Coating composition, preparation method and coating process for enteric-coated aspirin tablets

Abstract

This application relates to the field of pharmaceutical coating technology, and discloses a coating composition, preparation process, and coating process for enteric-coated aspirin tablets. The coating composition includes hydroxypropyl methylcellulose acetate succinate, triethyl citrate, and polyvinylpyrrolidone. Through synergistic stabilization by plasticizers and interface stabilizers, and a three-stage gradient coating process, the stability of the coating solution, the flexibility of the film layer, and the acid resistance integrity are improved, while reducing aspirin hydrolysis and salicylic acid impurity formation, thus enhancing the long-term storage stability of the product.

Description

Technical Field

[0001] This invention relates to the technical field of enteric-coated aspirin tablets, and in particular to a coating composition, preparation method, and coating process for enteric-coated aspirin tablets. Background Technology

[0002] Aspirin is a commonly used nonsteroidal anti-inflammatory drug (NSAID) in clinical practice, possessing antipyretic, analgesic, anti-inflammatory, and antiplatelet aggregation effects. It is widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases. However, because aspirin itself is highly acidic, ordinary tablets can easily irritate the gastric mucosa after disintegrating in the stomach. Long-term use can easily lead to adverse reactions such as stomach discomfort, gastric ulcers, and even gastric bleeding. Therefore, current technologies typically employ enteric coating to encapsulate the aspirin tablet core, ensuring the drug remains stable and does not release in the acidic environment of the stomach, while rapidly disintegrating and releasing in the alkaline environment of the intestine. This reduces gastrointestinal irritation and improves drug safety and patient compliance.

[0003] Currently, enteric coating materials mostly utilize methacrylate-ethyl acrylate copolymers and their aqueous dispersion systems. These materials exhibit good acid resistance and enteric release characteristics, maintaining the integrity of the coating film in the stomach and achieving rapid dissolution under intestinal pH conditions. Therefore, they are widely used in formulations such as enteric-coated aspirin tablets and diclofenac sodium enteric-coated tablets. To improve the film-forming properties of these polymers, existing technologies typically incorporate hydrophobic polyol ester plasticizers to lower the polymer's glass transition temperature and enhance film flexibility and resistance to cracking.

[0004] However, existing coating systems still have significant drawbacks. Methacrylate-ethyl acrylate copolymers are inherently brittle anionic polymers, and their film-forming process is highly dependent on the softening effect of plasticizers on polymer segments. While existing systems use hydrophobic polyol esters as plasticizers, these plasticizers have poor compatibility with high-water-content systems. Under conditions of high distilled water content, micro-phase separation easily occurs, leading to insufficient storage stability of the coating solution and problems such as emulsion stratification, viscosity drift, and localized aggregation. Furthermore, during prolonged stirring, circulation, or spray coating, plasticizers are prone to migration, causing differences in the flexibility of the coating film in different areas. This results in localized stress concentration in the film layer, ultimately causing a decrease in the mechanical strength of the coating film, fluctuations in acid resistance, and even film cracking. In addition, insufficient plasticizer dispersion stability can easily lead to uneven droplet size during spraying, causing fluctuations in coating thickness and further affecting product dissolution consistency and batch stability. Summary of the Invention

[0005] This application provides a coating composition for enteric-coated aspirin tablets, comprising the following components by weight percentage: Hydroxypropyl methylcellulose acetate succinate 12-22%; Distilled water 68-82%; Plasticizer 1-6%; Interface stabilizer 0.1-3%; Filler 1-6%; pH adjuster 0.05-0.5%; The plasticizer is triethyl citrate; the interface stabilizer is polyvinylpyrrolidone.

[0006] It should be noted that this application uses hydroxypropyl methylcellulose acetate succinate (HPMCAS) as the main material for enteric coating, and constructs a synergistic stabilization coating system in conjunction with triethyl citrate plasticizer and polyvinylpyrrolidone interface stabilizer. HPMCAS not only provides enteric acid resistance but also improves interfacial compatibility with the plasticizer through its ester and succinyl groups, reducing the film flexibility fluctuations caused by plasticizer migration and redistribution in traditional enteric coating systems. Polyvinylpyrrolidone further stabilizes the interfacial relationship between the plasticizer and the high-water-content system. A stable interface layer is formed, inhibiting the micro-phase separation and local aggregation of plasticizers, thereby improving the storage stability and spray uniformity of the coating solution. At the same time, by controlling the system to a weakly acidic to near-neutral environment through pH adjustment agents, the corrosive effect of excessive ionization of HPMCAS segments and the local acidic environment of aspirin on the film layer can be reduced, thereby improving the long-term acid resistance integrity and storage stability of the coating film. Therefore, this application is not a simple replacement of enteric coating materials, but rather a construction of an interface synergistic stabilization system that can inhibit plasticizer migration, alleviate film embrittlement, and improve the long-term stability of the coating.

[0007] In a preferred embodiment of a coating composition for enteric-coated aspirin tablets, the hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 5-12% and a succinyl substitution degree of 10-18%.

[0008] It should be noted that by limiting the degree of acetyl substitution of hydroxypropyl methylcellulose acetate succinate to 5-12% and the degree of succinyl substitution to 10-18%, the hydrophobicity and ionization ability of the polymer can be balanced, thereby improving its interfacial compatibility with plasticizers and reducing film embrittlement and acid resistance fluctuations caused by plasticizer migration during the storage of the coating film.

[0009] In a preferred embodiment of a coating composition for enteric-coated aspirin tablets, the amount of the interface stabilizer added is 10-50% of the mass of the plasticizer.

[0010] It should be noted that controlling the amount of interface stabilizer added to 10-50% of the plasticizer mass can form a stable interface layer between the plasticizer and the high water content coating system, reduce the problem of local aggregation of plasticizer and micro-phase separation, thereby improving the storage stability of the coating solution and the consistency of film flexibility.

