Esomeprazole lyophilized enteric-coated tablet and preparation method thereof

Abstract

The present disclosure provides a kind of ilaprazole freeze-dried enteric-coated tablets and its preparation method.The above-mentioned ilaprazole freeze-dried enteric-coated tablets include tablet core and coating layer, tablet core includes ilaprazole, tablet core also includes disintegrating agent, freeze-drying protective agent and pharmaceutical excipient, the tablet core after freeze-drying treatment is formed with loose porous structure, and the moisture content of tablet core is <5%.The above-mentioned ilaprazole freeze-dried enteric-coated tablets, since the tablet core after freeze-drying treatment is formed with loose porous structure, and the moisture content of tablet core is <5%, both can improve the long-term storage stability of tablet core, effectively avoid the increase of related substances in long-term storage process, to improve the efficacy of ilaprazole and the safety of drug;It can also speed up the rapid release of tablet core in the intestine, improve the absorption efficiency of ilaprazole in the intestine, to enhance the curative effect of drug.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the technical field of enteric-coated tablets containing proton pump inhibitors, in particular to an ilaprazole lyophilized enteric-coated tablet and a preparation method thereof. BACKGROUND

[0002] Ilaprazole is a new generation of proton pump inhibitor, which is widely used in various acid-related digestive diseases, such as duodenal ulcer, gastric ulcer, reflux esophagitis, etc. Since ilaprazole is unstable in an acidic environment, the enteric-coated method is usually used in the prescription of the tablet core of the common proton pump inhibitor oral preparation to prevent the degradation of the active ingredient in the stomach acid. In order to improve the stability of ilaprazole, a stabilizer is usually added to the tablet core, as disclosed in Chinese Patent Document No. CN 102552190 A, or a pH adjuster is added to the tablet core, as disclosed in Chinese Patent Document No. CN 115715808 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 application, the conventional production process, such as tabletting or granulation, due to the high moisture content of the raw materials, the moisture content of the ilaprazole enteric-coated tablets prepared finally is usually > 5%, and most of the common excipients of ilaprazole enteric-coated tablets are weakly acidic excipients, which causes the weakly acidic excipients to form an acidic environment under the condition of high moisture during the long-term storage of ilaprazole enteric-coated tablets, i.e. the long-term storage stability of ilaprazole enteric-coated tablets is poor, which leads to the degradation of ilaprazole and the obvious increase of related substances, not only reducing the efficacy of ilaprazole, but also seriously affecting the safety of ilaprazole drugs. SUMMARY

[0004] The purpose of the present disclosure is to overcome the deficiencies in the prior art, and to provide an ilaprazole lyophilized enteric-coated tablet and a preparation method thereof, which can not only improve the long-term storage stability of the tablet core, but also accelerate the rapid release of the tablet core in the intestinal tract and improve the absorption efficiency of ilaprazole in the intestinal tract.

[0005] The purpose of the present disclosure is achieved by the following technical solutions:

[0006] A preparation method of an ilaprazole lyophilized enteric-coated tablet, comprising a tablet core and a coating layer, the tablet core comprising ilaprazole, the tablet core further comprising a disintegrant, a lyophilization protective agent and a pharmaceutical excipient, the tablet core after freeze-drying treatment forms a loose porous structure, and the moisture content of the tablet core is < 5%.

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

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

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

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

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

[0012] The tablet core has a uniform appearance, no shrinkage, no yellowing, and no delamination.

[0013] In one of the embodiments, the freeze-drying protective agent includes at least one of dextran-70, sucrose, glycerol, and polyethylene glycol.

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

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

[0016] In one of the embodiments, the pharmaceutical excipient includes a skeleton support agent and a binder.

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

[0018] The binder includes at least one of copovidone, pregelatinized starch, gelatin, and hydrolyzed gelatin; and / or,

[0019] The coating layer includes a separation coating layer and an enteric coating layer.

[0020] A preparation method of an ilaprazole freeze-dried enteric tablet includes the following steps:

[0021] The disintegrant is prepared into a thickening liquid;

[0022] The ilaprazole is added to the thickening liquid for stirring and mixing to obtain an ilaprazole thick liquid;

[0023] The freeze-drying protective agent, the pharmaceutical excipient, and the ilaprazole thick liquid are mixed to obtain an ilaprazole matrix liquid;

[0024] degassing operation is performed on the ilaprazole base solution;

[0025] molding fixing is performed on the ilaprazole base solution after the degassing operation, to obtain an ilaprazole semi-product;

[0026] freeze-drying is performed on the ilaprazole semi-product, to obtain the tablet core according to any one of claims 1-9;

[0027] coating drying is performed on the tablet core, to obtain the ilaprazole freeze-dried enteric-coated tablet according to any one of claims 1-9.

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

[0029] 1) Since the tablet core after freeze-drying treatment forms a loose porous structure, the loose porous structure not only enables the tablet core to quickly absorb water, but also greatly increases the contact area with the liquid in the intestinal tract, especially in combination with the use of disintegrating agents, so that the tablet core absorbs water and disintegrates at a very fast speed in the intestinal tract, releases the drug, which is equivalent to increasing the time of direct contact between the active ingredients of the drug and the intestinal tract, thereby improving the absorption rate of the intestinal tract to the drug and enhancing the therapeutic effect.

[0030] 2) Since the moisture content of the tablet core after freeze-drying treatment is <5%, the water 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, and further improving the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablet, effectively avoiding the increase of related substances during long-term storage, thereby improving the efficacy of ilaprazole and the safety of the drug.

[0031] 3) The freeze-drying protectant added can effectively prevent physical damage to ilaprazole molecules, prevent dehydration damage to ilaprazole molecules, improve the stability of ilaprazole molecules in freeze-drying, improve the looseness of the tablet core to ensure the formation of a loose porous structure, ensure the stability and activity of ilaprazole during freeze-drying, and provide a strong guarantee for the preparation, storage and use of ilaprazole; especially in combination 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 stable complexes or wrapping layers, to prevent ilaprazole molecules from aggregating during freeze-drying, thereby ensuring that ilaprazole molecules can be evenly dispersed on the tablet core, which is conducive to the preparation of a tablet core with uniform surface pores, no atrophy and no yellowing. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure, the following will briefly introduce the drawings needed to be used in the embodiments. It should be understood that the following drawings only show some of the embodiments of the present disclosure, and therefore should not be considered as a limitation to the scope. For those skilled in the art, other related drawings can also be obtained without creative labor.

