Ilaprazole enteric-coated tablet and preparation method thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to an ilaprazole enteric-coated tablet and a preparation method thereof. The ilaprazole enteric-coated tablet sequentially comprises a tablet core, an isolating layer and an enteric-coated layer from inside to outside, the tablet core at least comprises an active ingredient ilaprazole or a pharmaceutically acceptable salt thereof, the particle size D90 of the ilaprazole or the pharmaceutically acceptable salt thereof is less than or equal to 10 microns, and a solvent used in a coating process of the isolating layer is water. By controlling the particle size D90 of the ilaprazole to be less than or equal to 10 microns and controlling the preparation method of the tablet core, the tablet core with relatively good content uniformity and appearance state is prepared, the problem that the tablet core is easy to generate spots is solved, and the problem that the intestinal tract is stimulated by over-high local drug concentration when the ilaprazole enteric-coated tablet is released and dissolved out is avoided. In the coating process of the isolating layer, solvent purified water is used for replacing traditional ethanol, so that the problems of pressure for removing an organic solvent in the preparation process of the tablet and environmental pollution in the preparation process are avoided under the condition of ensuring the quality of the tablet.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and more specifically to an ilaprazole enteric-coated tablet and a preparation method thereof. Background Art

[0002] Isomeprazole is a proton pump inhibitor used to treat peptic ulcers, gastroesophageal reflux disease and duodenal ulcers. Isomeprazole is unstable in acidic and neutral media and is easily destroyed in gastric acid. Therefore, the ilaprazole dosage forms used clinically are all enteric-coated. The enteric layer in enteric-coated preparations is generally acidic. In order to reduce the effect of the enteric layer on ilaprazole, an isolation layer needs to be set between the enteric layer and the drug. The isolation layer should not only protect the drug, but also achieve an enteric effect.

[0003] For example, the existing patent CN102525990B discloses an enteric-coated tablet of ilaprazole and a preparation method thereof. The enteric-coated tablet of ilaprazole in the patent comprises a micropellet core, a drug-carrying layer, an isolation layer and an enteric coating layer from the inside to the outside. The components in the isolation layer include hydroxypropyl methylcellulose and talcum powder. The solvent used in the isolation layer is ethanol aqueous solution. The use of ethanol aqueous solution not only increases the environmental pressure, but also increases the pressure to remove organic solvents from the enteric preparation. Patent CN111686083B discloses an enteric-coated ilaprazole tablet. The enteric-coated ilaprazole tablet in the patent includes a tablet core, a separation layer and an enteric layer from the inside to the outside. The tablet core contains ilaprazole, a stabilizer, a filler and a lubricant. The filler is composed of granular lactose and starch. The separation layer contains a film-forming material and a sunscreen. The enteric layer contains a plasticizer and an enteric coating material. From the content uniformity performance tested in the examples of the patent, it can be seen that the prepared enteric-coated ilaprazole tablet has poor content uniformity and poor reproducibility. Poor content uniformity can easily change the drug release behavior of the preparation, resulting in excessive local drug concentration to stimulate the intestine. The existing patent CN118252810A discloses a method for preparing an enteric-coated tablet of ilaprazole. The enteric-coated tablet of ilaprazole in the patent includes a blank tablet core, a drug layer coating, a separation layer coating and an enteric layer coating from the inside to the outside. The blank tablet core includes a filler, a disintegrant and a lubricant, the lubricant is magnesium stearate, the drug coating layer includes a binder, a stabilizer and ilaprazole, the binder is hydroxypropyl methylcellulose, the stabilizer is disodium hydrogen phosphate or magnesium hydroxide, the separation layer coating includes a binder, a plasticizer and a sunscreen, the binder is hydroxypropyl methylcellulose, the plasticizer is triethyl citrate or propylene glycol, the sunscreen is titanium dioxide, and the enteric layer coating includes a plasticizer polyethylene glycol, a surfactant polysorbate 80, and an anti-adhesive glyceryl monostearate. However, the mixing of the binder and ilaprazole in the patent will make the stability of the prepared enteric-coated tablet of ilaprazole poor.

[0004] Therefore, it is very important to avoid the use of organic solvents and prepare ilaprazole enteric-coated tablets with good content uniformity and stability during the preparation of ilaprazole enteric-coated tablets. Summary of the invention

[0005] In order to solve the problems existing in the prior art of ilaprazole enteric-coated tablets, the present invention discloses an ilaprazole enteric-coated tablet, which comprises a tablet core, an isolation layer and an enteric layer from the inside to the outside, wherein the tablet core comprises at least an active ingredient ilaprazole or a pharmaceutically acceptable salt thereof, and the particle size D90 of the ilaprazole or the pharmaceutically acceptable salt thereof is ≤10 μm, and the isolation layer comprises a gastric-soluble film coating premix and an inorganic base, wherein the gastric-soluble film coating premix accounts for 90-99.8% of the total weight of the isolation layer, and the solvent used in the isolation layer coating process is water. The gastric-soluble film coating premix in the present invention comprises hydroxypropyl methylcellulose, talc and triethylglycerol, which are purchased from Shanghai Colorcon Coating Technology Co., Ltd. and are branded as 03K19229-CN.

[0006] As a preferred technical solution, the isolation layer includes a gastric-soluble film coating premix and a stabilizer, and the gastric-soluble film coating premix accounts for 99-99.8% of the total weight of the isolation layer.

[0007] As a preferred technical solution, the inorganic base is selected from one or more of magnesium hydroxide, sodium hydroxide and magnesium oxide.

[0008] As a preferred technical solution, the inorganic base is sodium hydroxide.

[0009] When the inventors began to prepare the core of ilaprazole enteric-coated tablets, they found that spots would appear on the surface of the core. After repeated exploration and research, they found that controlling the particle size of ilaprazole or its pharmaceutically acceptable salt within the range of D90≤10μm could solve the problem of spots on the surface of the core. The inventors found that the solvent purified water used in the isolation layer coating process replaced the traditional solvent ethanol, which, while ensuring the quality of the tablets, avoided the problems of high pressure to remove organic solvents during the preparation of the tablets, flammable and explosive ethanol, and environmental pollution during the preparation process. The inventors found that adding sodium hydroxide to the isolation layer could further improve the stability of ilaprazole enteric-coated tablets.

