technical solutions provided in the embodiments of the present application at least have the following technical effects or advantages: In the synthesis of Vonoprazan fumarate, the chemical structure of a target molecule is constructed through three steps of continuous chemical reactions, namely, firstly, under the low-temperature alkaline condition, five-membered heterocyclic aldehyde and sulfonyl chloride undergo nucleophilic s