Vonoprazan fumarate tablet with high stability and dissolution stability and preparation method of Vonoprazan fumarate tablet

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a high-stability and stable-dissolution Vonoprazan fumarate tablet and a preparation method thereof. According to the preparation method disclosed by the invention, only the Vonoprazan fumarate, the mannitol, the auxiliary agent, the solvent, the lubricant and the disintegrating agent are taken as raw materials, and the problems that a preparation method of the Vonoprazan fumarate tablet in the prior art is complicated, the dissolution rate of the obtained product is relatively low and the content of related substances is high are solved by optimizing the dosage ratio of the raw materials and a preparation process. According to the preparation method disclosed by the invention, the size and the shape of the particles can be better controlled by granulating the raw material and the auxiliary material of the fumaric acid Vonoprazan, uniform and stable medicine particles can be produced so as to achieve the purposes of good medicine dissolution expression and control of related substances, and meanwhile, the problem that the uniformity is poor after the fumaric acid Vonoprazan and the auxiliary material particles are mixed is solved. The method is simple to operate, does not need special reaction conditions and equipment, is more suitable for industrial production, and conforms to the concept of green development.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a vonoprazan fumarate tablet with high stability and stable dissolution and a preparation method thereof. Background Art

[0002] Vonoprazan Fumarate Tablets is a new type of potassium ion competitive acid blocker.

[0003] Unlike traditional proton pump inhibitors (PPIs, such as omeprazole), vonoprazan directly blocks the final step of gastric acid secretion by competitively inhibiting the potassium ion binding site of H+ / K+-ATPase (proton pump) in gastric parietal cells.

[0004] PPI needs to be activated in an acidic environment, while vonoprazan can take effect without activation, so it takes effect faster (reaching the maximum acid suppression effect within 2 hours after taking the medicine) and the acid suppression effect is more stable (not affected by meals or administration time).

[0005] Powerful acid inhibition: Vonoprazan is significantly better than PPI in inhibiting basal gastric acid and stimulated gastric acid, and its effect lasts longer (a higher proportion of time in which the intragastric pH is maintained at >4 within 24 hours).

[0006] Rapidly relieve symptoms: It has better efficacy in the treatment of reflux esophagitis (GERD) and Helicobacter pylori (Hp) eradication, especially better control of nocturnal acid breakthrough.

[0007] High bioavailability: Rapid oral absorption, not affected by gastric acid, no need to make enteric-coated preparations. Metabolic pathway: Mainly metabolized by CYP3A4, with a half-life of about 9 hours, suitable for once-daily administration.

[0008] Vonoprazan fumarate tablets have broken through the limitations of traditional PPIs through innovative mechanisms of action and excellent pharmacological properties, becoming an important advance in the treatment of gastric acid-related diseases. Its technical core lies in the competitive inhibition of potassium ions targeting the proton pump, stable pharmacokinetic design, and the combination of highly difficult salt forms and formulation processes. With the expansion of clinical applications, it may occupy a more important position in the field of digestion in the future.

[0009] In view of this, the present invention provides a vonoprazan fumarate tablet with high stability and stable dissolution and a preparation method thereof, in order to solve various problems existing in the vonoprazan fumarate tablet in the prior art. Summary of the invention

[0010] The object of the present invention is to provide a vonoprazan fumarate immediate-release tablet with high stability and stable dissolution, and a preparation method thereof. The present invention only uses vonoprazan fumarate, mannitol, an auxiliary agent, a solvent, a lubricant, and a disintegrant as raw materials, and solves the problems in the prior art that the preparation method of vonoprazan fumarate tablets is complex, the dissolution degree of the obtained product is low, and the related substances are high by optimizing the dosage ratio of the raw materials and the preparation process.