[0010] As a preferred technical solution, based on the weight of the tablet core, the tablet core includes 2-10% of ilaprazole or a pharmaceutically acceptable salt thereof, 3-8% of a stabilizer, 80-90% of a filler, 2-6% of a disintegrant, and 1-1.5% of a lubricant.

[0011] As a preferred technical solution, the coating weight gain of the isolation layer is 4-9% based on the weight of the tablet core.

[0012] As a preferred technical solution, the coating weight gain of the isolation layer is 5-8% based on the weight of the tablet core.

[0013] The core tablet in the technical solution is coated with an isolation layer to obtain an isolation tablet.

[0014] As a preferred technical solution, the tablet core is coated with an isolation layer to obtain an isolation tablet, and the coating weight gain of the enteric layer is 8-16% based on the weight of the isolation tablet.

[0015] As a preferred technical solution, the core tablet is coated with an isolation layer to obtain an isolation tablet, and the coating weight gain of the enteric layer is 10-14% based on the weight of the isolation tablet.

[0016] As a preferred technical solution, the enteric layer includes a coating material, a plasticizer, a surfactant, an anti-adherent and a colorant, wherein the coating material accounts for 85-90% of the total weight of the enteric layer, the plasticizer accounts for 6-10% of the total weight of the enteric layer, the surfactant accounts for 0.5-2% of the total weight of the enteric layer, the anti-adherent accounts for 1.5-4% of the total weight of the enteric layer, and the rest is the colorant.

[0017] As a preferred technical solution, the stabilizer is selected from one or more of magnesium hydroxide, sodium hydroxide, and magnesium oxide, the filler is selected from one or a combination of microcrystalline cellulose, lactose, and cellulose-lactose complex, the disintegrant is selected from one or more of carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose sodium, the lubricant is selected from one or more of magnesium stearate and sodium stearyl fumarate, the coating material is selected from one or more of methacrylic acid-ethyl acrylate, methacrylic acid-ethyl acrylate aqueous dispersion, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate, the plasticizer is selected from one or more of polyethylene glycol 6000, triethyl citrate, and dibutyl sebacate, the surfactant is selected from at least one of sodium lauryl sulfate, polysorbate 80, and low-viscosity carboxymethyl cellulose sodium, the anti-adhesive is selected from at least one of talc, magnesium stearate, and mono- and distearic acid glyceryl, and the colorant is selected from sunset yellow aluminum lake.

[0018] As a preferred technical solution, the solid content of the methacrylic acid-ethyl acrylate aqueous dispersion is 30wt%.

[0019] When the coating material is methacrylic acid-ethyl acrylate aqueous dispersion, the weight of the coating material is calculated based on solid content.

[0020] As a preferred technical solution, the stabilizer in the tablet core is magnesium hydroxide.

[0021] As a preferred technical solution, the filler in the tablet core is cellulose-lactose.

[0022] As a preferred technical solution, the disintegrant in the tablet core is sodium carboxymethyl starch.

[0023] As a preferred technical solution, the lubricant in the tablet core is magnesium stearate.

[0024] The second aspect of the present invention provides a method for preparing the ilaprazole enteric-coated tablets, wherein the method for preparing the tablet core comprises at least the following steps:

[0025] (1) grinding a prescribed amount of ilaprazole or a pharmaceutically acceptable salt thereof to control the particle size D90 ≤ 10 μm, mixing with a stabilizer, a filler and a disintegrant, and sieving and sieving the granules in a granulator, wherein the granulation sieve has a mesh size of 1.0 to 2.0 mm and the granulation speed is 10 to 30 Hz to obtain a sieved mixed powder;

[0026] (2) Add the sieved mixed powder to the hopper mixer and mix evenly, then add the prescribed amount of lubricant and mix again to obtain the total mixed powder after mixing evenly;

[0027] (3) The total mixed powder is compressed into tablets to obtain tablet cores.

[0028] When preparing the tablet core, the inventor controlled the particle size of ilaprazole or its pharmaceutically acceptable salt, D90≤10μm, and used a sieve with a hole of 1.0~2.0mm to mix and pulverize the raw materials of ilaprazole or its pharmaceutically acceptable salt, stabilizer, filler and disintegrant, so that the raw material and the excipients are fully mixed, the mixing uniformity between the raw and excipients is improved, and the problem of spots on the surface of the tablet core is avoided.

[0029] The inventors added an alkaline stabilizer to the tablet core to maintain the stability of ilaprazole or a pharmaceutically acceptable salt thereof. Since the enteric layer in the ilaprazole enteric-coated tablets is an acidic material, in order to improve the overall stability of the preparation, an isolation layer needs to be added between the tablet core and the enteric layer to prevent interaction between the tablet core and the enteric layer. The inventors found that adding sodium hydroxide to the isolation layer can further improve the stability of the ilaprazole enteric-coated tablets.

[0030] As a preferred technical solution, the coating method of the isolation layer comprises at least the following steps:

[0031] (1) Preparation of coating solution: weigh the prescribed amount of purified water into a container, add the prescribed amount of inorganic base under stirring, and after dissolution, add the gastric soluble film coating premix under stirring, stir evenly, and set aside. During the coating process, keep the coating solution in a stirring state;

[0032] (2) Isolation layer coating: Place the tablet core in the coating pan, turn on the heating to control the isolation bed temperature at 38~40℃, and set the air volume at 1500~1800m 3 / h, air inlet temperature at 35~50℃, pot speed at 2~10rpm, when the tablet core temperature rises to 40±2℃, open the spray gun, spray at 60~400g / min, set the atomization pressure at 1.0~3.0bar, the fan pressure at 1.0~3.0bar, the spray flow rate at 60~400g / min, and control the tablet core temperature at 38~40℃ until the coating weight gain meets the requirements, dry, and cool to obtain the isolation tablet.

