Rebaudioside b and a method for producing the same

Abstract

This invention relates to the field of pharmaceutical formulation technology, and discloses a rebamipide tablet formulation and its preparation process. The formulation, by weight, mainly comprises 100 parts rebamipide, 5 to 15 parts L-arginine, 2 to 8 parts poloxamer 188, 10 to 20 parts hydroxypropyl cellulose, and excipients such as low-substituted hydroxypropyl cellulose and microcrystalline cellulose. The preparation process includes: preparing a composite binder solution containing L-arginine, poloxamer 188, and hydroxypropyl cellulose at 10°C to 15°C; adding rebamipide and cold-curing to obtain a suspension; subsequently, during fluidized bed granulation, by adjusting the absolute humidity and temperature of the inlet air in stages, sequentially performing high-humidity delayed drying and spreading followed by dehumidification and temperature-increasing curing. This invention prevents hydrophobic drug agglomeration and nozzle clogging through low-temperature processing; the in-situ crystallization of L-arginine creates a weakly alkaline microenvironment, significantly improving the drug dissolution rate in acidic media; and achieving high granulation yield and batch-to-batch uniformity of content.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a rebamipide tablet formulation and its preparation process. Background Technology

[0002] Rebamipide is a commonly used gastric mucosal protectant, mainly used to treat gastric ulcers and acute and chronic gastritis. Rebamipide is a weakly acidic drug with strong hydrophobicity. In the acidic physiological environment of the human stomach, its thermodynamic solubility is low, which leads to slow dissolution of conventional oral solid dosage forms, thereby affecting the drug's bioavailability and early onset of action.

[0003] To improve the dissolution characteristics of rebamipide, micronization technology is commonly used in industrial production to reduce drug particle size and increase specific surface area. However, the micronized, highly hydrophobic drug is difficult to disperse uniformly in aqueous binder systems during processes such as fluidized bed spray granulation, and is prone to hydrophobic association to form agglomerates. In conventional fluidized bed suspension spray granulation, polymer binders and surfactants are required to maintain the drug's suspension state. However, during the room temperature solution preparation and high pressure supply stages, polymer materials are prone to physical gelation under the action of mechanical shearing and pipeline heat transfer, leading to an increase in the apparent viscosity of the liquid, which in turn causes nozzle clogging, reducing the continuity of production and product yield.

[0004] Furthermore, in the existing fluidized bed drying stage, a higher inlet air temperature and a lower humidity are usually set to improve drying efficiency. This causes the surface moisture of the droplets to evaporate rapidly after contacting the material matrix. The rapid evaporation of moisture will cause the polymer binder on the particle surface to undergo glass transition prematurely, forming a dense polymer outer layer on the particle surface. When the formulation enters the human body and comes into contact with digestive fluids, this dense outer layer will hinder the penetration of acidic dissolution media into the particle interior. Not only will the specific surface area advantage of the micronized drug not be utilized, but it will also cause drug release lag. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a rebamipide tablet formulation and its preparation process, solving the problem of skin formation caused by binder transformation, which hinders the penetration of the dissolution medium.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution: a rebamipide tablet formulation, made from raw materials comprising the following parts by weight: 100 parts rebamipide; 5 to 15 parts L-arginine; 2 to 8 parts poloxamer 188; 10 to 20 parts hydroxypropyl cellulose; 30 to 60 parts low-substituted hydroxypropyl cellulose; 50 to 100 parts microcrystalline cellulose; 1 to 3 parts silica; and 1 to 3 parts magnesium stearate.

[0007] By adopting the above technical solution, due to the synergistic effect of the specific ratio of polymer and microenvironment modifier in terms of microscopic physical structure and dissolution kinetics, the dissolution rate of weakly acidic poorly soluble drugs in acidic media is improved.

[0008] The mechanism of this invention is mainly reflected in the following process: Poloxamer 188 and hydroxypropyl cellulose are in a highly hydrated state in a low-temperature liquid phase environment, with the macromolecular chains fully extended. The hydrophobic segments of poloxamer 188 are adsorbed onto the surface of rebapamide particles, and its hydrophilic segments together with hydroxypropyl cellulose construct a network framework with steric hindrance effect. This network framework can effectively block the hydrophobic association between highly hydrophobic rebapamide particles and maintain the physical stability of the monodisperse homogeneous system.

[0009] L-arginine particles are interspersed and distributed in the gaps of the aforementioned network framework. When the solid formulation comes into contact with an acidic dissolution medium, the L-arginine microcrystals in the polymer framework dissolve rapidly, forming initial dissolution capillary channels in situ. At the same time, a microscale weakly alkaline buffer pool is formed around the rebamipide particles to neutralize the infiltrated acidic medium.

[0010] The aforementioned weakly alkaline buffer pool increases the pH value of the local microenvironment, breaks down the dissolution barrier of weakly acidic drugs in gastric acid, and establishes a concentration gradient that is conducive to the dissociation and precipitation of rebamipide molecules, thereby driving drug molecules to leave the solid phase and enter the dissolution medium.

[0011] Preferably, the rebamipide is a raw material obtained through micronization pretreatment, and its particle size distribution satisfies D90 less than or equal to 20 μm; the remaining raw materials in the formulation are all commercially available pharmaceutical-grade products with publicly disclosed acquisition methods.

[0012] By adopting the above technical solution, the micronization process increases the specific surface area of ​​drug particles, and combined with the subsequent microenvironment pH adjustment mechanism, it further improves the dissolution rate and final dissolution degree of the drug in acidic media.

[0013] Preferably, the hydroxypropyl cellulose is an EF grade low viscosity type with an average molecular weight of 80,000, and its kinetic viscosity ranges from 6.0 mPa·s to 10.0 mPa·s in a 2% aqueous solution at 20°C; the hydroxypropoxy group mass fraction of the low-substituted hydroxypropyl cellulose ranges from 5.0% to 16.0%.

[0014] By adopting the above technical solutions, hydroxypropyl cellulose with specific molecular weight and viscosity levels ensures that the suspension maintains suitable low-viscosity fluid dynamics for industrial pumping at low temperatures, avoiding gelation during the atomization process; low-substituted hydroxypropyl cellulose with a specific degree of substitution provides a suitable water absorption and swelling rate, assisting the particles to disintegrate rapidly after entering the dissolution medium.

[0015] Preferably, the poloxamer 188 is a block copolymer composed of polyoxyethylene a, polyoxypropylene b, and polyoxyethylene a, wherein the value of a is 80, the value of b is 27, and its average molecular weight ranges from 7680 to 9510.

[0016] By adopting the above technical solution, poloxamer 188 with a specific block ratio has matching low critical dissolution temperature characteristics, ensuring that it exhibits a relaxed random coil conformation in the temperature range of 10℃ to 15℃, providing sufficient interfacial wetting and spatial encapsulation to cover the surface of drug powder.

