Ilaprazole freeze-dried enteric-coated tablet and preparation method thereof

Abstract

The invention provides an ilaprazole freeze-dried enteric-coated tablet and a preparation method thereof. The ilaprazole freeze-dried enteric-coated tablet comprises a plain tablet core and a coating layer, the plain tablet core comprises ilaprazole, a disintegrating agent, a freeze-drying protective agent and a medicinal excipient, the plain tablet core subjected to freeze-drying treatment forms a loose porous structure, and the moisture content of the plain tablet core is 1t; 5%. According to the ilaprazole freeze-dried enteric-coated tablet, the plain tablet core subjected to freeze drying treatment forms a loose porous structure, and the moisture content of the plain tablet core is 1t; the long-term storage stability of the tablet core can be improved, and the growth of related substances in the long-term storage process is effectively avoided, so that the drug effect and the drug safety of ilaprazole are improved; the quick release of the tablet core in the intestinal tract can be accelerated, and the absorption efficiency of the intestinal tract on ilaprazole is improved, so that the curative effect of the medicine is enhanced.

Description

Technical Field

[0001] The present disclosure relates to the technical field of enteric-coated tablets containing proton pump inhibitors, and in particular to ilaprazole freeze-dried enteric-coated tablets and a preparation method thereof. Background Art

[0002] Ilaprazole is the latest generation of proton pump inhibitors, which are widely used for various acid-related digestive tract diseases, such as duodenal ulcers, gastric ulcers, reflux esophagitis, etc. Since ilaprazole is unstable in an acidic environment, enteric coating is used in the conventional proton pump inhibitor oral tablet core formulation to prevent the active ingredient from being degraded in gastric acid. In order to improve the stability of ilaprazole, a stabilizer is usually added to the plain tablet core, as disclosed in Chinese patent document No. CN 102552190 A, or a pH adjuster is added to the plain tablet core, as disclosed in Chinese patent document No. CN115715808 A, so that the added stabilizer and pH adjuster can effectively prevent the enteric-coated tablet from generating an acidic environment during long-term storage.

[0003] However, in actual applications, conventional production processes, such as tableting or granulation, usually result in the moisture content of the final prepared ilaprazole enteric-coated tablets being greater than 5% due to the high moisture content of the raw materials themselves. In addition, most of the commonly used excipients for ilaprazole enteric-coated tablets are weakly acidic excipients, which causes the weakly acidic excipients to form an acidic environment under high moisture conditions during long-term storage of ilaprazole enteric-coated tablets. That is, the long-term storage stability of ilaprazole enteric-coated tablets is poor, resulting in the degradation of ilaprazole and a significant increase in related substances, which not only reduces the efficacy of ilaprazole, but also seriously affects the safety of ilaprazole. Summary of the invention

[0004] The purpose of the present invention is to overcome the deficiencies in the prior art and to provide a freeze-dried enteric-coated tablet of ilaprazole and a preparation method thereof, which can improve the long-term storage stability of the plain tablet core and accelerate the rapid release of the plain tablet core in the intestine and improve the absorption efficiency of ilaprazole by the intestine.

[0005] The purpose of this disclosure is achieved through the following technical solutions:

[0006] A method for preparing ilaprazole freeze-dried enteric-coated tablets comprises a plain tablet core and a coating layer, wherein the plain tablet core comprises ilaprazole, and further comprises a disintegrant, a lyoprotectant and a pharmaceutical excipient. After freeze-drying, the plain tablet core forms a crisp and porous structure, and the moisture content of the plain tablet core is less than 5%.

[0007] In one embodiment, the moisture content of the plain tablet core is ≤2%.

[0008] In one embodiment, the plain tablet core is freeze-dried at a pressure of 10Pa to 50Pa and a temperature of -35°C to 30°C for 1h to 12h.

[0009] In one embodiment, the particle size of the ilaprazole after micronization is D90≤10 μm; and / or,

[0010] The disintegration time of the plain tablet core is ≤10s; and / or,

[0011] The weight difference of the plain core tablets is 4.7% to 6.1%; and / or,

[0012] The plain tablet core has a uniform appearance, is not shrunk, is not browned, and has no stratification.

[0013] In one embodiment, the lyoprotectant comprises at least one of dextran-70, sucrose, glycerol and polyethylene glycol.

[0014] In one embodiment, the weight of the disintegrant accounts for 5% to 25% of the total weight of the plain tablet core.

[0015] In one embodiment, the disintegrant includes at least one of hydroxypropyl-β-cyclodextrin, maltodextrin and povidone K30.

[0016] In one embodiment, the pharmaceutical excipients include a matrix support agent and a binder.

[0017] In one embodiment, the skeleton support agent includes at least one of glycine, erythritol, maltitol, arginine, mannitol, glucose, sorbitol, lactitol, isomalt, dextran, xylose, sodium chloride, serine, raffinose, maltose, galactose, trehalose, xylitol, dextrin, hydroxypropyl cyclodextrin, sodium phosphate and aluminum silicate; and / or,

[0018] The adhesive comprises at least one of copolyvidone, pregelatinized starch, gelatin and hydrolyzed gelatin; and / or,

[0019] The coating layer includes an isolation coating layer and an enteric coating layer.

[0020] A method for preparing ilaprazole freeze-dried enteric-coated tablets comprises the following steps:

[0021] Disintegrants are formulated into thickening liquids;

[0022] adding ilaprazole to the thickened liquid and stirring and mixing to obtain an ilaprazole thick liquid;

[0023] Mixing a lyophilization protective agent, a pharmaceutical excipient and the ilaprazole thick solution to obtain an ilaprazole matrix solution;

[0024] Degassing the ilaprazole matrix solution;

[0025] The degassed ilaprazole matrix solution is fixed by injection molding to obtain an ilaprazole semi-product;

[0026] Freeze-drying the ilaprazole semi-product to obtain the plain tablet core according to any one of claims 1 to 9;

[0027] The plain tablet core is coated and dried to obtain the ilaprazole freeze-dried enteric-coated tablets according to any one of claims 1 to 9.

[0028] Compared with the prior art, the present invention has at least the following advantages:

[0029] 1) Since the tablet core has a loose and porous structure after freeze-drying, the loose and porous structure not only enables the tablet core to quickly absorb water, but also greatly increases the contact area with the liquid in the intestine. In particular, when used in conjunction with the use of a disintegrant, the tablet core absorbs water and disintegrates at a very fast speed in the intestine to release the drug, which is equivalent to increasing the time that the active ingredients of the drug are in direct contact with the intestine, which can improve the intestinal absorption rate of the drug and enhance the therapeutic effect.

[0030] 2) Since the moisture content of the tablet core after freeze-drying is less than 5%, the moisture content of the tablet core is effectively reduced, thereby effectively preventing the weakly acidic excipients inside the tablet core from forming a slightly acidic environment, thereby improving the long-term storage stability of ilaprazole freeze-dried enteric-coated tablets, and effectively avoiding the growth of related substances during long-term storage, thereby improving the efficacy of ilaprazole and the safety of the drug.