[0033] In the present invention, the amount of magnesium stearate is increased to form a hydrophobic film of magnesium stearate to prevent water from penetrating into the tablet core. At the same time, sodium hydroxide is added to the isolation layer coating solution and water is used as a solvent. During the isolation layer coating process, the isolation bed temperature is controlled at 38-40° C. and the air volume is controlled at 1500-1800 m 3 / h, the coating pan speed is 2~10rpm, the exhaust temperature is 35~50℃, the atomization pressure is 1.0~3.0bar, the fan pressure is 1.0~3.0bar, and the spray flow rate is 60~400g / min, so that the water evaporates quickly on the surface after contacting the tablet core, achieving no water penetration. The density of the isolation layer coating film and the stability of ilaprazole enteric-coated tablets are improved by the selection of excipients and the control of isolation layer coating parameters.

[0034] As a preferred technical solution, the enteric layer coating method comprises at least the following steps:

[0035] (1) Preparation of enteric coating solution A: Weigh 1 / 2 of the amount of purified water in the enteric layer prescription, heat to 80-90°C, then add the prescribed amount of surfactant and anti-adhesive agent, and homogenize at a shear frequency of 1000-3000 rpm for 10-30 min;

[0036] (2) Preparation of enteric coating solution B: Weigh the plasticizer and colorant of the enteric coating formulation and add them to the remaining purified water of the enteric coating formulation while stirring, and continue stirring until uniform;

[0037] (3) Preparation of enteric coating liquid C: slowly add enteric coating liquid B into enteric coating liquid A, homogenize for 10-30 min at a shear frequency of 1000-3000 rpm, and cool to 10-30°C to obtain enteric coating liquid C;

[0038] (4) Enteric coating solution: Weigh the coating material of the enteric layer prescription, add enteric coating solution C while stirring, and stir until uniform to obtain the enteric coating solution, which is set aside;

[0039] (5) The enteric layer is coated under the conditions of a coating pan speed of 4-12 rpm, an exhaust temperature of 30-45°C, an atomizing pressure of 1.0-3.0 bar, a fan pressure of 1.0-3.0 bar, and a spray flow rate of 60-400 g / min until the coating weight gain meets the requirements, and then dried and cooled to obtain ilaprazole enteric-coated tablets.

[0040] Beneficial Effects

[0041] (1) In this technical solution, by controlling the particle size D90 of ilaprazole ≤ 10 μm and controlling the preparation method of the tablet core, tablet cores with good content uniformity and appearance are prepared, thereby solving the problem of spots on the tablet core and avoiding the problem of excessive local drug concentration causing intestinal irritation during the release and dissolution of ilaprazole enteric-coated tablets.

[0042] (2) In this technical solution, the density of the isolation layer coating film and the stability of ilaprazole enteric-coated tablets are improved by controlling the amount of magnesium stearate in the tablet core, adding sodium hydroxide to the isolation layer, and controlling the coating parameters of the isolation layer coating. At the same time, the addition of mono- and distearic acid glyceryl in the enteric layer formula not only improves the process smoothness and solves the problems of gun blockage, but also further solves the problems of acid-resistant disintegration and dissolution failure of ilaprazole enteric-coated tablets due to its hydrophobicity and low permeability.

[0043] (3) The isolation layer in the technical solution uses purified water as the solvent in the coating process instead of the traditional solvent ethanol. While ensuring the quality of the tablets, it avoids the problems of removing organic solvents during the tablet preparation process, ethanol being flammable and explosive, and polluting the environment during the preparation process. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the tablet core prepared in Example 1-1.

[0045] Figure 2 This is the tablet core prepared in Example 1-2. DETAILED DESCRIPTION

[0046] The specific implementation of the present invention is further described below in conjunction with the examples, but the protection content of the present invention is not limited to the examples listed below. It should be noted that if there are any details not particularly described in the following examples, they can be realized or understood by those skilled in the art with reference to the prior art. The materials used in the following examples without indicating the manufacturer are all conventional materials that can be purchased commercially.

[0047] Particle size determination method: Using Malvern 3000 laser particle size analyzer, take 0.1g of the substance to be determined and place it in a beaker, add 0.1g of Tween 80, stir to make a uniform paste, add 25ml of purified water, stir to make a turbid liquid, as the particle size determination reserve solution; take the above reserve solution dropwise and add it to the sample pool containing 500ml of dispersion medium, the shading rate is controlled at 8%~20%, and 3 samples are measured in parallel, each sample is read 3 times, and the average value is taken as the result. Determination parameters: dispersion medium refractive index 1.330; sample refractive index 1.710, absorbance 0.100; particle density 1.00; background and sample measurement time are both 15s; stirring speed 1700rpm.

[0048] Prescription 1 Screening

[0049] Ilaprazole enteric-coated tablets

[0050] The proportions in the prescriptions of Example 1-1 and Example 1-2 are based on the weight of the core of the Aprag Enteric-coated Tablets of the unit dose (145 mg / tablet), as shown in Table 1 for details.

[0051] Table 1-Specific ratios of prescriptions for Examples 1-1 and 1-2

[0052]

[0053] Examples 1-1, 1-2 Preparation method: Take ilaprazole raw material and grind it to obtain raw material of required particle size. Mix the ground ilaprazole, magnesium hydroxide, cellulose-lactose and sodium carboxymethyl starch and sieve them in a granulator. The mesh of the granulator sieve is 1.0 mm and the granulator speed is 25 Hz to obtain a sieved mixed powder; add the sieved mixed powder to a hopper mixer and mix it evenly, then add magnesium stearate to mix and obtain a total mixed powder; press the total mixed powder into tablets to obtain tablet cores.