[0017] Preferably, the cumulative dissolution rate of the formulation in hydrochloric acid medium at pH 1.2 for 15 minutes is greater than or equal to 75%, and the radial compressive hardness of the finished tablet is controlled between 60N and 120N.

[0018] By adopting the above technical solutions, macroscopic physicochemical indicators are limited to verify the effectiveness of microstructure shaping and granulation process, ensuring that the formulation has early rapid drug release kinetic characteristics and meets the mechanical strength requirements of industrial packaging and transportation.

[0019] This invention provides a preparation process for rebamipide tablets, using the following technical solution: A preparation process for a rebamipide tablet formulation includes the following steps: S1. At 10℃ to 15℃, L-arginine, poloxamer 188 and hydroxypropyl cellulose are dissolved to form a composite adhesive solution. Rebamipide is added and the mixture is cold-cured for 2 to 4 hours to obtain a suspension. S2. Low-substituted hydroxypropyl cellulose and microcrystalline cellulose are added to a fluidized bed for preheating and sprayed into the suspension obtained in S1. Granulation is carried out by adjusting the absolute humidity and temperature of the incoming air in stages. S3. The obtained granules are mixed with silicon dioxide and magnesium stearate and then compressed into tablets.

[0020] By adopting the above technical solution, and by using a coupled process of cold liquid pulping and hydrothermal kinetics, good granulation yield and batch-to-batch content uniformity are achieved.

[0021] The specific process mechanism of this invention is as follows: In a cold liquid phase environment of 10℃ to 15℃, the excessive stretching and physical cross-linking of polymer chains are suppressed. The suspension containing hydrophobic drug particles remains in a homogeneous and low-viscosity fluid state before entering the nozzle, thereby reducing the drug concentration gradient in the supply system from the source and avoiding the risk of nozzle blockage caused by high shear force and heat transfer.

[0022] By introducing a hot gas stream with high absolute humidity, the driving force of gas-liquid mass transfer during the evaporation of water on the droplet surface is reduced. When the cold suspension comes into contact with the preheated matrix, the phase change evaporation rate is slowed down. The plasticized water retained in the system prolongs the relaxation time of hydroxypropyl cellulose and poloxamer 188 molecules. The polymer network completes monolayer self-assembly wetting on the matrix skeleton and drug particle surface.

[0023] By reducing the absolute humidity of the incoming air and increasing the temperature of the incoming air, the moisture evaporates at a constant rate. This process avoids the polymer film from prematurely crossing the glass transition temperature and forming a dense hydrophobic skin caused by instantaneous flash evaporation of moisture. It maintains the connectivity of the micropores and overcomes the phenomenon of early dissolution lag.

[0024] Preferably, in S1, the temperature of the suspension is controlled below 15°C throughout the entire preparation process, and the apparent viscosity of the suspension is stable between 17.2 mPa·s and 21.8 mPa·s under conditions of 10°C to 15°C, so as to ensure that poloxamer 188 is in a highly hydrated state.

[0025] By adopting the above technical solution, the apparent viscosity is controlled in a low range, proving that the polymer solution is in a thermodynamically stable region and there is no tendency for physical gelation inside the system, thus providing fluid dynamics support for continuous atomization.

[0026] Preferably, the specific implementation of S2 is as follows: Set the absolute humidity of the incoming air to 12 to 15 g / kg dry air and the incoming air temperature to 40°C to 45°C. By reducing the mass transfer driving force at the gas-liquid interface, the evaporation of water is delayed, allowing the polymer chain segments to have sufficient relaxation time for interface self-assembly. This stage is stopped when the volume of the injected suspension reaches 40% to 50% of the total volume. Subsequently, the absolute humidity of the incoming air is reduced to less than 8g / kg of dry air, and the incoming air temperature is linearly increased to 60℃ to 65℃ for forced dehumidification.

[0027] By adopting the above technical solution, the switching point of the humidity-delayed drying stage is defined. When the total volume of the sprayed material is 40% to 50%, the surface of the matrix has completed the initial uniform coating and shaping. At this time, the low humidity and high temperature conditions are switched to improve the drying efficiency while ensuring the uniform spatial distribution of the drug and preventing local agglomeration or bed collapse caused by excessive wetting inside the material bed.

[0028] Preferably, in S1, before adding rebamipide, a composite adhesive solution equivalent to 10% of the total weight of purified water is taken out as a rinsing solution. After the rebamipide is added, the rinsing solution is used to introduce the residue on the pot wall into the liquid phase.

[0029] By adopting the above technical solution, the strong hydrophobic active pharmaceutical ingredient in dry powder form is prevented from adhering to the container wall, reducing material loss during the liquid preparation process and ensuring the consistency of solid content in the liquid stage and the uniformity of tablet content in the final product.

[0030] Preferably, in S2, after the liquid spraying is completed, the inlet air temperature is raised to 75°C to 80°C. When the temperature of the material in the flake bed reaches 50°C, heating is stopped. The material is discharged when the hot air temperature drops to less than or equal to 45°C to complete the shaping of the microstructure.

[0031] By adopting the above technical solution, high heat input is provided in the pure drying stage after the spraying is completed, which promotes the evaporation of residual solvent and drives L-arginine to crystallize and precipitate in situ along the water migration path, thus completing the spatial distribution shaping of the micro-alkaline buffer pool and capillary channel.

[0032] This invention provides a rebamipide tablet formulation and its preparation process. It has the following beneficial effects: 1. This invention utilizes the synergistic effect of L-arginine and the polymer backbone. During the drying process of solid dosage forms, L-arginine crystallizes in situ inside the particles. When the dosage form comes into contact with an acidic gastric juice medium, these L-arginine microcrystals dissolve rapidly, forming not only interconnected dissolution capillary channels inside the particles, but also constructing a microscopic weakly alkaline buffer pool around the rebamipide particles, significantly improving the dissolution rate of rebamipide in acidic media.

[0033] 2. This invention employs a reverse low-temperature high-hydration pulping process at 10℃ to 15℃, ensuring that poloxamer 188, which has a low critical dissolution temperature, and hydroxypropyl cellulose are in a highly hydrated state. The steric network formed by these two components can block hydrophobic association between rebamipide particles, maintaining the homogeneous stability of the suspension. Simultaneously, the low-temperature condition inhibits excessive stretching and physical cross-linking of the polymer chains, maintaining the low-viscosity fluid properties of the liquid before it enters the nozzle, thus mitigating the risk of nozzle gelation caused by high shear forces at the source.