[0033] Figure 1 The flow chart of the preparation method of the ilaprazole lyophilized enteric-coated tablet according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0034] In order to facilitate the understanding of the present disclosure, the following will make a more comprehensive description of the present disclosure with reference to the related drawings. The preferred embodiments of the present disclosure are shown 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 thorough and comprehensive.

[0035] It should be noted that when an element is referred to as being "fixed" to another element, it can be directly on the other element or there can be an intervening element. When an element is referred to as being "connected" to another element, it can be directly connected to the other element or there can be an intervening element. The terms "vertical", "horizontal", "left", "right", and similar expressions used herein are for illustrative purposes only and are not intended to be limiting.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. The terminology used in the description of the present disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0037] The present disclosure provides an ilaprazole lyophilized enteric-coated tablet, which comprises a tablet core and a coating layer. The tablet core comprises ilaprazole, a disintegrant, a lyophilization protective agent and a pharmaceutical excipient. The tablet core has a porous structure after lyophilization, and the moisture content of the tablet core is less than 5%.

[0038] The above-mentioned ilaprazole freeze-dried enteric-coated tablet, due to the porous structure formed by the freeze-drying treatment of the tablet core, not only enables the tablet core to quickly absorb water, but also greatly increases the contact area of the tablet core with the liquid in the intestinal tract, especially in combination with the use of the disintegrating agent, so that the tablet core absorbs water and disintegrates at a very fast speed in the intestinal tract to release the drug, which is equivalent to increasing the time of direct contact of the effective components of the drug with the intestinal tract, thereby improving the absorption rate of the drug by the intestinal tract and enhancing the curative effect. In addition, due to the water content of the tablet core after the freeze-drying treatment being less than 5%, the water content of the tablet core is effectively reduced, thereby effectively preventing the weakly acidic adjuvant inside the tablet core from forming a slightly acidic environment, and further improving the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablet, effectively avoiding the increase of related substances during long-term storage, and improving the drug efficacy and safety of ilaprazole.

[0039] In order to better understand the technical solutions and beneficial effects of the present disclosure, the present disclosure will be further described in detail below in combination with specific embodiments,

[0040] The ilaprazole freeze-dried enteric-coated tablet of one embodiment comprises a tablet core and a coating layer, the tablet core comprises ilaprazole, the tablet core further comprises a disintegrating agent, a freeze-drying protective agent and a pharmaceutical excipient, the tablet core after the freeze-drying treatment forms a porous structure, and the water content of the tablet core is less than 5%.

[0041] It can be understood that, due to the coating layer of the ilaprazole freeze-dried enteric-coated tablet, the increased coating layer can effectively prevent ilaprazole from being degraded in gastric acid, so as to ensure that most of ilaprazole can enter the area of the gastrointestinal tract in contact with gastric juice, such as the lesser curvature of the stomach, the pyloric canal, the duodenal bulb, the postbulbar duodenum, the marginal anastomotic ulcer or the jejunum ulcer caused by gastrojejunal anastomosis.

[0042] It can be understood that, due to the porous structure formed by the freeze-drying treatment of the tablet core, not only can the tablet core quickly absorb water, but also the porous structure of the tablet core greatly increases the contact area of the tablet core with the liquid in the intestinal tract, especially in combination with the use of the disintegrating agent, so that the tablet core absorbs water and disintegrates at a very fast speed in the intestinal tract to release the drug, which is equivalent to increasing the time of direct contact of the effective components of the drug with the intestinal tract, thereby improving the absorption rate of the drug by the intestinal tract and enhancing the curative effect; in addition, due to the water content of the tablet core after the freeze-drying treatment being less than 5%, the water content of the tablet core is effectively reduced, thereby effectively preventing the weakly acidic adjuvant inside the tablet core from forming a slightly acidic environment, and further improving the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablet, effectively avoiding the increase of related substances during long-term storage, and improving the drug efficacy and safety of ilaprazole.

[0043] It can also be understood that the added freeze-drying protectant can protect the ilaprazole molecules from being extruded or damaged by ice crystals during the freeze-drying process, thereby maintaining the integrity of the ilaprazole molecular structure and better ensuring the drug efficacy of ilaprazole; and the cryoprotectant can interact with the ilaprazole molecules to form a protective layer, reducing the influence of water molecule removal on the intermolecular interaction force of ilaprazole, thereby preventing the occurrence of 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 prolonging the shelf life of the tablet core; and the added cryoprotectant can also improve the porosity of the tablet core to ensure the formation of a loose porous structure. That is, the added freeze-drying protectant can effectively prevent physical damage to ilaprazole molecules, prevent ilaprazole molecules from being damaged by dehydration, improve the stability of ilaprazole molecules during freeze-drying, improve the porosity of the tablet core to ensure the formation of a loose porous structure, ensure the stability and activity of ilaprazole during freeze-drying, and provide a strong guarantee for the preparation, storage and use of ilaprazole.

[0044] It can also be understood that the added pharmaceutical excipient 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 ilaprazole molecules; the pharmaceutical excipient can also interact with ilaprazole molecules to form a stable complex or a wrapping layer to protect the structural stability of ilaprazole molecules during freezing and drying, prevent ilaprazole molecules from aggregating during freeze-drying, and thereby ensure that ilaprazole molecules can be uniformly dispersed on the tablet core, which is conducive to the preparation of a tablet core with uniform surface porosity, no shrinkage and no yellowing.

[0045] In a more preferred embodiment, the moisture content of the tablet core is ≤2%, which removes most of the water in the raw materials and further prevents the weakly acidic excipients in 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 preventing the increase of related substances during long-term storage, thereby improving the drug efficacy of ilaprazole and the safety of the drug.