[0054] The ilaprazole raw materials in Example 1-1 and Example 1-2 were crushed, and the D90 of ilaprazole in Example 1-1 was controlled to be ≤10 μm, and the D90 of ilaprazole in Example 1-2 was controlled to be >10 μm. The particle sizes in Example 1-1 and Example 1-2 were measured, and the content uniformity of ilaprazole in the tablet core was calculated and the properties of the tablet core were checked according to the calculation method of tablet content uniformity A++2.2S (qualified when A++2.2S≤15.0) and the property inspection method specified in the Pharmacopoeia of the People's Republic of China. The results are shown in Table 2.

[0055] Table 2 - Test results

[0056]

[0057] The tablet core prepared in Example 1-1 is shown in Figure 1 ,from Figure 1 It can be seen that the core tablets are uniformly white. The core tablets prepared in Example 1-2 are Figure 2 ,from Figure 2 It can be seen that there are black spots on the surface of the tablet core. By controlling the particle size of the raw material ilaprazole, the problem of black spots on the tablet core can be avoided. The proportions in the prescriptions of Example 2-1 and Example 2-2 are based on the weight of the ilaprazole enteric-coated tablet core of the unit dose (145 mg / tablet), as shown in Table 3.

[0058] Table 3 - Specific ratios of prescriptions for Example 2-1 and Example 2-2

[0059]

[0060] The preparation methods of Example 2-1 and Example 2-2 are the same, specifically as follows: crushing ilaprazole, mixing the crushed ilaprazole with magnesium hydroxide, cellulose-lactose and sodium carboxymethyl starch, and sieving and sieving in a granulator, wherein the mesh of the granulation sieve is 1.0 mm, and the granulation speed is 10 Hz, to obtain a sieved mixed powder; adding the sieved mixed powder to a hopper mixer and mixing evenly, and then adding a lubricant and mixing again to obtain a total mixed powder; tableting the total mixed powder to obtain a tablet core. When crushing ilaprazole, the ilaprazole particle size D90 is controlled to be ≤10 μm. The ilaprazole particle size D90 in Example 2-1 is measured to be 5.4 μm, and the ilaprazole particle size D90 in Example 2-2 is 5.4 μm.

[0061] Performance Testing

[0062] Properties: Visual method

[0063] Relevant substance content detection:

[0064] Determined by high performance liquid chromatography (General Chapter 0512, Part 4 of the Chinese Pharmacopoeia 2020 Edition).

[0065] Commercially available preparations: Trade name: Yilian®, manufacturer: Livzon Pharmaceutical Factory of Livzon Group, specification: 5 mg, batch number: 230901.

[0066] The properties and related substance contents of the core tablets of ilaprazole enteric-coated tablets prepared in Example 2-1 and Example 2-2 and the commercially available preparations were tested. The results are shown in Table 4.

[0067] Table 4 - Test results of properties and related substances

[0068]

[0069] The results show that the cores of ilaprazole enteric-coated tablets prepared with magnesium hydroxide dosage of 6.0 mg / tablet and 8.0 mg / tablet were placed at 60°C for 10 days. Compared with 0 days, the properties did not change, the related substances increased, and the growth trend was not significantly different. The growth trend of the related substances in the cores of ilaprazole enteric-coated tablets prepared in Example 2-1 and Example 2-2 was comparable to that of the commercially available preparations, indicating that the quality requirements of this product can be met when the magnesium hydroxide dosage is 6.0 mg / tablet and 8.0 mg / tablet.

[0070] Mixing uniformity test: Samples were taken at various locations of the total mixed powder in Example 2-1 to determine the content of ilaprazole. A total of 11 points were taken to determine the content difference at each point and calculate the RSD (%) value. The RSD (%) must be ≤5.0% to determine that the mixing is uniform.

[0071] The tablet core prescription of Example 2-1 was used to prepare the total mixed powder before tableting. The mixing uniformity of the total mixed powder was measured and shown in Table 5 below.

[0072] Table 5 - Mixing uniformity test results

[0073]

[0074] The results showed that the ilaprazole content in the total mixed powder of Example 2-1 had good mixing uniformity.

[0075] Uniformity of the central controlled dose unit: The tablet cores were prepared using the tablet core formulation of Example 2-1. The uniformity of the central controlled dose unit of the tablet cores was measured and shown in Table 6 below.

[0076] Table 6-Uniformity of in-process control dosage units

[0077]

[0078] The above table shows the results of the uniformity of the in-process controlled dosage units.

[0079] From the above results, it can be seen that the uniformity of the controlled dosage unit in Example 2-1 meets the qualified standard, indicating that when the particle size D90 of ilaprazole in Example 2-1 is controlled to be ≤10 μm, a uniformly mixed tablet core can be obtained, which is beneficial to the stable release of the preparation and avoids excessive local drug concentration from irritating the intestine.

[0080] Prescription Screening 2

[0081] Ilaprazole enteric-coated tablets

[0082] The proportions in the prescriptions of Example 3 and Example 4 are based on the weight of the core of the Apragmat enteric-coated tablets of the unit dose (145 mg / tablet), as shown in Table 7.

[0083] Table 7-Specific ratio of prescription of Example 3-4

[0084]

[0085] The preparation of Example 3 and Example 4 is the same, specifically as follows: crush ilaprazole and then mix it with magnesium hydroxide, cellulose-lactose and sodium carboxymethyl starch, and then sieve and granulate it in a granulator, the mesh of the granulation sieve is 1.0 mm, and the granulation speed is 25 Hz to obtain a sieved mixed powder; add the sieved mixed powder to a hopper mixer and mix it evenly, then add a lubricant and mix it again to obtain a total mixed powder; press the total mixed powder to obtain the ilaprazole enteric-coated tablet core. The particle size D90 of ilaprazole in Example 3 and Example 4 was measured to be 5.4 μm.

[0086] Performance Testing

[0087] Disintegration method: Refer to the tablet disintegration time test method under General Chapter 0921 Disintegration Time Test Method in Part 4 of the 2020 edition of the Chinese Pharmacopoeia. The medium is purified water, the temperature is 37±1°C, and the average value is taken as the disintegration time.

[0088] Commercially available preparation 1: Trade name: Yilian®, manufacturer: Livzon Pharmaceutical Factory of Livzon Group, specification: 5 mg, batch number: 230901.

