CN118236338B - Preparation method of voronoi fumarate preparation - Google Patents

Abstract

The invention discloses a preparation method of a fumarase preparation, which belongs to the technical field of fumarase preparation, and comprises the following steps: pretreatment of the active ingredients of the medicine, preparation of adhesive liquid, one-step granulation, finishing, total mixing, tabletting, preparation of organic acid layer coated tablets, preparation of medicine layer coated tablets and preparation of film coated tablets; the preparation method can improve the stability and the dissolution rate of the voronoi fumarate preparation and improve the taste masking effect.

Description

A preparation method of vonoprazan fumarate preparation

Technical Field

The invention relates to the technical field of preparation of vonoprazan fumarate preparations, and in particular to a preparation method of vonoprazan fumarate preparations.

Background Art

Vonoprazan fumarate is a new type of potassium ion competitive acid blocker (P-CAB) that can terminate gastric acid secretion prematurely in the last link of gastric acid secretion in gastric parietal cells by inhibiting the binding of K ⁺ to H ⁺ -K ⁺ -ATPase (proton pump). It has a strong and lasting effect in inhibiting gastric acid secretion, and has the characteristics of full effect in the first dose, long-lasting efficacy, and easy to take. It has definite therapeutic effects in the treatment of gastroesophageal reflux disease (GERD), synergistic antibiotics to eradicate Helicobacter pylori (Hp), and treatment of Helicobacter pylori-induced peptic ulcers. It has few adverse reactions and better safety and tolerability.

Helicobacter pylori exists in the human mouth, stomach and duodenum. It is an important cause of gastritis, gastric cancer, gastric and duodenal ulcers, and is contagious. Currently, the commonly used treatment for Helicobacter pylori infection is triple therapy, which is a proton pump inhibitor plus two antibiotics, most of which are amoxicillin, clarithromycin, etc. Since the metabolic enzymes of vonoprazan fumarate and clarithromycin are both CYP3A4, the two drugs will inhibit each other's metabolism, resulting in an increase in the blood concentration of vonoprazan fumarate.

Related studies have shown that dual therapy with vonoprazan fumarate and amoxicillin is more effective than triple therapy with vonoprazan fumarate, clarithromycin, and amoxicillin.

After vonoprazan fumarate is taken orally and enters the stomach, it can reach the peak blood concentration in 2 hours, and the pH value in the stomach can be increased to above 4.0 within 4 hours. The half-life of the drug is about 5.7-8.8 hours. The in vitro protein binding rate of vonoprazan fumarate is 85.2-88.0%, and it is mainly metabolized in the liver. 168 hours after the oral administration of radiolabeled drugs (vonoprazan 15 mg) to healthy adult male subjects, 98.5% of the radioactive drugs were excreted into urine and feces: 67.4% of the drugs were excreted in urine, and 31.1% of the drugs were excreted into feces.

Amoxicillin is rapidly absorbed after oral administration. The bioavailability of amoxicillin after oral administration is about 70%, and the peak time of blood drug concentration is about 1-2 hours. Food has no significant effect on drug absorption. The protein binding rate of amoxicillin is 17-20%, and the average elimination half-life is about 1 hour. After a single administration of 250mg or 500mg amoxicillin, about 45-68% of amoxicillin is excreted from the urine in the form of the original drug within 6 hours.

The existing triple therapy for eradicating Helicobacter pylori has the problem of multiple daily medications and large dosages. If quadruple therapy is used, the dosage will be greatly increased, which reduces the patient's willingness to take medication and their degree of cooperation. The treatment cycle for eradicating Helicobacter pylori often takes two weeks or more, and different drugs require different quantities and frequencies of medication, and whether to take them before or after meals. This is not friendly to the treatment process of middle-aged and elderly patients, and increases the burden on the kidneys.

Among the existing compound preparations of vonoprazan fumarate and amoxicillin, most are prepared by adding amoxicillin to the original prescription of vonoprazan fumarate. This preparation method ignores the differences in drug microenvironment and pH required for different active ingredients of the drugs. The prepared compound preparations often have unstable drug dissolution within and between batches. After the storage stability test, the release and dissolution of the drug slow down or the drug degradation occurs, which has a serious impact on the quality of the drug.

Chinese patent CN114053239A discloses a vonoprazan fumarate pharmaceutical composition and a preparation method thereof. The vonoprazan fumarate and its compound preparation prepared by adding copolyvidone in the coating process have good coating film stability and low related substances under high temperature, high humidity and strong light, but also produce more uncontrollable risks due to the addition of copolyvidone. Since copolyvidone is highly hygroscopic, its product will have a slow dissolution rate during long-term storage, and since copolyvidone has high viscosity, the tablets will stick together after absorbing moisture, resulting in poor stability of the prepared pharmaceutical composition, and high requirements are placed on the packaging form and storage conditions of the drug.

Summary of the invention

In view of the deficiencies in the prior art, the present invention provides a method for preparing a vonoprazan fumarate preparation, which can improve the stability and solubility of the preparation and improve the taste-masking effect.

In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

A preparation method of vonoprazan fumarate preparation, comprising the following steps: pretreatment of active pharmaceutical ingredients, preparation of a binding liquid, one-step granulation, granulation, total mixing, tableting, preparation of organic acid layer-coated tablets, preparation of drug layer-coated tablets, and preparation of film-coated tablets;

Pretreatment of the active ingredients of the medicine, crushing amoxicillin and vonoprazan fumarate respectively to obtain crushed amoxicillin and vonoprazan fumarate;

In the pretreatment of the active pharmaceutical ingredient, the particle size D90 of the crushed amoxicillin and vonoprazan fumarate is ≤50 μm;

The adhesive liquid is prepared by mixing the sieved adhesive with purified water to obtain an adhesive liquid;

In the preparation of the adhesive solution, the adhesive is one or a combination of povidone or hypromellose;

The particle size of the sieved adhesive is 80-100 mesh;

The one-step granulation comprises the following steps: material mixing and granulation;

The materials are mixed, and the crushed amoxicillin and filler are added into the fluidized bed material chamber for mixing to obtain an amoxicillin mixture;

In the material mixing, the filler is one or more of microcrystalline cellulose, mannitol, pregelatinized starch, and cellulose-lactose;

The inlet air temperature of the fluidized bed material chamber is 60-70°C, the inlet air volume is 50-60m ³ /h, and the fluidization mixing time is 3-5min;