[0011] A preferred technical solution for a coating composition of enteric-coated aspirin tablets is that the filler is one or two of talc, titanium dioxide, or colloidal silica.

[0012] It should be noted that using talc, titanium dioxide, or colloidal silica as fillers can improve the density and structural uniformity of the coating film, and reduce the risk of microcrack formation caused by local stress concentration inside the film, thereby improving the acid resistance integrity and long-term stability of the coating film.

[0013] In a preferred embodiment of a coating composition for enteric-coated aspirin tablets, the pH adjuster is one or two of ammonia, sodium bicarbonate, or sodium hydroxide.

[0014] It should be noted that by adjusting the pH of the system with ammonia, sodium bicarbonate or sodium hydroxide, the excessive ionization of hydroxypropyl methylcellulose acetate succinate segments and the corrosive effect of the local acidic environment of aspirin on the film layer can be reduced, thereby improving the dispersion stability of the coating system and the long-term acid resistance of the film layer.

[0015] This application provides a process for preparing a coating composition, characterized by comprising the following steps: S1. Hydroxypropyl methylcellulose acetate succinate was added to distilled water and stirred and dispersed at 25-45°C to obtain a polymer dispersion system; S2. Premix the plasticizer and the interface stabilizer at 40-65℃ for 10-60 min to obtain the plasticized stabilized liquid; S3. Under stirring conditions, the plasticizer stabilizer is slowly added to the polymer dispersion system obtained in step S1 to reduce local aggregation of plasticizer. S4. Add filler to the system obtained in step S3 and disperse it using a staged variable speed stirring method to improve the uniformity of filler dispersion in the coating system. S5. Add a pH adjuster to adjust the pH of the system to 5.0-6.0, and obtain the enteric-coated composition after degassing and filtration.

[0016] It should be noted that by pre-mixing the plasticizer and interface stabilizer to form a plasticized stabilized liquid, a stable interface structure can be formed before the plasticizer enters the high water content polymer system, reducing the local aggregation and micro-phase separation problems of the plasticizer in the aqueous phase. Subsequently, the instantaneous concentration fluctuation of the plasticizer is further reduced by slow addition, improving its dispersion uniformity in the HPMCAS system. At the same time, combined with the staged variable speed stirring and dispersion process of the filler, the stress concentration problem of the film layer caused by filler agglomeration and local deposition can be reduced, thereby improving the density and flexibility consistency of the coating film. In addition, by controlling the pH of the system at 5.0 to 6.0, the corrosive effect of excessive ionization of HPMCAS segments and the local acidic environment of aspirin on the film layer can be reduced, thereby improving the storage stability of the coating liquid and the long-term acid resistance integrity of the coating film. Therefore, the preparation process of this application can effectively inhibit plasticizer migration and film performance fluctuation, and improve the long-term stability of the aspirin enteric coating system.

[0017] In a preferred technical solution for the preparation process of a coating composition, the plasticizer stabilizer is added in step S3 for 15 to 90 minutes.

[0018] It should be noted that in step S3, the addition time of the plasticizer stabilizer is controlled to be 15-90 min, which can reduce the problem of excessive local concentration and interface instability caused by instantaneous addition of plasticizer, thereby improving the dispersion uniformity of plasticizer in HPMCAS system and reducing the risk of plasticizer migration and flexibility fluctuation in subsequent film layers.

[0019] As a preferred technical solution for the preparation process of a coating composition, the staged variable speed stirring in step S4 includes: first stirring at 300-800 rpm for 5-20 min; then stirring at 1000-3000 rpm for 10-40 min; and finally stirring at 200-500 rpm for 5-15 min.

[0020] It should be noted that step S4 adopts a staged variable speed stirring method, which can reduce the problems of filler agglomeration and bubble entrainment through the synergistic effect of low-speed pre-dispersion, high-speed deagglomeration and low-speed steady-state degassing, thereby improving the dispersion uniformity of filler in the coating system and the compactness of the film structure.

[0021] In a preferred technical solution for the preparation process of a coating composition, the filler in step S4 is added in two parts: 30-70% of the total amount is added in the first part, and the remaining part is added in the second part.

[0022] It should be noted that the filler in step S4 is added in two stages, which can reduce the problems of local agglomeration and insufficient shear dispersion caused by one-time filling of filler, thereby improving the spatial distribution uniformity of filler in the coating film and reducing the risk of microcrack formation caused by local stress concentration in the film layer.

[0023] In addition, a coating process for enteric-coated aspirin tablets includes the following steps: Step S1. Preheating the coating machine under no-load: Control the air inlet temperature to 50℃, the negative pressure inside the pot to -70~-130Pa, the coating machine speed to 1rpm, turn on the dehumidification device, and feed the material after the air inlet humidity is ≤15%; Step S2. Coating material feeding: Put the drug tablet core into the high-efficiency coating machine, adjust the position of the spray gun so that the distance from the nozzle to the tablet bed is 25±5cm, and make the spray area aim at the upper part of the middle of the tablet bed; Step S3. Preheat the wafer core: After controlling the wafer core temperature to reach 40℃, preheat the wafer core for 10 minutes and check the wafer core weight; Step S4. First stage of coating: Control the initial flow rate of the peristaltic pump to 200 mL / min, the speed of the coating machine to 3 rpm, and the inlet air temperature to 45℃. Increase the flow rate by 20 mL / min every 10 minutes until the tablet core temperature drops to 34℃. Adjust the speed of the coating machine by 1 rpm each time according to the fluidity of the tablet core, and fine-tune the inlet air temperature according to the tablet core temperature of 30-34℃. When the coating weight gain reaches 2±0.5%, proceed to the next stage. Step S5. Second stage of coating: Adjust the coating machine speed to 6 rpm, and increase the flow rate by 20 mL / min based on the first stage, increasing by 20 mL / min every 10 minutes; when the tablet core temperature drops to 30℃, simultaneously increase the inlet air temperature to 50℃ each time the flow rate is increased; adjust the flow rate according to the tablet core temperature of 28~32℃, adjusting by 20 mL / min each time; when the coating weight gain reaches 6±0.5%, proceed to the next stage; Step S6. Coating Stage 3: Based on the second stage, increase the flow rate by 20 mL / min again, and increase it by 20 mL / min every 10 min until the tablet core temperature drops to 27℃; adjust the flow rate according to the tablet core temperature of 25-30℃, adjusting by 20 mL / min each time; stop spraying when the coating weight gain reaches 13%-15%; Step S7. Curing: Adjust the coating machine speed to 4 rpm, control the core temperature to 40-45℃, and cure for 2 hours to achieve a coating weight gain of 12%-15% after curing.