[0089] Commercially available preparation 2: Trade name: Yilian®, manufacturer: Livzon Pharmaceutical Factory of Livzon Group, specification: 5 mg, batch number: 230802.

[0090] The disintegration performance test was performed on Example 2-1, Example 3, Example 4, Commercially Available Preparation 1, and Commercially Available Preparation 2. The test results are shown in Table 8 below.

[0091] Table 8 - Disintegration time test results

[0092]

[0093] The results showed that the disintegration time of the core of ilaprazole enteric-coated tablets prepared when the disintegrant dosage was 2%~3.5% shortened with the increase of disintegrant dosage. Among them, when the disintegrant dosage was 2.8%, the disintegration time of the core of ilaprazole enteric-coated tablets was slightly faster than that of the commercially available preparations. Considering that the commercially available preparations peel off the coating film, theoretically the disintegration speed of the core tablets is slower than that of the uncoated tablets. Taking this factor into consideration, the disintegration time of the plain tablets when the disintegrant dosage was 2.8% was closer to that of the commercially available preparations, so the disintegrant dosage of this product was determined to be 2.8%.

[0094] Prescription Screening 3

[0095] Separation tablet (a tablet obtained by coating the core tablet with a separation layer is called a separation tablet).

[0096] The proportions in the prescriptions of Examples 5-7 are based on the weight of the tablet core of ilaprazole enteric-coated tablets at a unit dose (145 mg tablet core / tablet). See Table 9 for details.

[0097] Table 9-Specific ratio of prescription of Example 5-7

[0098]

[0099]

[0100] The preparation methods of Examples 5-7 are the same, specifically, the following preparation methods: crush ilaprazole, mix it with magnesium hydroxide, cellulose-lactose and sodium carboxymethyl starch, and then sieve and granulate it in a granulator, the mesh of the granulation sieve is 1.0 mm, and the granulation speed is 25 Hz, to obtain a sieved mixed powder; add the sieved mixed powder to a hopper mixer and mix it evenly, then add magnesium stearate to mix it to obtain a total mixed powder; and compress the total mixed powder to obtain ilaprazole enteric-coated tablet cores. The particle size D90 of ilaprazole in Examples 5, 6 and 7 was measured to be 5.4 μm.

[0101] The isolation layer of ilaprazole enteric-coated tablets was coated according to the formulation in Table 9 and the following method:

[0102] (1) Prepare coating solution: weigh the prescribed amount of purified water into a container, add the prescribed amount of sodium hydroxide to dissolve it while stirring, then add the gastric soluble film coating premix while stirring, continue stirring for 50 minutes, and set aside. During the coating process, keep the coating solution in a stirring state;

[0103] (2) Isolation layer coating: Place the tablet core in the coating pan, turn on the heating to control the isolation bed temperature at 39±1℃ and set the air volume at 1500m 3 / h, inlet air temperature at 35℃, pot speed at 2rpm, when the tablet core temperature rises to 40±2℃, open the spray gun, spray 60g / min, set the atomization pressure at 1.0bar, the fan pressure at 1.0bar, the spray flow rate at 60g / min~400g / min (the spray flow rate increases from 60g / min to 400g / min during the spraying process), control the tablet core temperature at 39±1℃, until the coating weight gain meets the requirements, dry, and cool to obtain the isolation tablet.

[0104] Performance Testing

[0105] Moisture test: Grind the isolation sheets prepared in Examples 5-7 into powder, take 1.0 g of the ground powder, and place it in a rapid moisture meter at 105° C. for 1 min to measure the moisture content.

[0106] Related substances: Determined by referring to the high performance liquid chromatography method (General Chapter 0512, Part 4 of the Chinese Pharmacopoeia 2020 Edition). The test results of water and related substances are shown in Table 10.

[0107] Table 10 - Water and related substances test results

[0108]

[0109] The results showed that tablets prepared with ethanol concentrations of 0%, 60% and 70% in the isolation layer coating solution were placed at 40°C for 10 days. Compared with 0 day, the related substances increased slightly, but the impurities met the standard requirements and the impurity increases of each prescription were similar, indicating that ethanol concentrations of 0%~70% in the isolation layer coating solution did not affect the stability of the preparation. In order to improve the production operability of this product, the preferred ethanol concentration of this product is 0, that is, the isolation layer uses purified water as the solvent. While ensuring the quality of the tablets, the problems of removing organic solvents during the preparation of the tablets, ethanol being flammable and explosive, and environmental pollution during the preparation process are avoided.

[0110] Prescription Screening 4

[0111] The coating weight gain of the isolation layer in the enteric-coated tablets of ilaprazole is calculated based on the weight of the core tablet of unit dose (145 mg / tablet), and the coating weight gain of the enteric layer is calculated based on the weight of the isolation tablet of unit dose (154.424 mg / tablet). The formula and preparation method of the core tablet and isolation layer in Examples 8-1, 8-2 and 8-3 are the same as those in Example 5, and the formula and preparation method of the core tablet and isolation layer in Examples 8-1, 8-2 and 8-3 are not listed below. The specific formula of the enteric layer in Examples 8-1, 8-2 and 8-3 is shown in Table 11.

[0112] Table 11 - Enteric layer formulations in Examples 8-1, 8-2 and 8-3

[0113]

[0114] In the above table, " / " means that the substance is not added. The enteric coating weight gain of Example 8-1 is 11.8%, the enteric coating weight gain of Example 8-2 is 11.9%, and the enteric coating weight gain of Example 8-3 is 12.1%.

[0115] The enteric coating method of Examples 8-1 and 8-2 is the same, as follows:

[0116] (1) Preparation of enteric coating solution A: Weigh 1 / 2 of the prescribed amount of purified water, heat to 85±5°C, then add the prescribed amount of polysorbate 80 and glyceryl monostearate and distearate, and homogenize at a shear frequency of 2000 rpm for 20 min.

