Ketotifen fumarate tablet and preparation method thereof

Abstract

The application discloses a kind of fumaric acid ketotifen tablets and preparation method thereof, it is related to pharmaceutical preparation technical field, the preparation is annular structure and has the central through-hole of throughout thickness, including core and the pH-sensitive shell of coating core;Core is formed by 3D printing and gradient crosslinking solidification from fumaric acid ketotifen raw material, synergistic dissolution component etc., shell inhibits drug release in oral cavity, allows release in gastric juice.Preparation method includes printing ink, composite coagulation bath and gradient crosslinking bath preparation, 3D printing forming, gradient crosslinking solidification, pH-sensitive layer coating and accurate post-processing.The preparation has fast dissolution rate, low friability, small weight difference, good stability and uniform content, preparation process is accurately controllable, solve the problem of poor performance of traditional preparation, suitable for industrialized production of fumaric acid ketotifen.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a ketotifen fumarate tablet and its preparation method. Background Technology

[0002] Ketotifen fumarate is an anti-allergic drug that combines histamine H1 receptor antagonism with inhibition of the release of allergy mediators. Clinically, it is mainly used to treat allergic rhinitis, bronchial asthma, and other diseases. However, existing ketotifen fumarate formulations have several technical drawbacks: traditional formulations are mostly prepared using conventional tableting processes, resulting in uneven drug dispersion, slow dissolution rates, and difficulty in achieving rapid onset of action; the formulations have poor taste and a noticeable odor, leading to low patient compliance; during long-term storage, the drug is prone to degradation, with a significant decrease in dissolution and poor stability; at the same time, traditional formulations have fixed specifications, failing to meet the personalized medication needs of different populations such as children and the elderly, and the direct release of the drug into the stomach can irritate the gastrointestinal tract, limiting its clinical application. Furthermore, the thermal processing in traditional manufacturing processes can easily lead to the degradation of the active pharmaceutical ingredient, affecting drug quality and efficacy stability. If not properly controlled, it can easily introduce pyrogens (such as endotoxins produced by Gram-positive bacteria), posing a potential threat to the safety of medication in children.

[0003] Currently, 3D printing technology is increasingly used in pharmaceutical formulations, offering advantages such as personalized customization, mold-free manufacturing, and high efficiency. However, existing 3D printing technologies for preparing ketotifen fumarate formulations often suffer from uneven cross-linking, poor stability, and significant gastrointestinal irritation. Furthermore, the lack of pH-sensitive targeted release design fails to address the issue of gastrointestinal irritation. In addition, existing formulations are mostly in the form of ordinary sheets, leaving room for improvement in disintegration rates. Moreover, current methods for flavor enhancement and stability improvement are limited, making it difficult to balance taste and long-term storage stability, further restricting the clinical application value of the products.

[0004] For example, invention patent application CN119235803A discloses a ketotifen fumarate fractionated tablet and its preparation method based on 3D printing technology. The ketotifen fumarate clinical fractionated tablet comprises the following components by mass percentage: 1-10% ketotifen fumarate powder, 90-99% cocoa butter, and 0-5% flavoring agent, and the sum of the mass percentages of each component equals 100%. This technical solution uses hot melt extrusion 3D printing technology to achieve rapid dissolution of fractionated tablets and precise clinical dosing. It applies 3D printing technology to the field of commercially available tablet fractionation. The printing material is prepared by uniformly mixing the tablet powder with heated and melted pharmaceutical excipients. The dosage of the 3D-printed fractionated tablets is precisely controlled by adjusting the drug content of the printing material and the volume of the printing model. By adding pharmaceutical excipients to dilute the drug content in commercially available tablets, smaller-dose tablets with lower drug content are prepared, achieving precise dosing and personalized drug administration. However, this technical solution only focuses on the accuracy of dosage distribution and does not design a pH-sensitive targeted release structure. Direct release of the drug in the stomach still has significant gastrointestinal irritation. Furthermore, the tablet structure and cross-linking process have not been optimized, and there is still considerable room for improvement in formulation stability, disintegration and dissolution performance, and taste. It cannot achieve synergistic optimization of stability, targeting, and personalized customization. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing ketotifen fumarate preparations, such as slow dissolution rate, poor stability, unpleasant taste, inability to meet personalized medication needs, high gastrointestinal irritation, and lack of targeted drug release. This invention provides a ketotifen fumarate tablet and its preparation method. Through the synergistic effect of 3D printing, gradient cross-linking curing, and pH-sensitive layer coating, combined with the combination of multiple synergistic components, a ring-shaped structure with a through-thickness central pore is prepared. This achieves simultaneous improvement in dissolution rate, stability, taste, personalization, and gastrointestinal compatibility, providing a safer, more efficient, and convenient anti-allergic drug formulation for clinical use.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is: a ketotifen fumarate tablet, wherein the formulation has a ring structure and a central through-hole extending through the thickness of the tablet; the formulation includes a core and a shell covering the core; the core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate raw material, synergistic solubilizing components, compound flavoring components and molding excipients, and forms a dense and porous ring structure after 3D printing and gradient crosslinking curing, wherein its central through-hole is connected to the overall through-hole of the tablet; the shell contains a pH-sensitive polymer, which is configured to inhibit drug release in the oral environment, while allowing drug release in gastric juice.