[0011] To achieve the above object, the present invention adopts the following technical solutions:

[0012] A preparation method of a vonoprazan fumarate tablet with high stability and stable dissolution, comprising the following steps:

[0013] (1) Vonoprazan fumarate, mannitol, and an auxiliary agent are sequentially added to a wet granulator for premixing to obtain a premixed material;

[0014] (2) After the premixing is completed, a solvent is added to the premixed material by means of adding slurry through a funnel. After adding, granulation is carried out to obtain a soft material;

[0015] (3) A sieve is installed at the inlet end of a granulating machine, and the soft material described in step (2) is placed in the granulating machine, screened, and wet granulated;

[0016] (4) When the temperature of the fluidized bed material reaches 40°C to 45°C, the wet granulated soft material in step (3) is poured into the fluidized bed, and fluidized drying is started. The fluidized drying is stopped when the moisture content of the granules reaches 2.0% to 5.0%; a sieve is used to perform dry granulation on the dried material;

[0017] (5) The dried and granulated material in step (4), a lubricant, and a disintegrant are sequentially added to a mixer for mixing, and then tabletted to obtain a mixed tablet core;

[0018] The obtained mixed tablet core is coated with a coating solution to obtain a vonoprazan fumarate tablet.

[0019] In a preferred embodiment, in step (1), the mass ratio of vonoprazan fumarate, mannitol, and the auxiliary agent is (7.0 to 10.0):(40 to 50):(7.5 to 20). Specifically, the auxiliary agent is a diluent, a binder, and / or a pH regulator; when the auxiliary agent is a diluent, a binder, and a pH regulator, the mass ratio of the diluent, the binder, and the pH regulator is (90 to 130):(20 to 40):1.

[0020] Preferably, the mass ratio of vonoprazan fumarate, mannitol, and the auxiliary agent is (8.0 to 9.0):(43 to 47):(7.9 to 12).

[0021] More preferably, the mass ratio of voruprazan fumarate, mannitol and the auxiliary agent is 8.1:46:8.55 or 8.1:46:7.97; specifically, the auxiliary agent is a diluent, a binder and / or a pH regulator; when the auxiliary agent is a diluent, a binder and a pH regulator, the mass ratio of the diluent, the binder and the pH regulator is 130:40:1.

[0022] In a preferred embodiment, in step (1), the mass ratio of voruprazan fumarate, mannitol, diluent, binder and pH regulator is (7.0-10.0):(40-50):(6-8):(1-2):(0.05-0.1).

[0023] In a preferred embodiment, in step (1), the particle size of voruprazan fumarate is 10 μm ≤ D90 ≤ 50 μm, and the particle size of mannitol is 30 mesh to 120 mesh.

[0024] In a preferred embodiment, in step (1), the diluent is at least one of mannitol, corn starch, microcrystalline cellulose and lactose.

[0025] In a preferred embodiment, in step (1), the binder is at least one of corn starch, hydroxypropyl cellulose and hypromellose.

[0026] In a preferred embodiment, in step (1), the pH regulator is at least one of fumaric acid, citric acid, sodium hydroxide and hydrochloric acid water.

[0027] In a preferred embodiment, in step (1), the premixing time is 5-20 min.

[0028] In a preferred embodiment, in step (1), during premixing, the stirring paddle speed is set to 100-120 rpm, and the cutter speed is 1000-1200 rpm.

[0029] In a preferred embodiment, in step (2), the solvent is at least one of water and absolute ethanol.

[0030] In a preferred embodiment, in step (2), the mass ratio of the premix to the solvent is (2-5):1.

[0031] In a preferred embodiment, in step (2), during the addition, the stirring paddle speed is maintained at 100-120 rpm, the cutter speed is 1000-1200 rpm, and the addition time is 70-90 s.

[0032] In a preferred embodiment, in step (2), the granulation time is 5-10 min.

[0033] In a preferred embodiment, in step (3), during wet granulation, the fluidized bed parameters are set. Specifically, the inlet air temperature is set to 50 - 60 °C, the inlet air humidity is 6.0 g / kg - 10.0 g / kg, and the fluidization air volume is 900 m 3 / h - 1200 m 3 / h, and the fluidized bed is preheated to a temperature not lower than 45 °C (preferably 45 - 50 °C).

[0034] In a preferred embodiment, in step (4), when pouring the soft material after wet granulation in step (3) into the fluidized bed, the inlet air temperature is set to 50 °C - 60 °C, the bag shaking period is 50 - 60 s, the bag shaking frequency is 2 - 5 times, and then, according to the boiling state of the material in the fluidized bed, the fluidization air volume is adjusted to 1000 m 3 / h - 1200 m 3 / h.

[0035] In a preferred embodiment, in step (5), the lubricant is at least one of magnesium stearate, stearic acid, and polyethylene glycol.