[0034] 3. This invention controls the temperature and humidity gradient through the coupling of hydrothermal dynamics. In the early spreading stage of spraying, a hot airflow with high absolute humidity is introduced, which reduces the gas-liquid mass transfer driving force when water evaporates from the droplet surface. This provides sufficient relaxation time for polymer chain segments to wet the interface and self-assemble, avoiding the premature glass transition of polymers caused by instantaneous evaporation of water, which would lead to the formation of a dense skin. The subsequent low-humidity and high-temperature dehumidification stage completes the shaping of micropores while ensuring uniform coating, reducing the generation of brittle fine powder and wall adhesion loss. Attached Figure Description

[0035] Figure 1 This is a step diagram of the present invention. Detailed Implementation

[0036] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] The composition involved in this preparation process, by mass parts: Rebapat, 100 servings; L-arginine, 5-15 parts; Poloxamer 188, 2–8 copies; Hydroxypropyl cellulose, 10-20 parts; Low-substituted hydroxypropyl cellulose, 30-60 parts; Microcrystalline cellulose, 50-100 parts; Silicon dioxide, 1 to 3 parts; Magnesium stearate, 1-3 parts; Gastric-soluble film-coated powder, 5-10 parts; Purified water, 300-500 parts.

[0038] Please see the appendix Figure 1 The formulation process is based on cold liquid-hygrothermal kinetic coupling technology. The specific process steps and parameters are defined as follows: S1. Add 300-500 parts of purified water to a JBJ-200L stirred tank equipped with a jacketed temperature control system. Turn on the cooling water circulation to lower the water temperature to 10℃-15℃ and maintain it throughout the process. Slowly add 5-15 parts of L-arginine and 2-8 parts of poloxamer 188 in sequence, set the stirring frequency to 20-30Hz, and continue stirring until the solutes are completely dissolved, forming a homogeneous and transparent bottom liquid.

[0039] In the above-mentioned base liquid at 10℃~15℃, turn on the homogenizer and slowly sieve in 10~20 parts of HPC-EF. Maintain homogenization stirring for 45~60 minutes to allow the polymer chain segments to fully expand and hydrate in a low temperature and high humidity environment, thereby obtaining a composite adhesive solution without gel blocks. Take out a solution equivalent to 30~50 parts by weight of purified water for use as rinsing.

[0040] Maintain a homogenization frequency of 30-40 Hz, slowly add 100 parts of micronized rebamipide active pharmaceutical ingredient. After the addition is complete, use a binder solution equivalent to 30-50 parts by weight of purified water to rinse the residual material on the pot wall into the liquid phase. Continue homogenizing and stirring for 20-30 minutes, then turn off the homogenizer and switch to mechanical stirring. Under constant temperature conditions of 10-15℃, perform cold maturation treatment on the suspension for 2-4 hours.

[0041] After maturation, the suspension is passed through a 100-mesh stainless steel sieve under continuous stirring and transferred to a temporary storage tank equipped with a stirring device for later use. The temperature of the liquid is strictly controlled below 15℃ throughout the process, and the storage time does not exceed 24 hours.

[0042] S2. Add 30-60 parts of L-HPC and 50-100 parts of microcrystalline cellulose into the fluidized bed reactor, set the inlet air temperature to 40℃-45℃, and control the air volume at 300-400m³ / h for premixing and preheating until the material bed temperature reaches equilibrium.

[0043] Begin spraying the above-mentioned cold suspension at 10℃~15℃, with the atomization pressure set at 0.10~0.15MPa. During this stage, maintain the fluidized bed inlet air temperature at 40℃~45℃ and adjust the absolute humidity of the inlet air to 12~15g / kg dry air. Stop this stage when the volume of the injected suspension reaches 40%~50% of the total volume.

[0044] Without interrupting the spraying, adjust the AHU system to reduce the absolute humidity of the incoming air to <8g / kg dry air, while linearly increasing the incoming air temperature to 60℃~65℃ and the air volume to 400~600m³ / h. Maintain this state until all the remaining liquid is sprayed out. During this stage, the material temperature should be controlled between 30℃ and 40℃.

[0045] Increase the inlet air temperature to 75℃~80℃, set the air volume to 500~700m³ / h, monitor the material temperature in real time, and immediately stop the system heating when the temperature of the material in the flake bed reaches 50℃; stop the machine and discharge the material when the hot air temperature drops to ≤45℃.

[0046] S3. After drying, the granules are sized by passing them through an S49 type ternary vibrating screen. The granules that pass through the screen are collected, and 1 to 3 parts of silica are added. The mixture is then premixed in a three-dimensional motion mixer for 15 to 20 minutes. Subsequently, 1 to 3 parts of magnesium stearate (calculated) are added, and the mixture is continued to be mixed for 5 minutes before being discharged.

[0047] Adjust the equipment parameters to control the tablet weight difference within ±5% and the radial compressive hardness of the tablets between 60 and 120 N.

[0048] Dissolve 5-10 parts of the gastric-soluble film coating premix in purified water, put the tablets into a high-efficiency coating machine, set the inlet air temperature, and maintain the tablet bed temperature at 40℃-55℃ during the spraying process. After the spraying is completed, dry the tablets at a hot air temperature of 60℃-70℃ for 30 minutes, and control the coating weight gain within the range of 1.0%-2.0%.

[0049] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0050] Rebapate is micronized to achieve a particle size distribution that satisfies D90≤20μm. L-arginine; Poloxamer 188 has an average molecular weight range of 7680 to 9510. Hydroxypropyl cellulose, using EF grade low viscosity type, is a hydroxypropyl etherified polymer of cellulose with an average molecular weight of 80,000. Its 2% aqueous solution has a kinetic viscosity range of 6.0 mPa·s to 10.0 mPa·s at 20°C. Low-substituted hydroxypropyl cellulose, which is a partially substituted hydroxypropyl etherified cellulose polymer with a hydroxypropoxy content ranging from 5.0% to 16.0% by mass.

[0051] The remaining ingredients in the formulation—microcrystalline cellulose, fumed silica, magnesium stearate, gastric-soluble film-coating premix, and purified water—are all well-known substances in the pharmaceutical field with publicly available sources. Their chemical structures and physical properties are clearly defined, and detailed descriptions are omitted here to save space. All raw materials and excipients used above are commercially available pharmaceutical-grade products.

[0052] Preparation Example 1: This preparation example provides a method for preparing a reverse low-temperature high-hydration suspension, including the following steps: Add 400 parts by weight of purified water to a mixing tank equipped with a jacketed temperature control system. Turn on the cooling water circulation to lower the water temperature to 12°C and maintain it throughout the process. Slowly add 10 parts by weight of L-arginine and 5 parts by weight of poloxamer 188 in sequence. Set the stirring frequency to 25 Hz and continue stirring until the solute is completely dissolved to form a bottom liquid.