[0046] It can be understood that since the weakly acidic excipients form an acidic environment under high moisture conditions, most scholars will choose to directly reduce the moisture content of the tablet core to 0%. However, since the moisture in the raw materials usually includes bound water and free water, removing the bound water in the raw materials requires extremely harsh conditions to achieve good removal effect, resulting in high cost of water removal. Moreover, if the moisture content of the tablet core is too low or has no moisture, the molecular interaction between ilaprazole and the disintegrating agent, pharmaceutical excipient and freeze-drying protectant will be reduced, leading to problems such as shrinkage, powdering, delamination or crystallization of the tablet core, 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%, so as to ensure that the moisture content of the tablet core after freeze-drying is appropriate, and the appropriate moisture can better maintain the molecular interaction between ilaprazole and the pharmaceutical excipients and freeze-drying protectants, effectively avoid the problems of shrinkage, powdering, delamination or crystallization of the tablet core, and be conducive to the formation of a porous structure with a loose structure of the tablet core; on the other hand, the appropriate moisture content is conducive to the dissolution and release of the tablet core in the intestine, effectively avoids the slow dissolution of the tablet core in the intestine due to low moisture content of the tablet core, and affects the absorption and onset time of ilaprazole; on the other hand, it also reduces the conditions for freeze-drying water removal, and good water removal effect of the tablet core can be achieved without harsh conditions.

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

[0049] It can be understood that if the pressure of freeze-drying is less than 10 Pa, then excessively large voids will be formed on the surface of the tablet core, so that a stable porous structure with a loose structure cannot be formed; if the pressure of freeze-drying is greater than 50 Pa, the higher pressure will reduce the pressure difference of water vapor from the sublimation interface to the external environment, thereby reducing the escape speed of water vapor to cause the tablet core to be unable to freeze solid; if the freezing temperature is lower than -35°C or the freeze-drying time is greater than 12 h, the energy consumption of freeze-drying is too high, causing energy waste; if the freezing temperature is higher than 30°C or the freeze-drying time is less than 1 h, the tablet core cannot be frozen solid. Therefore, in the present disclosure, the tablet core is freeze-dried at a pressure of 10 Pa to 50 Pa and a temperature of -35°C to 30°C for 1 h to 12 h, so that the tablet core after freeze-drying has a porous structure with a loose structure, and the moisture content of the tablet core is ≤2%.

[0050] In one of the embodiments, the step of freeze-drying the core for 1-12 hours under a pressure of 10-50 Pa and at a temperature of -35-30°C comprises the following specific steps: first, the esomeprazole semi-product is placed in a freezer, then the esomeprazole semi-product is pre-frozen under no pressure for 150-200 minutes at a temperature of -35- -25°C to form a fixed shape, then the esomeprazole semi-product is sublimation dried for 100-150 minutes under a pressure of 30-40 Pa and at a temperature of -5-8°C; then the esomeprazole semi-product is first desorption dried for 180-200 minutes under a pressure of 30-40 Pa and at a temperature of 20-30°C, and finally the esomeprazole semi-product is second desorption dried for 40-80 minutes under no pressure and at a temperature of 20-30°C, so as to obtain the core with a moisture content of 0.5-2%, a uniform color and luster, a uniform surface porosity, a smooth surface, no atrophy, no yellowing, no delamination, no collapse, and a stable structure of a porous and crisp structure.

[0051] It can be understood that, if the pre-freezing cooling speed is too slow, large ice crystals will be formed in the esomeprazole semi-product, which will result in the formation of holes of different sizes on the surface of the core in the subsequent sublimation drying process, causing the surface of the core to be rough and the porosity to be uneven; and, if the cooling speed is too slow, the surface of the core will crystallize to form flaky crystals, and the flaky crystals are loosely combined with the powder cake of the core, which not only makes the appearance of the freeze-dried core more rough, but also causes the problem of easy chipping; if the pre-freezing cooling time is too fast, small ice crystals will be formed in the esomeprazole semi-product, and the small ice crystals will form a small number of sublimation channels, resulting in a small number of water escape channels in the sublimation drying process, which not only causes the porosity of the porous and crisp structure to be too low, but also causes the sublimation drying cycle of the esomeprazole semi-product to be prolonged, thereby affecting the freeze-drying efficiency. Therefore, in one of the embodiments, the cooling speed of the pre-freezing operation is -1- -2°C / min, so as to ensure that the pre-freezing cooling speed is appropriate, so that the esomeprazole semi-product can form ice crystals of uniform size in the pre-freezing cooling process, so as to ensure that the core can form a porous and crisp structure with a stable structure, a high porosity, a smooth surface, and no chipping, effectively avoiding the problem of flaky crystals caused by ice crystals of different sizes in the pre-freezing cooling process, and also avoiding the problem of too low porosity of the porous and crisp structure and prolonged sublimation drying cycle caused by too small crystals in the pre-freezing cooling process.

[0052] It can also be understood that if the sublimation drying and the first desorption drying are too fast, the ice crystals will escape too fast, causing the collapse of the porous structure. If the sublimation drying and the first desorption drying are too slow, the freeze-drying cycle will be too long, affecting the freeze-drying efficiency. Therefore, in the present disclosure, by controlling the sublimation drying temperature at 0.01℃ / min-1.0℃ / min, the first desorption drying temperature at 0.1℃ / min-0.5℃ / min, and the cooling rate of the pre-freezing operation at-1℃ / min--2℃ / min, the moisture content of the core is low, and the porous structure formed by the core has the characteristics of structural stability, high porosity, smooth surface and no chipping, and the freeze-drying cycle of the core is shortened.