[0031] 3) The added lyoprotectant can effectively prevent the physical damage of ilaprazole molecules, prevent the dehydration damage of ilaprazole molecules, improve the stability of ilaprazole molecules during freeze-drying, and improve the looseness of the plain tablet core to ensure the formation of a loose and porous structure, thereby ensuring the stability and activity of ilaprazole during the freeze-drying process, and providing a strong guarantee for the preparation, storage and use of ilaprazole; in particular, in conjunction with the use of pharmaceutical excipients, the added pharmaceutical excipients can reduce the damage of ice crystals to ilaprazole molecules, interact with ilaprazole molecules to form a stable complex or coating layer to prevent ilaprazole molecules from aggregating during the freeze-drying process, thereby ensuring that ilaprazole molecules can be more evenly dispersed on the plain tablet core, which is conducive to the preparation of a plain tablet core with uniform surface pores, no shrinkage and no scorching. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present disclosure and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0033] Figure 1 The present invention is a flow chart of a method for preparing ilaprazole freeze-dried enteric-coated tablets according to an embodiment of the present invention. DETAILED DESCRIPTION

[0034] In order to facilitate the understanding of the present disclosure, the present disclosure will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present disclosure are given in the drawings. However, the present disclosure can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present disclosure more thoroughly and comprehensively understood.

[0035] It should be noted that when an element is referred to as being "fixed to" another element, it may be directly on the other element or there may be a central element. When an element is considered to be "connected to" another element, it may be directly connected to the other element or there may be a central element at the same time. The terms "vertical", "horizontal", "left", "right" and similar expressions used herein are for illustrative purposes only and do not represent the only implementation method.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present disclosure. The terms used herein in the specification of the present disclosure are only for the purpose of describing specific embodiments and are not intended to limit the present disclosure. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0037] The present invention provides an ilaprazole freeze-dried enteric-coated tablet comprising a plain tablet core and a coating layer, wherein the plain tablet core comprises ilaprazole, and the plain tablet core also comprises a disintegrant, a lyoprotectant and a pharmaceutical excipient. After freeze-drying treatment, the plain tablet core forms a loose porous structure, and the moisture content of the plain tablet core is less than 5%.

[0038] The above-mentioned ilaprazole freeze-dried enteric-coated tablets have a loose porous structure formed in the core of the tablet after freeze-drying. The loose porous structure not only enables the core of the tablet to absorb water quickly, but also greatly increases the contact area with the liquid in the intestine. In particular, when used in conjunction with a disintegrant, the core of the tablet absorbs water and disintegrates at a very fast speed in the intestine to release the drug, which is equivalent to increasing the time for the active ingredients of the drug to be in direct contact with the intestine, which can improve the absorption rate of the drug by the intestine and enhance the efficacy. In addition, since the moisture content of the core of the tablet after freeze-drying is less than 5%, the moisture content of the core of the tablet is effectively reduced, thereby effectively preventing the weakly acidic excipients inside the core of the tablet from forming a slightly acidic environment, thereby improving the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablets, and effectively avoiding the growth of related substances during long-term storage, so as to improve the efficacy of ilaprazole and the safety of the drug.

[0039] In order to better understand the technical solutions and beneficial effects of the present invention, the present invention is further described in detail below in conjunction with specific embodiments.

[0040] The ilaprazole freeze-dried enteric-coated tablets of one embodiment include a plain tablet core and a coating layer, wherein the plain tablet core includes ilaprazole, and the plain tablet core also includes a disintegrant, a lyoprotectant, and a pharmaceutical excipient. After freeze-drying, the plain tablet core forms a loose porous structure, and the moisture content of the plain tablet core is <5%.

[0041] It is understood that since the ilaprazole freeze-dried enteric-coated tablets include a coating layer, the added coating layer can effectively prevent ilaprazole from being degraded in gastric acid, thereby ensuring that most of the ilaprazole can enter the areas of the gastrointestinal tract that are in contact with gastric juice, such as the lesser curvature of the stomach, the pyloric canal, the duodenal bulb, the post-duodenal bulb, and the marginal anastomotic ulcer or jejunal ulcer caused by gastrojejunostomy.

[0042] It can be understood that since the tablet core after freeze-drying has a loose and porous structure, the loose and porous structure not only enables the tablet core to absorb water quickly, but also the loose and porous nature of the tablet core greatly increases the contact area with the liquid in the intestine. In particular, when used in conjunction with a disintegrant, the tablet core absorbs water and disintegrates at a very fast rate in the intestine to release the drug, which is equivalent to increasing the time that the active ingredients of the drug are in direct contact with the intestine, thereby increasing the intestinal absorption rate of the drug and enhancing the efficacy. Furthermore, since the moisture content of the tablet core after freeze-drying is <5%, the moisture content of the tablet core is effectively reduced, thereby effectively preventing the weakly acidic excipients inside the tablet core from forming a slightly acidic environment, thereby improving the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablets, and effectively avoiding the growth of related substances during long-term storage, thereby improving the efficacy of ilaprazole and the safety of the drug.

[0043] It can also be understood that the added lyoprotectant can protect the ilaprazole molecules from being squeezed or damaged by ice crystals during the freeze-drying process, thereby maintaining the integrity of the ilaprazole molecular structure, and thus better ensuring the efficacy of ilaprazole; and the cryoprotectant can interact with the ilaprazole molecules to form a protective layer, reducing the effect of water molecule removal on the interaction force between ilaprazole molecules, thereby preventing dehydration damage; and the cryoprotectant can also ensure the stability of ilaprazole during the freeze-drying process, protecting the ilaprazole molecules from oxidation and hydrolysis, thereby extending the shelf life of the plain tablet core; and the added cryoprotectant can also increase the looseness of the plain tablet core to ensure that a loose and porous structure is formed. In other words, the added lyoprotectant can effectively prevent the ilaprazole molecules from physical damage, prevent the ilaprazole molecules from dehydration damage, improve the stability of the ilaprazole molecules during freeze-drying, and improve the looseness of the plain tablet core to ensure that the plain tablet core forms a loose and porous structure, while ensuring the stability and activity of ilaprazole during the freeze-drying process, providing a strong guarantee for the preparation, storage and use of ilaprazole.

[0044] It can also be understood that the added pharmaceutical excipients can lower the freezing point of the solution and slow down the growth rate of ice crystals, thereby reducing the damage of ice crystals to the ilaprazole molecules; the pharmaceutical excipients can also interact with the ilaprazole molecules to form a stable complex or coating layer to protect the structural stability of the ilaprazole molecules during the freezing and drying process, prevent the ilaprazole molecules from aggregating during the freeze-drying process, thereby ensuring that the ilaprazole molecules can be more evenly dispersed on the plain tablet core, which is conducive to the preparation of a plain tablet core with uniform surface pores, no shrinkage and no browning.