[0053] Turn on the homogenizer in the base liquid, slowly sieve in 15 parts by weight of hydroxypropyl cellulose, maintain homogenization stirring for 50 minutes to obtain a composite adhesive solution, and take out a solution equivalent to 40 parts by weight of purified water for later use. Maintain the homogenization frequency at 35 Hz, and slowly add 100 parts by weight of micronized rebapide.

[0054] After feeding is complete, the remaining material on the pot wall is rinsed into the liquid phase using the reserved solution. After continuous homogenization and stirring for 25 minutes, the homogenizer is turned off and mechanical stirring is switched to. The suspension is then subjected to cold maturation treatment for 3 hours at a constant temperature of 12°C.

[0055] After maturation, the suspension is passed through a 100-mesh stainless steel sieve under continuous stirring and transferred to a temporary storage tank equipped with a stirring device for later use. The temperature of the liquid is controlled below 15℃ throughout the process.

[0056] Preparation Example 2: This preparation example provides a method for preparing a reverse low-temperature high-hydration suspension, including the following steps: Add 300 parts by weight of purified water to a mixing tank equipped with a jacketed temperature control system. Turn on the cooling water circulation to lower the water temperature to 10°C and maintain it throughout the process. Slowly add 5 parts by weight of L-arginine and 2 parts by weight of poloxamer 188 in sequence. Set the stirring frequency to 20Hz and continue stirring until the solute is completely dissolved to form a bottom liquid.

[0057] Turn on the homogenizer in the base liquid, slowly sieve in 10 parts by weight of hydroxypropyl cellulose, maintain homogenization stirring for 45 minutes to obtain a composite adhesive solution, and take out a solution equivalent to 30 parts by weight of purified water for later use. Maintain the homogenization frequency at 30 Hz, and slowly add 100 parts by weight of micronized rebapide.

[0058] After feeding is complete, the remaining material on the pot wall is rinsed into the liquid phase using the reserved solution. After continuous homogenization and stirring for 20 minutes, the homogenizer is turned off and mechanical stirring is switched to. The suspension is then subjected to cold maturation treatment for 2 hours at a constant temperature of 10°C.

[0059] After maturation, the suspension is passed through a 100-mesh stainless steel sieve under continuous stirring and transferred to a temporary storage tank equipped with a stirring device for later use. The temperature of the liquid is controlled below 15℃ throughout the process.

[0060] Preparation Example 3: This preparation example provides a method for preparing a reverse low-temperature high-hydration suspension, including the following steps: Add 500 parts by weight of purified water to a mixing tank equipped with a jacketed temperature control system. Turn on the cooling water circulation to lower the water temperature to 15°C and maintain it throughout the process. Slowly add 15 parts by weight of L-arginine and 8 parts by weight of poloxamer 188 in sequence. Set the stirring frequency to 30Hz and continue stirring until the solute is completely dissolved to form a base liquid.

[0061] Turn on the homogenizer in the base liquid, slowly sieve in 20 parts by weight of hydroxypropyl cellulose, maintain homogenization stirring for 60 minutes to obtain a composite adhesive solution, and take out a solution equivalent to 50 parts by weight of purified water for later use. Maintain the homogenization frequency at 40 Hz, and slowly add 100 parts by weight of micronized rebapide.

[0062] After feeding is complete, the remaining material on the pot wall is rinsed into the liquid phase using the reserved solution. After continuous homogenization and stirring for 30 minutes, the homogenizer is turned off and mechanical stirring is switched to. The suspension is then subjected to cold maturation treatment for 4 hours at a constant temperature of 15°C.

[0063] After maturation, the suspension is passed through a 100-mesh stainless steel sieve under continuous stirring and transferred to a temporary storage tank equipped with a stirring device for later use. The temperature of the liquid is controlled below 15℃ throughout the process.

[0064] Example 1: This example provides a method for preparing rebamipide tablets based on cold liquid-hygrothermal kinetic coupling, including the following steps: S1. Add 45 parts by weight of low-substituted hydroxypropyl cellulose and 75 parts by weight of microcrystalline cellulose into a multi-functional fluidized bed reactor. Set the inlet air temperature to 42°C, turn on the blower and adjust the air volume to maintain good fluidization of the material for preheating until the material bed temperature reaches equilibrium.

[0065] S2. Using the suspension obtained in Preparation Example 1 as the spray liquid, keep the liquid temperature below 15°C, turn on the top spray, set the absolute humidity of the incoming air to 13 g / kg dry air, and maintain the incoming air temperature at 42°C. Stop this stage when the volume of the sprayed suspension reaches 45% of the total volume.

[0066] S3. Without interrupting the spraying, reduce the absolute humidity of the incoming air to less than 8g / kg dry air, linearly increase the incoming air temperature to 62℃, maintain the fluidization state until all the remaining liquid is sprayed, and control the material temperature between 30℃ and 40℃ during the spraying period.

[0067] S4. Increase the inlet air temperature to 78℃, monitor the material temperature in real time, and stop heating when the material temperature in the flake bed reaches 50℃; stop the machine and discharge the material when the hot air temperature drops to 45℃ or below.

[0068] S5. After drying, the granules are sized through a 24-mesh stainless steel sieve. The granules that pass through the sieve are added to 2 parts by weight of fumed silica and premixed for 20 minutes. Then, 2 parts by weight of magnesium stearate are added and mixed for another 5 minutes before discharging. The tablets are then compressed on a tableting machine using an 8mm die, and the radial compressive hardness of the tablets is controlled between 80N and 100N.

[0069] S6. Dissolve 7.5 parts by weight of gastric-soluble film coating premix in an appropriate amount of purified water to prepare a coating solution. Put the uncoated tablets into the coating machine, set the air inlet parameters to maintain the tablet bed temperature at 45°C to 50°C during the spraying process, and dry at 65°C for 30 minutes after the spraying is completed. The coating weight gain is controlled at 1.5%.

[0070] Example 2: This example provides a method for preparing rebamipide tablets based on cold liquid-hygrothermal kinetic coupling, including the following steps: S1. Add 30 parts by weight of low-substituted hydroxypropyl cellulose and 100 parts by weight of microcrystalline cellulose into a multi-functional fluidized bed reactor, set the air inlet temperature to 40°C, and turn on the blower to maintain the material in a good fluidized state for preheating.

[0071] S2. Using the suspension obtained in Preparation Example 2, keep the liquid temperature below 15°C, turn on the top spray, set the absolute humidity of the incoming air to 12 g / kg dry air, and maintain the incoming air temperature at 40°C. Stop this stage when the volume of the injected suspension reaches 40% of the total volume.