[0053] It should be noted that in some medical fields, freeze-drying technology is also commonly used, but usually one desorption drying operation is adopted, such as the freeze-dried flash release tablet disclosed in Chinese patent document CN 115429764 A, and the pressure of one desorption is usually 10 Pa-20 Pa, resulting in a higher content of bound water in the final prepared freeze-dried flash release tablet. If the traditional one desorption drying operation is used for the preparation of the esoprazole enteric-coated tablet, the moisture content of the final prepared esoprazole enteric-coated tablet will usually be >5%, which, as mentioned in the background, leads to poor long-term storage stability of the esoprazole enteric-coated tablet. Therefore, in the present disclosure, by performing the first desorption drying and the second desorption drying on the esoprazole semi-product, and by increasing the pressure of the first desorption drying to 30 Pa-40 Pa, the bound water in the esoprazole semi-product can be removed more comprehensively, the moisture content of the core is low, and the porous structure formed by the core has the characteristics of structural stability, high porosity, smooth surface and no chipping, and the freeze-drying cycle of the core is shortened.

[0054] It also needs to be explained that, since the first time the dry pressure is 30 Pa to 40 Pa, relative to the conventional 10 Pa to 20 Pa, the pressure is doubled to improve the removal of water of hydration in the esomeprazole semi-product, but under the condition of a larger pressure, the loose porous structure of the base frame formed in the esomeprazole semi-product is prone to collapse or chipping problems in the first time. Therefore, in the present disclosure, since the added esomeprazole is a micro-powder treated esomeprazole with a particle size of D90≤10 μm, the micro-powder treated esomeprazole with a particle size of D90≤10 μm can be better dispersed in the esomeprazole base liquid, thereby improving the stability of the esomeprazole base liquid, effectively avoiding the problem that the loose porous structure of the base frame formed in the esomeprazole semi-product is prone to collapse or chipping in the first time under the condition of a larger pressure, so as to ensure that the water content of the tablet core is 0.5% to 2%, the color and luster of the appearance are uniform, the surface porosity is uniform, the surface is smooth, there is no atrophy, no yellowing, no delamination, no collapse, and the structure is stable. The loose porous structure is prepared quickly under a shorter freeze-drying cycle and a larger desorption drying pressure.

[0055] It also needs to be explained that, when the esomeprazole semi-product enters the second time desorption drying, the free water of the esomeprazole semi-product at this time has been basically removed, the molecular interaction between the esomeprazole molecules and the disintegrating agent, the pharmaceutical excipient, and the freeze-drying protective agent is relatively weak, and the loose porous structure of the base frame has been initially formed in the tablet core. If the second time desorption drying is still operated at a higher pressure of 30 Pa to 40 Pa, the loose porous structure of the base frame is prone to collapse and chipping. Therefore, in the present disclosure, by controlling the second time desorption drying of the esomeprazole semi-product under the condition of no pressure and 20°C to 30°C for 40 min to 80 min, the water content of the tablet core is 0.5% to 2%, the color and luster of the appearance are uniform, the surface porosity is uniform, the surface is smooth, there is no atrophy, no yellowing, no delamination, no collapse, and the structure is stable. The loose porous structure is prepared quickly under a shorter freeze-drying cycle and a larger desorption drying pressure.

[0056] It also needs to be explained that, since the removal sequence of water of hydration is: freeze-drying protective agent > pharmaceutical excipient > disintegrating agent > esomeprazole, the added freeze-drying protective agent, pharmaceutical excipient, and disintegrating agent can protect the esomeprazole from the higher pressure and long-time drying temperature in the first time desorption drying, and the long-time drying temperature in the second time desorption drying, effectively avoiding the problem that the molecular structure of the esomeprazole changes and causes the pharmaceutical failure of the esomeprazole.

[0057] In one of the embodiments, the particle size of the ilaprazole after the micronization treatment is D90≤10 μm. It can be understood that if the ilaprazole raw material is not subjected to the micronization treatment, the ilaprazole base solution prepared therefrom will have a serious sedimentation problem, and the tablet weight difference of the tablet cores prepared in the same preparation tank will be large. Therefore, in the present disclosure, by subjecting the ilaprazole raw material to the micronization treatment, the stability of the ilaprazole base solution is improved, and the serious sedimentation problem of the ilaprazole base solution is effectively avoided.

[0058] It can also be understood that although the micronization treatment of the ilaprazole raw material can solve the problem of serious sedimentation of the ilaprazole base solution to some extent, when the particle size of the ilaprazole after the micronization treatment is D90>10 μm, and the ilaprazole lyophilized enteric-coated tablets are usually produced in batches in actual production, the amount used in the same preparation tank is usually large, which causes that the ilaprazole base solution in the same preparation tank cannot be quickly filled and packaged in a short time, and the ilaprazole base solution will have a small amount of sediment at the bottom after a long standing time. Therefore, in the present disclosure, by controlling the particle size of the ilaprazole after the micronization treatment to be D90≤10 μm, D90≤10 μm can effectively prevent the ilaprazole base solution from sedimentation during a long standing time, so as to ensure that the ilaprazole base solution can still remain uniform, stable and without sedimentation within 3 h of standing, thereby prolonging the standing time of the ilaprazole base solution prepared in the same preparation tank, so as to ensure that the ilaprazole base solution can meet the requirements of batch injection molding and packaging without stirring in a long standing time, and thus effectively reducing the small tablet weight difference of the tablet cores in the batch production process, so as to ensure that the weight fluctuation range of the tablet cores in the batch production is small, and thus ensuring that the active ingredient content of ilaprazole in each ilaprazole lyophilized enteric-coated tablet is more uniform, which helps to ensure that each patient takes the same dose of medicine, and ensures that the absorption and metabolism of the ilaprazole lyophilized enteric-coated tablets in the patient's body are more stable, thereby improving the therapeutic effect and reducing the problem of unstable efficacy caused by large dose fluctuation.

[0059] Further, when the particle size of the ilaprazole after the micronization treatment is D90≤10 μm, the tablet weight difference of the tablet cores in batch production is controlled to be 4.7% to 6.1%, so as to better reduce the fluctuation of the tablet weight difference of the tablet cores in the batch production process.