[0007] Preferably, the preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to a mixed solvent to prepare a dispersion system with a drug concentration of 24-26 mg / mL. Then add a co-solvent component, stir evenly, centrifuge at 2800-3200 rpm for 4-6 minutes, and then degas under vacuum for 13-16 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient Crosslinking Bath Preparation: Prepare two concentrations of crosslinking curing solution respectively. The first stage is a calcium chloride aqueous solution with a mass percentage concentration of 2.8-3.2% and the second stage is a calcium chloride aqueous solution with a mass percentage concentration of 4.8-5.2%. Step S4, 3D Printing: A semi-solid / micro-extrusion 3D printer is used. The barrel temperature is set to 23-26℃, the platform temperature to 23-26℃, the printing speed to 12-18mm / s, the extrusion pressure to 0.2-0.4MPa, the infill density to 40%-60%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 3-1 / 2 of the tablet diameter. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed at the same time, resulting in an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 4-6 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 5-7 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 3.5-4.0 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 30-35℃ for 10-15 minutes, and then the temperature is raised to 38-40℃ for 15-20 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

[0008] Preferably, the mixed solvent in step S1 is a mixture of THF and anhydrous ethanol in a volume ratio of (7-9):2; the synergistic solubilizing component is a mixture of pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin in a mass ratio of (1-3):(0.5-1); the mass of the synergistic solubilizing component is 0.015-0.04% (w / v) of the total volume of the printing ink.

[0009] Preferably, the compound flavoring component in step S2 is a mixture of pharmaceutical-grade mannitol, food-grade strawberry flavoring, and food-grade steviol glycosides in a mass ratio of (8-12):0.5:0.3.

[0010] Preferably, the ratio of purified water, compound flavoring component, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na in step S2 is 1000mL:10.8g:5g:1g:0.2g:0.1g.

[0011] Preferably, the ratio of the initial product, the first cross-linking curing solution, and the second cross-linking curing solution in step S5 is 1g:(10-15)mL:(10-15)mL.

[0012] Preferably, the volume ratio of ethanol to water in the ethanol-water mixed solution in step S6 is 3:2.

[0013] Preferably, in step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and ethanol-water mixed solution is 100:(15-20):(5-10):(800-1000); and the average particle size of the pharmaceutical talc is 5-10 μm.

[0014] Preferably, in step S6, the rotation speed of the spray-coated pan is 12-15 rpm, the inlet air temperature is 45-50℃, the outlet air temperature is 28-32℃, the spray pressure is 1.8-2.2 bar, and the spray is carried out at a rate of 8-12 mL / min until the tablet core gains 4-5% weight.

[0015] Preferably, the gradient rinsing in step S7 specifically involves: first rinsing rapidly with a mixture of purified water and anhydrous ethanol for 5-10 seconds, and then rinsing with purified water for 4-6 seconds; the volume ratio of purified water to anhydrous ethanol is 9:1.

[0016] Preferably, the gradient temperature freeze-drying process in step S7 is as follows: the pre-freezing temperature is -80℃, maintained for 1.8-2.2 hours, and then the temperature is increased to 24-26℃ at a rate of 4-6℃ / h, with a vacuum degree of <10Pa throughout the process.

[0017] Due to the application of the above technical solution, the present invention has the following beneficial effects: (1) The ketotifen fumarate tablets and their preparation method disclosed in this invention, through the special structural design of the annular belt with a central through hole, combined with the gradient cross-linking curing process, greatly increases the drug dissolution contact area. With the combination of synergistic solubilizing components, the dissolution rate is significantly improved, and the rapid onset of action is achieved. The central through hole can also act as a "life-saving airway" to prevent suffocation when children accidentally swallow it. At the same time, the pH-sensitive layer design of the outer shell can inhibit drug release in the oral cavity and avoid odor stimulation. It can accurately release the drug in the gastric juice, which completely solves the problem of high gastrointestinal irritation of existing preparations. It achieves a synergistic improvement of targeted release and taste optimization. This is a breakthrough that has not been achieved by traditional tableting process and existing 3D printed preparations.