[0045] In a preferred embodiment, the moisture content of the plain tablet core is ≤2%, so as to remove most of the moisture in the raw materials, further preventing the weakly acidic excipients inside the plain tablet core from forming a slightly acidic environment, thereby improving the long-term storage stability of ilaprazole freeze-dried enteric-coated tablets, and effectively avoiding the growth of related substances during long-term storage, thereby improving the efficacy of ilaprazole and the safety of the drug.

[0046] It is understandable that since weakly acidic excipients form an acidic environment under high moisture conditions, most scholars would choose to directly reduce the moisture content of the tablet core to 0%. However, since the moisture content of the raw materials usually includes bound water and free water, the removal of bound water in the raw materials requires extremely harsh conditions to achieve a better removal effect, resulting in a high cost of water removal; and, if the moisture content of the tablet core is too low or there is no moisture, the molecular interaction between ilaprazole and the disintegrant, pharmaceutical excipient, and lyophilization protective agent will be reduced, resulting in the tablet core shrinking, powdering, stratification or crystallization, which is not conducive to the formation of a loose porous structure in the tablet core.

[0047] Therefore, in a more preferred embodiment, the moisture content of the tablet core is 0.5% to 2% to ensure that the moisture content of the tablet core after freeze-drying is more appropriate. On the one hand, the more appropriate moisture content can better maintain the molecular interaction between ilaprazole and the pharmaceutical excipients and lyoprotectants, effectively avoiding the problems of shrinkage, powdering, stratification or crystallization of the tablet core, which is conducive to the formation of a loose porous structure of the tablet core; on the other hand, the appropriate moisture content helps the dissolution and release of the tablet core in the intestine, effectively avoiding the low moisture content of the tablet core causing the tablet core to dissolve more slowly in the intestine, thereby affecting the absorption and onset time of ilaprazole; on the other hand, it also reduces the conditions for freeze-drying dehydration, and a better dehydration effect on the tablet core can be achieved without harsh conditions.

[0048] In one embodiment, the plain tablet core is freeze-dried at a pressure of 10Pa to 50Pa and a temperature of -35°C to 30°C for 1h to 12h.

[0049] It can be understood that if the freeze-drying pressure is less than 10Pa, excessively large gaps will be formed on the surface of the plain core, thereby failing to form a structurally stable, loose, porous structure; if the freeze-drying pressure is greater than 50Pa, the higher pressure will reduce the pressure difference of water vapor from the sublimation interface to the external environment, thereby reducing the escape rate of water vapor to cause the plain core to fail to freeze solid; if the freezing temperature is lower than -35°C or the freeze-drying time is greater than 12h, the energy consumption of freeze-drying is too high, resulting in energy waste; if the freezing temperature is higher than 30°C or the freeze-drying time is less than 1h, the plain core will fail to freeze solid. Therefore, in the present disclosure, the plain core is freeze-dried for 1h to 12h under a pressure of 10Pa to 50Pa and a condition of -35°C to 30°C, so that the plain core after freeze-drying is formed with a loose, porous structure, and the moisture content of the plain core is ≤2%.

[0050] In one embodiment, the step of freeze-drying the plain tablet core for 1 hour to 12 hours under a pressure of 10Pa to 50Pa and a temperature of -35°C to 30°C comprises the following specific steps: first, placing the ilaprazole semi-product in a freezer, and then pre-freezing the ilaprazole semi-product under a pressure-free condition, so that the ilaprazole semi-product is pre-frozen at -35°C to -25°C for 150 minutes to 200 minutes to be formed and fixed, and then heating the ilaprazole semi-product under a pressure of 30Pa to 40Pa and a temperature of -5°C to 8°C. The semi-product of ilaprazole is subjected to a first desorption drying at 30Pa-40Pa and 20°C-30°C for 180min-200min, and finally the semi-product of ilaprazole is subjected to a second desorption drying at no pressure and 20°C-30°C for 40min-80min, so as to obtain a loose porous structure with a moisture content of 0.5%-2%, uniform appearance color, uniform surface pores, smooth surface, no shrinkage, no browning, no stratification, no collapse, and a stable structure.

[0051] It is understandable that if the pre-freezing cooling speed is too slow, large ice crystals will form in the ilaprazole semi-product, which will cause holes of different sizes to appear on the surface of the tablet core in the subsequent sublimation drying process, resulting in a rough surface and uneven porosity of the tablet core; and, when the cooling speed is too slow, it will also cause the surface of the tablet core to crystallize to form flaky crystals, and the flaky crystals are loosely combined with the powder of the tablet core, which not only makes the appearance of the freeze-dried tablet core rougher, but also easily causes the problem of chipping; if the pre-freezing cooling time is too fast, tiny ice crystals will form in the ilaprazole semi-product, and the small ice crystals will form a small number of sublimation channels in series, resulting in a small number of water escape channels during the sublimation drying process, which not only causes the porosity of the loose porous structure to be too low, but also causes the sublimation drying cycle of the ilaprazole semi-product to be extended, thereby affecting the freeze-drying efficiency. Therefore, in one of the embodiments, the cooling rate of the pre-freezing operation is -1°C / min to -2°C / min to ensure that the pre-freezing cooling rate is more appropriate, and to ensure that the ilaprazole semi-product can form ice crystals of uniform size during the pre-freezing cooling process, thereby ensuring that the plain tablet core can form a loose porous structure with stable structure, high porosity, smooth surface, and no chipping, and effectively avoid the problem of flaky crystallization caused by ice crystals of different sizes during the pre-freezing cooling process of the ilaprazole semi-product, and at the same time, avoid the problem of too low porosity of the loose porous structure and prolonged sublimation drying cycle due to too small crystals during the pre-freezing cooling process of the ilaprazole semi-product.

[0052] It can also be understood that if the heating rate of sublimation drying and the first analytical drying is too fast, the ice crystal escape rate will be too fast, resulting in the collapse of the loose porous structure. If the heating rate of sublimation drying and the first analytical drying is too slow, the freeze-drying cycle will be prolonged to affect the freeze-drying efficiency. Therefore, in the present disclosure, by controlling the heating rate of sublimation drying to 0.01°C / min to 1.0°C / min, the heating rate of the first analytical drying to 0.1°C / min to 0.5°C / min, especially in conjunction with the cooling rate of the pre-freezing operation to -1°C / min to -2°C / min, the moisture content of the plain tablet core is quickly prepared, and the loose porous structure formed by the plain tablet core has the characteristics of stable structure, high porosity, smooth surface and no chipping, and the freeze-drying cycle of the plain tablet core is shortened.