[0060] It can also be understood that, since the particle size of the ilaprazole after the micro-powder treatment is D90≤10 μm, it is ensured that the ilaprazole after the micro-powder treatment can be well dispersed in the ilaprazole base liquid, thereby improving the stability of the ilaprazole base liquid, so as to ensure that the ilaprazole semi-product can be quickly prepared into a tablet core with a moisture content of 0.5% to 2%, a uniform color and luster, a uniform surface pore, a smooth surface, a stable and porous structure, no shrinkage, no yellowing, no delamination, no collapse, and a stable structure in a short freezing cycle and a large desorption drying pressure.

[0061] It can also be understood that, since the particle size of the ilaprazole after the micro-powder treatment is D90≤10 μm, it is beneficial for the ilaprazole freeze-dried enteric-coated tablets to quickly disintegrate in the intestinal tract to form a fine powder, further improving the contact area of the ilaprazole with the intestinal tract, further increasing the time for the effective components of the drug to directly contact with the intestinal tract, and better improving the absorption rate of the drug by the intestinal tract, so as to better enhance the curative effect.

[0062] It can also be understood that, since the particle size of the ilaprazole after the micro-powder treatment is D90≤10 μm, it is ensured that the ilaprazole after the micro-powder treatment can be well dispersed in the ilaprazole base liquid, thereby improving the stability of the ilaprazole base liquid, so as to ensure that the ilaprazole semi-product can be quickly prepared into a tablet core with a moisture content of 0.5% to 2%, a uniform color and luster, a uniform surface pore, a smooth surface, a stable and porous structure, no shrinkage, no yellowing, no delamination, no collapse, and a stable structure in a short freezing cycle and a large desorption drying pressure.

[0063] In one embodiment, the step of micronizing the ilaprazole is performed to have a particle size D90 of 10 μm or less. Specifically, the ilaprazole bulk drug is subjected to jet milling and sieving to obtain ilaprazole micropowder having a particle size D90 of 10 μm or less. The jet milling is performed at a feed pressure of 7 bar, a milling pressure of 6 bar, and a feed speed of 5 rpm to obtain ilaprazole micropowder having 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. Further, the lyoprotectant is dextran-70, which can significantly improve the mechanical strength of the ilaprazole lyophilized enteric-coated tablet, so that the ilaprazole lyophilized enteric-coated tablet is not easily broken during the lyophilization process.

[0065] It can be understood that if the weight of the disintegrant is less than 40% of the total weight of the tablet core, the thickening effect cannot be achieved to obtain a uniform and stable ilaprazole base solution; if the weight of the disintegrant is greater than 55% of the total weight of the tablet core, the ilaprazole base solution is too thick to realize the filling operation of continuous batch production. Therefore, in one embodiment, the weight of the disintegrant is 5% to 25% of the total weight of the tablet core, so as to ensure that the content of the disintegrant in the tablet core is appropriate, thereby ensuring that the ilaprazole base solution prepared has a uniform and stable, appropriate thickening, and no precipitate, which is not only conducive to the subsequent preparation of the tablet core with low moisture content, but also enables the tablet core to have a structure with stable structure, high porosity, smooth surface, and no chipping, and better meets the filling needs of continuous batch production.

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

[0067] Further, in a more preferred embodiment, the disintegrant is hydroxypropyl-β-cyclodextrin (HP-β-CD). It can be understood that hydroxypropyl-β-cyclodextrin has good disintegrating efficiency, and can reduce the ice-water interfacial tension during the lyophilization process, reduce freezing and dehydration denaturation, thereby protecting the active ingredients of the ilaprazole lyophilized enteric-coated tablet from damage.

[0068] In one embodiment, the pharmaceutical excipient includes 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, so that the tablet core can form a porous structure after being subjected to the freeze-drying process, thereby improving the disintegration rate of the tablet core.

[0069] In one embodiment, the skeletal support agent comprises 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 skeletal support agent is mannitol. It is understood that mannitol is a commonly used skeletal support agent, and its presence during the freeze-drying process helps to regulate the internal and external moisture migration of the esomeprazole semi-product, promotes uniform moisture removal, and avoids uneven freeze-drying phenomena.

[0071] In a preferred embodiment, the binding agent comprises at least one of copovidone, pregelatinized starch, gelatin, and hydrolyzed gelatin. Further, in a preferred embodiment, the binding agent is copovidone, which has excellent binding properties and high surface activity, can stably bind with the skeletal support agent, the disintegrating agent, esomeprazole, and the freeze-drying protective agent during the freeze-drying process, helps to form a structurally stable porous structure, and can promote the in vivo absorption of the esomeprazole freeze-dried enteric-coated tablet.

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

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

[0074] The present disclosure also provides a preparation method of an esomeprazole freeze-dried enteric-coated tablet, comprising the following steps: preparing a thickened liquid by mixing a disintegrating agent; adding esomeprazole, a freeze-drying protective agent, and a pharmaceutical excipient to the thickened liquid to obtain an esomeprazole base liquid; performing a degassing operation on the esomeprazole base liquid; performing injection molding fixation on the esomeprazole base liquid after the degassing operation to obtain an esomeprazole semi-product; performing freeze-drying on the esomeprazole semi-product to obtain the tablet core described in any one of the above embodiments; and performing coating and drying on the tablet core to obtain the esomeprazole freeze-dried enteric-coated tablet described in any one of the above embodiments.

[0075] The above-described method for preparing lysoprazole lyophilized enteric-coated tablets involves freeze-drying the lysoprazole semi-product to create a stable, non-collapsed, and non-flaking porous structure in the tablet core. This ensures the resulting tablet core has low moisture content, uniform color, uniform surface pores, a smooth surface, and is free from shrinkage, scorching, and delamination. This not only improves the disintegration rate of the tablet core, thereby increasing the intestinal absorption rate of the drug, but also enhances the long-term storage stability of the lysoprazole lyophilized enteric-coated tablets, thus improving the efficacy and safety of lysoprazole.

[0076] Please see Figure 1 To better understand the technical solution and beneficial effects of this disclosure, the following detailed description is provided in conjunction with specific embodiments. One embodiment of the preparation method of lyophilized enteric-coated esomeprazole tablets includes some or all of the following steps:

[0077] S101. Prepare the disintegrant into a thickening solution.