[0072] S3. Without interrupting the liquid spraying, reduce the absolute humidity of the incoming air to less than 8g / kg dry air, linearly increase the incoming air temperature to 60℃, maintain this state until the liquid spraying is completed, and control the material temperature between 30℃ and 40℃.

[0073] S4. After the liquid spraying is completed, raise the air inlet temperature to 75°C. Stop heating when the temperature of the material in the flake bed reaches 50°C. Stop the machine and discharge the material when the hot air temperature drops to 45°C or below.

[0074] S5. After granulation, add 1 part by weight of fumed silica and premix for 15 minutes; add 1 part by weight of magnesium stearate and mix for 5 minutes. Press the mixture into tablets using a die, and control the hardness between 60N and 80N.

[0075] S6. Dissolve 5 parts by weight of the gastrointestinal film coating premix in purified water. During the spraying process, maintain the tablet bed temperature at 40°C to 45°C. After the process, dry at 60°C. The coating weight gain is controlled at 1.0%.

[0076] Example 3: This example provides a method for preparing rebamipide tablets based on cold liquid-hygrothermal kinetic coupling, including the following steps: S1. Add 60 parts by weight of low-substituted hydroxypropyl cellulose and 50 parts by weight of microcrystalline cellulose into a multifunctional fluidized bed reactor, and preheat the reactor by setting the inlet air temperature to 45°C.

[0077] S2. Using the suspension obtained in Preparation Example 3, keep the liquid temperature below 15°C, turn on the spray, set the absolute humidity of the incoming air to 15 g / kg dry air, and maintain the incoming air temperature at 45°C. Stop this stage when the volume of the injected suspension reaches 50% of the total volume.

[0078] S3. Without interrupting the spraying, reduce the absolute humidity of the incoming air to less than 8g / kg dry air, raise the incoming air temperature to 65℃, maintain this state until the liquid is sprayed out, and control the material temperature between 35℃ and 40℃.

[0079] S4. After the liquid spraying is completed, raise the air inlet temperature to 80°C and stop heating when the bed temperature reaches 50°C; stop the machine and discharge the material when the hot air temperature drops to 45°C or below.

[0080] S5. After granulation, add 3 parts by weight of fumed silica and premix for 20 minutes; add 3 parts by weight of magnesium stearate and mix for 5 minutes. The tablet hardness is controlled between 100N and 120N.

[0081] S6. Dissolve 10 parts by weight of coating premix in purified water. Maintain the tablet bed temperature at 50°C to 55°C during the spraying process. After the process, dry at 70°C. Control the coating weight gain to 2.0%.

[0082] Example 4: This example provides a method for preparing rebamipide tablets based on cold liquid-hygrothermal kinetic coupling, including the following steps: The process steps, temperature and humidity parameters, and tableting and coating parameters in this embodiment are exactly the same as those in Example 1. The only difference is the adjustment of the ratio of matrix excipients: in the matrix preheating stage, the materials added to the multifunctional fluidized bed are changed to 50 parts by weight of low-substituted hydroxypropyl cellulose and 90 parts by weight of microcrystalline cellulose to verify the process compatibility of different proportions of hydrophilic matrix skeletons with the high-humidity spreading period of the fluidized bed.

[0083] Comparative Example 1: Compared with Example 1, the difference is that the suspension was prepared at room temperature, L-arginine and poloxamer 188 were not added, the fluidized bed granulation process used conventional air intake at 80°C throughout, and there was no absolute humidity control of the air intake. All other aspects were the same.

[0084] Comparative Example 2: Compared with Example 1, the difference is that 10 parts by weight of L-arginine in the prescription were replaced with citric acid in equal amounts, and the rest were the same.

[0085] Comparative Example 3: The difference from Example 1 is that 5 parts by weight of poloxamer 188 were removed from the formulation, otherwise the same.

[0086] Comparative Example 4: Compared with Example 1, the difference is that the suspension preparation process is carried out at room temperature of 25°C, without the 12°C low-temperature cold curing treatment, and the temperature of the liquid entering the spray gun is not controlled, while the rest are the same.

[0087] Comparative Example 5: Compared with Example 1, the difference is that: in the first stage of the fluidized bed, high humidity control is not performed, and a dry airflow of 42°C with an absolute humidity of less than 8g / kg is directly introduced for spraying, while the rest are the same.

[0088] The technical mechanism and process feasibility verification test of this invention: without relying on microscopic images, purely through macroscopic physicochemical data and equipment operation data, it positively confirms the effectiveness of this innovative mechanism of cold liquid protection and hydrothermal dynamics in the real physical world.

[0089] Test Example 1: Rheology and Sedimentation Volume Ratio Test of Cold Suspension; The suspensions of Examples 1-3, and the suspensions of Comparative Examples 3 and 4.

[0090] Recording the percentage of macroscopic settling height after 24 hours of standing confirms that the system of the embodiment has excellent physical stability against aggregation and settling in the cold state.

[0091] The kinetic viscosity at a specific shear rate was measured using a rotational viscometer, confirming that the example did not gel at low temperatures and the viscosity was at an extremely low level suitable for industrial pumping.

[0092] Test Example 2: Evaluation of fluidized bed spray process smoothness and granulation yield; Examples 1-4, and Comparative Examples 4 and 5.

[0093] Record the number of times the granulation gun is blocked and the machine stops during a single batch granulation process.

[0094] Weighing records show the weight of waste adhering to the fluidized bed boiler wall and the total weight of qualified particles after sieving. The extremely high yield and zero-clogging records objectively demonstrate that the high humidity window period successfully avoided the "skinning and deadlocking" of polymers and premature drying.

[0095] The comprehensive performance advantages of the embodiments and comparative examples were compared and tested. By comparing the various physicochemical indicators of the finished products, the significant advantages of the present invention in clinical drug release and quality control were highlighted by utilizing the numerical differences.

[0096] Test Example 3: Comparative determination of in vitro dissolution in multiple media; Examples 1-3 are finished tablets, and Comparative Examples 1, 2, and 5 are finished tablets.

[0097] The determination was carried out in two conventional dissolution media, pH 1.2 and pH 6.8, using the paddle method.

[0098] Record the cumulative dissolution percentage at the early and final stages.

[0099] The high dissolution rate data of the examples will directly prove the microenvironmental regulation ability of L-arginine; while the extremely low early dissolution rate of Comparative Example 5 will indirectly confirm that without high humidity to delay drying, the drug will indeed be locked by the polymer.

[0100] Test Example 4: Evaluation of inter-batch content uniformity and reproducibility; Example 1 and Comparative Example 1 and Comparative Example 5.

[0101] The percentage of rebamipide labeled in each batch of sampled tablets was determined by high performance liquid chromatography, and the relative standard deviation was calculated.