In the granulation, the binding liquid is evenly sprayed onto the surface of the amoxicillin mixture in the fluidized bed material chamber, and dried to obtain dry granules;

The inlet air temperature of the fluidized bed material chamber is 60-70°C, the inlet air volume is 45-55m ³ /h, the atomization pressure is 1.5-2bar, and the peristaltic pump speed is 10-15rpm;

The LOD of the dry particles is ≤1.5%;

The granulation comprises adding the dry granules into a granulator for granulation to obtain granulated granules;

In the granulation, the particle size of the granulated particles is 1.2-1.5 mm;

The speed of the pelletizing machine is 400-600rpm;

The total mixing includes adding the whole granules, disintegrant, and granule lubricant into a mixer and mixing them evenly to obtain total mixed granules;

In the total mixture, the disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, and crospovidone;

The granular lubricant is one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate;

The main motor speed of the mixer is 40-50HZ at high speed and 20-25HZ at low speed, and the mixing time is 8-10min;

The tableting comprises adding the total mixed granules into a tablet press according to the central tablet weight requirement to perform tableting to obtain a plain tablet;

The main machine speed of the tablet press is 20-30rpm, the main pressure is 10-20KN, and the pre-pressure is 3-6KN;

The preparation of the organic acid layer-coated tablets comprises the following steps: preparing an organic acid coating solution, and coating the organic acid layer;

The organic acid coating solution is prepared by uniformly mixing the sieved film-forming material and the organic acid with purified water to obtain the organic acid coating solution;

In the preparation of the organic acid coating solution, the film-forming material is one or more of hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and povidone;

The organic acid is fumaric acid;

The particle size of the film-forming material and the organic acid after screening is 80-100 mesh;

The organic acid layer coating comprises spraying the organic acid coating liquid evenly onto the surface of the plain tablet in a coating machine, and drying after the coating is completed to obtain the organic acid layer coated tablet;

In the organic acid layer coating, the hot air temperature of the coating machine is 60-80°C, the exhaust fan speed is 55-65%, the coating machine speed is 2-8rpm, the atomization pressure is 0.4-0.6Mpa, the peristaltic pump speed is 3.6-7rpm, and the tablet core temperature is 40-50°C;

The preparation of the drug layer coated tablet comprises the following steps: preparing the drug layer coating solution and coating the drug layer;

The drug layer coating solution is prepared by mixing the sieved film-forming material and plasticizer with purified water, adding the crushed vonoprazan fumarate, and mixing them evenly to obtain the drug layer coating solution;

In the preparation of the drug layer coating solution, the film-forming material is one or a combination of hydroxypropyl methylcellulose or hydroxypropyl cellulose;

The plasticizer is one or more of polyethylene glycol 6000, propylene glycol, and triethyl citrate;

The particle sizes of the film-forming material and plasticizer after screening are both 80-100 mesh;

The drug layer coating comprises spraying the drug layer coating liquid evenly onto the surface of the organic acid layer coated tablet in a coating machine, and drying after the coating is completed to obtain the drug layer coated tablet;

In the drug layer coating, the hot air temperature of the coating machine is 40-60°C, the exhaust fan speed is 55-65%, the coating machine speed is 2-8rpm, the atomization pressure is 0.4-0.6Mpa, the peristaltic pump speed is 4-10rpm, and the tablet core temperature is 35-40°C;

The preparation of the film-coated tablets comprises the following steps: preparing a film-coating solution and film coating;

The film coating solution is prepared by dissolving the sieved film-forming material in the first portion of purified water to obtain a film-forming material solution; mixing the sieved sunscreen and colorant with the second portion of purified water and homogenizing to obtain a homogenous dispersion; adding the homogenized dispersion to the film-forming material solution and stirring evenly to obtain a film coating solution;

In the preparation of the film coating solution, the film-forming material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethyl cellulose;

The sunscreen agent is one or a combination of titanium dioxide or talc;

The colorant is one or more of sunset yellow, red iron oxide, and yellow iron oxide;

The particle sizes of the sieved film-forming material, sieved sunscreen agent and colorant are all 80-100 meshes;

The mass ratio of the first portion of purified water to the second portion of purified water is 1.5-2.5:1;

The homogenization time of the homogenization is 15-20min;

The film coating comprises spraying the film coating liquid evenly onto the drug layer coated tablets in a coating machine, and drying after the coating is completed to obtain the vonoprazan fumarate preparation;

In the film coating, the hot air temperature of the coating machine is 60-80°C, the exhaust fan speed is 55-65%, the coating machine speed is 2-8rpm, the atomization pressure is 0.4-0.6Mpa, the peristaltic pump speed is 4-8rpm, and the tablet core temperature is 38-42°C;

The mass fraction of the crushed amoxicillin used in the plain tablets accounts for 45-50% of the total solid raw materials in the vonoprazan fumarate preparation;

The filler used in the plain tablet accounts for 23-25% of the mass fraction of all solid raw materials in the vonoprazan fumarate preparation;

The mass fraction of the sieved binder used in the plain tablets to all solid raw materials in the vonoprazan fumarate preparation is 1.7-1.8%;

The mass fraction of the disintegrant used in the plain tablets to all solid raw materials in the vonoprazan fumarate preparation is 2.2-3%;

The mass fraction of the granular lubricant used in the plain tablets to all solid raw materials in the vonoprazan fumarate preparation is 0.28-0.3%;

The mass fraction of the sieved film-forming material used in the organic acid coating solution to all solid raw materials in the vonoprazan fumarate preparation is 2.5-2.8%;

The mass fraction of the sieved organic acid used in the organic acid coating solution to all solid raw materials in the vonoprazan fumarate preparation is 0.07-0.08%;

The mass fraction of the crushed vonoprazan fumarate used in the drug layer coating liquid to all solid raw materials in the vonoprazan fumarate preparation is 2.5-2.8%;

The mass fraction of the sieved film-forming material used in the drug layer coating solution to all solid raw materials in the vonoprazan fumarate preparation is 13-13.5%;

The mass fraction of the sieved plasticizer used in the drug layer coating solution to all solid raw materials in the vonoprazan fumarate preparation is 0.8-0.9%;

The mass fraction of the sieved film-forming material used in the film coating liquid to all solid raw materials in the vonoprazan fumarate preparation is 3.2-3.5%;

The mass fraction of the sieved opacifier used in the film coating solution to all solid raw materials in the vonoprazan fumarate preparation is 0.75-1.1%;