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

[0079] Specifically, the formulation of the unprocessed tablet core is as follows: based on the total weight of the unprocessed tablet core, 11%–14% of ilaprazole, 5%–25% of hydroxypropyl-β-cyclodextrin (HP-β-CD), 20%–70% of dextran-70, 10%–15% of copovidone, and 15%–25% of mannitol are weighed and prepared.

[0080] S102. Add ipramazole to the thickening liquid and stir to obtain ipramazole thick liquid.

[0081] In one embodiment, a cantilever stirrer is used to stir the viscous esomeprazole solution, and the stirring speed is controlled at 1000 rpm to 1500 rpm for 10 min to 20 min. In particular, the particle size D90 of the micronized esomeprazole is ≤10 μm to ensure a uniform and stable viscous esomeprazole solution. This is beneficial for the subsequent addition of freeze-drying protectants and pharmaceutical excipients to be well dispersed in the viscous esomeprazole solution, thereby ensuring the preparation of a uniform and stable esomeprazole matrix solution.

[0082] S103. The freeze-drying protectant, pharmaceutical excipient and the esomeprazole viscous liquid are mixed to prepare a uniform and stable esomeprazole matrix solution.

[0083] In one embodiment, the esomeprazole base solution is continuously stirred with a cantilever stirrer, and the stirring speed is controlled at 1000 rpm to 1500 rpm, and the stirring time is 10 min to 20 min, so that the freeze-drying protectant and the pharmaceutical excipient can be fully mixed with the esomeprazole thick liquid, to ensure the preparation of a uniform and stable esomeprazole base solution.

[0084] In one embodiment, the esomeprazole base solution is continuously stirred with a cantilever stirrer, and the stirring speed is controlled at 1000 rpm to 1500 rpm, and the stirring time is 10 min to 20 min, so that the freeze-drying protectant and the pharmaceutical excipient can be fully mixed with the esomeprazole thick liquid, to ensure the preparation of a uniform and stable esomeprazole base solution.

[0085] In one embodiment, the esomeprazole base solution is continuously stirred with a cantilever stirrer, and the stirring speed is controlled at 1000 rpm to 1500 rpm, and the stirring time is 10 min to 20 min, so that the freeze-drying protectant and the pharmaceutical excipient can be fully mixed with the esomeprazole thick liquid, to ensure the preparation of a uniform and stable esomeprazole base solution.

[0086] Further, the conditions of the vacuum emulsifier are as follows: the stirring speed of the emulsifier is 2000 rpm to 3000 rpm, the emulsification time is 5 min to 10 min, and the degassing time is 5 min to 10 min, to ensure the preparation of a uniform and stable esomeprazole base solution with small particle size, no obvious bubbles visible to the naked eye, and no sediment, thereby facilitating the preparation of a structure-stable, uniformly-pored, smooth-surfaced, non-shedding, non-layered, and non-yellowing porous structure.

[0087] S105, the esomeprazole base solution after the degassing operation is injection molded and fixed to obtain an esomeprazole semi-product, to prepare a dosage form required for production.

[0088] It can be understood that, since the esomeprazole base solution after the degassing operation has good stability, and the particle size D90 of esomeprazole is ≤10 μm, the bottom of the esomeprazole base solution prepared will not produce sediment in a longer standing time, effectively prolonging the standing time of the esomeprazole base solution prepared in the same batching tank, to ensure that the esomeprazole base solution can still meet the batch injection and filling requirements in a longer standing time, thereby effectively reducing the small differences in the weight of the tablet cores in the batch production process, to ensure that the weight of the tablet cores in the batch production has a small fluctuation range, and further ensure that the active ingredient content of esomeprazole in each esomeprazole lyophilized enteric-coated tablet is more uniform, to ensure that the absorption and metabolism of the esomeprazole lyophilized enteric-coated tablet in the patient's body are more stable, thereby improving the treatment effect and reducing the problem of unstable efficacy caused by large dose fluctuations. Further, the esomeprazole base solution will not produce sediment at the bottom in a 3 h standing time.

[0089] S106, freeze-drying the esomeprazole semi-product to obtain the core tablet of any one of the embodiments described above. After the esomeprazole semi-product is freeze-dried, the water content of the esomeprazole semi-product can be effectively removed, and a porous structure can be formed in the esomeprazole semi-product. In this way, the long-term storage stability of the core tablet can be improved, the increase of related substances during long-term storage can be effectively avoided, the drug efficacy and safety of esomeprazole can be improved, the rapid release of the core tablet in the intestinal tract can be accelerated, and the absorption efficiency of the intestinal tract for esomeprazole can be improved.

[0090] In a preferred embodiment, freeze-drying the esomeprazole semi-product comprises the following specific steps: first, pre-freezing the esomeprazole semi-product under pressureless conditions to form and fix the esomeprazole semi-product at -35℃ to -25℃ for 150 min to 200 min, then sublimation drying the esomeprazole semi-product at 30 Pa to 40 Pa and -5℃ to 8℃ for 100 min to 150 min, then first desorption drying the esomeprazole semi-product at 30 Pa to 40 Pa and 20℃ to 30℃ for 180 min to 200 min, and finally second desorption drying the esomeprazole semi-product at 20℃ to 30℃ under pressureless conditions for 40 min to 80 min, so as to obtain a porous structure with low water content, uniform color and luster, uniform surface porosity, smooth surface, no atrophy, no yellowing, no delamination, no collapse, stable structure, and high porosity.

[0091] S107, coating and drying the core tablet to obtain the esomeprazole freeze-dried enteric-coated tablet of any one of the embodiments described above. The coating layer is formed on the surface of the core tablet, so that the core tablet can be better protected.