[0102] The smaller the RSD value, the more uniform the self-assembly of the polymer and drug during the high-humidity spreading period in the fluidized bed, with no dead zones of agglomeration, reflecting the extremely high industrial quality limit of the process.

[0103] Test Example 1: Rheology and Sedimentation Volume Ratio Test of Cold Suspension; The suspensions obtained in the preparation stages of Examples 1 to 3, and the suspensions obtained in the preparation stages of Comparative Examples 3 and 4 were measured and used as independent test samples.

[0104] Accurately measure 100 mL of each group of test samples and slowly inject them into a 100 mL stoppered glass graduated cylinder. Seal the cylinder tightly and place the graduated cylinders of Examples 1 to 3 and Comparative Example 3 in a cold environment consistent with their preparation temperature for constant temperature and stand. Place the graduated cylinder of Comparative Example 4 in a constant temperature environment of 25°C for stand. After standing for 24 hours, read the apparent volume of the lower sediment in each graduated cylinder at eye level and calculate the sedimentation volume ratio. The above determination is performed three times in parallel for each group, and the arithmetic mean is recorded.

[0105] An NDJ type rotary viscometer was used, with an appropriate rotor selected. Each group of test samples was placed in a corresponding constant temperature water bath. After the system temperature was balanced, a fixed shear rate was set to measure the kinetic apparent viscosity of each suspension and record the stable readings.

[0106] Table 1. Sedimentation volume ratio and apparent viscosity test data of each suspension

[0107] According to the data in Table 1, the sedimentation volume ratio of the suspensions obtained in Examples 1 to 3 remained above 0.97 after 24 hours at a low temperature of 10℃ to 15℃, and the apparent viscosity remained stable in the low range of 17.2 mPa·s to 21.8 mPa·s. This confirms that the rebamipide powder formed a highly stable monodisperse homogeneous system in the cold liquid phase without significant flocculation. This result objectively verifies the cold liquid protection mechanism of this scheme: under specific low temperature conditions, poloxamer 188 and hydroxypropyl cellulose, which have low critical dissolution temperature characteristics, are in a highly hydrated state, and the macromolecular chain segments are fully extended. With the intervention of the polar microenvironment of L-arginine, a thick hydration layer of steric hindrance is formed on the surface of the extremely hydrophobic rebamipide particles through self-assembly. This steric hindrance network completely blocks the hydrophobic association between particles. The low apparent viscosity proves that the polymer solution is in the thermodynamically most stable region at this time, and there is no tendency for chemical cross-linking or physical gelation inside the system, which provides reliable fluid dynamic support for the continuous and smooth atomization of the subsequent fluidized bed.

[0108] In contrast, Comparative Example 3, due to the removal of poloxamer 188 from its formulation, showed a significant decrease in sedimentation volume ratio to 0.831. This difference directly confirms that hydroxypropyl cellulose alone cannot provide sufficient interfacial wetting and spatial encapsulation to cover the entire powder surface. The lack of the block copolymer anchoring effect of poloxamer 188 resulted in uncontrolled surface free energy of some drug particles, leading to Oswald ripening and hydrophobic agglomeration sedimentation. Comparative Example 4, prepared at room temperature (25°C), showed a sharp drop in sedimentation volume ratio to 0.745, while its apparent... The viscosity suddenly increased to 85.3 mPa·s. This abrupt change confirms that after breaking the low-temperature cold curing conditions, the polymer's hydration ability significantly declined, the physical entanglement between molecular chains intensified, and the macroscopic viscosity of the liquid soared, completely losing the low viscosity fluid dynamics advantage required for anti-clogging nozzles. At the same time, because the spatial structure was not fully expanded, it could not effectively encapsulate rebappetite, ultimately leading to irreversible flocculation and sedimentation of the particles. The test results fully confirm the absolute necessity of the reverse low-temperature high hydration process of this invention in establishing fluid operability and material stability.

[0109] Test Example 2: Evaluation of the smoothness and granulation yield of fluidized bed spray process.

[0110] Batch preparation operations were carried out according to the fluidized bed granulation process parameters described in Examples 1 to 3 and Comparative Examples 4 to 5, and the continuous operation status of the fluidized bed system and the liquid supply system in each group during the jet suspension stage was monitored.

[0111] Throughout the spray granulation stage, record the number of times the machine was shut down for cleaning due to physical fluid blockage at the nozzle position or abnormal increase in liquid supply pressure, which is recorded as the number of times the machine was shut down; record the number of times the machine was shut down due to complete loss of fluidization state caused by local excessive wetting and agglomeration of material, which is recorded as the number of times the machine collapsed.

[0112] After the drying and granulation process is completed, the total weight of qualified particles sieved through a 24-mesh stainless steel sieve is collected and accurately weighed. This weight is divided by the theoretical total weight of particles designed for this batch of formulation to calculate the effective particle yield. The total weight of the trapped material adhering to the fluidized bed pot wall, guide tube, and collection bag is collected and weighed. This weight is divided by the theoretical total weight of particles to calculate the pot wall adhesion rate.

[0113] Table 2. Operating parameters and yield data of fluidized bed spray granulation process for each group.

[0114] According to the data in Table 2, under the set temperature and humidity gradient fluidized bed process, Examples 1 to 3 did not experience nozzle clogging or bed collapse. The effective particle yield was consistently above 94.67%, and the pot wall adhesion rate was controlled below 4.11%. This objectively demonstrates the engineering applicability of the humidity-delayed drying and polymer relaxation kinetic matching mechanism. During the spreading period, a hot gas flow with an absolute humidity of 12 g / kg to 15 g / kg was introduced, which reduced the gas-liquid mass transfer driving force when water evaporated from the droplet surface. When the cold suspension came into contact with the preheated matrix, a forced slowed phase change volatilization occurred. The plasticized water retained in the system prolonged the relaxation time of hydroxypropyl cellulose and poloxamer 188 molecules. The polymer network completed uniform monolayer self-assembly wetting on the surface of the drug particles, effectively preventing local enrichment of the binder, thereby ensuring uniform adhesion between powders and maximizing the control of fine powder entrainment and wall adhesion loss.

[0115] Comparative Example 4 experienced 5 nozzle blockages and 2 bed collapses in fluidized bed spraying, resulting in a yield drop to 72.41%. This deviation confirms that the suspension prepared at room temperature lacks the low-viscosity fluid dynamic advantages provided by cold hydration. Under the combined effects of high shear force and heat transfer in the delivery pipeline and inside the nozzle, the polymer chain segments entangle and gel, blocking the atomization channel. Nozzle dripping caused an abnormal surge in local matrix water content, ultimately leading to the collapse of the flow field within the fluidized bed. Comparative Example 5 eliminated the high-humidity environment control during the spreading period, resulting in a lower adhesion rate to the pot wall. The effective particle yield decreased to 80.25% after the humidity rose to 15.68%. This result reflects that under the instantaneous flash evaporation effect of low humidity and hot air, the evaporation rate of water in the droplets exceeded the conformational rearrangement rate of the macromolecular chains. The polymer film was forced to undergo glass transition prematurely and form a hydrophobic skin, which not only hindered the uniform coating of drug particles, but also led to a decrease in adhesion during the granulation process. A large amount of brittle fine powder was drawn into the bag by the exhaust system or adsorbed onto the pot wall due to electrostatics. This, in turn, confirms the decisive influence of high humidity and delayed drying on the microstructure shaping and macroscopic process yield.