[0036] In a preferred embodiment, in step (5), the disintegrant is at least one of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose.

[0037] In a preferred embodiment, in step (5), the mass ratio of the material after dry granulation in step (4) to the lubricant is (9 - 12):(0.02 - 1).

[0038] In a preferred embodiment, in step (5), the mass ratio of the lubricant to the disintegrant is 1:(3 - 4).

[0039] In a preferred embodiment, in step (5), when mixing the material after dry granulation in step (4), the lubricant, and the disintegrant, the mass ratio is (61 - 65):1:(3 - 4).

[0040] In a preferred embodiment, in step (5), the mixing time is 3 min - 5 min.

[0041] In a preferred embodiment, in step (5), the mixing speed is 10 rpm - 12 rpm.

[0042] In a preferred embodiment, in step (5), a 11*6 mm oval punch is used for tableting.

[0043] In a preferred embodiment, in step (5), during tableting, the average hardness is 2.5 - 3.5 kg, the weight variation is ±5%, and the friability is not more than 0.8%.

[0044] In a preferred embodiment, in step (5), the mass ratio of the coating solution to the obtained mixed tablet core is (0.03 - 0.08):1.

[0045] In a preferred embodiment, in step (5), during the entire coating process, the temperature does not exceed 50 °C (preferably 30 - 50 °C). During the use of the coating solution, it is necessary to maintain a slow and uniform stirring state to minimize foaming.

[0046] Furthermore, the present invention also provides a method for preparing the coating solution, and the specific steps are as follows:

[0047] Mix hypromellose, lactose monohydrate, titanium dioxide, triacetin, and ferric oxide evenly to obtain a coating premix.

[0048] Add the coating premix to water under stirring, continue to stir evenly, and filter to obtain the coating solution.

[0049] In a preferred embodiment, the mass ratio of hypromellose, lactose monohydrate, titanium dioxide, triacetin, and ferric oxide in the coating premix is (1.0 - 1.7):(1.1 - 1.5):(0.1 - 1):(0.1 - 1):(0.1 - 0.5).

[0050] Preferably, the mass ratio of hypromellose, lactose monohydrate, titanium dioxide, triacetin, and ferric oxide is (1.0 - 1.5):(1.2 - 1.4):(0.5 - 1):(0.3 - 0.5):(0.1 - 0.3).

[0051] More preferably, the mass ratio of hypromellose, lactose monohydrate, titanium dioxide, triacetin, and ferric oxide is 1.20:1.30:0.75:0.35:0.20.

[0052] In a preferred embodiment, the mass ratio of water to the coating premix is 1:(0.1 - 0.2); preferably, the mass ratio of purified water to the coating premix is 1:0.15.

[0053] Another object of the present invention is to provide a vonoprazan fumarate tablet prepared by any of the above methods, which has high stability and stable dissolution. It has been detected that the vonoprazan fumarate tablet prepared by the method of the present invention has high dissolution rate, excellent product quality, reliable stability, and very small differences between batches, showing excellent drug dissolution performance.

[0054] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0055] 1. The preparation method of the vonoprazan fumarate tablet of the present invention is simple and easy to produce. The vonoprazan fumarate tablet prepared by this method has good stability and low related substances.

[0056] 2. The present invention uses wet granulation for the granulation operation of vorolanib fumarate. The reason is that the wet granulation process can improve the fluidity of the granules, enhance the compressibility, improve the mixing uniformity of the granules, reduce dust, and facilitate subsequent processing. By granulating the raw and auxiliary materials of vorolanib fumarate, the size and shape of the granules can be better controlled, and uniform and stable drug granules can be produced to achieve good drug dissolution performance and control related substances. At the same time, the problem of poor uniformity after mixing vorolanib fumarate and auxiliary material granules is solved.

[0057] 3. The present invention controls the particle size of vorolanib fumarate to be 10 μm ≤ D90 ≤ 50 μm and the particle size of mannitol to be 30 mesh - 120 mesh, so that the finished product shows stable and rapid dissolution performance in different media. Detailed implementation mode

[0058] The technical solutions of the present application will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application without creative efforts shall fall within the scope of protection of the present application.