[0092] In one embodiment, the coating and drying comprises isolation coating and drying and enteric-coated coating. Specifically, the gastric-soluble film coating premix is dissolved in 95% ethanol to prepare an isolation coating liquid, and then the core tablet is spray-dried to form an isolation coating layer on the surface of the core tablet. Then, the enteric-soluble film coating premix is dissolved in 95% ethanol to prepare an enteric-coated coating liquid, and then the core tablet is spray-dried to form an enteric-coated coating layer on the surface of the isolation coating layer, so as to prepare the esomeprazole freeze-dried enteric-coated tablet.

[0093] In one embodiment, when the core tablet is spray-dried with the isolation coating liquid, the relative humidity of the environment is ≤30% RH, so as to avoid the problem that the core tablet with low water content is absorbed by water due to high humidity of the environment during spray-drying of the isolation coating liquid, and the water content of the core tablet becomes high.

[0094] The preparation method of the above-mentioned ilaprazole freeze-dried enteric-coated tablets, by freeze-drying the ilaprazole semi-product, makes the tablet core after the freeze-drying treatment form a structure stable, non-collapsed, non-chipping, crisp and porous structure, and ensures that the obtained tablet core has a low water content, uniform color and luster, uniform surface porosity, smooth surface, no atrophy, no yellowing and no delamination, not only improves the disintegration rate of the tablet core, thereby improving the absorption rate of the drug in the intestinal tract, but also improves the long-term storage stability of the ilaprazole freeze-dried enteric-coated tablets, thereby improving the drug efficacy and safety of ilaprazole.

[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 cases, and the materials used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0096] Example 1

[0097] (1) Take 20 kg of HP-β-CD and 800 kg of purified water (800 kg of water per tablet), and mix them in a container to form a thickening liquid.

[0098] (2) Add 5 kg of ilaprazole after micro-powder treatment (D90 is 7.36 μm) to the thickening liquid and mix by using a cantilever stirrer at a speed of 1500 rpm for 20 min to obtain an ilaprazole thick liquid; wherein the ilaprazole raw material is subjected to air-jet pulverization, the feeding pressure is 7 bar, the pulverization pressure is 6 bar, and the feeding speed is 5 rpm.

[0099] (3) Add 40 kg of dextran, 5 kg of copolymerized povidone and 10 kg of mannitol to the ilaprazole thick liquid obtained in step (2) and continue to stir at a speed of 1500 rpm for 20 min to obtain an ilaprazole base liquid.

[0100] (4) Emulsify and shear the ilaprazole base liquid obtained in step (3) in a vacuum emulsifier at a speed of 2500 rpm for 10 min, and degas until there are no obvious bubbles.

[0101] (5) Reduce the stirring speed of the vacuum emulsifier to 1000 rpm, then take 1.2 ml of the ilaprazole base liquid in step (4) and inject it into the bubble cap to obtain an ilaprazole semi-product.

[0102] (6) The blistered esomeprazole semi-product obtained by perfusion in step (5) is placed in a freezer, and then pre-cooled for 180 min at a cooling rate of-1℃ / min to-35℃ under pressureless conditions, followed by sublimation drying for 120 min at a large pressure of 40 Pa and a heating rate of 0.5℃ / min to 5℃, then first desiccation drying for 180 min at a pressure of 30 Pa and a heating rate of 0.1℃ / min to 30℃, and finally second desiccation drying for 60 min at a temperature of 30℃ under pressureless conditions, to obtain the core.

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

[0104] (8) The enteric film coating premix is dissolved in 95% ethanol to obtain an enteric coating liquid, and the core in step (7) is spray dried to obtain the esomeprazole lyophilized enteric tablet.

[0105] Comparative Examples 1-4 differ from Example 1 in that the freeze-drying conditions in step (6) are different, and the rest are unchanged. For details, see Table 1 below for the comparison of freeze-drying conditions.

[0106] Table 1

[0107]

[0108]

[0109] The core obtained by preparing Comparative Examples 1-4 and Example 1 is detected for moisture, appearance, disintegration time, and freeze-drying cycle to obtain the experimental data in Table 2:

[0110] Moisture: detected by a moisture detector.

[0111] Appearance: observed under strong light.

[0112] Disintegration time: determined according to the Disintegration Time Determination Method (Chinese Pharmacopoeia 2020 Edition General Chapter 0921).

[0113] Freeze-drying cycle: the time used for the entire freeze-drying is recorded by a chronograph.

[0114] Table 2

[0115]

[0116]

[0117] From Table 2, it can be seen that, since the first analytical drying with strong pressure and the second analytical drying without pressure are used in combination in Example 1, the esomeprazole semi-product can be quickly prepared to have a stable structure, uniform porosity, higher porosity, smooth surface and no chipping in a shorter freeze-drying cycle. The moisture content of the core is as low as 0.8%, the appearance color is uniform, the surface porosity is uniform, the surface is smooth, there is no shrinkage, no yellowing and no delamination, so that the comprehensive indexes of Example 1 are obviously better than those of Comparative Examples 1-4.

[0118] Comparative Examples 5 and 6 are different from Example 1 in that the particle size of esomeprazole in step (2) is different, and the rest is unchanged. For details, please refer to the following Table 3 for the comparison of the particle size of esomeprazole.

[0119] Table 3

[0120]

[0121] From Table 3, it can be seen that, since the particle size of esomeprazole used in Example 1 reaches D90≤10 μm, the solution stability of the esomeprazole base solution prepared in Example 1 is good, the weight fluctuation range of the core in continuous batch production is small, and there is no powder falling at the bottom during shaking, so that the comprehensive indexes of Example 1 are obviously better than those of Comparative Examples 5-6.

[0122] Comparative Examples 7-8 are different from Example 1 in that the type of disintegrant (HP-β-CD) in step (1) in Example 1 is different, and the rest is unchanged. For details, please refer to the following Table 4 for the comparison of the types of disintegrants used in Comparative Examples 7-8 and Example 1.

[0123] Table 4

[0124]

[0125] The cores prepared in Comparative Examples 7 and 8 and Example 1 are detected for dispersion, sedimentation, filling and disintegration time, and the experimental data in Table 5 are obtained.