The mass fraction of the sieved colorant used in the film coating liquid to all solid raw materials in the vonoprazan fumarate preparation is 0.02-0.03%;

The mass ratio of the crushed amoxicillin used in the plain tablet to the purified water used is 250:80-90;

The mass ratio of the sieved organic acid used in the organic acid coating solution to the purified water used is 0.4:150-170;

The mass ratio of the crushed vonoprazan fumarate used in the drug layer coating liquid to the purified water used is 13-14:490-500;

The mass ratio of the sieved film-forming material used in the film coating solution to the total amount of purified water used is 17-18:150-170.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The preparation method of the vonoprazan fumarate preparation of the present invention is no longer limited to treating Helicobacter pylori by providing a combination of drugs or a pharmaceutical composition, but adopts a preparation method to prepare two active ingredients of the drug in the same tablet form, so that a single dose can achieve the same therapeutic effect as multiple doses of multiple drugs, greatly reducing the number of medications and the amount of medication, which is particularly friendly to middle-aged and elderly patients;

(2) The preparation method of the vonoprazan fumarate preparation of the present invention adopts a coating form to improve the oral compliance and avoid the discomfort caused by direct contact between the drug and the tongue;

(3) The preparation method of the vonoprazan fumarate preparation of the present invention can improve the stability of the vonoprazan fumarate preparation. The prepared vonoprazan fumarate preparation has no significant decrease in dissolution structure after being accelerated for 3 months at 40±2°C and 75±5%RH, and no significant increase in impurities after being accelerated for 6 months at 25±2°C and 60±5%RH.

(4) The preparation method of the vonoprazan fumarate preparation of the present invention can improve the solubility of the vonoprazan fumarate preparation. In the vonoprazan fumarate dissolution test, the solubility after 60 minutes is 99.3-100%, and in the amoxicillin dissolution test, the solubility after 150 minutes is 94.4-96.3%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a schematic diagram of the dosage form of the vonoprazan fumarate preparation prepared in Example 1;

FIG2 is a dissolution curve of vonoprazan fumarate of Examples 1-4, Comparative Example 2, and Walker's vonoprazan fumarate tablets reference preparation in the test examples;

FIG. 3 is a dissolution curve of amoxicillin of Examples 1-4, Comparative Example 2, and Sawacillin Amoxicillin Tablets Reference Preparation in the Test Examples.

DETAILED DESCRIPTION

In order to have a clearer understanding of the technical features, purposes and effects of the present invention, the specific implementation methods of the present invention are now described.

Example 1

A vonoprazan fumarate preparation, the dosage form diagram of which is shown in FIG1 .

A vonoprazan fumarate preparation, wherein the amount of raw materials used in a unit preparation is:

A method for preparing a vonoprazan fumarate preparation, specifically comprising:

1. Pretreatment of active pharmaceutical ingredients: Amoxicillin and vonoprazan fumarate are pulverized separately to control the particle size D90 of the raw materials to ≤50 μm, thereby obtaining pulverized amoxicillin and vonoprazan fumarate.

2. Preparation of adhesive solution: According to the raw material dosage in the above table, after passing the polyvidone through an 80-mesh sieve, weigh the prescribed amount of polyvidone and purified water, dissolve the polyvidone in the purified water, stir and disperse evenly, and obtain the adhesive solution.

3. One-step granulation

3.1 Material mixing: According to the raw material dosage in the above table, weigh the prescribed amount of crushed amoxicillin and cellulose-lactose, transfer the materials to the fluidized bed material chamber, set the inlet air temperature to 60°C, the inlet air volume to ^50m3 /h, and fluidize and mix for 3 minutes.

3.2 Granulation: Set the air inlet temperature to 70°C, the air volume to 55m ³ /h, the atomization pressure to 1.5bar, and the peristaltic pump speed to 10rpm. Spray the binding liquid evenly onto the material surface of the fluidized bed material chamber and evenly wrap it with the material. After granulation, dry it and LOD ≤ 1.5% to obtain dry granules.

4. Granulation: The dry granules are passed through a granulator equipped with a 1.2 mm screen, and the speed of the multifunctional granulator is set to 500 rpm to obtain granules.

5. Total mixing: According to the raw material dosage in the above table, weigh the prescribed amount of sodium carboxymethyl starch and sodium stearyl fumarate, put the whole granules, sodium carboxymethyl starch and sodium stearyl fumarate into the material barrel of the hopper mixer in sequence, adjust the speed of the material barrel of the mixer, set the main motor speed to high speed 40HZ, low speed 20HZ, and the mixing time to 8min to obtain the total mixed granules.

6. Tablet pressing: Add the total mixed granules into the tablet press for tablet pressing according to the central tablet weight requirements, set the main machine speed to 20rpm, the main pressure to 15KN, and the pre-pressure to 4KN to obtain qualified plain tablets.

7. Preparation of organic acid layer-coated tablets

7.1 Preparation of organic acid coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of hydroxypropyl methylcellulose, fumaric acid and purified water, dissolve the hydroxypropyl methylcellulose and fumaric acid in purified water and stir until the solution is clear and transparent to obtain the organic acid coating solution. The raw materials used should be passed through an 80-mesh sieve before weighing.

7.2 Organic acid layer coating: Put the plain tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the organic acid coating liquid evenly onto the surface of the plain tablets. During the coating process, the tablet core temperature is controlled at 45°C. After coating, dry it to obtain organic acid layer coated tablets.

8. Preparation of drug-layer coated tablets

8.1 Preparation of drug layer coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of crushed vonoprazan fumarate, hydroxypropyl methylcellulose, triethyl citrate and purified water, dissolve hydroxypropyl methylcellulose and triethyl citrate in purified water and stir until the solution is transparent, add vonoprazan fumarate and continue stirring until dissolved to obtain a drug layer coating solution. The raw materials are sieved through an 80-mesh sieve before weighing.

8.2 Drug layer coating: Put the organic acid layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 65%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 5rpm, and spray the drug layer coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 38°C. After coating, dry it to obtain the drug layer coated tablets.

9. Preparation of Film-Coated Tablets

9.1 Preparation of film coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of hydroxypropyl methylcellulose, titanium dioxide, red iron oxide and 2/3 of the prescribed amount of purified water, dissolve the hydroxypropyl methylcellulose in 2/3 of the prescribed amount of purified water and stir to dissolve to obtain a hydroxypropyl methylcellulose solution; add titanium dioxide and red iron oxide to 1/3 of the prescribed amount of purified water, use a homogenizer to homogenize for 15 minutes to obtain a homogenous dispersion; then add the homogenized dispersion to the hydroxypropyl methylcellulose solution, continue stirring for 60 minutes to obtain a film coating solution. The raw materials are sieved through an 80-mesh sieve before being weighed.