[0059] For the experimental methods without specific conditions in the following embodiments, they are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. The raw materials and reagents used are all conventional commercially available products without special instructions.

[0060] Unless otherwise specified, the technical means used in the present invention are conventional means well known to those skilled in the art. All kinds of raw materials, reagents, instruments and equipment used in the present invention can be obtained through market purchase or can be prepared by existing methods. The reagents used in the present invention are all of analytical purity unless otherwise specified.

[0061] The particle size of the vorolanib fumarate is 10 μm ≤ D90 ≤ 50 μm, and the particle size of the mannitol is 30 mesh - 120 mesh.

[0062] Example 1

[0063] A method for preparing a coating solution, the specific steps are as follows:

[0064] Mix hypromellose (E5), lactose monohydrate, titanium dioxide, triacetin and ferric oxide in a mass ratio of 1.20:1.30:0.75:0.35:0.20 to obtain a coating premix;

[0065] Slowly add the coating premix to the purified water under stirring, wherein the mass ratio of purified water to coating premix is ​​1:0.15, continue stirring evenly, and filter through a 200-mesh steel wire mesh to obtain the coating solution. The coating solution needs to be stirred slowly and evenly during use, and try not to foam or to produce as little foam as possible.

[0066] Example 2

[0067] A method for preparing vonola fumarate raw tablets with high stability and stable dissolution, preparing vonola fumarate tablets (specification 20 mg, hardness 5.0 kg), the specific steps are as follows:

[0068] 1) 8.10 kg of vonoprazan fumarate, 46.0 kg of mannitol, 6.5 kg of microcrystalline cellulose, 2.0 kg of hydroxypropyl cellulose and 0.05 kg of fumaric acid were added to a wet granulator in this order, and the stirring blade speed was set to 120 rpm and the cutting blade speed was set to 1200 rpm to start premixing for 5 minutes to obtain a premix.

[0069] 2) After the premixing is completed, 16.0 kg of purified water is added to the premix by means of a funnel slurry. During the addition process, the stirring paddle speed is maintained at 120 rpm, the cutting knife speed is maintained at 1200 rpm, and the addition time is controlled to be 70-90 s. After the addition is completed, granulate for 5 minutes, stop the machine and remove from the pot to obtain a soft material.

[0070] 3) Install a 20-mesh stainless steel screen at the inlet of the granulator, place the soft material in step 2) in the granulator, pass it through a 20-mesh screen, and wet granulate it;

[0071] At the same time, the fluidized bed inlet air temperature is set to 60°C, the inlet air humidity is 6.0g / kg-10.0g / kg, and the fluidizing air volume is 900m 3 / h-1200m 3 / h, preheat the fluidized bed to 45°C and set aside.

[0072] 4) When the material temperature of the fluidized bed reaches 40℃-45℃, adjust the inlet air temperature to 50℃-60℃, shake the bag for 60s, shake the bag for 5 times, pour the wet granulated soft material in step 3) into the fluidized bed, and then adjust the fluidizing air volume to 1000m according to the boiling state of the material in the fluidized bed. 3 / h-1200m 3 / h, start fluidized drying, and stop fluidized drying when the moisture content of the particles is 2.0%-5.0%. Then use a 1.0mm round hole screen to dry granulate the dried material.

[0073] 5) Add the 63.74 kg of the whole granulated material, 1.0 kg of lubricant (magnesium stearate), and 3.5 kg of croscarmellose sodium to the mixer in sequence for mixing. The mixing speed is 10 rpm - 12 rpm, and the mixing time is 3 min - 5 min; Select an 11*6 mm oval punch for tabletting, with an average hardness of 4 kg - 6 kg, a weight variation of ±6.5%, and a friability not greater than 0.8% to obtain the mixed tablet core;

[0074] Coat the mixed tablet core according to 6% of the weight of the coating solution accounting for the mixed tablet core to obtain the final product.

[0075] Example 3

[0076] A preparation method of vonoprazan fumarate tablets with high stability and stable dissolution, for preparing vonoprazan fumarate tablets (specification 20 mg, hardness 7.0 kg). The difference between the preparation method in Example 3 and that in Example 2 is that the specific steps of step 1) are as follows: Add 8.0 kg of vonoprazan fumarate, 47.0 kg of mannitol, 6.5 kg of diluent, 2.0 kg of binder, and 0.05 kg of pH regulator to the wet granulator in this order, set the stirring paddle speed at 120 rpm and the cutter speed at 1200 rpm to start premixing for 5 min to obtain the premixed material.