[0024] It should be noted that in step S1, by controlling the inlet air temperature, negative pressure inside the coating machine, and inlet air humidity, a low-humidity and stable environment is created before feeding the aspirin tablet core. This reduces the risk of the aspirin tablet core absorbing moisture during the initial coating process, avoiding localized adhesion, uneven coating, and drug hydrolysis caused by fluctuations in the surface moisture content of the tablet core during subsequent coating. It also improves the stability of the subsequent spray film formation. In step S2, by limiting the distance between the spray gun and the tablet bed and directing the spray area towards the upper center of the tablet bed, the droplets form a uniform coverage area on the tablet bed surface. This reduces the risk of tablet cores becoming overly wet and sticking due to concentrated localized spraying, while also improving the uniformity of the coating solution distribution in the tablet bed, which is beneficial for forming a continuous and uniform coating film. In step S3, by preheating the tablet core to 40°C and maintaining this temperature for 10 minutes, the surface temperature of the tablet core becomes uniform and stable, improving the solvent evaporation efficiency during the initial spraying stage. This reduces the risk of tablet core adhesion caused by localized over-wetting during the initial spraying stage, and also facilitates the uniform spreading and adhesion of the coating film on the tablet core surface. In steps S4 to S6, by setting three progressively increasing weight ranges of 2±0.5%, 6±0.5%, and 13%–15%, the coating film is gradually spread and densified layer by layer, forming a gradient composite film structure. Specifically, the first stage achieves uniform priming on the tablet core surface, reducing exposed areas; the second stage reinforces the film thickness, improving overall film continuity; and the third stage seals pores, reducing internal defects and micropores, thereby improving the acid resistance and integrity of the coating layer. Compared to traditional single-stage rapid thickening methods, the gradient film structure formed in this application exhibits a smaller coating thickness fluctuation range, effectively improving quality consistency between batches and different batches, and reducing product defect rates. In steps S4 to S6, the tablet core temperature is controlled within the ranges of 30–34℃, 28–32℃, and 25–30℃, respectively, and the core temperature is gradually reduced as the coating process progresses, allowing the aspirin tablet core to remain in a low-humidity and heat load environment for extended periods. Because aspirin is prone to hydrolysis and the formation of salicylic acid impurities under humid and hot conditions, this application effectively reduces the risk of aspirin hydrolysis and degradation, reduces the formation of salicylic acid impurities, and improves the control level of related substances and long-term storage stability of the product through staged temperature control and linkage adjustment of spray flow rate and inlet air temperature. Steps S4 to S6 employ a coating pan rotation speed and spray flow rate control method matched to the coating stage, forming a dynamic linkage mode of low-speed, low-flow base coating, medium-speed, medium-flow thickening, and high-speed, controllable-flow sealing. Specifically, the lower rotation speed and flow rate in the initial stage reduce the risk of tablet core collision and adhesion; the increased flow rate and rotation speed in the intermediate stage improve film thicknessing efficiency; and the higher rotation speed combined with controllable flow rate in the later stage achieves film sealing and uniform curing, thereby avoiding tablet wear and coating layer peeling caused by high-speed turning later, improving tablet appearance integrity and finished product qualification rate.Steps S4 to S6 establish a three-parameter linkage dynamic control mechanism for the spray flow rate, inlet air temperature, and coating pan rotation speed. Using the wafer core temperature as the core control benchmark, the spray flow rate is increased in steps every 10 minutes. Simultaneously, the inlet air temperature and spray flow rate are fine-tuned in real time based on the wafer core temperature, achieving a dynamic thermal balance between the spray rate and heat input. When the wafer core temperature is too high, the spray flow rate is reduced; when the wafer core temperature is too low, the inlet air temperature is increased and the spray flow rate is adjusted. This reduces problems such as localized over-wetting, insufficient spray drying, and film defects caused by parameter fluctuations in traditional coating processes, improving coating film stability and batch consistency. In step S7, by controlling the tablet core temperature to 40-45℃ and curing for 2 hours, the coating film can be further fused and densified, allowing residual moisture inside the film to be gradually released and reducing the accumulation of local internal stress during the curing process. This improves the mechanical stability of the coating film and its acid resistance integrity after long-term storage, making the formed coating layer less prone to dissolution and penetration in the acidic environment of the stomach within 2 hours. This effectively avoids premature release of aspirin, reduces the risk of gastrointestinal irritation, and improves the safety of the product.

[0025] This application utilizes hydroxypropyl methylcellulose acetate succinate as the main material for enteric coating, combined with a triethyl citrate / polyvinylpyrrolidone interface synergistic stabilization system and a three-stage gradient coating process. This effectively reduces the local aggregation and migration of plasticizers in high-water-content coating systems, improves the storage stability and spray uniformity of the coating solution, and forms an enteric film layer with high flexibility, dense structure, and excellent acid resistance and integrity. This reduces the risk of hydrolysis of aspirin during coating and storage, reduces the generation of salicylic acid impurities, and improves the long-term storage stability, acid resistance, and batch consistency of enteric tablets. Detailed Implementation

[0026] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0027] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0028] Secondly, the term "an embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places throughout this specification does not necessarily refer to the same embodiment, nor is it a single embodiment or an embodiment selectively excluded from other embodiments.