[0117] (2) Preparation of enteric coating solution B: Weigh the prescribed amount of polyethylene glycol 6000 and sunset yellow aluminum lake, add them to the remaining prescribed amount of purified water while stirring, and continue stirring until uniform;

[0118] (3) Preparation of enteric coating liquid C: slowly add enteric coating liquid B into enteric coating liquid A, homogenize for 20 min at a shear frequency of 2000 rpm, and cool to 20±10°C to obtain enteric coating liquid C;

[0119] (4) Enteric coating solution: Weigh the prescribed amount of methacrylic acid-ethyl acrylate copolymer aqueous dispersion, add enteric coating solution C while stirring, and stir until uniform to obtain the enteric coating solution, which is set aside;

[0120] (5) Carry out enteric layer coating under the conditions of coating pan speed of 8 rpm, exhaust temperature of 35±5℃, atomization pressure of 2.0 bar, fan pressure of 2.0 bar, and spray flow rate of 200 g / min. During the coating process, observe whether there is sticking of tablets or blocking of the gun, and record it.

[0121] Example 8-3 Enteric coating method is as follows:

[0122] (1) Weigh 1 / 2 of the prescribed amount of purified water, add the prescribed amount of talc, and homogenize for 10 to 30 minutes at a shear frequency of 1000 to 3000 rpm to obtain a suspension;

[0123] (2) Weigh the prescribed amount of methacrylic acid-ethyl acrylate copolymer aqueous dispersion, slowly add the slow suspension into the aqueous dispersion while stirring, add the remaining amount of purified water, and continue stirring for more than 30 minutes to obtain the enteric coating solution, which is set aside.

[0124] Acid resistance test: Take the enteric-coated tablets of Examples 8-1, 8-2 and 8-3, and put them in a dissolution apparatus to resist acid for 2 hours (method: 0.1 mol / L hydrochloric acid solution containing sodium chloride, 900 ml, paddle method, 100 rpm). After taking out the acid-resistant enteric-coated tablets, wash the surface of the tablets with hydrochloric acid, and then put them in a dissolution apparatus to observe the disintegration phenomenon (method: pH 6.8 phosphate buffer solution, 900 ml, paddle method, 50 rpm).

[0125] It can be seen from the enteric coating results of Examples 8-1, 8-2 and 8-3 that the inventors avoided the risks of tablet sticking and gun clogging by adding surfactants and anti-adherents to the enteric layer and controlling the parameters of the enteric coating process, thereby greatly improving the coating efficiency and solving the problem of tablet core not disintegrating and dissolution failure of ilaprazole enteric-coated tablets after acid resistance.

[0126] Prescription Screening 5

[0127] The coating weight gain of the isolation layer in the enteric-coated ilaprazole tablets is calculated based on the weight of the tablet core per unit dose (145 mg / tablet), and the coating weight gain of the enteric layer is calculated based on the weight of the isolation tablet per unit dose (154.424 mg / tablet). The specific prescriptions of Examples 9, 10, and 11 are shown in Table 12.

[0128] The preparation methods of Example 9, Example 10 and Example 11 (sodium hydroxide is not added in Example 11, and the other preparation methods are the same) are the same, and ilaprazole enteric-coated tablets are prepared according to the prescription in Table 12 and the following method:

[0129] 1. Preparation of core

[0130] The ilaprazole was crushed and then mixed with magnesium hydroxide, cellulose-lactose and sodium carboxymethyl starch, and then sieved and granulated in a granulator, wherein the mesh size of the granulation sieve was 1.0 mm and the granulation speed was 25 Hz to obtain a sieved mixed powder; the sieved mixed powder was added to a hopper mixer and mixed evenly, and magnesium stearate was added and mixed to obtain a total mixed powder; the total mixed powder was tableted to obtain a tablet core, and the particle size D90 of the ilaprazole in Example 9, Example 10 and Example 11 was measured to be 5.4 μm.

[0131] 2. Preparation of isolation film

[0132] (1) Prepare coating solution: weigh the prescribed amount of purified water into a container, add the prescribed amount of sodium hydroxide to dissolve it while stirring, then add the gastric soluble film coating premix while stirring, continue stirring for 50 minutes, and set aside. During the coating process, keep the coating solution in a stirring state;

[0133] (2) Isolation layer coating: Place the tablet core in the coating pan, turn on the heating to control the isolation bed temperature at 39±1℃ and set the air volume at 1500m 3 / h, inlet air temperature at 35℃, pot speed at 2rpm, when the tablet core temperature rises to 40±2℃, open the spray gun, spray 60g / min, set the atomization pressure at 1.0bar, the fan pressure at 1.0bar, the spray flow rate at 60g / min~400g / min, control the tablet core temperature at 39±1℃, until the coating weight gain meets the requirements, dry, and cool to obtain the isolation tablet.

[0134] 3. Preparation of Ilaprazole Enteric-coated Tablets

[0135] (1) Preparation of enteric coating solution A: Weigh 1 / 2 of the amount of purified water in the enteric layer prescription, heat to 85±5°C, then add the prescribed amount of surfactant and anti-adhesive agent, and homogenize at a shear frequency of 2000 rpm for 20 min;

[0136] (2) Preparation of enteric coating solution B: Weigh the plasticizer and colorant of the enteric coating formulation and add them to the remaining purified water of the enteric coating formulation while stirring, and continue stirring until uniform;

[0137] (3) Preparation of enteric coating liquid C: slowly add enteric coating liquid B into enteric coating liquid A, homogenize for 20 min at a shear frequency of 2000 rpm, and cool to 20±10°C to obtain enteric coating liquid C;

[0138] (4) Enteric coating solution: weigh the enteric layer prescription amount of methacrylic acid-ethyl acrylate copolymer aqueous dispersion, add enteric coating solution C while stirring, and stir until uniform to obtain the enteric coating solution, which is set aside;

[0139] (5) Enteric layer coating was carried out under the conditions of coating pan speed of 8 rpm, exhaust temperature of 35±5°C, atomization pressure of 2.0 bar, fan pressure of 2.0 bar, and spray flow rate of 200 g / min.