[0116] Test Example 3: Comparative determination of in vitro dissolution in multiple media.

[0117] Prepare the experimental equipment according to the paddle method of dissolution determination as specified in the current Chinese Pharmacopoeia. Prepare hydrochloric acid solution with pH 1.2 and phosphate buffer solution with pH 6.8 as in vitro dissolution media. For each experiment, take 900 mL of dissolution media and inject it into the dissolution cup. Turn on the water bath to heat and maintain the system temperature at 37℃±0.5℃.

[0118] The finished rebamipide tablets prepared in Examples 1 to 3, as well as the tablets prepared in Comparative Examples 1, 2 and 5, were taken as test samples. The stirring speed was set to 50 rpm, and each test sample was put into the corresponding dissolution vessel and the timing was started.

[0119] At the designated time points of 15, 30 and 45 minutes after drug administration, 5 mL of dissolution solution was accurately taken from the designated sampling point of each dissolution vessel as the sample to be tested. At the same time, the same volume and temperature of the dissolution vessel were added to the dissolution vessel. The sample was then filtered through a 0.45 μm microporous membrane and the filtrate was collected.

[0120] High-performance liquid chromatography (HPLC) was used to quantitatively analyze the concentration of rebamipide in the test samples. The chromatographic conditions were set as follows: an octadecylsilane-bonded silica column was used, and isocratic elution was performed using a specific ratio of buffer salt and organic solvent as the mobile phase. The detection wavelength was set at the specific absorption peak of rebamipide. The peak area was recorded and substituted into the standard curve to calculate the cumulative dissolution percentage at each time point. All test groups were measured in parallel with six tablets, and the arithmetic mean was taken as the dissolution data at that time point.

[0121] Table 3. Cumulative dissolution percentage data of each group of test samples in different pH media.

[0122] According to the data in Table 3, the early dissolution rate of Examples 1 to 3 in simulated gastric juice medium at pH 1.2 exceeded 75% at 15 minutes and reached over 94% at 45 minutes. They also exhibited extremely rapid and complete drug release characteristics in medium at pH 6.8. Rebamipide itself is an extremely hydrophobic weakly acidic drug with extremely poor thermodynamic solubility in low pH environments. The data from these examples verified the microenvironment pH and capillary channel construction mechanism dominated by the in-situ crystallization precipitation of L-arginine within the polymer backbone after liquid suspension and hot air drying. Solid-phase L-arginine dissolves rapidly upon contact with the dissolution medium, forming numerous microscale weakly alkaline buffer pools around the rebamipide particles. This neutralizes the infiltrated acidic medium, thereby forcibly increasing the microenvironment pH in this region, breaking the dissolution barrier of the weakly acidic drug in gastric acid, and establishing a concentration gradient conducive to the dissociation and precipitation of drug molecules.

[0123] Comparative Example 1 represents the product prepared by a conventional process that does not include the technical solution of this application. Its dissolution rate in a pH 1.2 medium was only 22.3% after 15 minutes. The significant difference between the two confirms the absence of a cold liquid homogeneous dispersion process and alkaline microenvironment intervention. The extremely hydrophobic API forms dense aggregates inside the particles, making it difficult for the medium to effectively wet and penetrate, resulting in delayed drug release. Comparative Example 2 replaced L-arginine with citric acid in equal amounts, and its dissolution rate in a pH 1.2 medium dropped further to 14.5% after 15 minutes. This data difference, in turn, confirms the specificity and irreplaceability of L-arginine's micro-acid-base regulation. The introduction of citric acid further reduced the pH of the microenvironment inside the particles, exacerbating the molecular polymerization state of rebamipide. Not only did it fail to promote dissolution, but it also completely blocked the dissolution channels with undissolved drug powder.

[0124] Comparative Example 5 eliminated the high-humidity environment control during the spreading stage in the fluidized granulation process, resulting in a sharp drop in early drug release rates in both dissolution media. The dissolution rates at 15 minutes under pH 1.2 and pH 6.8 conditions were only 38.7% and 45.3%, respectively. This macroscopic test data fully verifies the key role of the matching mechanism between humidity-delayed drying and polymer relaxation kinetics. Due to the lack of forced plasticization and moisture retention during the high-humidity window, the water in the droplets flashed instantly upon contact with the tablet bed. The polymer segments were forced to cross the glass transition temperature before fully spreading and wetting the drug particles, freezing on the matrix surface to form a dense and irregular hydrophobic skin. This skin significantly increased the steric hindrance for the dissolution medium to penetrate into the particle interior, causing the drug to be locked by the polymer network. Examples 1 to 3, through precise coupling of hydrothermal kinetics, provided sufficient relaxation time for the macromolecules, ensuring the uniformity of the coating layer and the connectivity of pores, thus eliminating the early dissolution lag phenomenon at the physical structure level.

[0125] Test Example 4: Evaluation of inter-batch content uniformity and reproducibility.

[0126] Ten tablets were randomly selected from each of the three independent batches of finished tablets prepared in Example 1 as test samples; ten tablets were randomly selected from each of the finished tablets prepared in Comparative Example 1 and Comparative Example 5 as control test samples.

[0127] Take each tablet separately and grind it finely in a dry mortar. Quantitatively transfer the powder to a 100mL volumetric flask, add an appropriate amount of methanol-water mixed solvent to the volumetric flask, sonicate for 20 minutes to completely dissolve the rebamipide, cool to room temperature, and then dilute to the mark with the above mixed solvent. Shake well, filter the extract through a 0.45μm microporous membrane, discard the initial filtrate, and use the subsequent filtrate as the test solution.

[0128] The determination was performed using high performance liquid chromatography (HPLC). The chromatographic column was an octadecylsilane-bonded silica column, and the mobile phase was an isocratic elution system consisting of a phosphate buffer and acetonitrile in a specific ratio. The detection wavelength was set to 227 nm.

[0129] Accurately measure the reference solution and each test solution and inject them into the liquid chromatograph. Record the chromatograms. Calculate the actual content of rebamipide in each tablet by peak area using the external standard method and convert it into a percentage of the labeled amount. Summarize the data of each group and calculate the relative standard deviation of the content of 10 tablets in a single batch.