[0029] Example 1

[0030] This embodiment provides a coating composition for enteric-coated aspirin tablets, comprising the following components by weight percentage: 12% hydroxypropyl methylcellulose acetate succinate; 82% distilled water; 1% triethyl citrate; 0.1% polyvinylpyrrolidone; 1% talc; and 0.05% ammonia. The hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 5% and a succinyl substitution degree of 10%, and the amount of polyvinylpyrrolidone added is 10% of the mass of triethyl citrate.

[0031] The preparation process of the coating composition described in this embodiment includes the following steps: Step S1: Slowly add 12 kg of hydroxypropyl methylcellulose acetate succinate to 82 kg of distilled water and stir at 300 rpm for 40 min at 25 °C using a paddle stirrer to fully wet and uniformly disperse the polymer to obtain a polymer dispersion system. Step S2: Add 1 kg of triethyl citrate and 0.1 kg of polyvinylpyrrolidone to a premixing tank and stir and premix at 40°C for 10 min to obtain a uniform and transparent plasticized stabilized liquid. Step S3: Under continuous stirring of the polymer dispersion system, the plasticizer stabilizer is slowly added to the system over 15 minutes using a metering pump. During the addition process, the stirring speed is maintained at 400 rpm to reduce local aggregation of the plasticizer. Step S4: Add 1 kg of talc powder to the system obtained in step S3 and disperse it by staged variable speed stirring. First, stir at 300 rpm for 5 min for pre-dispersion, then stir at 1000 rpm for 10 min for high-speed depolymerization, and finally stir at 200 rpm for 5 min for steady-state degassing. In step S5, 0.05 kg of ammonia water was added to adjust the pH of the system to 5.0. After filtering through a 100-mesh sieve, the mixture was allowed to stand for 30 minutes to remove bubbles, thus obtaining the enteric coating composition.

[0032] This embodiment also provides a coating process for enteric-coated aspirin tablets, including the following steps: Step P1: Preheat the coating machine under no-load conditions, control the air inlet temperature to 50℃, the negative pressure inside the pot to -70Pa, the coating machine speed to 1rpm, turn on the dehumidification device, and feed the material after the air inlet humidity is ≤15%. Step P2: Put the aspirin tablet core into the high-efficiency coating machine, adjust the position of the spray gun so that the distance between the nozzle and the tablet bed is 20cm, and make the spray area aim at the upper part of the middle of the tablet bed; Step P3: After controlling the core temperature to reach 40°C, preheat the core for 10 minutes and check the initial weight of the core. In step P4, during the first stage of coating, the initial flow rate of the peristaltic pump is controlled at 200 mL / min, the coating machine speed is 3 rpm, and the inlet air temperature is 45℃. The flow rate is increased by 20 mL / min every 10 minutes until the core temperature drops to 34℃. When the coating weight gain reaches 1.5%, the next stage begins. Step P5: In the second stage of coating, adjust the coating machine speed to 6 rpm and increase the flow rate by 20 mL / min based on the first stage, increasing by 20 mL / min every 10 minutes; when the core temperature drops to 30°C, simultaneously increase the inlet air temperature to 50°C; when the coating weight gain reaches 5.5%, proceed to the next stage. In step P6, during the third stage of coating, the flow rate is increased again by 20 mL / min, and then increased by 20 mL / min every 10 min until the core temperature drops to 27°C; the spraying is stopped when the coating weight gain reaches 13%. In step P7, during the curing stage, the coating machine speed is adjusted to 4 rpm, the core temperature is controlled at 40℃, and the curing time is 2 hours, so that the weight gain of the coating after curing is 12%.

[0033] Example 2

[0034] This embodiment provides a coating composition for enteric-coated aspirin tablets, comprising the following components by weight percentage: 17% hydroxypropyl methylcellulose acetate succinate; 74% distilled water; 3% triethyl citrate; 0.9% polyvinylpyrrolidone; 4% titanium dioxide; and 0.2% sodium bicarbonate. The hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 8% and a succinyl substitution degree of 14%, and the amount of polyvinylpyrrolidone added is 30% of the mass of triethyl citrate.

[0035] The preparation process of the coating composition described in this embodiment includes the following steps: Step S1: Slowly add 17 kg of hydroxypropyl methylcellulose acetate succinate to 74 kg of distilled water. Stir at 600 rpm for 50 min at 35°C using a paddle stirrer to allow the hydroxypropyl methylcellulose acetate succinate to fully absorb water and form a uniform and stable polymer dispersion system. During the stirring process, control the temperature fluctuation of the system to not exceed ±2°C to avoid local overheating that could lead to polymer chain aggregation. Step S2: Add 3 kg of triethyl citrate and 0.9 kg of polyvinylpyrrolidone to a premixing tank and premix at 400 rpm for 30 min at 50°C to allow polyvinylpyrrolidone to be fully adsorbed onto the surface of triethyl citrate to form a stable interface layer, resulting in a uniform and transparent plasticized stabilized liquid. Step S3: Under continuous stirring of the polymer dispersion system, the plasticizer stabilized liquid obtained in step S2 is slowly added to the polymer dispersion system obtained in step S1 within 45 minutes using a metering pump. During the addition process, the stirring speed is maintained at 500 rpm, and the addition speed is controlled to be uniform and stable, so as to reduce the problem of local aggregation and micro-phase separation caused by excessively high instantaneous concentration of plasticizer. Step S4: Add 4 kg of titanium dioxide to the system obtained in step S3 in two portions. The first portion is 50% of the total amount, and the second portion is the remaining 50%. After the first addition, stir at 500 rpm for 10 min for pre-dispersion, and then stir at 2000 rpm for 25 min for high-speed depolymerization to ensure that the titanium dioxide is uniformly dispersed in the system. After the remaining filler is added for the second time, stir at 300 rpm for 10 min for steady-state degassing to reduce the problem of bubble entrainment and localized filler deposition in the system. In step S5, 0.2 kg of sodium bicarbonate was added to adjust the pH of the system to 5.5, and the mixture was filtered through a 100-mesh sieve. The mixture was then allowed to stand for 40 minutes to remove bubbles, resulting in a stable and uniform enteric coating composition.