[0018] (2) The ketotifen fumarate tablets and their preparation method disclosed in this invention break through the bottleneck of poor stability and easy degradation of active ingredients in existing 3D printed ketotifen fumarate preparations. The gradient cross-linking curing process can form a dense and porous stable structure. With the addition of stabilizers such as EDTA-2Na, the degradation of the drug during long-term storage is effectively inhibited, and the dissolution stability is improved. At the same time, the loss of drug activity and the risk of heat source introduction caused by traditional thermal processing processes are avoided. In particular, the safety of children's medication is improved. Compared with the shortcomings of existing 3D printing technology that only focuses on dosage and ignores stability and safety, the dual improvement of stability and safety is achieved.

[0019] (3) The ketotifen fumarate tablets and their preparation method disclosed in this invention adopt semi-solid / micro-extrusion 3D printing technology, which can flexibly adjust the tablet dosage and size by adjusting the printing parameters to meet the personalized medication needs of different groups such as children and the elderly; at the same time, the scientific combination of compound flavoring components, combined with the odor isolation effect of pH sensitive layer, significantly improves the taste of the preparation, solves the problem of poor taste and low patient medication compliance of traditional preparations, and breaks the limitation of existing technology that it is difficult to take into account personalization, taste and stability.

[0020] (4) The synergistic application of gradient crosslinking, gradient rinsing, and gradient temperature freeze drying processes disclosed in this invention not only ensures the quality of tablet molding and uniform drug dispersion, but also further improves the stability of the formulation. Compared with the problems of uneven crosslinking and rough process of existing 3D printed formulations, the process of this invention can accurately control the performance of the formulation, reduce the failure rate in the production process, and improve the clinical application value of the product. Detailed Implementation

[0021] The following description is intended to disclose the invention and enable those skilled in the art to implement it. The preferred embodiments described below are merely examples, and other obvious variations will occur to those skilled in the art.

[0022] Example 1

[0023] A ketotifen fumarate tablet, the formulation having a ring structure with a central through-hole extending through the thickness of the tablet; the formulation includes a core and a shell covering the core; the core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate active pharmaceutical ingredient, co-solubilizing components, compound flavoring components and molding excipients, and is formed into a dense and porous ring structure after 3D printing and gradient cross-linking curing, with its central through-hole communicating with the overall through-hole of the tablet; the shell contains a pH-sensitive polymer configured to inhibit drug release in the oral environment while allowing drug release in gastric juice.

[0024] The preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to the mixed solvent to prepare a dispersion system with a drug concentration of 24 mg / mL. Then add the co-solvent component, stir evenly, centrifuge at 2800 rpm for 4 minutes, and then degas under vacuum for 13 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient crosslinking bath preparation: Prepare two concentrations of crosslinking curing solution respectively. The first concentration is a calcium chloride aqueous solution with a mass percentage concentration of 2.8% and the second concentration is a calcium chloride aqueous solution with a mass percentage concentration of 4.8%. Step S4, 3D Printing: A semi-solid / micro-extrusion 3D printer is used, with the barrel temperature and platform temperature set to 23℃, the printing speed to 12mm / s, the extrusion pressure to 0.2MPa, the infill density to 40%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 3 of the tablet diameter. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed simultaneously to obtain an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 4 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 5 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 3.5 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 30°C for 10 minutes, and then the temperature is increased to 38°C for 15 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

[0025] In step S1, the mixed solvent is a mixture of THF and anhydrous ethanol at a volume ratio of 7:2; the synergistic solubilizing component is a mixture of pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin at a mass ratio of 1:0.5; the mass of the synergistic solubilizing component is 0.015% (w / v) of the total volume of the printing ink; in step S2, the compound flavoring component is a mixture of pharmaceutical grade mannitol, food grade strawberry flavor, and food grade steviol glycosides at a mass ratio of 8:0.5:0.3; in step S2, the mass ratio of purified water, compound flavoring component, pharmaceutical grade low-viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na is 1000mL:10.8g:5g:1g:0.2g:0.1g.

[0026] In step S5, the ratio of the initial product, the first-stage crosslinking curing solution, and the second-stage crosslinking curing solution is 1g:10mL:10mL; in step S6, the volume ratio of ethanol to water in the ethanol-water mixed solution is 3:2; in step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and the ethanol-water mixed solution is 100:15:5:800; the average particle size of the pharmaceutical talc is 5μm; in step S6, the spray coating pan rotates at 12rpm, the inlet air temperature is 45℃, the outlet air temperature is 28℃, the spray pressure is 1.8bar, and the spray is carried out at a rate of 8mL / min until the tablet core gains 4% weight.

[0027] The gradient rinsing in step S7 specifically involves: first rinsing rapidly with a mixture of purified water and anhydrous ethanol for 5 seconds, then rinsing with purified water for 4 seconds; the volume ratio of purified water to anhydrous ethanol is 9:1; the gradient temperature freeze-drying process in step S7 specifically involves: pre-freezing at -80℃ for 1.8 hours, then increasing the temperature to 24℃ at a rate of 4℃ / h, with a vacuum degree of <10Pa throughout the process.