9.2 Film coating: Put the drug layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the film coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 40°C. After coating, dry it to obtain the vonoprazan fumarate preparation.

Example 2

A vonoprazan fumarate preparation, wherein the amount of raw materials used in a unit preparation is:

A method for preparing a vonoprazan fumarate preparation, specifically comprising:

1. Pretreatment of active pharmaceutical ingredients: Amoxicillin and vonoprazan fumarate are pulverized separately to control the particle size D90 of the raw materials to ≤50 μm, thereby obtaining pulverized amoxicillin and vonoprazan fumarate.

2. Preparation of adhesive solution: According to the raw material dosage in the above table, after passing the polyvidone through an 80-mesh sieve, weigh the prescribed amount of polyvidone and purified water, dissolve the polyvidone in the purified water, stir and disperse evenly, and obtain the adhesive solution.

3. One-step granulation

3.1 Material mixing: According to the raw material dosage in the above table, weigh the prescribed amount of crushed amoxicillin and pregelatinized starch, transfer the materials to the fluidized bed material chamber, set the inlet air temperature to 60°C, the inlet air volume to ^50m3 /h, and fluidize and mix for 3 minutes.

3.2 Granulation: Set the air inlet temperature to 70℃, the air volume to ^55m3 /h, the atomization pressure to 1.5bar, and the peristaltic pump speed to 10rpm. Spray the adhesive liquid evenly onto the surface of the material and wrap it evenly with the material. After granulation, dry it and LOD≤1.5% to obtain dry granules.

4. Granulation: The dry granules are passed through a granulator equipped with a 1.2 mm screen, and the speed of the multifunctional granulator is set to 500 rpm to obtain granules.

5. Total mixing: According to the raw material dosage in the above table, weigh the prescribed amount of cross-linked polyvinylpyrrolidone and magnesium stearate, put the whole granules, cross-linked polyvinylpyrrolidone and magnesium stearate into the material barrel of the hopper mixer in sequence, adjust the speed of the material barrel of the mixer, set the main motor speed to high speed 40HZ, low speed 20HZ, and the mixing time to 8min to obtain total mixed granules.

6. Tablet pressing: Add the total mixed granules into the tablet press for tablet pressing according to the central tablet weight requirements, set the main machine speed to 20rpm, the main pressure to 15KN, and the pre-pressure to 4KN to obtain qualified plain tablets.

7. Preparation of organic acid layer-coated tablets

7.1 Preparation of organic acid coating solution: According to the raw material dosage in the above table, weigh povidone, fumaric acid and purified water according to the prescription amount, dissolve povidone and fumaric acid in purified water and stir until the solution is clear and transparent to obtain organic acid coating solution, which should be sieved through an 80-mesh sieve before weighing.

7.2 Organic acid layer coating: Put the plain tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the organic acid coating liquid evenly onto the surface of the plain tablets. During the coating process, the tablet core temperature is controlled at 45°C. After coating, dry it to obtain organic acid layer coated tablets.

8. Preparation of drug-layer coated tablets

8.1 Preparation of drug layer coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of vonoprazan fumarate, hydroxypropyl methylcellulose, triethyl citrate and purified water, dissolve hydroxypropyl methylcellulose and triethyl citrate in purified water and stir until the solution is transparent, add vonoprazan fumarate and continue stirring until dissolved to obtain a drug layer coating solution. The raw materials are all sieved with an 80-mesh screen before being weighed.

8.2 Drug layer coating: Put the organic acid layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 65%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 5rpm, and spray the drug layer coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 38°C. After coating, dry it to obtain the drug layer coated tablets.

9. Preparation of Film-Coated Tablets

9.1 Preparation of film coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of hydroxypropyl cellulose, titanium dioxide, yellow iron oxide and 2/3 of the prescribed amount of purified water, dissolve the hydroxypropyl cellulose in 2/3 of the prescribed amount of purified water and stir to dissolve to obtain a hydroxypropyl cellulose solution; add titanium dioxide and yellow iron oxide to 1/3 of the prescribed amount of purified water, use a homogenizer to homogenize for 15 minutes to obtain a homogeneous dispersion; then add the homogenized dispersion to the hydroxypropyl cellulose solution, continue stirring for 60 minutes to obtain a film coating solution. The raw materials are sieved through an 80-mesh sieve before weighing.

9.2 Film coating: Put the drug layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the film coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 40°C. After coating, dry it to obtain the vonoprazan fumarate preparation.

Experimental Example 3

A vonoprazan fumarate preparation, wherein the amount of raw materials used in a unit preparation is:

A method for preparing a vonoprazan fumarate preparation, specifically comprising:

1. Pretreatment of active pharmaceutical ingredients: Amoxicillin and vonoprazan fumarate are pulverized separately to control the particle size D90 of the raw materials to ≤50 μm, thereby obtaining pulverized amoxicillin and vonoprazan fumarate.

2. Preparation of adhesive solution: According to the raw material dosage in the above table, weigh the prescribed amount of hypromellose and purified water, dissolve the hypromellose in purified water, stir and disperse evenly to obtain an adhesive solution.

3. One-step granulation

3.1 Material mixing: According to the raw material dosage in the above table, weigh the prescribed amount of crushed amoxicillin and mannitol, transfer the materials to the fluidized bed material chamber, set the inlet air temperature to 60°C, the inlet air volume to ^50m3 /h, and fluidize and mix for 3 minutes.

3.2 Granulation: Set the air inlet temperature to 70℃, the air volume to ^55m3 /h, the atomization pressure to 1.5bar, and the peristaltic pump speed to 10rpm. Spray the adhesive liquid evenly onto the surface of the material and wrap it evenly with the material. After granulation, dry it and LOD≤1.5% to obtain dry granules.

4. Granulation: The dry granules are passed through a granulator equipped with a 1.2 mm screen, and the speed of the multifunctional granulator is set to 500 rpm to obtain granules.

5. Total mixing: According to the raw material dosage in the above table, weigh the prescribed amount of sodium carboxymethyl starch and sodium stearyl fumarate, put the whole granules, sodium carboxymethyl starch and sodium stearyl fumarate into the material barrel of the hopper mixer in sequence, adjust the speed of the material barrel of the mixer, set the main motor speed to high speed 40HZ, low speed 20HZ, and the mixing time to 8min to obtain the total mixed granules.