[0036] This embodiment also provides a coating process for enteric-coated aspirin tablets, including the following steps: Step P1: Preheat the coating machine under no-load conditions, control the inlet air temperature to 50℃, the negative pressure inside the pot to -100Pa, the coating machine speed to 1rpm, turn on the dehumidification device, and feed the material after the inlet air humidity is ≤15% to reduce the impact of internal humidity fluctuations on the moisture absorption of aspirin tablet cores. Step P2: Put the aspirin tablet core into the high-efficiency coating machine, adjust the position of the spray gun so that the distance between the nozzle and the tablet bed is 25cm, and make the spray area aim at the upper part of the middle of the tablet bed, thereby improving the uniformity of spray coverage and reducing the risk of local over-wetting. Step P3: After controlling the core temperature to reach 40°C, preheat the core for 10 minutes and check the core weight to ensure uniform and stable core surface temperature and improve solvent evaporation efficiency in the initial spraying stage. Step P4: In the first stage of coating, the initial flow rate of the peristaltic pump is controlled at 200 mL / min, the speed of the coating machine is 4 rpm, and the inlet air temperature is 46℃. The flow rate is increased by 20 mL / min every 10 minutes until the core temperature drops to 33℃. The speed of the coating pan is adjusted according to the core flow state, and the inlet air temperature is finely adjusted according to the core temperature change. When the coating weight gain reaches 2%, the next stage begins. Step P5: In the second stage of coating, adjust the coating machine speed to 6 rpm and increase the flow rate by 20 mL / min based on the first stage, increasing by 20 mL / min every 10 minutes. When the tablet core temperature drops to 30°C, simultaneously increase the inlet air temperature to 50°C each time the flow rate is increased. Adjust the spray flow rate according to the tablet core temperature range of 28–32°C to keep the tablet core in a stable thermal equilibrium state. When the coating weight gain reaches 6%, proceed to the next stage. In step P6, during the third stage of coating, the spray flow rate is increased by 20 mL / min based on the second stage, and then increased by 20 mL / min every 10 min until the core temperature drops to 28°C. The flow rate is adjusted according to the core temperature of 25-30°C to gradually seal and densify the film layer. Spraying is stopped when the coating weight gain reaches 14%. In step P7, during the curing stage, the coating machine speed is adjusted to 4 rpm, the core temperature is controlled at 42℃, and the curing time is 2 hours. This allows the coating film to further fuse and become dense, and reduces the residual stress inside the film layer, resulting in a final weight gain of 13% after curing.

[0037] Example 3

[0038] This embodiment provides a coating composition for enteric-coated aspirin tablets, comprising the following components by weight percentage: 22% hydroxypropyl methylcellulose acetate succinate; 68% distilled water; 6% triethyl citrate; 3% polyvinylpyrrolidone; 6% colloidal silica; and 0.5% sodium hydroxide. The hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 12% and a succinyl substitution degree of 18%, and the amount of polyvinylpyrrolidone added is 50% of the mass of triethyl citrate.

[0039] The preparation process of the coating composition described in this embodiment includes the following steps: Step S1: Slowly add 22 kg of hydroxypropyl methylcellulose acetate succinate to 68 kg of distilled water and stir at 800 rpm for 60 min at 45 °C using a high-speed disperser to allow the polymer to fully absorb water, swell, and disperse evenly to form a stable system. At the same time, control the system temperature to keep it stable and avoid local agglomeration of the polymer. Step S2: Add 6 kg of triethyl citrate and 3 kg of polyvinylpyrrolidone to a premix container and stir at 600 rpm for 60 min at 65°C to form a stable adsorption layer on the surface of the plasticizer, thereby obtaining a uniform and stable plasticized stabilized liquid. Step S3: Under continuous stirring of the polymer dispersion system, the plasticizer stabilizer is slowly added to the polymer dispersion system obtained in step S1 within 90 minutes using a metering pump. During the addition process, the stirring speed is maintained at 700 rpm to reduce local enrichment of plasticizer and improve the dispersion uniformity of the system. Step S4: Add 6 kg of colloidal silica to the system obtained in step S3 in two portions, with 70% of the total amount added in the first portion and the remaining 30% added in the second portion. After the first addition, stir at 800 rpm for 20 min for pre-dispersion, then stir at 3000 rpm for 40 min for high-speed depolymerization to ensure uniform dispersion of colloidal silica. Subsequently, stir at 500 rpm for 15 min for low-speed steady-state degassing to reduce bubble entrainment and filler agglomeration. In step S5, 0.5 kg of sodium hydroxide was added to adjust the pH of the system to 6.0, and the mixture was filtered through a 150-mesh sieve and then vacuum degassed for 50 min to obtain a uniform and stable enteric coating composition.