[0126] Table 5

[0127]

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

[0129] Comparative Examples 9-10 are different from Example 1 in that the type of binder (copovidone) in step (3) in Example 1 is different, and the rest is unchanged. For details, please refer to the following Table 6 for the comparison of the types of binders used in Comparative Examples 9 and 10 and Example 1.

[0130] Table 6

[0131] Material name Example 1 Comparative Example 9 Comparative Example 10 Eprazinol 5 kg 5 kg 5 kg Mannitol 10 kg 10 kg 10 kg Copolymers of vinylpyrrolidone 5 kg / / Ethyl cellulose / 12 kg / Sodium alginate / / 16 kg HP-β-CD 20 kg 20 kg 20 kg Dextran-70 40 kg 40 kg 40 kg

[0132] The dispersing, settling, filling and disintegrating time of the tablet cores prepared in Comparative Examples 9 and 10 and Example 1 were detected to obtain the experimental data in Table 7 below.

[0133] Table 7

[0134]

[0135] As can be seen from Table 7, the comprehensive indicators of the tablet cores prepared in Example 1 using copolymerized povidone as the binder are obviously superior to those of Comparative Examples 9 and 10.

[0136] Comparative Example 11

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

[0138] The release of the esomeprazole lyophilized enteric-coated tablets of Example 1 and Comparative Example 11 was studied to obtain the experimental data in Table 8 below.

[0139] The release determination method is as follows: according to the release determination method (Chinese Pharmacopoeia 2020 edition four general rules 0931 enteric-coated preparation method 2), 0.1 mol / L hydrochloric acid solution 900 ml is used as the release medium, and the rotation speed is 50 revolutions per minute. According to the law, after 120 minutes, 10 ml of solution was taken, filtered, and the filtrate was taken as the test sample, measured, and the release amount was calculated. It should not be higher than 10% of the marked amount, and whether the tablet is discolored or not. In the above acid solution, 0.2 mol / L sodium phosphate solution 250 ml with a temperature of 37℃±0.5℃ was added, and the operation was continued for 20 minutes. 10 ml of solution was taken, filtered, and the filtrate was taken as the test sample solution, and the determination was carried out.

[0140] Table 8

[0141]

[0142] As can be seen from the data in Table 8, the release speed of the esomeprazole lyophilized enteric-coated tablets of Example 1 in the buffer is obviously higher than that of Comparative Example 11, indicating that the esomeprazole lyophilized enteric-coated tablets of Example 1 can be quickly released in the intestinal tract.

[0143] The influence factors and accelerated experimental conditions of the esomeprazole lyophilized enteric-coated tablets of Example 1, Comparative Examples 4, 6, 7, 8, 10 and 11 were studied, wherein the influence factors and accelerated experimental conditions are shown in 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 increase rate of related substances of the ilaprazole lyophilized enteric-coated tablets prepared in Example 1 is obviously superior to that of Comparative Example 11 during the influence factor and accelerated test processes, proving that the ilaprazole lyophilized enteric-coated tablets prepared in Example 1 have good long-term storage stability.

[0150] The above-described examples only express several embodiments of the present disclosure, and the description is relatively specific and detailed, but it should not be understood as a limitation on the scope of the disclosed patent. It should be noted that for ordinary skilled persons in the art, several modifications 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 present disclosure patent should be subject to the appended claims.

Claims

1. A lyophilized enteric-coated tablet of ilaprazole comprising a tablet core and a coating layer, the tablet core comprising ilaprazole, characterized in that, The tablet core further comprises a disintegrant, a freeze-drying protective agent and a pharmaceutical excipient, and the tablet core has a porous structure after freeze-drying treatment, and the moisture content of the tablet core is less than 5%; wherein, The tablet core is freeze-dried at a pressure of 10 Pa to 50 Pa and a temperature of -35 ℃ to 30 ℃ for 1 h to 12 h; The particle size of the ilaprazole after micronization treatment is D90≤10 μm; The disintegration time of the tablet core is less than or equal to 10 s; The freeze-drying protective agent comprises dextran-70; The disintegrant comprises hydroxypropyl-β-cyclodextrin; The pharmaceutical excipient comprises a skeleton support agent and a binder; The skeleton support agent comprises at least one of glycine, erythritol, maltitol, arginine, mannitol, glucose, sorbitol, lactitol, isomaltitol, dextran, xylose, sodium chloride, serine, raffinose, maltose, galactose, trehalose, xylitol, dextrin, hydroxypropyl cyclodextrin, sodium phosphate and aluminum silicate; The binder comprises copovidone; The ilaprazole is 11% to 14%, the hydroxypropyl-β-cyclodextrin (HP-β-CD) is 5% to 25%, the dextran-70 is 20% to 70% and the copovidone is 10% to 15% based on the total weight of the tablet core.

2. The ilaprazole lyophilized enteric-coated tablet according to claim 1, which is characterized by The moisture content of the tablet core is less than or equal to 2%.

3. The ilaprazole lyophilized enteric-coated tablet according to claim 1, which is characterized by The tablet weight difference of the tablet core is 4.7% to 6.1%; and / or, The tablet core has a uniform appearance, no atrophy, no yellowing and no delamination.

4. The ilaprazole lyophilized enteric-coated tablet according to claim 1, wherein The coating layer comprises a separation coating layer and an enteric coating layer.

5. A process for the preparation of the lyophilized enteric coated tablet of ilaprazole according to any one of claims 1 to 4, characterized in that, The method comprises the following steps: The disintegrant is prepared into a thickened liquid; The ilaprazole is added to the thickened liquid for stirring and mixing to obtain an ilaprazole thickened liquid; The freeze-drying protective agent, the pharmaceutical excipient and the ilaprazole thickened liquid are mixed to obtain an ilaprazole matrix liquid; The ilaprazole matrix liquid is subjected to a degassing operation; The ilaprazole matrix liquid after the degassing operation is subjected to injection molding fixation to obtain an ilaprazole semi-product; The ilaprazole semi-product is subjected to freeze-drying to obtain the tablet core; The tablet core is subjected to coating and drying to obtain the ilaprazole freeze-dried enteric-coated tablet.

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