6. Tablet pressing: Add the total mixed granules into the tablet press according to the central tablet weight requirements for tablet pressing, set the main machine speed to 20rpm, the main pressure to 15KN, and the pre-pressure to 4KN to obtain qualified plain tablets.

7. Preparation of organic acid layer-coated tablets

7.1 Preparation of organic acid coating solution: According to the raw material dosage in the above table, weigh sodium carboxymethyl cellulose, fumaric acid and purified water according to the prescription amount, dissolve sodium carboxymethyl cellulose and fumaric acid in purified water and stir until the solution is clear and transparent to obtain organic acid coating solution, which should be sieved through an 80-mesh sieve before weighing.

7.2 Organic acid layer coating: Put the plain tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the organic acid coating liquid evenly onto the surface of the plain tablets. During the coating process, the tablet core temperature is controlled at 45°C. After coating, dry it to obtain organic acid layer coated tablets.

8. Preparation of drug-layer coated tablets

8.1 Preparation of drug layer coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of vonoprazan fumarate, hypromellose, propylene glycol, and purified water, dissolve the hypromellose and propylene glycol in purified water and stir until the solution is transparent, add vonoprazan fumarate and continue stirring until dissolved to obtain the drug layer coating solution. The raw materials are all sieved with an 80-mesh screen before being weighed.

8.2 Drug layer coating: Put the organic acid layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 65%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 5rpm, and spray the drug layer coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 38°C. After coating, dry it to obtain the drug layer coated tablets.

9. Preparation of Film-Coated Tablets

9.1 Preparation of film coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of hydroxypropyl methylcellulose, talcum powder, red iron oxide and 2/3 of the prescribed amount of purified water, dissolve the hydroxypropyl methylcellulose in 2/3 of the prescribed amount of purified water and stir to dissolve to obtain a hydroxypropyl methylcellulose solution; add talcum powder and red iron oxide to 1/3 of the prescribed amount of purified water, use a homogenizer to homogenize for 15 minutes to obtain a homogenous dispersion; then add the homogenized dispersion to the hydroxypropyl methylcellulose solution, continue stirring for 60 minutes to obtain a film coating solution. The raw materials are sieved through an 80-mesh sieve before being weighed.

9.2 Film coating: Put the drug layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the film coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 40°C. After coating, dry it to obtain the vonoprazan fumarate preparation.

Example 4

A vonoprazan fumarate preparation, wherein the amount of raw materials used in a unit preparation is:

A method for preparing a vonoprazan fumarate preparation, specifically comprising:

1. Pretreatment of active pharmaceutical ingredients: Amoxicillin and vonoprazan fumarate are pulverized separately to control the particle size D90 of the raw materials to ≤50 μm, thereby obtaining pulverized amoxicillin and vonoprazan fumarate.

2. Preparation of adhesive liquid: according to the raw material dosage in the above table, after passing the polyvidone through an 80-mesh sieve, weigh the prescribed amount of polyvidone and purified water, dissolve the polyvidone in the purified water, stir and disperse evenly to obtain an adhesive liquid, and pass the weighed liquid through an 80-mesh sieve.

3. One-step granulation

3.1 Material mixing: According to the raw material dosage in the above table, weigh the prescribed amount of amoxicillin and microcrystalline cellulose, transfer the materials to the fluidized bed material chamber, set the inlet air temperature to 60°C, the inlet air volume to ^50m3 /h, and fluidize and mix for 3 minutes.

3.2 Granulation: Set the air inlet temperature to 70℃, the air volume to ^55m3 /h, the atomization pressure to 1.5bar, and the peristaltic pump speed to 10rpm. Spray the adhesive liquid evenly onto the surface of the material in the material chamber and wrap it evenly with the material. After granulation, dry it and LOD≤1.5% to obtain dry granules.

4. Granulation: The dry granules are passed through a granulator equipped with a 1.2 mm screen, and the speed of the multifunctional granulator is set to 500 rpm to obtain granules.

5. Total mixing: According to the raw material dosage in the above table, weigh the prescribed amount of cross-linked carboxymethyl cellulose sodium and stearic acid, put the whole granules, cross-linked carboxymethyl cellulose sodium and stearic acid into the material barrel of the hopper mixer in sequence, adjust the speed of the mixer material barrel, set the main motor speed to high speed 40HZ, low speed 20HZ, and the mixing time to 8min to obtain total mixed particles.

6. Tablet pressing: Add the total mixed granules into the tablet press according to the central tablet weight requirements for tablet pressing, set the main machine speed to 20rpm, the main pressure to 15KN, and the pre-pressure to 4KN to obtain qualified plain tablets.

7. Preparation of organic acid layer-coated tablets

7.1 Preparation of organic acid coating solution: According to the raw material dosage in the above table, weigh out hydroxypropyl methylcellulose, fumaric acid and purified water according to the prescription amount, dissolve hydroxypropyl methylcellulose and fumaric acid in purified water and stir until the solution is clear and transparent to obtain the organic acid coating solution. The raw materials used should be sieved through an 80-mesh sieve before weighing and set aside.

7.2 Organic acid layer coating: Put the plain tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the organic acid coating liquid evenly onto the surface of the plain tablets. During the coating process, the tablet core temperature is controlled at 45°C. After coating, dry it to obtain organic acid layer coated tablets.

8. Preparation of drug-layer coated tablets

8.1 Preparation of drug layer coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of vonoprazan fumarate, hydroxypropyl cellulose, triethyl citrate and purified water, dissolve hydroxypropyl cellulose and triethyl citrate in purified water and stir until the solution is transparent, add vonoprazan fumarate and continue stirring until dissolved to obtain a drug layer coating solution. The raw materials are all sieved with an 80-mesh screen before being weighed.

8.2 Drug layer coating: Put the organic acid layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 65%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 5rpm, and spray the drug layer coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 38°C. After coating, dry it to obtain the drug layer coated tablets.

9. Preparation of Film-Coated Tablets

9.1 Preparation of film coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of sodium carboxymethyl cellulose, titanium dioxide, sunset yellow and 2/3 of the prescribed amount of purified water, dissolve sodium carboxymethyl cellulose in 2/3 of the prescribed amount of purified water and stir to dissolve to obtain sodium carboxymethyl cellulose solution; add titanium dioxide and sunset yellow to 1/3 of the prescribed amount of purified water, use a homogenizer to homogenize for 15 minutes to obtain a homogenous dispersion; then add the homogenized dispersion to the sodium carboxymethyl cellulose solution, continue stirring for 60 minutes to obtain a film coating solution. The raw materials are sieved through an 80-mesh sieve before being weighed.