[0028] Example 2

[0029] A ketotifen fumarate tablet, the formulation having a ring structure with a central through-hole extending through the thickness of the tablet; the formulation includes a core and a shell covering the core; the core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate active pharmaceutical ingredient, co-solubilizing components, compound flavoring components and molding excipients, and is formed into a dense and porous ring structure after 3D printing and gradient cross-linking curing, with its central through-hole communicating with the overall through-hole of the tablet; the shell contains a pH-sensitive polymer configured to inhibit drug release in the oral environment while allowing drug release in gastric juice.

[0030] The preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to a mixed solvent to prepare a dispersion system with a drug concentration of 24.5 mg / mL. Then add a co-solvent component, stir evenly, centrifuge at 2900 rpm for 4.5 minutes, and then degas under vacuum for 14 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient crosslinking bath preparation: Prepare two concentrations of crosslinking curing solution respectively. The first concentration is a calcium chloride aqueous solution with a mass percentage concentration of 2.9% and the second concentration is a calcium chloride aqueous solution with a mass percentage concentration of 4.9%. Step S4, 3D Printing: A semi-solid / micro-extrusion 3D printer is used, with the barrel temperature and platform temperature set to 24℃, the printing speed to 14mm / s, the extrusion pressure to 0.25MPa, the infill density to 45%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 3 of the tablet diameter. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed simultaneously to obtain an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 4.5 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 5.5 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 3.6 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 32°C for 12 minutes, and then the temperature is increased to 38.5°C for 16 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

[0031] The mixed solvent in step S1 is a mixture of THF and anhydrous ethanol at a volume ratio of 7.5:2; the synergistic solubilizing component is a mixture of pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin at a mass ratio of 1.5:0.6; the mass of the synergistic solubilizing component is 0.02% (w / v) of the total volume of the printing ink; the compound flavoring component in step S2 is a mixture of pharmaceutical grade mannitol, food grade strawberry flavor, and food grade steviol glycosides at a mass ratio of 9:0.5:0.3; the mass ratio of purified water, compound flavoring component, pharmaceutical grade low-viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na in step S2 is 1000mL:10.8g:5g:1g:0.2g:0.1g.

[0032] In step S5, the ratio of the initial product, the first-stage crosslinking curing solution, and the second-stage crosslinking curing solution is 1g:12mL:12mL; in step S6, the volume ratio of ethanol to water in the ethanol-water mixed solution is 3:2; in step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and the ethanol-water mixed solution is 100:17:6:850; and the average particle size of the pharmaceutical talc is 7μm.

[0033] In step S6, the spray coating pan rotates at 13.5 rpm, the inlet air temperature is 48℃, the outlet air temperature is 30℃, and the spray pressure is 2 bar. The spray is carried out at a rate of 10 mL / min until the tablet core gains 4.5% in weight. In step S7, the gradient rinsing is carried out by first rinsing with a mixture of purified water and anhydrous ethanol for 8 seconds, and then rinsing with purified water for 5 seconds. The volume ratio of purified water to anhydrous ethanol is 9:1. In step S7, the gradient temperature freeze-drying process is carried out by pre-freezing at -80℃ for 2 hours, and then heating up to 25℃ at a rate of 5℃ / h, with a vacuum degree of <10Pa throughout the process.

[0034] Example 3

[0035] A ketotifen fumarate tablet, the formulation having a ring structure with a central through-hole extending through the thickness of the tablet; the formulation includes a core and a shell covering the core; the core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate active pharmaceutical ingredient, co-solubilizing components, compound flavoring components and molding excipients, and is formed into a dense and porous ring structure after 3D printing and gradient cross-linking curing, with its central through-hole communicating with the overall through-hole of the tablet; the shell contains a pH-sensitive polymer configured to inhibit drug release in the oral environment while allowing drug release in gastric juice.

[0036] The preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to the mixed solvent to prepare a dispersion system with a drug concentration of 25 mg / mL. Then add the co-solvent component, stir evenly, centrifuge at 3000 rpm for 5 minutes, and then degas under vacuum for 15 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient Crosslinking Bath Preparation: Prepare two concentrations of crosslinking curing solution respectively. The first concentration is a 3% (w / w) calcium chloride aqueous solution, and the second concentration is a 5% (w / w) calcium chloride aqueous solution. Step S4, 3D printing: A semi-solid / micro-extrusion 3D printer is used, with the barrel temperature set to 24.5℃, the platform temperature to 24.5℃, the printing speed to 15mm / s, the extrusion pressure to 0.3MPa, the infill density to 50%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 2 the diameter of the tablet. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed at the same time, resulting in an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 5 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 6 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 3.8 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 33°C for 13 minutes, and then the temperature is increased to 39°C for 18 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