[0053] It should be noted that in some medical fields, freeze drying processes are also commonly used, but a single desorption drying operation is usually adopted, such as the freeze-dried flash-release tablets disclosed in Chinese patent document CN 115429764 A, and the pressure of the single desorption is usually 10Pa to 20Pa, resulting in a high content of bound water in the freeze-dried flash-release tablets. If the ilaprazole freeze-dried enteric-coated tablets adopt the traditional single desorption drying operation, the moisture content of the ilaprazole enteric-coated tablets prepared will usually be >5%, which, as mentioned in the background technology, leads to poor long-term storage stability of the ilaprazole enteric-coated tablets. Therefore, in the present disclosure, the ilaprazole semi-product is subjected to a first desorption drying and a second desorption drying, and the pressure of the first desorption drying is increased to 30Pa to 40Pa. In this way, under high pressure and long-term desorption drying, the bound water in the ilaprazole semi-product is more completely removed, the moisture content of the tablet core is low, and the loose porous structure formed by the tablet core has the characteristics of stable structure, high porosity, smooth surface and no chipping, and the freeze-drying cycle of the tablet core is shortened.

[0054] It should also be noted that since the pressure of the first analytical drying is 30Pa to 40Pa, the pressure is doubled compared to the conventional 10Pa to 20Pa, so as to achieve a more comprehensive removal of bound water in the ilaprazole semi-product. However, under high pressure conditions, the loose porous structure of the base frame formed in the ilaprazole semi-product is prone to collapse or chipping during the first analytical drying process. Therefore, in the present disclosure, since the added ilaprazole is a micronized ilaprazole having a particle size of D90≤10 μm, the ilaprazole having a particle size of D90≤10 μm after micronized treatment can be well dispersed in the ilaprazole matrix liquid, thereby improving the stability of the ilaprazole matrix liquid, and effectively avoiding the problem of collapse or chipping of the loose porous structure frame formed in the ilaprazole semi-product under high pressure conditions during the first analytical drying process, so as to ensure that the moisture content of the plain tablet core is 0.5% to 2%, the appearance color is uniform, the surface pores are uniform, the surface is smooth, there is no shrinkage, no browning, no stratification, no collapse, and the structure is stable. The loose porous structure can be quickly prepared under a short freeze-drying cycle and a large analytical drying pressure.

[0055] It should also be noted that when the ilaprazole semi-product enters the second desorption drying, the free water of the ilaprazole semi-product at this time has been basically removed, so that the molecular interaction between the ilaprazole molecules and the disintegrant, the pharmaceutical excipient, and the lyophilization protective agent is relatively weak, and a loose porous structure frame has been initially formed in the plain tablet core. If the second desorption drying is still maintained at a relatively high pressure of 30Pa to 40Pa, it is very easy to cause the loose porous structure frame to collapse and fall off. Therefore, in the present disclosure, the ilaprazole semi-product is subjected to a second desorption drying for 40min to 80min under the condition of no pressure and 20°C to 30°C, so as to obtain a plain tablet core with a moisture content of 0.5% to 2%, a uniform appearance color, uniform surface pores, a smooth surface, no shrinkage, no browning, no stratification, no collapse, and a stable structure of the loose porous structure, and the freeze-drying cycle of the plain tablet core is shortened.

[0056] It should also be noted that since the order of removal of bound water is: lyoprotectant>pharmaceutical excipient>disintegrant>ilaprazole, the added lyoprotectant, pharmaceutical excipient, and disintegrant can protect ilaprazole at the higher pressure and long-term drying temperature of the first desorption and drying, as well as the long-term drying temperature of the second desorption and drying, effectively avoiding the problem of ilaprazole's pharmaceutical ineffectiveness caused by changes in the molecular structure of ilaprazole.

[0057] In one embodiment, the particle size of the ilaprazole after micronization is D90≤10 μm. It is understood that if the API of ilaprazole is not micronized, the prepared ilaprazole matrix solution will have serious sedimentation problems, resulting in large differences in the weight of the plain tablets produced by the same batching tank. Therefore, in the present disclosure, the stability of the ilaprazole matrix solution is improved by micronizing the API of ilaprazole, and the serious sedimentation problem of the ilaprazole matrix solution is effectively avoided.

[0058] It is also understandable that although micronizing the raw material of ilaprazole can solve the serious sedimentation problem of ilaprazole matrix solution to a certain extent, when the particle size of the ilaprazole after micronizing is D90>10 μm, the ilaprazole freeze-dried enteric-coated tablets in actual production are usually mass-produced, so the amount used in the same batching tank is usually large, resulting in the ilaprazole matrix solution in the same batching tank being unable to complete the rapid injection and filling operation in a short period of time, causing the ilaprazole matrix solution to precipitate a small amount at the bottom after a long standing time. Therefore, in the present disclosure, by controlling the particle size of the ilaprazole after micronization treatment to be D90≤10μm, so that D90≤10μm can effectively prevent the ilaprazole matrix solution from settling during a long period of standing, so as to ensure that the ilaprazole matrix solution can remain uniform, stable and free of sedimentation within 3 hours of standing, thereby extending the standing time of the ilaprazole matrix solution prepared in the same batching tank, so as to ensure that the ilaprazole matrix solution can meet the batch injection molding and filling requirements without stirring during a longer standing time, thereby effectively reducing the difference in the weight of the plain tablet cores during the batch production process, so as to ensure that the weight fluctuation range of the plain tablet cores produced in batches is small, thereby ensuring that the active ingredient content of ilaprazole in each ilaprazole freeze-dried enteric-coated tablet is more consistent, which helps to ensure that each patient takes the same dose of the drug, so as to ensure that the absorption and metabolism process of the ilaprazole freeze-dried enteric-coated tablets in the patient's body is more stable, thereby improving the therapeutic effect and reducing the problem of unstable efficacy caused by large dosage fluctuations.

[0059] Furthermore, when the particle size of the ilaprazole after micronization is D90≤10 μm, the weight difference of the raw tablets produced in batches is controlled to be 4.7% to 6.1%, thereby better reducing the fluctuation of the weight difference of the raw tablets in the batch production process.

[0060] It can also be understood that since the particle size of the ilaprazole after the micronization treatment is D90≤10μm, the ilaprazole after the micronization treatment can be better dispersed in the ilaprazole matrix liquid, thereby improving the stability of the ilaprazole matrix liquid, so as to ensure that the ilaprazole semi-product can be quickly prepared under a shorter freeze-drying cycle and a larger analytical drying pressure to obtain a loose porous structure with a moisture content of 0.5% to 2% of the plain tablet core, uniform appearance color, uniform surface pores, smooth surface, no shrinkage, no browning, no stratification, no collapse, and a stable structure.

[0061] It can also be understood that since the particle size of ilaprazole after micronization is D90≤10 μm, it is beneficial for the ilaprazole freeze-dried enteric-coated tablets to quickly disintegrate in the intestine to form a finer powder, further increasing the contact area between ilaprazole and the intestine, further increasing the time of direct contact between the active ingredients of the drug and the intestine, and better improving the intestinal absorption rate of the drug, so as to better enhance the efficacy.