9.2 Film coating: Put the drug layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the film coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 40°C. After coating, dry it to obtain the vonoprazan fumarate preparation.

Comparative Example 1

The preparation method disclosed in Chinese patent CN114053239A was used to prepare vonoprazan fumarate tablets, and the stability test was compared with the vonoprazan fumarate preparation prepared in Example 1. The test was carried out under accelerated conditions of 40±2°C and 75±5%RH, and the dissolution results of accelerated 1 month, accelerated 2 months, and accelerated 3 months were tested.

The amount of raw materials used in the unit preparation of the vonoprazan fumarate tablets in this comparative example is:

The preparation method of the vonolazepam fumarate tablets of this comparative example is:

1. Tablet core preparation: vornorazen fumarate, mannitol, and microcrystalline cellulose pH 101 are sieved and placed in a wet mixing granulator (stirring speed 400rpm, shear speed 800rpm) for 300s, and hydroxypropyl cellulose and fumaric acid aqueous solution accounting for 20% of the total weight of the aqueous solution are added to prepare a soft material, and the granulator is granulated (0.8mm screen, sieving at a speed of 500rpm), and the wet granules are placed in a fluidized bed granulator to make the material reach a fluidized state, maintain the material temperature at 30°C, and spray the remaining hydroxypropyl cellulose and fumaric acid aqueous solution to obtain dry granules (water content less than 2%). The obtained dry granules are passed through a 20-mesh sieve to obtain sieved granules. The sieved granules, cross-linked sodium carboxymethyl cellulose, and magnesium stearate are placed in a mixer and set at a high speed of 40HZ and a low speed of 20HZ, and mixed for 15min to obtain a mixed material.

The mixed material is tableted using a rotary tablet press to obtain tablet cores.

2. Coating: Place the above tablet cores in a coating machine and spray with a pre-configured 10% mass concentration coating aqueous solution (main machine speed 6 r/min, spray pressure 0.6 MPa, set inlet air temperature 60°C, tablet bed temperature controlled at 40°C, spray speed 8 rpm) to obtain vonopraz fumarate raw tablets.

The dissolution results of the vonoprazan fumarate preparation prepared in Example 1 and the vonoprazan fumarate tablets prepared in Comparative Example 1 are as follows:

As can be seen from the above table, with the extension of the accelerated test, the vonoprazan fumarate tablets prepared using the technical solution of Chinese patent CN114053239A showed a rapid downward trend in the dissolution data, and the vonoprazan fumarate tablets prepared by the patented method were prone to adhesion during the placement process, and the surface smoothness of the tablets decreased, while the vonoprazan fumarate preparation prepared in Example 1 did not have this problem.

Comparative Example 2

The same technical scheme as Example 1 is adopted, except that vonoprazan fumarate is added to the tablet core component, and amoxicillin is added to the drug layer. The amount of raw materials used in the vonoprazan fumarate preparation per unit preparation of this comparative example is:

The preparation method of the vonoprazan fumarate preparation of this comparative example is:

1. Pretreatment of active pharmaceutical ingredients: Amoxicillin and vonoprazan fumarate are pulverized separately to control the particle size D90 of the raw materials to ≤50 μm, thereby obtaining pulverized amoxicillin and vonoprazan fumarate.

2. Preparation of adhesive solution: According to the raw material dosage in the above table, after passing the polyvidone through an 80-mesh sieve, weigh the prescribed amount of polyvidone and purified water, dissolve the polyvidone in the purified water, stir and disperse evenly, and obtain the adhesive solution.

3. One-step granulation

3.1 Material mixing: According to the raw material dosage in the above table, weigh the prescribed amount of vonoprazan fumarate and cellulose-lactose, transfer the materials to the fluidized bed material chamber, set the inlet air temperature to 60°C, the inlet air volume to ^50m3 /h, and fluidize and mix for 3 minutes.

3.2 Granulation: Set the air inlet temperature to 70℃, the air volume to ^55m3 /h, the atomization pressure to 1.5bar, and the peristaltic pump speed to 10rpm. Spray the adhesive liquid evenly onto the surface of the material in the material chamber and wrap it evenly with the material. After granulation, dry it and LOD≤1.5% to obtain dry granules.

4. Granulation: The dry granules are passed through a granulator equipped with a 1.2 mm screen, and the speed of the multifunctional granulator is set to 500 rpm to obtain granules.

5. Total mixing: According to the raw material dosage in the above table, weigh the prescribed amount of sodium carboxymethyl starch and sodium stearyl fumarate, put the whole granules, sodium carboxymethyl starch and sodium stearyl fumarate into the material barrel of the hopper mixer in sequence, adjust the speed of the material barrel of the mixer, set the main motor speed to high speed 40HZ, low speed 20HZ, and the mixing time to 8min to obtain the total mixed granules.

6. Tablet pressing: Add the total mixed granules into the tablet press for tablet pressing according to the central tablet weight requirements, set the main machine speed to 20rpm, the main pressure to 15KN, and the pre-pressure to 4KN to obtain qualified plain tablets.

7. Preparation of organic acid layer-coated tablets

7.1 Preparation of organic acid coating solution: According to the raw material dosage in the above table, weigh hydroxypropyl methylcellulose, fumaric acid and purified water according to the prescription amount, dissolve hydroxypropyl methylcellulose and fumaric acid in purified water and stir until the solution is clear and transparent to obtain organic acid coating solution. The raw materials used should be passed through an 80-mesh sieve before weighing.

7.2 Organic acid layer coating: Put the plain tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the organic acid coating liquid evenly onto the surface of the plain tablets. During the coating process, the tablet core temperature is controlled at 45°C. After coating, dry it to obtain organic acid layer coated tablets.

8. Preparation of drug-layer coated tablets

8.1 Preparation of drug layer coating solution: Weigh the prescribed amount of amoxicillin, hypromellose, triethyl citrate and purified water, dissolve the hypromellose and triethyl citrate in purified water and stir until the solution is transparent, add amoxicillin and continue stirring until dissolved to obtain the drug layer coating solution. All raw materials are sieved through an 80-mesh sieve before weighing.