[0037] In step S1, the mixed solvent is a mixture of THF and anhydrous ethanol at a volume ratio of 8:2; the synergistic solubilizing component is a mixture of pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin at a mass ratio of 2:0.7; the mass of the synergistic solubilizing component is 0.03% (w / v) of the total volume of the printing ink; in step S2, the compound flavoring component is a mixture of pharmaceutical grade mannitol, food grade strawberry flavor, and food grade steviol glycosides at a mass ratio of 10:0.5:0.3; in step S2, the mass ratio of purified water, compound flavoring component, pharmaceutical grade low-viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na is 1000mL:10.8g:5g:1g:0.2g:0.1g.

[0038] In step S5, the ratio of the initial product, the first-stage crosslinking curing solution, and the second-stage crosslinking curing solution is 1g:13mL:13mL; in step S6, the volume ratio of ethanol to water in the ethanol-water mixed solution is 3:2; in step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and the ethanol-water mixed solution is 100:18:8:900; and the average particle size of the pharmaceutical talc is 8μm.

[0039] In step S6, the spray coating pan rotates at 13.5 rpm, the inlet air temperature is 48℃, the outlet air temperature is 30℃, and the spray pressure is 2 bar. The spray is carried out at a rate of 10 mL / min until the tablet core gains 4.5% in weight. In step S7, the gradient rinsing is carried out by first rinsing with a mixture of purified water and anhydrous ethanol for 8 seconds, and then rinsing with purified water for 5 seconds. The volume ratio of purified water to anhydrous ethanol is 9:1. In step S7, the gradient temperature freeze-drying process is carried out by pre-freezing at -80℃ for 2 hours, and then heating up to 25℃ at a rate of 5℃ / h, with a vacuum degree of <10Pa throughout the process.

[0040] Example 4

[0041] A ketotifen fumarate tablet, the formulation having a ring structure with a central through-hole extending through the thickness of the tablet; the formulation includes a core and a shell covering the core; the core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate active pharmaceutical ingredient, co-solubilizing components, compound flavoring components and molding excipients, and is formed into a dense and porous ring structure after 3D printing and gradient cross-linking curing, with its central through-hole communicating with the overall through-hole of the tablet; the shell contains a pH-sensitive polymer configured to inhibit drug release in the oral environment while allowing drug release in gastric juice.

[0042] The preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to a mixed solvent to prepare a dispersion system with a drug concentration of 25.5 mg / mL. Then add a co-solvent component, stir evenly, centrifuge at 3100 rpm for 5.5 minutes, and then degas under vacuum for 15.5 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient crosslinking bath preparation: Prepare two concentrations of crosslinking curing solution respectively. The first concentration is a calcium chloride aqueous solution with a mass percentage concentration of 3.1% and the second concentration is a calcium chloride aqueous solution with a mass percentage concentration of 5.1%. Step S4, 3D Printing: A semi-solid / micro-extrusion 3D printer is used, with the barrel temperature set to 25.5℃, the platform temperature to 25.5℃, the printing speed to 17mm / s, the extrusion pressure to 0.35MPa, the infill density to 55%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 2 the diameter of the tablet. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed simultaneously to obtain an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 5.5 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 6.5 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 3.9 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 34°C for 14 minutes, and then the temperature is increased to 39.5°C for 19 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

[0043] The mixed solvent in step S1 is a mixture of THF and anhydrous ethanol at a volume ratio of 8.5:2; the synergistic solubilizing component is a mixture of pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin at a mass ratio of 2.5:0.9; the mass of the synergistic solubilizing component is 0.035% (w / v) of the total volume of the printing ink; the compound flavoring component in step S2 is a mixture of pharmaceutical grade mannitol, food grade strawberry flavor, and food grade steviol glycosides at a mass ratio of 11:0.5:0.3; the mass ratio of purified water, compound flavoring component, pharmaceutical grade low-viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na in step S2 is 1000mL:10.8g:5g:1g:0.2g:0.1g.

[0044] In step S5, the ratio of the initial product, the first-stage crosslinking curing solution, and the second-stage crosslinking curing solution is 1g:14mL:14mL; in step S6, the volume ratio of ethanol to water in the ethanol-water mixed solution is 3:2; in step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and the ethanol-water mixed solution is 100:19:9:950; the average particle size of the pharmaceutical talc is 9μm; in step S6, the spray coating pan rotates at 14rpm, the inlet air temperature is 49℃, the outlet air temperature is 31℃, the spray pressure is 2.1bar, and the spray is applied at a rate of 11mL / min until the tablet core gains 4.8% weight.