[0062] It can also be understood that since the particle size of ilaprazole after micronization is D90≤10 μm, the particle size is relatively small, so as to ensure that the number of ilaprazole with a smaller particle size is larger under the same unit volume, thereby increasing the distribution points of ilaprazole in the ilaprazole semi-product, so that after freeze-drying, most of the bound water in the lyoprotectant, pharmaceutical excipients, and disintegrants has been removed and pores have been formed, and the ilaprazole without bound water can form more connection points with the lyoprotectant, pharmaceutical excipients, and disintegrants from which most of the bound water has been removed, thereby ensuring that the ilaprazole semi-product after freeze-drying can form a loose porous structure with stable structure, uniform pores, and no falling of crumbs. , thereby better ensuring that the bottom of the plain tablet core does not fall off during the shaking process; and, the smaller particle size of ilaprazole increases the specific surface area of ​​the ilaprazole semi-product, which is conducive to better heat entering the interior of the ilaprazole semi-product, thereby improving the heat exchange rate between the ilaprazole semi-product and the external environment, so that the water inside the ilaprazole semi-product can quickly and evenly form ice crystals of relatively uniform size, and the relatively uniform size of ice crystals can quickly, evenly and stably complete the sublimation of ice crystals in the subsequent sublimation drying operation, so as to quickly form a loose porous structure with stable structure, uniform pores, high porosity, smooth surface and no falling debris inside the ilaprazole semi-product. Further, the smaller particle size of ilaprazole itself has a smaller volume, that is, the blocking surface formed in the loose porous structure is smaller, so that the heat of the first analytical drying and the second analytical drying can better enter the interior of the ilaprazole semi-product, so as to achieve a more comprehensive removal of the bound water inside the lyophilization protectant, pharmaceutical excipients and disintegrant in the ilaprazole semi-product, and is conducive to shortening the lyophilization cycle of the ilaprazole semi-product.

[0063] In one embodiment, the step of micronizing is: micronizing the ilaprazole powder to a particle size D90 ≤ 10 μm. Specifically, the ilaprazole API is subjected to air flow milling and sieving to obtain ilaprazole micronized powder with a particle size D90 ≤ 10 μm; the conditions of air flow milling are: a feed pressure of 7 bar, a milling pressure of 6 bar, and a feed speed of 5 rpm, so as to obtain a particle size D90 of 7.36 μm to 7.95 μm.

[0064] In one embodiment, the lyoprotectant includes at least one of dextran-70, sucrose, glycerol and polyethylene glycol. Furthermore, the lyoprotectant is dextran-70, which can significantly improve the mechanical strength of the ilaprazole freeze-dried enteric-coated tablets, making the ilaprazole freeze-dried enteric-coated tablets less likely to break during the freeze-drying process.

[0065] It is understood that if the weight of the disintegrant accounts for less than 40% of the total weight of the plain tablet core, the thickening effect cannot be achieved and a uniform and stable ilaprazole matrix liquid cannot be prepared; if the weight of the disintegrant accounts for more than 55% of the total weight of the plain tablet core, the ilaprazole matrix liquid has too high a viscosity and cannot be filled in continuous batch production. Therefore, in one embodiment, the weight of the disintegrant accounts for 5% to 25% of the total weight of the plain tablet core to ensure that the content of the disintegrant in the plain tablet core is more appropriate, thereby ensuring that a uniform and stable ilaprazole matrix liquid with appropriate viscosity and no sediment is prepared, which is not only conducive to the subsequent preparation of the plain tablet core with a lower moisture content, but also makes the loose porous structure formed by the plain tablet core have the characteristics of stable structure, high porosity, smooth surface and no debris, and better meets the filling requirements of continuous batch production.

[0066] In one embodiment, the disintegrant comprises at least one of hydroxypropyl-β-cyclodextrin, maltodextrin and povidone K30.

[0067] Furthermore, in a preferred embodiment, the disintegrant is hydroxypropyl-β-cyclodextrin (HP-β-CD). It is understood that since hydroxypropyl-β-cyclodextrin has good disintegration performance and can reduce ice-water interfacial tension during the freeze-drying process, reduce freezing and dehydration denaturation, and thus protect the active ingredients of ilaprazole freeze-dried enteric-coated tablets from damage.

[0068] In one embodiment, the pharmaceutical excipients include a skeleton support agent and a binder to ensure that the added skeleton support agent and binder can provide better structural support for the tablet core, thereby ensuring that the tablet core can form a crisp and porous structure after freeze-drying, thereby increasing the disintegration rate of the tablet core.

[0069] In one embodiment, the skeleton support agent includes at least one of glycine, erythritol, maltitol, arginine, mannitol, glucose, sorbitol, lactitol, isomalt, dextran, xylose, sodium chloride, serine, raffinose, maltose, galactose, trehalose, xylitol, dextrin, hydroxypropyl cyclodextrin, sodium phosphate and aluminum silicate.

[0070] In a preferred embodiment, the skeleton support agent is mannitol. It is understood that mannitol is a commonly used skeleton support agent, and its presence during the freeze-drying process helps to regulate the internal and external water migration of the ilaprazole semi-product, promotes uniform water removal, and avoids uneven freeze-drying.

[0071] In a preferred embodiment, the binder includes at least one of copovidone, pregelatinized starch, gelatin and hydrolyzed gelatin. Further, in a preferred embodiment, the binder is copovidone. Since copovidone has excellent adhesiveness and high surface activity, it can be stably combined with the skeleton support agent, disintegrant, ilaprazole and lyophilization protective agent during the freeze-drying process, which helps to form a structurally stable loose porous structure; it can also promote the absorption of ilaprazole freeze-dried enteric-coated tablets in the body.

[0072] In one embodiment, based on the total weight of the plain tablet core, ilaprazole is 11% to 14%, hydroxypropyl-β-cyclodextrin (HP-β-CD) is 5% to 20%, and dextran-70 is 20% to 70%; copovidone is 10% to 15%, and mannitol is 15% to 25%, so as to ensure that the plain tablet core after freeze-drying forms a crisp porous structure, and the moisture content of the plain tablet core is ≤2%, and the disintegration time of the plain tablet core is ≤10s; the weight difference of the plain tablet core is 4.7% to 6.1%, and the appearance of the plain tablet core is uniform, the pores are uniform, there is no shrinkage, no browning, and no stratification.

[0073] In one embodiment, the coating layer includes an isolation coating layer and an enteric coating layer. Specifically, the isolation coating layer is prepared by dissolving a gastric film coating premix in 95% ethanol, and the enteric coating layer is prepared by dissolving an enteric film coating premix in 95% ethanol.

[0074] The present disclosure also provides a method for preparing ilaprazole freeze-dried enteric-coated tablets, comprising the following steps: preparing a disintegrant into a thickening liquid; adding ilaprazole, a lyoprotectant, and a pharmaceutical excipient to the thickening liquid to obtain an ilaprazole matrix liquid; degassing the ilaprazole matrix liquid; injection molding and fixing the degassed ilaprazole matrix liquid to obtain an ilaprazole semi-product; freeze-drying the ilaprazole semi-product to obtain a plain tablet core as described in any of the above embodiments; coating and drying the plain tablet core to obtain the ilaprazole freeze-dried enteric-coated tablets as described in any of the above embodiments.