[0140] Table 12 - Formulations in Examples 9-11

[0141]

[0142] Performance Testing

[0143] Breakdown time: The enteric-coated ilaprazole tablets in Examples 9-11 were placed at high temperature (60°C) for 10 days to detect related substances and the breakdown time in a sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.0). The test results are shown in Table 13 below.

[0144] Related substances: The relevant substances were determined by referring to the high performance liquid chromatography method (General Chapter 0512 of Part 4 of the Chinese Pharmacopoeia 2020 Edition). The breakthrough time and related substance detection results are shown in Table 13.

[0145] Table 13 - Breach time and related substance test results

[0146]

[0147] The results showed that the total impurities of the ilaprazole enteric-coated tablets with sodium hydroxide added in the isolation layer increased less after being placed at 60°C for 10 days, while the total impurities of the ilaprazole enteric-coated tablets without sodium hydroxide added in the isolation layer increased more after being placed at 60°C for 10 days. The stability of the ilaprazole enteric-coated tablets without sodium hydroxide added was poor.

[0148] Prescription Screening6

[0149] The coating weight gain of the isolation layer in the enteric-coated ilaprazole tablets is calculated based on the weight of the tablet core per unit dose (145 mg / tablet), and the coating weight gain of the enteric layer is calculated based on the weight of the isolation tablet per unit dose (154.424 mg / tablet). The specific prescriptions of Examples 12-13 are shown in Table 14.

[0150] The preparation methods of Examples 12-13 are the same, and ilaprazole enteric-coated tablets are prepared according to the prescription in Table 14 and the following method:

[0151] 1. Preparation of core

[0152] The ilaprazole was crushed and then mixed with magnesium hydroxide, cellulose-lactose and sodium carboxymethyl starch, and then sieved and granulated in a granulator, wherein the mesh size of the granulation sieve was 1.0-2.0 mm and the granulation speed was 10-30 Hz to obtain a sieved mixed powder; the sieved mixed powder was added to a hopper mixer and mixed evenly, and magnesium stearate was added to mix to obtain a total mixed powder; the total mixed powder was tableted to obtain a tablet core, and the particle size D90 of the ilaprazole in Example 12 and Example 13 was measured to be 5.4 μm.

[0153] 2. Preparation of isolation film

[0154] (1) Prepare coating solution: weigh the prescribed amount of purified water into a container, add the prescribed amount of sodium hydroxide to dissolve it while stirring, then add the gastric soluble film coating premix while stirring, continue stirring for 50 minutes, and set aside. During the coating process, keep the coating solution in a stirring state;

[0155] (2) Isolation layer coating: Place the tablet core in the coating pan, turn on the heating to control the isolation bed temperature at 39±1℃ and set the air volume at 1500m 3 / h, inlet air temperature at 35℃, pot speed at 2rpm, when the tablet core temperature rises to 40±2℃, open the spray gun, spray 60g / min, set the atomization pressure at 1.0bar, the fan pressure at 1.0bar, the spray flow rate at 60g / min~400g / min, control the tablet core temperature at 39±1℃, until the coating weight gain meets the requirements, dry, and cool to obtain the isolation tablet.

[0156] 3. Preparation of Ilaprazole Enteric-coated Tablets

[0157] (1) Preparation of enteric coating solution A: Weigh 1 / 2 of the amount of purified water in the enteric layer prescription, heat to 85±5°C, then add the prescribed amount of surfactant and anti-adhesive agent, and homogenize at a shear frequency of 2000 rpm for 20 min;

[0158] (2) Preparation of enteric coating solution B: Weigh the plasticizer and colorant of the enteric coating formulation and add them to the remaining purified water of the enteric coating formulation while stirring, and continue stirring until uniform;

[0159] (3) Preparation of enteric coating liquid C: slowly add enteric coating liquid B into enteric coating liquid A, homogenize for 20 min at a shear frequency of 2000 rpm, and cool to 20±10°C to obtain enteric coating liquid C;

[0160] (4) Enteric coating solution: weigh the enteric layer prescription amount of methacrylic acid-ethyl acrylate copolymer aqueous dispersion, add enteric coating solution C while stirring, and stir until uniform to obtain the enteric coating solution, which is set aside;

[0161] (5) Enteric layer coating was carried out under the conditions of coating pan speed of 8 rpm, exhaust temperature of 35±5°C, atomization pressure of 2.0 bar, fan pressure of 2.0 bar, and spray flow rate of 200 g / min.

[0162] Table 14 - Prescriptions for Examples 12-13

[0163]

[0164]

[0165] Performance Testing

[0166] The rupture time of the enteric layer samples with different weight gain in Example 12 and Example 13 was investigated in a sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.0), and the test results are shown in Table 15. The rupture time of the enteric layer samples with different weight gain in Example 12 and Example 13 was investigated in a sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.8), and the test results are shown in Table 16.

[0167] Table 15 - Breakdown time of sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.0)

[0168]

[0169] Table 16 - Breakdown time of sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.8)

[0170]

[0171] The results showed that when the weight gain of the enteric layer coating was 11-13%, the rupture time of the prepared ilaprazole enteric-coated tablets in sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.0) was 48-68 minutes, which was within the quality limit of 45-70 minutes. The rupture time of the prepared ilaprazole enteric-coated tablets in sodium chloride hydrochloric acid solution + phosphate buffer (pH 6.8) was 12-16 minutes, which was within the quality limit of 10-18 minutes.

[0172] Dissolution testing

[0173] The ilaprazole enteric-coated tablets prepared in Example 13 were subjected to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2), using sodium chloride hydrochloric acid solution + acetic acid-sodium acetate buffer (pH 4.5) as the dissolution medium. The dissolution results are shown in Table 17.

[0174] Table 17 - Dissolution test results

[0175]

[0176] The results showed that the prepared ilaprazole enteric-coated tablets had good solubility and were within the dissolution limit.