[0045] The gradient rinsing in step S7 specifically involves: first rinsing rapidly with a mixture of purified water and anhydrous ethanol for 9 seconds, then rinsing with purified water for 5.5 seconds; the volume ratio of purified water to anhydrous ethanol is 9:1; the gradient temperature freeze-drying process in step S7 specifically involves: pre-freezing at -80℃ for 2.1 hours, then increasing the temperature to 25.5℃ at a rate of 5.5℃ / h, with a vacuum degree of <10Pa throughout the process.

[0046] Example 5

[0047] A ketotifen fumarate tablet, the formulation having a ring structure with a central through-hole extending through the thickness of the tablet; the formulation includes a core and a shell covering the core; the core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate active pharmaceutical ingredient, co-solubilizing components, compound flavoring components and molding excipients, and is formed into a dense and porous ring structure after 3D printing and gradient cross-linking curing, with its central through-hole communicating with the overall through-hole of the tablet; the shell contains a pH-sensitive polymer configured to inhibit drug release in the oral environment while allowing drug release in gastric juice.

[0048] The preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to the mixed solvent to prepare a dispersion system with a drug concentration of 26 mg / mL. Then add the co-solvent component, stir evenly, centrifuge at 3200 rpm for 4-6 minutes, and then degas under vacuum for 16 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient Crosslinking Bath Preparation: Prepare two concentrations of crosslinking curing solution respectively. The first concentration is a calcium chloride aqueous solution with a mass percentage concentration of 3.2% and the second concentration is a calcium chloride aqueous solution with a mass percentage concentration of 5.2%. Step S4, 3D Printing: A semi-solid / micro-extrusion 3D printer is used, with the barrel temperature set to 26℃, the platform temperature to 26℃, the printing speed to 18mm / s, the extrusion pressure to 0.4MPa, the infill density to 60%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 2 the diameter of the tablet. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed simultaneously to obtain an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 6 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 7 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 4.0 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 35°C for 15 minutes, and then the temperature is increased to 40°C for 20 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

[0049] In step S1, the mixed solvent is a mixture of THF and anhydrous ethanol at a volume ratio of 9:2; the synergistic solubilizing component is a mixture of pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin at a mass ratio of 3:1; the mass of the synergistic solubilizing component is 0.04% (w / v) of the total volume of the printing ink; in step S2, the compound flavoring component is a mixture of pharmaceutical grade mannitol, food grade strawberry flavor, and food grade steviol glycosides at a mass ratio of 12:0.5:0.3; in step S2, the mass ratio of purified water, compound flavoring component, pharmaceutical grade low-viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na is 1000mL:10.8g:5g:1g:0.2g:0.1g.

[0050] In step S5, the ratio of the initial product, the first-stage crosslinking curing solution, and the second-stage crosslinking curing solution is 1g:15mL:15mL; in step S6, the volume ratio of ethanol to water in the ethanol-water mixed solution is 3:2; in step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and the ethanol-water mixed solution is 100:20:10:1000; the average particle size of the pharmaceutical talc is 10μm; in step S6, the spray coating pan rotates at 15rpm, the inlet air temperature is 50℃, the outlet air temperature is 32℃, the spray pressure is 2.2bar, and the spray is carried out at a rate of 12mL / min until the tablet core gains 5% weight.

[0051] The gradient rinsing in step S7 specifically involves: first rinsing rapidly with a mixture of purified water and anhydrous ethanol for 10 seconds, then rinsing with purified water for 6 seconds; the volume ratio of purified water to anhydrous ethanol is 9:1; the gradient temperature freeze-drying process in step S7 specifically involves: pre-freezing at -80℃ for 2.2 hours, then increasing the temperature to 26℃ at a rate of 6℃ / h, with a vacuum degree of <10Pa throughout the process.

[0052] Comparative Example 1 A ketotifen fumarate tablet and its preparation method are the same as those in Example 1 of CN119235803A.

[0053] Comparative Example 2 A ketotifen fumarate tablet and its preparation method are disclosed. The traditional powder mixing and direct compression process is adopted. The formula is: 1 part ketotifen fumarate, 80 parts 100-mesh lactose, 20 parts corn starch, 10 parts pregelatinized corn starch, and 1 part magnesium stearate. After the components are mixed evenly, they are directly compressed into tablets with the pressure controlled at 10 kN.