[0077] In step 5), the average hardness during tabletting is 5 kg - 8 kg.

[0078] Example 4

[0079] A preparation method of vonoprazan fumarate tablets with high stability and stable dissolution, for preparing vonoprazan fumarate tablets (specification 20 mg, hardness 6.0 kg). The difference between the preparation method in Example 4 and that in Example 2 is that the specific steps of step 1) are as follows: Add 8.10 kg of vonoprazan fumarate, 46.0 kg of mannitol, 6.4 kg of diluent, 1.5 kg of binder, and 0.07 kg of pH regulator to the wet granulator in this order, set the stirring paddle speed at 120 rpm and the cutter speed at 1200 rpm to start premixing for 5 min to obtain the premixed material.

[0080] In step 5), the average hardness during tabletting is 5 kg - 7 kg.

[0081] In vitro dissolution test and related substances test were carried out on the vonoprazan fumarate tablets of the present invention, and the results are as follows:

[0082] I. Related substances (refer to the imported drug registration standard (JX20190049))

[0083] Mobile phase: Mobile phase A: 0.025 mol / L phosphate buffer (pH 6.8) - methanol - acetonitrile (14:5:1), Mobile phase B: acetonitrile - 0.025 mol / L phosphate buffer (pH 6.8) (7:3);

[0084] Chromatographic column: Octadecylsilyl silica gel as filler [(CAPCELL PAK C18 MGII, 4.6 mm × 100 mm, 3 μm or a chromatographic column with equivalent performance);

[0085] Detection wavelength: 230 nm;

[0086] Flow rate: 1.0 ml / min;

[0087] Column temperature: 25 °C;

[0088] Injection volume: 20 μl;

[0089] Concentration of test solution: 0.3 mg / ml;

[0090] Diluent: water - acetonitrile (19:1);

[0091] Calculation method: External standard method for the main component;

[0092] Table 1: Results of related substances

[0093]

[0094] II. Dissolution

[0095] Method: paddle method (refer to the second method in General Chapter 0931 of the Chinese Pharmacopoeia 2020 edition);

[0096] Medium: 900 ml of acetate buffer (pH 4.5);

[0097] Rotation speed: 50 rpm;

[0098] Detection method: HPLC;

[0099] Limit: 85% of the labeled amount (30 min);

[0100] Table 2: Dissolution results

[0101]

[0102] III. Dissolution curve

[0103] Dissolution medium: pH 6.8 phosphate buffer: Weigh 0.896 g of sodium hydroxide and 6.805 g of potassium dihydrogen phosphate, place them in 1000 ml of degassed water, stir to dissolve, and measure the pH value;

[0104] Medium volume: 900 ml;

[0105] Rotation speed: 50 rpm;

[0106] Sampling volume: 10 ml;

[0107] Detection method: UV method;

[0108] Detection wavelength: 260 nm;

[0109] Table 3: Dissolution results

[0110]

[0111] IV. Dissolution curve

[0112] Dissolution medium: pH 1.2 hydrochloric acid medium: Measure 7.65 ml of hydrochloric acid and place it in 1000 ml of degassed water, stir evenly, and measure the pH value;

[0113] Medium volume: 900 ml;

[0114] Rotation speed: 50 rpm;

[0115] Sampling volume: 10 ml;

[0116] Detection method: UV method;

[0117] Detection wavelength: 260 nm;

[0118] Table 4: Dissolution results

[0119]

[0120] V. Conclusion

[0121] Examples 2-4 showed high dissolution rates under different conditions (pH 1.2, pH 6.8), with excellent product quality, reliable stability, very small differences between batches, low related substances content, and high dissolution rate, indicating that these examples have excellent drug dissolution performance.

[0122] The above describes the embodiments of the present invention. The present invention includes but is not limited to the above methods. Modifications, substitutions, etc. made within a reasonable range are all included in the protection scope of the present invention.