[0075] The preparation method of the above-mentioned ilaprazole freeze-dried enteric-coated tablets comprises freeze-drying the ilaprazole semi-product so that the freeze-dried raw tablet core forms a loose porous structure with a stable structure, no collapse, and no falling crumbs, and ensures that the obtained raw tablet core has a low moisture content, uniform appearance color, uniform surface pores, a smooth surface, no shrinkage, no browning, and no stratification, which not only improves the disintegration speed of the raw tablet core, thereby improving the intestinal absorption rate of the drug, but also improves the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablets, thereby improving the efficacy of ilaprazole and the safety of the drug.

[0076] See also Figure 1 In order to better understand the technical solutions and beneficial effects of the present disclosure, the present disclosure is further described in detail below in conjunction with specific embodiments. The preparation method of ilaprazole freeze-dried enteric-coated tablets in one embodiment includes some or all of the following steps:

[0077] S101. Prepare a disintegrant into a thickening liquid.

[0078] It can be understood that hydroxypropyl-β-cyclodextrin (HP-β-CD) and purified water are weighed according to the formula, and hydroxypropyl-β-cyclodextrin (HP-β-CD) is dissolved in purified water to prepare a thickening solution for use.

[0079] Specifically, the formula of the plain tablet core is: based on the total weight of the plain tablet core, ilaprazole is 11% to 14%, hydroxypropyl-β-cyclodextrin (HP-β-CD) is 5% to 25%, dextran-70 is 20% to 70%; copovidone is 10% to 15%, and mannitol is 15% to 25% for weighing and preparation.

[0080] S102, adding ilaprazole to the thickened solution and stirring to obtain an ilaprazole thick solution.

[0081] In one embodiment, a cantilever stirrer is used to stir the ilaprazole viscous solution, and the stirring speed is controlled to be 1000 rpm to 1500 rpm, and the stirring time is 10 min to 20 min. In particular, the particle size D90 of the ilaprazole after micronization treatment is ≤10 μm, so as to ensure a uniform and stable ilaprazole viscous solution, which is conducive to the subsequent addition of lyophilization protectants and pharmaceutical excipients to be well dispersed in the ilaprazole viscous solution, thereby ensuring the preparation of a uniform and stable ilaprazole matrix solution.

[0082] S103, mixing the lyophilization protective agent, the pharmaceutical excipient and the ilaprazole thick solution to prepare a uniform and stable ilaprazole matrix solution.

[0083] In one embodiment, the ilaprazole matrix solution is continuously stirred using a cantilever stirrer, and the stirring speed is controlled to be 1000 rpm to 1500 rpm, and the stirring time is 10 min to 20 min, so that the lyoprotectant and the pharmaceutical excipient can be fully mixed with the ilaprazole viscous solution to ensure that a uniform and stable ilaprazole matrix solution is prepared.

[0084] S104, degassing the ilaprazole matrix solution to effectively remove bubbles in the ilaprazole matrix solution, thereby effectively avoiding the problem that the ilaprazole semi-product is doped with a large number of bubbles, resulting in uneven pores and easy collapse of the final prepared plain tablet core.

[0085] In one embodiment, a vacuum emulsifier is used to emulsify, shear and stir the ilaprazole matrix liquid, and deaerate until there are no obvious bubbles visible to the naked eye, so as to ensure that a uniform, stable ilaprazole matrix liquid with fewer bubbles and no sediment is prepared, so as to provide a strong guarantee for the final preparation of a plain tablet core with a stable structure, uniform porosity, smooth surface, no shrinkage, no browning, and no stratification.

[0086] Furthermore, the conditions of the vacuum emulsifier are as follows: the speed of the emulsifier is 2000rpm to 3000rpm, the emulsification time is 5min to 10min, and the degassing time is 5min to 10min, so as to ensure that a uniform and stable ilaprazole matrix liquid with a small particle size, no obvious bubbles visible to the naked eye and no sediment is prepared, which is conducive to the preparation of a loose porous structure with stable structure, uniform porosity, smooth surface, no chipping, no stratification, and no browning.

[0087] S105, performing injection molding to fix the degassed ilaprazole matrix solution to obtain an ilaprazole semi-product, so as to prepare a dosage form required for production.

[0088] It can be understood that, since the ilaprazole matrix liquid has good stability after the degassing operation, and the use of ilaprazole with a particle size D90 ≤ 10 μm is used to ensure that the prepared ilaprazole matrix liquid will not have the problem of sedimentation at the bottom during a long standing time, the standing time of the ilaprazole matrix liquid prepared in the same batching tank is effectively extended to ensure that the ilaprazole matrix liquid can still meet the batch injection molding filling requirements during a long standing time, thereby effectively reducing the difference in the weight of the plain tablet cores during the batch production process to ensure that the weight fluctuation range of the plain tablet cores produced in batches is small, thereby ensuring that the active ingredient content of ilaprazole in each ilaprazole freeze-dried enteric-coated tablet is more consistent, so as to ensure that the absorption and metabolism process of the ilaprazole freeze-dried enteric-coated tablets in the patient's body is more stable, thereby improving the therapeutic effect and reducing the problem of unstable efficacy caused by large dosage fluctuations. Further, the ilaprazole matrix liquid will not have the problem of sedimentation at the bottom during the standing time of 3 hours.

[0089] S106. Freeze-drying the ilaprazole semi-product to obtain the plain tablet core described in any of the above embodiments, so that after freeze-drying, the ilaprazole semi-product can not only effectively remove moisture from the ilaprazole semi-product, but also form a loose porous structure in the ilaprazole semi-product, thereby improving the long-term storage stability of the plain tablet core and effectively avoiding the growth of related substances during long-term storage, thereby improving the efficacy and safety of the ilaprazole; and accelerating the rapid release of the plain tablet core in the intestine, thereby improving the intestinal absorption efficiency of ilaprazole and enhancing the efficacy of the drug.

[0090] In a preferred embodiment, freeze-drying the ilaprazole semi-product comprises the following specific steps: first, pre-freezing the ilaprazole semi-product under pressure-free conditions, so that the ilaprazole semi-product is pre-frozen at -35°C to -25°C for 150min to 200min to be formed and fixed; then, sublimation drying the ilaprazole semi-product under the conditions of 30Pa to 40Pa and -5°C to 8°C for 100min to 150min; then, performing a first desorption drying of the ilaprazole semi-product at 30Pa to 40Pa and 20°C to 30°C for 180min to 200min; finally, performing a second desorption drying of the ilaprazole semi-product under pressure-free conditions and 20°C to 30°C for 40min to 80min, so as to obtain a core tablet having a low moisture content, uniform appearance color, uniform surface pores, a smooth surface, no shrinkage, no browning, no stratification, no collapse, a stable structure, and a crisp porous structure with a high porosity.