[0054] To further illustrate the unexpected positive technical effects achieved by the present invention, the relevant performance of ketotifen fumarate tablets in Example 5 and Comparative Examples 1-2 was tested. The test results are shown in Table 1, and the test methods are as follows: (1) Dissolution test: Refer to the General Chapter 0931, Method 3 (Dissolution and Release Determination) of Part II of the Pharmacopoeia of the People's Republic of China (2020 Edition). Use 200 mL of water as the dissolution medium, rotate at 75 rpm, and maintain a temperature of 37 ± 0.5 °C. Take a 10 mL sample after 30 min, filter it, and take the filtrate. Measure the absorbance at a wavelength of 301 nm using ultraviolet-visible spectrophotometry (General Chapter 0401). Follow the instructions in section C. 19 H 19 The absorption coefficient (E1%1cm) of NOS is 465. Calculate the dissolution amount per tablet and the dissolution rate over 15 minutes.

[0055] (2) Friability test: Refer to the 0923 Friability test method in General Chapter II of the Pharmacopoeia of the People's Republic of China (2020 edition). Take 20 tablets from each group, accurately weigh the total weight, place them in the friability tester, set the rotation speed to 25 r / min, rotate 100 times, take them out, remove the powder, accurately weigh the total weight of the remaining tablets, and calculate the friability (friability = (initial total weight - remaining total weight) / initial total weight × 100%).

[0056] (3) Weight difference test: Refer to the weight difference test method under the General Chapter 0101 Tablets in Part II of the Pharmacopoeia of the People's Republic of China (2020 Edition). Take 20 tablets from each group, accurately weigh each tablet, calculate the average weight, and then calculate the difference between the weight of each tablet and the average weight.

[0057] (4) Stability test: Each group of tablets was placed in an environment with a temperature of 40℃ and a relative humidity of 80% for accelerated stability test. Samples were taken at 0 months and 3 months to test dissolution and calculate the dissolution change rate at 15 min. Dissolution change rate = (0-month dissolution - 3-month dissolution) / 0-month dissolution × 100%.

[0058] (5) Content uniformity test: Refer to the content uniformity test method in General Chapter 0941 of Part II of the Pharmacopoeia of the People's Republic of China (2020 Edition). Take 10 tablets of each group, place each tablet in a 100mL volumetric flask, add an appropriate amount of water, shake to dissolve ketotifen fumarate, dilute with water to the mark, shake well, filter, take the filtrate, and measure the absorbance at a wavelength of 301nm using ultraviolet-visible spectrophotometry (General Chapter 0401). 19 H 19 The absorption coefficient (E1%1cm) of NOS is 465. Calculate the content per tablet and the content uniformity RSD value.

[0059] As can be seen from the test results in Table 1, the ketotifen fumarate tablets prepared in Example 5 are significantly superior to Comparative Example 1 and Comparative Example 2 in all performance indicators. The dissolution rate at 15 min is as high as 96.8%, the friability is only 0.32%, the weight difference is controlled within ±1.2%, the dissolution rate change rate in the accelerated stability test is only 1.86%, and the content uniformity RSD is 1.0%. In contrast, the indicators of Comparative Example 1 (existing patented process) and Comparative Example 2 (traditional powder mixing and direct pressing process) all show a gradient deterioration, which fully demonstrates the technical advantages of the 3D printing, gradient cross-linking curing and pH-sensitive coating processes used in Example 5.

[0060] Table 1 The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A ketotifen fumarate tablet, characterized in that, The formulation has a ring-shaped structure with a central through-hole extending through the thickness of the tablet. The formulation includes a core and a shell covering the core. The core is the active core of ketotifen fumarate, mainly composed of ketotifen fumarate active pharmaceutical ingredient, co-solubilizing components, compound flavoring components, and molding excipients. After 3D printing and gradient cross-linking curing, it forms a dense and porous ring structure with its central through-hole communicating with the overall through-hole of the tablet. The shell contains a pH-sensitive polymer configured to inhibit drug release in the oral environment while allowing drug release in gastric juice.