[0130] Table 4. Test data on the content distribution and uniformity of rebamipide tablets in each batch of test samples.

[0131] According to the data in Table 4, in three consecutive independent production batches of Example 1, the single-tablet content measurements were closely distributed within a narrow range of 97.9% to 101.5%, and the relative standard deviations of each batch were distributed between 1.05% and 1.08%, with no abnormal extreme values ​​exceeding the control limits. This data confirms the effectiveness of this technical solution in solving the uniformity problem in the large-scale production of poorly soluble drug formulations. The high uniformity of the bottom layer of the example stems from the coupling effect of reverse low-temperature high-hydration pulping and temperature and humidity gradient fluidized bed process. In the feed preparation stage, low temperature suppression... The excessive stretching and physical cross-linking of polymer chains were controlled, ensuring that the suspension containing extremely hydrophobic drug particles remained in a highly homogeneous and low-viscosity fluid state before entering the nozzle. This eliminated the drug concentration gradient within the supply system at the source. During the spray granulation stage, the high absolute humidity environment reduced the evaporation rate, providing the polymer solution with sufficient relaxation time to fully wet and spread on the surface of the matrix matrix such as microcrystalline cellulose. This ensured that the micron-sized droplets containing rebamipide and L-arginine could be uniformly coated on the surface of the excipients, avoiding the formation of localized high-concentration drug agglomerates.

[0132] Comparative Example 1 did not employ the composite stabilization mechanism and temperature / humidity control described in this application. Its single-piece content determination showed drastic fluctuations ranging from 85.1% to 108.4%, with a relative standard deviation of 8.52%, failing to meet the pharmacopoeia's requirements for uniformity of formulation content. The test data reflected severe flocculation and sedimentation of the hydrophobic drug powder in the aqueous phase under conventional processes, leading to inconsistent solid content in the liquid at different stages of the fluidized bed injection. Conventional high-temperature drying caused localized over-wetting and adhesion within the material bed, resulting in a severe imbalance in the distribution of the drug in the final particles. Comparative Example 5 removed... The relative standard deviation of the fluidized bed high-humidity spreading period control increased to 5.34%. This deviation confirms that under the action of instantaneous flash evaporation of low-humidity hot air, the water in the droplets undergoes rapid phase change, the polymer undergoes premature glass transition to form a skin, and some droplets are dried into brittle fine powder with extremely high drug content before reaching the tablet bed. Subsequently, a segregation effect occurs in the fluidized airflow, and the powder is drawn away by the exhaust air or randomly carried into some particles, which destroys the macroscopic quality uniformity of the formulation. This result demonstrates the engineering significance of the high-humidity delayed drying mechanism for establishing the spatial distribution uniformity of active ingredients.

[0133] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A rebamipide tablet formulation, characterized in that, It is made from raw materials containing the following parts by weight: 100 parts rebamipide; 5-15 parts L-arginine; 2-8 parts poloxamer; 10-20 parts hydroxypropyl cellulose; 30-60 parts low-substituted hydroxypropyl cellulose; 50-100 parts microcrystalline cellulose; 1-3 parts silicon dioxide; and 1-3 parts magnesium stearate.

2. The rebamipide tablet formulation according to claim 1, characterized in that, The rebamipide is a raw material obtained through micronization pretreatment, and its particle size distribution satisfies D90≤20μm.

3. The rebamipide tablet formulation according to claim 1, characterized in that, The hydroxypropyl cellulose is an EF grade low viscosity type with an average molecular weight of 80,000, and its kinetic viscosity ranges from 6.0 mPa·s to 10.0 mPa·s in a 2% aqueous solution at 20°C; the hydroxypropoxy group mass fraction of the low-substituted hydroxypropyl cellulose ranges from 5.0% to 16.0%.

4. The rebamipide tablet formulation according to claim 1, characterized in that, The poloxamer 188 is a block copolymer of polyoxyethylene a, polyoxypropylene b, and polyoxyethylene a, with an average molecular weight ranging from 7680 to 9510.

5. The rebamipide tablet formulation according to claim 1, characterized in that, The cumulative dissolution rate of the formulation is ≥75% in hydrochloric acid medium at pH 1.2 for 15 minutes, and the radial compressive hardness of the finished tablets is controlled between 60N and 120N.

6. A preparation process for a rebamipide tablet formulation, wherein the rebamipide tablet formulation according to any one of claims 1-5 is characterized in that, Includes the following steps: S1. At 10℃~15℃, L-arginine, poloxamer 188 and hydroxypropyl cellulose are dissolved to form a composite adhesive solution. Rebamipide is added and the mixture is cold-cured for 2~4 hours to obtain a suspension. S2. Low-substituted hydroxypropyl cellulose and microcrystalline cellulose are added to a fluidized bed for preheating and sprayed into the suspension obtained in S1. Granulation is carried out by adjusting the absolute humidity and temperature of the incoming air in stages. S3. The obtained granules are mixed with silicon dioxide and magnesium stearate and then compressed into tablets.

7. The preparation process of a rebamipide tablet formulation according to claim 6, characterized in that, In S1, the temperature of the suspension is controlled below 15°C throughout the entire preparation process, and the apparent viscosity of the suspension is stable between 17.2 mPa·s and 21.8 mPa·s under the condition of 10°C to 15°C, so as to ensure that poloxamer 188 is in a highly hydrated state.

8. The preparation process of a rebamipide tablet formulation according to claim 6, characterized in that, The specific implementation method of S2 is as follows: The absolute humidity of the incoming air is set to 12-15 g / kg dry air, and the air temperature is 40℃-45℃. By reducing the mass transfer driving force at the gas-liquid interface, the evaporation of water is delayed, allowing the polymer chain segments to have sufficient relaxation time for interface self-assembly. This stage is stopped when the volume of the injected suspension reaches 40%-50% of the total volume. Subsequently, the absolute humidity of the incoming air is reduced to <8g / kg dry air, and the incoming air temperature is linearly increased to 60℃~65℃ for forced dehumidification.

9. The preparation process of a rebamipide tablet formulation according to claim 6, characterized in that, In S1, before adding rebapate, a composite adhesive solution equivalent to 10% of the total weight of purified water is taken out as a rinsing solution. After the rebapate is added, the rinsing solution is used to introduce the residue on the pot wall into the liquid phase.

10. The preparation process of a rebamipide tablet formulation according to claim 6, characterized in that, In S2, after the liquid spraying is completed, the inlet air temperature is raised to 75℃~80℃. When the temperature of the material in the flake bed reaches 50℃, heating is stopped. The material is discharged when the hot air temperature drops to ≤45℃ to complete the shaping of the microstructure.

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