Claims

1. An enteric-coated ilaprazole tablet, characterized in that: From the inside to the outside, the tablet comprises a core, an isolation layer and an enteric layer, wherein the core comprises at least an active ingredient, ilaprazole or a pharmaceutically acceptable salt thereof, the particle size D90 of the ilaprazole or the pharmaceutically acceptable salt thereof is ≤10 μm, the isolation layer comprises a gastric-soluble film coating premix and an inorganic base, the gastric-soluble film coating premix accounts for 90-99.8% of the total weight of the isolation layer, and the solvent used in the coating process of the isolation layer is water.

2. The ilaprazole enteric-coated tablets according to claim 1, characterized in that: The inorganic base is selected from one or more of magnesium hydroxide, sodium hydroxide and magnesium oxide.

3. The enteric-coated ilaprazole tablets according to claim 1, characterized in that: Based on the weight of the tablet core, the tablet core includes 2-10% of ilaprazole or a pharmaceutically acceptable salt thereof, 3-8% of a stabilizer, 80-90% of a filler, 2-6% of a disintegrant, and 1-1.5% of a lubricant.

4. The enteric-coated ilaprazole tablets according to claim 3, characterized in that: Based on the weight of the tablet core, the coating weight gain of the isolation layer is 4-9%.

5. The ilaprazole enteric-coated tablets according to claim 4, characterized in that: The tablet core is coated with an isolation layer to obtain an isolation tablet. The coating weight gain of the enteric layer is 8-16% based on the weight of the isolation tablet.

6. The enteric-coated ilaprazole tablets according to claim 5, characterized in that: The enteric layer includes a coating material, a plasticizer, a surfactant, an anti-adherent and a colorant, wherein the coating material accounts for 85-90% of the total weight of the enteric layer, the plasticizer accounts for 6-10% of the total weight of the enteric layer, the surfactant accounts for 0.5-2% of the total weight of the enteric layer, the anti-adherent accounts for 1.5-4% of the total weight of the enteric layer, and the rest is the colorant.

7. The enteric-coated ilaprazole tablets according to claim 6, characterized in that: The stabilizer is selected from one or more of magnesium hydroxide, sodium hydroxide, and magnesium oxide, the filler is selected from one or a combination of microcrystalline cellulose, lactose, and cellulose-lactose complex, the disintegrant is selected from one or more of carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose sodium, the lubricant is selected from one or more of magnesium stearate and sodium stearyl fumarate, the coating material is selected from one or more of methacrylic acid-ethyl acrylate, methacrylic acid-ethyl acrylate aqueous dispersion, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate, the plasticizer is selected from one or more of polyethylene glycol 6000, triethyl citrate, and dibutyl sebacate, the surfactant is selected from at least one of sodium lauryl sulfate, polysorbate 80, and low-viscosity carboxymethyl cellulose sodium, the anti-adhesive is selected from at least one of talc, magnesium stearate, and mono- and distearic acid glyceryl, and the colorant is selected from sunset yellow aluminum lake.

8. A method for preparing the ilaprazole enteric-coated tablets according to any one of claims 3 to 7, characterized in that: The method for preparing the core comprises at least the following steps: (1) grinding a prescribed amount of ilaprazole or a pharmaceutically acceptable salt thereof to control the particle size D90 ≤ 10 μm, mixing with a stabilizer, a filler and a disintegrant, and sieving and sieving the granules in a granulator, wherein the granulation sieve has a mesh size of 1.0 to 2.0 mm and the granulation speed is 10 to 30 Hz to obtain a sieved mixed powder; (2) Add the sieved mixed powder to the hopper mixer and mix evenly, then add the prescribed amount of lubricant and mix again to obtain the total mixed powder after mixing evenly; (3) The total mixed powder is compressed into tablets to obtain tablet cores.

9. The method for preparing ilaprazole enteric-coated tablets according to claim 8, characterized in that: The coating method of the isolation layer comprises at least the following steps: (1) Preparation of coating solution: weigh the prescribed amount of purified water into a container, add the prescribed amount of inorganic base under stirring, and after dissolution, add the gastric soluble film coating premix under stirring, stir evenly, and set aside. During the coating process, keep the coating solution in a stirring state; (2) Isolation layer coating: Place the tablet core in the coating pan, turn on the heating to control the isolation bed temperature at 38~40℃, and set the air volume at 1500~1800m 3 / h, air inlet temperature at 35~50℃, pot speed at 2~10rpm, when the tablet core temperature rises to 40±2℃, open the spray gun, spray at 60~400g / min, set the atomization pressure at 1.0~3.0bar, the fan pressure at 1.0~3.0bar, the spray flow rate at 60~400g / min, and control the tablet core temperature at 38~40℃ until the coating weight gain meets the requirements, dry, and cool to obtain the isolation tablet.

10. The method for preparing ilaprazole enteric-coated tablets according to claim 9, characterized in that: The enteric layer coating method comprises at least the following steps: (1) Preparation of enteric coating solution A: Weigh 1 / 2 of the amount of purified water in the enteric layer prescription, heat to 80-90°C, then add the prescribed amount of surfactant and anti-adhesive agent, and homogenize at a shear frequency of 1000-3000 rpm for 10-30 min; (2) Preparation of enteric coating solution B: Weigh the plasticizer and colorant of the enteric coating formulation and add them to the remaining purified water of the enteric coating formulation while stirring, and continue stirring until uniform; (3) Preparation of enteric coating liquid C: slowly add enteric coating liquid B into enteric coating liquid A, homogenize for 10-30 min at a shear frequency of 1000-3000 rpm, and cool to 10-30°C to obtain enteric coating liquid C; (4) Enteric coating solution: Weigh the coating material of the enteric layer prescription, add enteric coating solution C while stirring, and stir until uniform to obtain the enteric coating solution, which is set aside; (5) The enteric layer is coated under the conditions of a coating pan speed of 4-12 rpm, an exhaust temperature of 30-45°C, an atomizing pressure of 1.0-3.0 bar, a fan pressure of 1.0-3.0 bar, and a spray flow rate of 60-400 g / min until the coating weight gain meets the requirements, and then dried and cooled to obtain ilaprazole enteric-coated tablets.

Images