2. The ketotifen fumarate tablets according to claim 1, characterized in that, The preparation method of the ketotifen fumarate tablets includes the following steps: Step S1, Preparation of printing ink: Add ketotifen fumarate raw material to a mixed solvent to prepare a dispersion system with a drug concentration of 24-26 mg / mL. Then add a co-solvent component, stir evenly, centrifuge at 2800-3200 rpm for 4-6 minutes, and then degas under vacuum for 13-16 minutes. Step S2, Preparation of composite coagulation bath: Using purified water as solvent, add composite flavoring components, pharmaceutical grade low viscosity sodium alginate, pharmaceutical grade poloxamer 188, pharmaceutical grade povidone K30, and pharmaceutical grade EDTA-2Na, stir until homogeneous, degas and set aside. Step S3, Gradient Crosslinking Bath Preparation: Prepare two concentrations of crosslinking curing solution respectively. The first stage is a calcium chloride aqueous solution with a mass percentage concentration of 2.8-3.2% and the second stage is a calcium chloride aqueous solution with a mass percentage concentration of 4.8-5.2%. Step S4, 3D Printing: A semi-solid / micro-extrusion 3D printer is used. The barrel temperature is set to 23-26℃, the platform temperature to 23-26℃, the printing speed to 12-18mm / s, the extrusion pressure to 0.2-0.4MPa, the infill density to 40%-60%, and the infill pattern to be a grid-spiral composite pattern. The 3D printing program is used to preset the annular structure and the central through-hole through the thickness. The diameter of the through-hole is designed to be 1 / 3-1 / 2 of the tablet diameter. The nozzle is placed 1cm below the surface of the composite coagulation bath. Printing is started, and the tablet structure is formed and the drug is evenly dispersed at the same time, resulting in an annular preliminary product with a central through-hole. Step S5, Gradient cross-linking curing: The printed ring-shaped preliminary product with a central through hole is first immersed in the first stage of the cross-linking curing solution for 4-6 minutes to achieve preliminary curing of the sample; then it is transferred to the second stage of the cross-linking curing solution and immersed for 5-7 minutes to achieve deep curing of the sample. After rinsing, it is freeze-dried to obtain the cross-linked cured tablet. Step S6, pH-sensitive layer coating: Using Eudragit® E100 as the film-forming material, polyethylene glycol 400 as the plasticizer, and pharmaceutical talc as the anti-adhesion agent, the above excipients are dispersed in an ethanol-water mixed solution, and the pH is adjusted to 3.5-4.0 with hydrochloric acid. The solution is stirred to obtain a coating solution. Then, a high-efficiency coating machine is used for spray coating. After coating, the tablets are placed in a vacuum drying oven and dried at 30-35℃ for 10-15 minutes, and then the temperature is raised to 38-40℃ for 15-20 minutes. Step S7, Precise Post-processing: The sample coated with the pH-sensitive layer is subjected to gradient rinsing; then dried using a gradient temperature freeze-drying process; after drying, it is graded and screened to remove unqualified samples, and vacuum-packed with aluminum foil to obtain the final ketotifen fumarate tablets.

3. The ketotifen fumarate tablets according to claim 2, characterized in that, The mixed solvent mentioned in step S1 is THF and anhydrous ethanol in a volume ratio of (7-9):2; the synergistic solubilizing component is pharmaceutical grade polyethylene glycol 400 and pharmaceutical grade hydroxypropyl-β-cyclodextrin in a mass ratio of (1-3):(0.5-1); the mass of the synergistic solubilizing component is 0.015-0.04% (w / v) of the total volume of the printing ink.

4. The ketotifen fumarate tablets according to claim 2, characterized in that, The compound flavoring component mentioned in step S2 is composed of pharmaceutical-grade mannitol, food-grade strawberry flavoring, and food-grade steviol glycosides in a mass ratio of (8-12):0.5:0.

3.

5. The ketotifen fumarate tablets according to claim 2, characterized in that, In step S2, the ratio of purified water, compound flavoring component, pharmaceutical-grade low-viscosity sodium alginate, pharmaceutical-grade poloxamer 188, pharmaceutical-grade povidone K30, and pharmaceutical-grade EDTA-2Na is 1000mL:10.8g:5g:1g:0.2g:0.1g; in step S5, the ratio of the initial product, the first-stage crosslinking curing solution, and the second-stage crosslinking curing solution is 1g:(10-15)mL:(10-15)mL.

6. The ketotifen fumarate tablets according to claim 2, characterized in that, In step S6, the volume ratio of ethanol to water in the ethanol-water mixed solution is 3:

2.

7. The ketotifen fumarate tablets according to claim 2, characterized in that, In step S6, the mass ratio of Eudragit® E100, polyethylene glycol 400, pharmaceutical talc, and ethanol-water mixed solution is 100:(15-20):(5-10):(800-1000); the average particle size of the pharmaceutical talc is 5-10 μm.

8. The ketotifen fumarate tablets according to claim 2, characterized in that, In step S6, the spray coating pan rotates at 12-15 rpm, the inlet air temperature is 45-50℃, the outlet air temperature is 28-32℃, the spray pressure is 1.8-2.2 bar, and the spray is carried out at a rate of 8-12 mL / min until the tablet core gains 4-5% weight.

9. The ketotifen fumarate tablets according to claim 2, characterized in that, The gradient rinsing in step S7 specifically involves: first rinsing rapidly with a mixture of purified water and anhydrous ethanol for 5-10 seconds, and then rinsing with purified water for 4-6 seconds; the volume ratio of purified water to anhydrous ethanol is 9:

1.

10. The ketotifen fumarate tablets according to claim 2, characterized in that, The gradient temperature freeze-drying process described in step S7 is as follows: the pre-freezing temperature is -80℃, maintained for 1.8-2.2 hours, and then the temperature is increased to 24-26℃ at a rate of 4-6℃ / h, with a vacuum degree of <10Pa throughout the process.

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