Claims

1. A preparation method of vonoprazan fumarate tablets with high stability and stable dissolution, characterized in that, It includes the following steps: (1) Premix vorinostat fumarate, mannitol, and an auxiliary agent to obtain a premixed material; (2) After the premixing is completed, add a solvent to the premixed material, and granulate after adding to obtain a soft material; (3) Install a sieve at the inlet end of the granulating machine, place the soft material described in step (2) in the granulating machine, sieve, and perform wet granulation; (4) After the temperature of the fluidized bed material reaches 40°C - 45°C, pour the wet granulated soft material from step (3) into the fluidized bed, start fluidized drying, stop fluidized drying when the moisture content of the granules is 2.0% - 5.0%, and use a sieve to perform dry granulation on the dried material; (5) Add the material after dry granulation in step (4), a lubricant, and a disintegrant to a mixer in sequence for mixing, and tablet press to obtain a mixed tablet core; Coat the obtained mixed tablet core with a coating solution to obtain vorinostat fumarate tablets.

2. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of vorinostat fumarate, mannitol, and the auxiliary agent is (7.0 - 10.0):(40 - 50):(7.5 - 20); the auxiliary agent is a diluent, a binder, and / or a pH regulator; when the auxiliary agent is a diluent, a binder, and a pH regulator, the mass ratio of the diluent, the binder, and the pH regulator is (90 - 130):(20 - 40):

1.

3. The preparation method according to claim 2, characterized in that, The diluent described in step (1) is at least one of mannitol, corn starch, microcrystalline cellulose, and lactose; In step (1), the binder is at least one of corn starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; In step (1), the pH regulator is at least one of fumaric acid, citric acid, sodium hydroxide, and hydrochloric acid water; 4. The preparation method according to claim 1, characterized in that, In step (2), the solvent is at least one of water and absolute ethanol; in step (2), the mass ratio of the premixed material to the solvent is (2 - 5):1; In step (2), during the adding process, keep the stirring paddle speed at 100 - 120 rpm, the cutter speed at 1000 - 1200 rpm, and the adding time at 70 - 90 s; In step (2), the granulation time is 5 - 10 min.

5. The preparation method according to claim 1, characterized in that, In step (3), during wet granulation, set the fluidized bed parameters, specifically, set the inlet air temperature to 50-60 °C, the inlet air humidity to 6.0 g / kg - 10.0 g / kg, and the fluidization air volume to 900 m 3 / h - 1200 m 3 / h, and preheat the fluidized bed to a temperature not lower than 45 °C.

6. The preparation method according to claim 1, wherein, In step (4), when pouring the wet granulated soft material after step (3) into the fluidized bed, set the inlet air temperature to 50°C - 60°C, the bag shaking cycle to 50 - 60 s, and the bag shaking frequency to 2 - 5 times. Then, adjust the fluidization air volume to 1000 m 3 / h - 1200 m 3 / h according to the boiling state of the material in the fluidized bed.

7. The preparation method according to claim 1, wherein In step (5), the lubricant is at least one of magnesium stearate, stearic acid, and polyethylene glycol; the disintegrant is at least one of corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium; In step (5), the mass ratio of the material after dry granulation in step (4) to the lubricant is (9 - 12):(0.02 - 1); In step (5), the mass ratio of the lubricant to the disintegrant is 1:(3 - 4).

8. The preparation method according to claim 1, characterized in that, In step (5), during the tablet pressing, the average hardness is 2.5 - 3.5 kg, the weight difference is ±5%, and the friability is not more than 0.8%; In step (5), the mass ratio of the coating solution to the obtained mixed tablet core is (0.03 - 0.08):

1.

9. The preparation method according to claim 1, characterized in that, The coating solution is prepared through the following steps: Mix hydroxypropyl methylcellulose, lactose monohydrate, titanium dioxide, triacetin, and ferric oxide evenly to obtain a coating premix; Add the coating premix to water under stirring, continue to stir evenly, and filter to obtain it. The mass ratio of hypromellose, lactose monohydrate, titanium dioxide, triacetin and ferric oxide in the coating premix is (1.0 - 1.7):(1.1 - 1.5):(0.1 - 1):(0.1 - 1):(0.1 - 0.5); The mass ratio of water to the coating premix is 1:(0.1 - 0.2).

10. Voriconazole fumarate tablets with high stability and stable dissolution prepared by the method according to any one of claims 1 to 9.

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