[0040] This embodiment also provides a coating process for enteric-coated aspirin tablets, including the following steps: Step P1: Preheat the coating machine under no-load conditions, control the air inlet temperature to 50℃, the negative pressure inside the pot to -130Pa, the coating machine speed to 1rpm, turn on the dehumidification device, and feed the material after the internal humidity of the equipment is ≤15%. Step P2: Put the aspirin tablet core into the high-efficiency coating machine, adjust the position of the spray gun so that the distance from the nozzle to the tablet bed is 30cm, and make the spray area evenly cover the upper part of the tablet bed. Step P3: Preheat the tablet core to 40°C and keep it at that temperature for 10 minutes. At the same time, check the initial weight of the tablet core to ensure that the tablet core temperature is stable in the initial stage of liquid spraying. Step P4: In the first stage of coating, control the initial flow rate of the peristaltic pump to be 200 mL / min, the speed of the coating machine to be 3 rpm, and the inlet air temperature to be 45℃. Increase the flow rate by 20 mL / min every 10 minutes until the core temperature drops to 34℃. Adjust the speed of the coating pan according to the core flow state and fine-tune the inlet air temperature according to the core temperature. When the coating weight gain reaches 2.5%, proceed to the next stage. Step P5: In the second stage of coating, adjust the coating machine speed to 6 rpm and increase the spray flow rate by 20 mL / min based on the first stage, increasing by 20 mL / min every 10 minutes. When the tablet core temperature drops to 30°C, simultaneously increase the inlet air temperature to 50°C. Adjust the spray flow rate in real time according to the tablet core temperature of 28–32°C to maintain a stable thermal balance for the tablet core. When the coating weight gain reaches 6.5%, proceed to the next stage. In step P6, during the third stage of coating, the spray flow rate is increased again by 20 mL / min, and then increased by 20 mL / min every 10 min until the core temperature drops to 27°C. The spray flow rate is adjusted according to the core temperature of 25-30°C to gradually form a sealed pore structure in the film layer. Spraying is stopped when the coating weight gain reaches 15%. In step P7, during the curing stage, the coating machine speed is adjusted to 4 rpm, the core temperature is controlled at 45°C, and the coating is cured for 2 hours to further fuse and densify the coating film and release residual moisture, so that the final weight gain of the coating after curing reaches 15%.

[0041] Example 4

[0042] This embodiment provides a coating composition for enteric-coated aspirin tablets, comprising the following components by weight percentage: 19% hydroxypropyl methylcellulose acetate succinate; 72% distilled water; 4% triethyl citrate; 1.6% polyvinylpyrrolidone; 3.2% talc and titanium dioxide mixed filler; and 0.2% ammonia and sodium bicarbonate mixed pH adjuster. The hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 10% and a succinyl substitution degree of 16%, and the amount of polyvinylpyrrolidone added is 40% of the mass of triethyl citrate.

[0043] The preparation process of the coating composition described in this embodiment includes the following steps: Step S1: Slowly add 19 kg of hydroxypropyl methylcellulose acetate succinate to 72 kg of distilled water and stir at 650 rpm for 45 min at 38 °C using a paddle stirrer to fully wet and uniformly disperse the polymer to form a stable polymer dispersion system. Step S2: Add 4 kg of triethyl citrate and 1.6 kg of polyvinylpyrrolidone to a premix tank and stir at 500 rpm for 40 min at 55°C to allow polyvinylpyrrolidone to be uniformly adsorbed onto the plasticizer surface and form a stable plasticizing stabilized liquid. Step S3: Under continuous stirring of the polymer dispersion system, the plasticizer stabilized liquid obtained in step S2 is slowly added to the polymer dispersion system obtained in step S1 within 60 min using a metering pump. During the addition process, the stirring speed is maintained at 600 rpm to reduce local concentration fluctuations of the plasticizer and improve the stability of the system. Step S4: Add 3.2 kg of mixed filler to the system obtained in step S3 in two portions, with 60% of the total amount added in the first portion and the remaining 40% added in the second portion. After the first addition, stir at 600 rpm for 15 min for pre-dispersion, then stir at 2500 rpm for 30 min for high-speed depolymerization, and then stir at 400 rpm for 10 min for low-speed degassing to improve the uniformity of the filler dispersion in the system. In step S5, add 0.2 kg of ammonia water and sodium bicarbonate mixed regulator to adjust the pH of the system to 5.8. After filtering through a 120-mesh filter, let it stand for 45 minutes to remove bubbles and obtain a stable and uniform enteric coating composition.

[0044] This embodiment also provides a coating process for enteric-coated aspirin tablets, including the following steps: Step P1: Preheat the coating machine under no-load conditions, control the air inlet temperature to 50℃, the negative pressure inside the pot to -90Pa, the coating machine speed to 1rpm, turn on the dehumidification device, and feed the material after the air inlet humidity is ≤15%. Step P2: Put the aspirin tablet core into the high-efficiency coating machine, adjust the position of the spray gun so that the distance from the nozzle to the tablet bed is 27cm, and make the spray area aim at the upper part of the middle of the tablet bed; Step P3: Preheat the wafer core to 40°C and keep it at that temperature for 10 minutes, and check the weight of the wafer core to ensure that the surface temperature of the wafer core remains uniform and stable. Step P4: In the first stage of coating, the initial flow rate of the peristaltic pump is controlled at 200 mL / min, the speed of the coating machine is 4 rpm, and the inlet air temperature is 46℃. The flow rate is increased by 20 mL / min every 10 minutes until the core temperature drops to 33℃. The speed of the coating pan is finely adjusted according to the core flow state, and the inlet air temperature is adjusted according to the core temperature change. When the coating weight gain reaches 2.2%, the next stage begins. Step P5: In the second stage of coating, adjust the coating machine speed to 6 rpm and increase the spray flow rate by 20 mL / min based on the first stage, increasing by 20 mL / min every 10 minutes. When the tablet core temperature drops to 30°C, simultaneously increase the inlet air temperature to 50°C. Adjust the spray flow rate according to the tablet core temperature of 28–32°C to maintain a stable thermal equilibrium state for the tablet core. When the coating weight gain reaches 6.2%, proceed to the next stage. In step P6, during the third stage of coating, the spray flow rate is increased again by 20 mL / min, and then increased by 20 mL / min every 10 min until the core temperature drops to 28°C. The spray flow rate is adjusted according to the core temperature of 25-30°C to gradually seal and densify the coating film. Spraying is stopped when the coating weight gain reaches 14%. In step P7, during the curing stage, the coating machine speed is adjusted to 4 rpm, the core temperature is controlled at 43°C, and the curing time is 2 hours. This allows the coating film to further fuse and release residual moisture, resulting in a final weight gain of 14% after curing.

[0045] Compare with Example 1 This comparative example provides a coating composition, preparation process, and coating process for enteric-coated aspirin tablets. Compared with Example 1, the difference is that in this comparative example, methacrylic acid-ethyl acrylate copolymer is used instead of hydroxypropyl methylcellulose acetate succinate as the main material for enteric coating. The composition of other components, preparation process parameters, and coating process conditions are the same as in Example 1.