8.2 Drug layer coating: Put the organic acid layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 65%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 5rpm, and spray the drug layer coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 38°C. After coating, dry it to obtain the drug layer coated tablets.

9. Preparation of Film-Coated Tablets

9.1 Preparation of film coating solution: According to the raw material dosage in the above table, weigh the prescribed amount of hydroxypropyl cellulose, titanium dioxide, red iron oxide and 2/3 of the prescribed amount of purified water, dissolve the hydroxypropyl cellulose in 2/3 of the prescribed amount of purified water and stir to dissolve to obtain a hydroxypropyl methylcellulose solution; add titanium dioxide and red iron oxide to 1/3 of the prescribed amount of purified water and use a homogenizer to homogenize for 15 minutes to obtain a homogenous dispersion; then add the homogenized dispersion to the hydroxypropyl cellulose solution and continue stirring for 60 minutes to obtain a film coating solution. The raw materials are sieved through an 80-mesh sieve before being weighed.

9.2 Film coating: Put the drug layer coated tablets into a high-efficiency coating machine, set the hot air temperature to 60°C, the exhaust fan speed to 55%, the coating machine speed to 6rpm, the atomization pressure to 0.5Mpa, the peristaltic pump speed to 6rpm, and spray the film coating liquid evenly onto the tablet surface. During the coating process, the tablet core temperature is controlled at 40°C. After coating, dry it to obtain the vonoprazan fumarate preparation.

Test example

The preparations prepared in the examples and comparative examples were subjected to product dissolution and stability tests, and the test methods and test results are as follows:

1. Vonoprazan fumarate dissolution test:

Dissolution method:

Required instruments: electronic balance, dissolution apparatus, high performance liquid chromatograph

Method: Dissolution method II (paddle method)

Temperature: 37.0℃

Speed: 50rpm

Detection wavelength: 230nm

Sampling time: 5min, 10min, 15min, 20min, 30min, 45min, 60min

Release medium: pH 4.5 acetate buffer;

Preparation method of release medium: Take 2.99 g of sodium acetate trihydrate (1.80 g of anhydrous sodium acetate), add 14.0 mL of 2 mol/L acetic acid solution (114 mL of anhydrous acetic acid plus water to 1000 mL), add water to dissolve and dilute to 1000 mL, adjust the pH to 4.5, and shake well.

The dissolution rate and dissolution curve of Examples 1-4, Comparative Example 2, and Walker's Vonoprazan Fumarate Tablets Reference Preparation (Walker's Vonoprazan Fumarate Tablets Reference Preparation is produced by Takeda Pharmaceuticals of Japan, with a trade name of Walker® and a drug specification of 20 mg) in the dissolution medium are as follows:

Dissolution Results:

The dissolution curves of vonoprazan fumarate of Examples 1-4, Comparative Example 2, and Walker's vonoprazan fumarate tablets reference preparation are shown in FIG2 .

2. Amoxicillin dissolution test:

Dissolution method:

Required instruments: electronic balance, dissolution apparatus, high performance liquid chromatograph

Method: Dissolution method II (paddle method)

Temperature: 37.0℃

Speed: 100rpm

Detection wavelength: 254nm

Sampling time: 5min, 10min, 15min, 30min, 45min, 60min, 90min, 120min, 150min

Release medium: pH 6.8 potassium dihydrogen phosphate-sodium hydroxide buffer solution

Preparation method of release medium: Take 250 ml of 0.2 mol/L potassium dihydrogen phosphate solution, add 118 ml of 0.2 mol/L sodium hydroxide solution, dilute with water to 1000 ml, and shake well.

The dissolution rate and dissolution curve of Examples 1-4, Comparative Example 2, Sawacillin Amoxicillin Tablets Reference Preparation (Amoxicillin Tablets Reference Preparation is produced by Astellas Pharma Inc. of Japan, with the trade name Sawacillin® and a drug specification of 0.25 g) in a pH 6.8 dissolution medium are as follows:

The amoxicillin dissolution curves of Examples 1-4, Comparative Example 2, and Sawacillin Amoxicillin Tablets Reference Preparation are shown in FIG3 .

It can be seen from the dissolution and dissolution curve results of vonoprazan fumarate and amoxicillin that the vonoprazan fumarate preparation prepared in Example 1-4 has a high similarity with the commercially available vonoprazan fumarate tablets (Walker) with a specification of 20 mg and the commercially available amoxicillin tablets (Sawacillin) with a specification of 0.25 g. Therefore, under the condition of equivalent efficacy, the vonoprazan fumarate preparation prepared in Example 1-4 can reduce the dosage and frequency of medication, which is particularly friendly to elderly patients. In Comparative Example 2, after vonoprazan fumarate is added to the tablet core component and amoxicillin is added to the drug layer, amoxicillin can be released normally, but due to the excessive weight gain of the coating outside the tablet core, the dissolution rate of vonoprazan fumarate is slowed down, so the method of adding amoxicillin to the drug layer for coating is not feasible.

3. Stability test

The preparation of Example 1 was subjected to a storage stability test, an accelerated test was performed at 25±2°C, 60±5%RH, and related substances were tested before and 6 months after the accelerated test.

Chromatographic conditions: Use a C18 column, with a 0.025 mol/L phosphoric acid-acetonitrile-methanol mixture (14:1:5) as mobile phase A; a 0.025 mol/L phosphoric acid-acetonitrile mixture (3:7) as mobile phase B. Detection wavelength 230 nm, gradient elution according to the following table:

The results of the stability test of related substances of vonoprazan fumarate are as follows:

Chromatographic conditions: C18 column, 0.05mol/L phosphate buffer (0.05mol/L potassium dihydrogen phosphate solution, pH adjusted to 5.0 with 2mol/L potassium hydroxide solution)-acetonitrile (99:1) as mobile phase A; 0.05mol/L phosphate buffer (pH5.0)-acetonitrile (80:20) as mobile phase B; detection wavelength 254nm; column temperature 35℃; injection volume 20μL; injection temperature: 4℃. Gradient elution according to the following table:

The results of the stability test of amoxicillin related substances are as follows:

It can be seen from the stability test results that the impurity content of the vonoprazan fumarate preparation prepared in Example 1 did not change much after the accelerated test for 6 months, indicating that the vonoprazan fumarate preparation prepared in Example 1 has excellent stability.

Unless otherwise specified, all percentages used in the present invention are by mass.

Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (9)

1. The preparation method of the voronoi fumarate preparation is characterized by comprising the following steps of: pretreatment of the active ingredients of the medicine, preparation of adhesive liquid, one-step granulation, finishing, total mixing, tabletting, preparation of organic acid layer coated tablets, preparation of medicine layer coated tablets and preparation of film coated tablets;

the one-step granulation consists of the following steps: mixing materials and granulating;

Mixing the materials, namely adding the crushed amoxicillin and the filler into a fluidized bed material chamber for mixing to obtain an amoxicillin mixture;

the granulating is carried out, the adhesive liquid is evenly sprayed to the surface of the amoxicillin mixture in the material chamber of the fluidized bed, and the dry granules are obtained;

adding the whole particles, the disintegrating agent and the particle lubricant into a mixer for uniform mixing to obtain total mixed particles;

the tabletting is carried out, and the total mixed particles are added into a tablet press for tabletting according to the important requirement of a central tablet, so as to obtain a plain tablet;

the preparation of the organic acid layer coated tablet comprises the following steps: preparing organic acid coating liquid and coating an organic acid layer;

The organic acid coating liquid is prepared, and the screened film-forming material, the organic acid and the purified water are uniformly mixed to obtain the organic acid coating liquid;

The organic acid is fumaric acid;

The organic acid layer coating is carried out, organic acid coating liquid is uniformly sprayed on the surface of a plain tablet in a coating machine, and the tablet is dried after the coating is finished, so that an organic acid layer coated tablet is obtained;

The preparation of the medicine layer coated tablet comprises the following steps: preparing a medicine layer coating liquid and coating the medicine layer;

The medicine layer coating liquid is prepared, the screened film forming material and the plasticizer are mixed with purified water uniformly, and the crushed fumaric acid Fu Nuola raw materials are added and mixed uniformly to obtain the medicine layer coating liquid;

the preparation of the film-coated tablet comprises the following steps: preparing film coating liquid and coating the film;

The film coating liquid is prepared, and the film forming material after sieving is dissolved in a first part of purified water to obtain film forming material solution; mixing the screened opacifier and colorant with a second part of purified water, and homogenizing to obtain a homogenized dispersion; adding the homogenized dispersion into a film forming material solution, and uniformly stirring to obtain a film coating solution;

and uniformly spraying the film coating liquid to the medicine layer coated tablet in a coating machine, and drying after coating to obtain the Fu Nuola raw fumaric acid preparation.

2. The preparation method of the Fu Nuola raw fumaric acid preparation according to claim 1, wherein the pretreatment of the pharmaceutical active ingredient comprises respectively crushing amoxicillin and fumaric acid Fu Nuola raw materials to obtain crushed amoxicillin and fumaric acid Fu Nuola raw materials;

the adhesive liquid is prepared, and the screened adhesive is uniformly mixed with purified water to obtain the adhesive liquid;

In the preparation of the binding liquid, the binding agent is one or a combination of povidone and hypromellose.

3. The method for preparing a raw preparation of fumaric acid Fu Nuola according to claim 1, wherein in the material mixture, the filler is one or more of microcrystalline cellulose, mannitol, pregelatinized starch, and cellulose-lactose.

4. The method for producing a raw fumaric acid Fu Nuola formulation according to claim 1, wherein the granulating is carried out by feeding dry granules into a granulator to obtain granules.

5. The method for preparing a raw fumaric acid Fu Nuola preparation according to claim 1, wherein in the total mixture, the disintegrating agent is one or more of carboxymethyl starch sodium, croscarmellose sodium and crospovidone;

the particle lubricant is one or more of magnesium stearate, stearic acid and sodium stearyl fumarate.

6. The method for preparing a Fu Nuola raw fumaric acid preparation according to claim 1, wherein in the preparation of the organic acid coating liquid, the film forming material is one or more of hypromellose, sodium carboxymethylcellulose and povidone.

7. The method of preparing a Fu Nuola raw fumarate formulation according to claim 1, wherein in the formulation of said pharmaceutical coating solution, said film-forming material is one or a combination of hypromellose or hypromellose;

The plasticizer is one or more of polyethylene glycol 6000, propylene glycol and triethyl citrate;

And uniformly spraying the drug layer coating liquid on the surface of the organic acid layer coated tablet in a coating machine, and drying after coating is finished to obtain the drug layer coated tablet.

8. The method for preparing a Fu Nuola raw fumaric acid preparation according to claim 1, wherein in the preparation of the film coating liquid, the film forming material is one or more of hypromellose, hydroxypropyl cellulose and sodium carboxymethyl cellulose;

The opacifier is one or the combination of titanium dioxide and talcum powder;

the colorant is one or more of sunset yellow, iron oxide red and iron oxide yellow.

9. The method for preparing a raw fumaric acid Fu Nuola preparation according to claim 2, wherein the mass fraction of the crushed amoxicillin used in the tablet is 45-50% of the total solid raw material dosage in the raw fumaric acid Fu Nuola preparation;

the filler used in the tablet accounts for 23-25% of the mass of the dosage of all solid raw materials in the raw preparation of the fumaric acid Fu Nuola;

the sieved adhesive used in the tablet accounts for 1.7-1.8% of the total solid raw material dosage in the Fu Nuola raw fumaric acid preparation;

the mass fraction of the disintegrating agent used in the tablet accounts for 2.2-3% of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

The particle lubricant used in the tablet accounts for 0.28-0.3% of the mass of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

the sieved film-forming material used in the organic acid coating liquid accounts for 2.5-2.8% of the mass fraction of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

The organic acid coating liquid contains the sieved organic acid which accounts for 0.07-0.08% of the total solid raw material dosage in the Fu Nuola raw fumaric acid preparation;

The crushed vonolamine fumarate used in the medicine layer coating liquid accounts for 2.5-2.8% of the mass fraction of the dosage of all solid raw materials in the Fu Nuola-raw fumaric acid preparation;

The sieved film forming material used in the medicine layer coating liquid accounts for 13-13.5% of the mass percent of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

The sieved plasticizer used in the medicine layer coating liquid accounts for 0.8-0.9% of the mass percent of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

The film forming material used in the film coating liquid after sieving accounts for 3.2 to 3.5 mass percent of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

the sieved opacifier used in the film coating liquid accounts for 0.75-1.1% of the mass of the dosage of all solid raw materials in the Fu Nuola raw fumaric acid preparation;

The mass fraction of the sieved colorant used in the film coating liquid is 0.02-0.03% of the total solid raw material dosage in the Fu Nuola raw fumaric acid preparation.