[0091] S107, coating and drying the plain tablet core to obtain the ilaprazole freeze-dried enteric-coated tablets described in any of the above embodiments, and forming a coating layer on the surface of the plain tablet core, thereby achieving better protection for the plain tablet core.

[0092] In one embodiment, the coating drying includes isolation coating drying and enteric coating drying. Specifically, the gastric film coating premix is ​​dissolved in 95% ethanol to prepare an isolation coating solution, and then the plain tablet core is spray-dried to coat the surface of the plain tablet core to form an isolation coating layer, and then the enteric film coating premix is ​​dissolved in 95% ethanol to prepare an enteric coating solution, and then the plain tablet core is spray-dried to coat the surface of the isolation coating layer to form an enteric coating layer, so as to prepare ilaprazole freeze-dried enteric-coated tablets.

[0093] In one embodiment, the relative humidity of the environment is ≤30% RH when the tablet cores are spray-dried with the isolation coating liquid, so as to avoid the problem that the treated low-moisture-content tablet cores absorb water due to the high humidity of the environment during the spray drying of the isolation coating liquid, thereby causing the moisture content of the tablet cores to increase.

[0094] The preparation method of the above-mentioned ilaprazole freeze-dried enteric-coated tablets comprises freeze-drying the ilaprazole semi-product so that the freeze-dried raw tablet core forms a loose porous structure with a stable structure, no collapse, and no falling crumbs, and ensures that the obtained raw tablet core has a low moisture content, uniform appearance color, uniform surface pores, a smooth surface, no shrinkage, no browning, and no stratification, which not only improves the disintegration speed of the raw tablet core, thereby improving the intestinal absorption rate of the drug, but also improves the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablets, thereby improving the efficacy of ilaprazole and the safety of the drug.

[0095] Some specific examples are given below, and if % is mentioned, it means percentage by weight. It should be noted that the following examples do not exhaust all possible situations, and the materials used in the following examples can be obtained from commercial sources unless otherwise specified.

[0096] Example 1

[0097] (1) Weigh 20 kg of HP-β-CD and 800 kg of purified water (800 kg of water per tablet) and place them in a container to prepare a thickening solution.

[0098] (2) 5 kg of micronized ilaprazole (D90: 7.36 μm) was added to the thickened liquid and stirred with a cantilever stirrer at a speed of 1500 rpm for 20 min to obtain an ilaprazole thick liquid; wherein the ilaprazole raw material was jet milled with a feed pressure of 7 bar, a grinding pressure of 6 bar, and a feed speed of 5 rpm.

[0099] (3) 40 kg of dextran, 5 kg of copovidone and 10 kg of mannitol were added to the ilaprazole thick solution of step (2), and the mixture was stirred at a speed of 1500 rpm for 20 min to obtain an ilaprazole matrix solution.

[0100] (4) The ilaprazole matrix solution obtained in step (3) was emulsified and sheared in a vacuum emulsifier at a speed of 2500 rpm for 10 min, and degassed until there were no obvious bubbles.

[0101] (5) The stirring speed of the vacuum emulsifier was reduced to 1000 rpm, and then 1.2 ml of the ilaprazole matrix solution in step (4) was pipetted into the blister to obtain the ilaprazole semi-product.

[0102] (6) The blister ilaprazole semi-product obtained by pouring in step (5) is placed in a freezer, and then, under pressureless conditions, the temperature is lowered to -35°C at a rate of -1°C / min for pre-cooling for 180 minutes to form and fix, and then, under a maximum pressure of 40 Pa, the temperature is raised to 5°C at a rate of 0.5°C / min for sublimation drying for 120 minutes; then, the temperature is raised to 30°C at a pressure of 30 Pa and a rate of 0.1°C / min for the first desorption drying for 180 minutes, and finally, the ilaprazole semi-product is subjected to a second desorption drying for 60 minutes under pressureless conditions at a temperature of 30°C to obtain a plain tablet core.

[0103] (7) The gastric soluble film coating premix is ​​dissolved in 95% ethanol to obtain an isolation coating solution, and then the plain tablet core is spray-dried to form an isolation coating layer on the surface of the plain tablet core, wherein the relative humidity of the environment during the spray drying of the isolation coating solution is controlled to be ≤30% RH.

[0104] (8) dissolving the enteric film coating premix in 95% ethanol to obtain an enteric coating solution, and spray-drying the plain tablet cores in step (7) to obtain ilaprazole freeze-dried enteric-coated tablets.

[0105] The difference between Comparative Examples 1 to 4 and Example 1 is that the freeze-drying conditions in step (6) are different, and the rest remain unchanged. For details, please refer to the freeze-drying condition comparison table in Table 1 below.

[0106] Table 1

[0107]

[0108]

[0109] The plain tablet cores prepared in Comparative Examples 1 to 4 and Example 1 were tested for moisture, appearance, disintegration time, and freeze-drying cycle to obtain the experimental data in Table 2:

[0110] Among them, moisture: use a moisture detector for detection.

[0111] Appearance: Visual inspection under strong light.

[0112] Disintegration time: Determined according to the disintegration time determination method (General Chapter 0921 of the "Chinese Pharmacopoeia 2020 Edition").

[0113] Freeze-drying cycle: Use a stopwatch to record the time used for the entire freeze-drying process.

[0114] Table 2

[0115]

[0116]

[0117] As can be seen from Table 2, since Example 1 uses a first high-pressure desorption drying and a second non-pressure desorption drying in combination, it ensures that the ilaprazole semi-product can be quickly prepared in a short freeze-drying cycle to obtain a loose porous structure with stable structure, uniform pores, high porosity, smooth surface and no chipping, and the moisture content of the plain tablet core is as low as 0.8%, the appearance color is uniform, the surface pores are uniform, the surface is smooth, there is no shrinkage, no browning and no stratification, so that the comprehensive indicators of Example 1 are significantly better than those of Comparative Examples 1 to 4.

[0118] The difference between Comparative Examples 5 and 6 and Example 1 is that the particle sizes of ilaprazole in step (2) are different, and the rest remain unchanged. For details, please refer to the particle size comparison table of ilaprazole in Table 3 below.

[0119] Table 3

[0120]

[0121] As can be seen from Table 3, since the particle size of ilaprazole used in Example 1 reaches D90≤10 μm, the ilaprazole matrix solution prepared in Example 1 has good solution stability, and the weight fluctuation range of the blank tablets produced in continuous batches is small, and the blank tablets do not fall off at the bottom during the shaking process, so that the comprehensive indicators of Example 1 are significantly better than those of Comparative Examples 5 to 6.

[0122] The difference between Comparative Examples 7 to 8 and Example 1 is that the type of disintegrant (HP-β-CD) in step (1) of Example 1 is different, and the rest remains unchanged. For details, please refer to the comparison table of disintegrant types used in Comparative Examples 7 to 8 and Example 1 in Table 4 below.