[0046] Specifically, the coating composition described in this comparative example comprises the following components by weight percentage: 12% methacrylate-ethyl acrylate copolymer; 82% distilled water; 1% triethyl citrate; 0.1% polyvinylpyrrolidone; 1% talc; and 0.05% ammonia.

[0047] In this comparative example, the plasticizer and interface stabilizer premixing method of Example 1 is still used, and a three-stage gradient coating process is adopted.

[0048] Compare with Example 2 This comparative example provides a coating composition, preparation process, and coating process for enteric-coated aspirin tablets. The difference from Example 1 is that the plasticizer and interface stabilizer are not premixed at 40-65°C for 10-60 minutes to form a plasticizing stabilized liquid, but are directly added to the polymer dispersion system. The composition of the remaining components, the type of polymer, and the coating process conditions are the same as in Example 1.

[0049] Specifically, in this comparative example, 1 kg of triethyl citrate and 0.1 kg of polyvinylpyrrolidone were directly added to the polymer dispersion system obtained in step S1 and mixed by stirring at 400 rpm for 20 min, without premixing.

[0050] Compare with Example 3 This comparative example provides a coating composition, preparation process, and coating process for aspirin enteric-coated tablets. The difference from Example 1 is that the coating process in this comparative example does not use a three-stage gradient coating method, but a single-stage continuous coating process. The composition of other components, polymer types, and coating solution preparation processes are the same as in Example 1.

[0051] Specifically, in this comparative example, a single-stage continuous spraying method was used for coating. The peristaltic pump flow rate was kept constant at 240 mL / min, the coating machine speed was kept constant at 5 rpm, and the inlet air temperature was kept constant at 45℃. During the spraying process, no first, second, or third stage weight gain control was set. Instead, the spraying continued until the coating weight gain reached 14% and then the spraying was stopped.

[0052] Performance testing methods 1. Storage stability test of coating solution The prepared coating composition was placed in a sealed glass container and stored at 25°C for 7 days. The appearance changes of the system were observed at 0, 1, 3 and 7 days, including whether there was stratification, sedimentation, flocculation or oil phase precipitation. At the same time, the viscosity change of the coating liquid was measured by a rotational viscometer and the viscosity fluctuation rate at different time points was recorded.

[0053] 2. Coating film flexibility test After peeling off the coating film, the samples were cut into specimens of the same size. Tensile tests were performed using an electronic tensile testing machine, and the elongation at break and tensile strength of the film were recorded. Alternatively, repeated bending tests were conducted to observe whether cracks or fractures occurred in the film. Higher elongation at break and fewer cracks after bending indicate better film flexibility.

[0054] 3. Acid resistance test of coating film The acid resistance test for enteric-coated preparations was conducted according to the method outlined in the Chinese Pharmacopoeia. Coated tablets were placed in 0.1 mol / L hydrochloric acid solution and continuously shaken at 37 ± 0.5℃ for 2 hours. The presence of cracks, disintegration, softening, or drug leakage was observed. Simultaneously, the aspirin content in the released solution was measured. A lower drug release within 2 hours indicates better acid resistance integrity of the coating film.

[0055] 4. Salicylic acid impurity content test The content of salicylic acid impurities in coated tablets was determined using high-performance liquid chromatography (HPLC). A certain amount of sample was weighed, dissolved in methanol, filtered, and then subjected to chromatographic analysis. A standard curve was established using salicylic acid standards, and the salicylic acid content in the sample was calculated.

[0056] Table 1 Performance test results of Examples 1-4 and Comparative Examples 1-3

[0057] As can be seen from Examples 1 to 4 and Table 1, the aspirin enteric-coated tablet coating system obtained in this application exhibits good storage stability, film flexibility, and acid resistance. Specifically, after 7 days of static storage at 25°C, no significant oil phase precipitation was observed in the coating solution, and the viscosity fluctuation rate was controlled within 2.1%–3.4%. The elongation at break of the coating film reached 68.7%–75.2%, and the tensile strength reached 17.6–19.4 MPa. After treatment with 0.1 mol / L hydrochloric acid solution for 2 hours, the aspirin release was only 0.6%–1.1%, all meeting the requirements for enteric acid resistance. Furthermore, after 30 days of storage at 40°C / 75%RH, the salicylic acid impurity content was only 0.13%–0.18%. This indicates that this application, through a synergistic system of hydroxypropyl methylcellulose acetate succinate, plasticizer / interface stabilizer, and gradient coating process, can effectively improve the stability of the coating solution, film flexibility, and long-term storage stability.

[0058] As can be seen from Example 1, Comparative Example 1, and Table 1, the 7-day viscosity fluctuation rate of Example 1 decreased from 15.6% in Comparative Example 1 to 2.8%, the elongation at break of the coating film increased from 42.3% to 71.5%, the 2-hour aspirin release decreased from 8.7% to 0.8%, and the salicylic acid impurity content after 30 days of storage at 40℃ / 75%RH decreased from 0.38% to 0.15%. This is mainly because Example 1 uses hydroxypropyl methylcellulose acetate succinate as the main material for enteric coating, which has better interfacial compatibility and flexibility adjustment ability with triethyl citrate, reducing plasticizer migration and film embrittlement, thereby improving the storage stability of the coating solution, film integrity, and long-term acid resistance.

[0059] As can be seen from Example 1, Comparative Example 2, and Table 1, the 7-day viscosity fluctuation rate of Example 1 decreased from 12.8% in Comparative Example 2 to 2.8%, the elongation at break of the coating film increased from 50.6% to 71.5%, the 2-hour aspirin release decreased from 6.5% to 0.8%, and the salicylic acid impurity content after 30 days of storage at 40℃ / 75%RH decreased from 0.31% to 0.15%. This is mainly due to the premixing of the plasticizer and polyvinylpyrrolidone in Example 1 at 40–65℃ to form a plasticized stable liquid. This allows polyvinylpyrrolidone to be pre-adsorbed onto the surface of the plasticizer to form a stable interface layer, thereby reducing local aggregation and microphase separation of the plasticizer in a high-water-content system, and improving the dispersion stability and film uniformity of the coating liquid.