[0123] Table 4

[0124]

[0125] The dispersion, sedimentation, filling and disintegration time of the plain tablet cores prepared in Comparative Examples 7 and 8 and Example 1 were tested to obtain the experimental data in Table 5 below.

[0126] Table 5

[0127]

[0128] From the comparison in Table 5, it can be seen that the comprehensive indicators of the plain tablet core prepared by Example 1 using HP-β-CD as a disintegrant are significantly better than those of Comparative Examples 7 and 8.

[0129] The difference between Comparative Examples 9 to 10 and Example 1 is that the type of adhesive (copolyvidone) in step (3) of Example 1 is different, and the rest remains unchanged. For details, please refer to the comparison table of adhesive types used in Comparative Examples 9, 10 and Example 1 in Table 6 below.

[0130] Table 6

[0131] Material Name Example 1 Comparative Example 9 Comparative Example 10 Ilaprazole 5kg 5kg 5kg Mannitol 10kg 10kg 10kg Copolyvidone 5kg / / Ethyl cellulose / 12kg / Sodium alginate / / 16kg HP-β-CD 20kg 20kg 20kg Dextran-70 40kg 40kg 40kg

[0132] The dispersion, sedimentation, filling and disintegration time of the plain tablet cores prepared in Comparative Examples 9 and 10 and Example 1 were tested to obtain the experimental data shown in Table 7 below.

[0133] Table 7

[0134]

[0135] From the comparison in Table 7, it can be seen that the comprehensive indicators of the plain tablet core prepared by using copolyvidone as the binder in Example 1 are significantly better than those in Comparative Examples 9 and 10.

[0136] Comparative Example 11

[0137] Comparative Example 11 is the commercially available "Yilian", which is prepared by a powder direct compression process.

[0138] The release of the ilaprazole freeze-dried enteric-coated tablets of Example 1 and Comparative Example 11 was studied to obtain the experimental data in Table 8 below;

[0139] Among them, the release determination method: according to the release determination method (Chinese Pharmacopoeia 2020 Edition Part Four General Rules 0931 Enteric-coated Preparations Method 2), 900ml of 0.1mol / L hydrochloric acid solution is used as the release medium, and the rotation speed is 50 rpm. Operate in accordance with the law. After 120 minutes, take 10ml of the solution, filter it, take the filtrate as the test sample, measure, calculate the release amount, and it shall not exceed 10% of the labeled amount. Observe whether the tablet changes color. Add 250ml of 0.2mol / L sodium phosphate solution at a temperature of 37℃±0.5℃ to the above acid solution, continue to operate for 20 minutes, take 10ml of the solution, filter it, take the filtrate as the test solution, and measure it.

[0140] Table 8

[0141]

[0142] It can be seen from the data in Table 8 that the release rate of the ilaprazole freeze-dried enteric-coated tablets of Example 1 in the buffer solution is significantly higher than that of Comparative Example 11, indicating that the ilaprazole freeze-dried enteric-coated tablets of Example 1 can be quickly released in the intestine.

[0143] The influencing factors and accelerated experimental conditions were performed on the ilaprazole freeze-dried enteric-coated tablets of Example 1 and Comparative Examples 4, 6, 7, 8, 10 and 11. For the influencing factors and accelerated experimental conditions, please refer to Table 9, and the experimental data in Table 10 were obtained.

[0144] Table 9

[0145]

[0146] Table 10

[0147]

[0148]

[0149] From the data in Table 10, it can be seen that the growth rate of related substances in the ilaprazole freeze-dried enteric-coated tablets prepared in Example 1 is significantly better than that in Comparative Example 11 under the influencing factors and accelerated experimental process, which proves that the ilaprazole freeze-dried enteric-coated tablets prepared in Example 1 have good long-term storage stability.

[0150] The above-mentioned embodiments only express several implementation methods of the present disclosure, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the disclosed patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present disclosure, and these all belong to the protection scope of the present disclosure. Therefore, the protection scope of the disclosed patent shall be subject to the attached claims.

Claims

1. A freeze-dried enteric-coated tablet of ilaprazole, comprising a plain tablet core and a coating layer, wherein the plain tablet core comprises ilaprazole, characterized in that: The plain tablet core also includes a disintegrant, a freeze-drying protective agent and a pharmaceutical excipient. After freeze-drying, the plain tablet core forms a crisp and porous structure, and the moisture content of the plain tablet core is less than 5%.

2. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The moisture content of the plain tablet core is ≤2%.

3. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The plain tablet core is freeze-dried at a pressure of 10Pa to 50Pa and a temperature of -35°C to 30°C for 1h to 12h.

4. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The particle size of the ilaprazole after micronization is D90≤10 μm; and / or, The disintegration time of the plain tablet core is ≤10s; and / or, The weight difference of the plain core tablets is 4.7% to 6.1%; and / or, The plain tablet core has a uniform appearance, is not shrunk, is not browned, and has no stratification.

5. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The lyoprotectant comprises at least one of dextran-70, sucrose, glycerol and polyethylene glycol.

6. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The weight of the disintegrant accounts for 5% to 25% of the total weight of the plain tablet core.

7. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The disintegrant includes at least one of hydroxypropyl-β-cyclodextrin, maltodextrin and povidone K30.

8. The ilaprazole freeze-dried enteric-coated tablets according to claim 1, characterized in that: The pharmaceutical excipients include a skeleton support and a binder.

9. The ilaprazole freeze-dried enteric-coated tablets according to claim 8, characterized in that: The skeleton support agent includes at least one of glycine, erythritol, maltitol, arginine, mannitol, glucose, sorbitol, lactitol, isomalt, dextran, xylose, sodium chloride, serine, raffinose, maltose, galactose, trehalose, xylitol, dextrin, hydroxypropyl cyclodextrin, sodium phosphate and aluminum silicate; and / or, The adhesive comprises at least one of copolyvidone, pregelatinized starch, gelatin and hydrolyzed gelatin; and / or, The coating layer includes an isolation coating layer and an enteric coating layer.

10. A method for preparing ilaprazole freeze-dried enteric-coated tablets, characterized in that: The steps include: Disintegrants are formulated into thickening liquids; adding ilaprazole to the thickened liquid and stirring and mixing to obtain an ilaprazole thick liquid; Mixing a lyophilization protective agent, a pharmaceutical excipient and the ilaprazole thick solution to obtain an ilaprazole matrix solution; Degassing the ilaprazole matrix solution; The degassed ilaprazole matrix solution is fixed by injection molding to obtain an ilaprazole semi-product; Freeze-drying the ilaprazole semi-product to obtain the plain tablet core according to any one of claims 1 to 9; The plain tablet core is coated and dried to obtain the ilaprazole freeze-dried enteric-coated tablets according to any one of claims 1 to 9.

Images