[0060] Combining Example 1, Comparative Example 3, and Table 1, it can be seen that the 7-day viscosity fluctuation rate of Example 1 decreased from 9.7% in Comparative Example 3 to 2.8%, the elongation at break of the coating film increased from 55.8% to 71.5%, the 2-hour aspirin release decreased from 4.8% to 0.8%, and the salicylic acid impurity content after 30 days of storage at 40℃ / 75%RH decreased from 0.26% to 0.15%. This is mainly due to the three-stage gradient coating process used in Example 1. By adjusting the spray flow rate, inlet air temperature, and core temperature in stages, the film layer can form a more uniform and dense structure during the gradual thickening process, reducing stress concentration within the film layer. In contrast, Comparative Example 3 uses a single-stage continuous thickening method, which easily leads to local pores and film defects, thereby reducing the acid resistance integrity and long-term storage stability of the coating film.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A coating composition for enteric-coated aspirin tablets, characterized in that, By weight percentage, it includes the following components: Hydroxypropyl methylcellulose acetate succinate 12-22%; Distilled water 68-82%; Plasticizer 1-6%; Interface stabilizer 0.1-3%; Filler 1-6%; pH adjuster 0.05-0.5%; The plasticizer is triethyl citrate; the interface stabilizer is polyvinylpyrrolidone.

2. The enteric coating composition according to claim 1, characterized in that, The hydroxypropyl methylcellulose acetate succinate has an acetyl substitution degree of 5-12% and a succinyl substitution degree of 10-18%.

3. The coating composition according to claim 1, characterized in that, The amount of the interface stabilizer added is 10-50% of the mass of the plasticizer.

4. The coating composition according to claim 1, characterized in that, The filler is one or two of talc, titanium dioxide, or colloidal silica.

5. The coating composition according to claim 1, characterized in that, The pH adjuster is one or two of ammonia, sodium bicarbonate, or sodium hydroxide.

6. A process for preparing the coating composition according to any one of claims 1 to 5, characterized in that, Includes the following steps: S1. Hydroxypropyl methylcellulose acetate succinate was added to distilled water and stirred and dispersed at 25-45°C to obtain a polymer dispersion system; S2. Premix the plasticizer and the interface stabilizer at 40-65℃ for 10-60 min to obtain the plasticized stabilized liquid; S3. Under stirring conditions, the plasticizer stabilizer is slowly added to the polymer dispersion system obtained in step S1 to reduce local aggregation of plasticizer. S4. Add filler to the system obtained in step S3 and disperse it using a staged variable speed stirring method to improve the uniformity of filler dispersion in the coating system. S5. Add a pH adjuster to adjust the pH of the system to 5.0-6.0, and obtain the enteric-coated composition after degassing and filtration.

7. The preparation process according to claim 6, characterized in that, The plasticizer stabilizer is added in step S3 over a period of 15 to 90 minutes.

8. The preparation process according to claim 7, characterized in that, The staged variable speed mixing in step S4 includes: first mixing at 300-800 rpm for 5-20 minutes; then mixing at 1000-3000 rpm for 10-40 minutes; and finally mixing at 200-500 rpm for 5-15 minutes.

9. The preparation process according to claim 7, characterized in that, The filler in step S4 is added in two parts: the first part is 30-70% of the total amount, and the second part is the remaining amount.

10. A coating process for enteric-coated aspirin tablets, characterized in that, Includes the following steps: Step S1. Preheating the coating machine under no-load: Control the air inlet temperature to 50℃, the negative pressure inside the pot to -70~-130Pa, the coating machine speed to 1rpm, turn on the dehumidification device, and feed the material after the air inlet humidity is ≤15%; Step S2. Coating material feeding: Put the drug tablet core into the high-efficiency coating machine, adjust the position of the spray gun so that the distance from the nozzle to the tablet bed is 25±5cm, and make the spray area aim at the upper part of the middle of the tablet bed; Step S3. Preheat the wafer core: After controlling the wafer core temperature to reach 40℃, preheat the wafer core for 10 minutes and check the wafer core weight; Step S4. First stage of coating: Control the initial flow rate of the peristaltic pump to 200 mL / min, the speed of the coating machine to 3 rpm, and the inlet air temperature to 45℃. Increase the flow rate by 20 mL / min every 10 minutes until the tablet core temperature drops to 34℃. Adjust the speed of the coating machine by 1 rpm each time according to the fluidity of the tablet core, and fine-tune the inlet air temperature according to the tablet core temperature of 30-34℃. When the coating weight gain reaches 2±0.5%, proceed to the next stage. Step S5. Second stage of coating: Adjust the coating machine speed to 6 rpm, and increase the flow rate by 20 mL / min based on the first stage, increasing by 20 mL / min every 10 minutes; when the tablet core temperature drops to 30℃, simultaneously increase the inlet air temperature to 50℃ each time the flow rate is increased; adjust the flow rate according to the tablet core temperature of 28~32℃, adjusting by 20 mL / min each time; when the coating weight gain reaches 6±0.5%, proceed to the next stage; Step S6. Coating Stage 3: Based on the second stage, increase the flow rate by 20 mL / min again, and increase it by 20 mL / min every 10 min until the tablet core temperature drops to 27℃; adjust the flow rate according to the tablet core temperature of 25-30℃, adjusting by 20 mL / min each time; stop spraying when the coating weight gain reaches 13%-15%; Step S7. Curing: Adjust the coating machine speed to 4 rpm, control the core temperature to 40-45℃, and cure for 2 hours to achieve a coating weight gain of 12%-15% after curing.

Images