A compound sulfamethoxazole enteric-soluble capsule and its preparation method

Abstract

The application discloses a compound sulfamethoxazole enteric-soluble capsule and a preparation method thereof, and relates to the technical field of pharmaceutical preparations.The capsule is composed of drug-containing pellets and a hollow hard capsule.The drug-containing pellets comprise a pellet core and, from the inside to the outside, a drug-containing layer, an isolation layer, a slow-release layer and an enteric-soluble layer.The drug is kept intact in gastric juice without being released by the enteric-soluble layer coating, and is rapidly disintegrated when the pH of intestinal juice is increased to above 6.0 after entering the duodenum and the jejunum, thereby significantly reducing the chemical stimulation of SMZ to the gastric mucosa, eliminating adverse reactions of the gastrointestinal tract such as nausea, vomiting and stomach burning pain, and reducing the risk of urinary tract crystallization caused by the precipitation of SMZ crystals in gastric acid.Meanwhile, the pellets are divided into a slow-release part and an immediate-release part, and are combined in a 60:40 ratio, so that the capsule has the characteristics of biphasic drug release, thereby significantly improving the medication compliance of patients, improving the medicinal effect, and avoiding medication interruption.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a compound sulfamethoxazole enteric-coated capsule and its preparation method. Background Technology

[0002] Compound sulfamethoxazole enteric-coated capsules are a compound antibacterial preparation composed of sulfamethoxazole (SMZ) and trimethoprim (TMP) in a 5:1 ratio. As a sulfonamide antibiotic, it is mainly used to treat urinary tract infections, intestinal infections, and some respiratory infections caused by susceptible bacteria. Its core manufacturing process lies in the use of enteric coating technology, which prevents the drug from disintegrating in the stomach, thus avoiding premature degradation due to gastric acid and ensuring concentrated release in the alkaline environment of the intestine. Currently, commercially available compound sulfamethoxazole preparations mainly include... The product is available in various dosage forms, including tablets, dispersible tablets, ordinary hard capsules, granules, and injections. The currently included compound sulfamethoxazole tablets are prepared using a wet granulation and compression process, with each tablet containing 0.4 g of SMZ and 80 mg of TMP. Existing technology discloses a compound sulfamethoxazole tablet and its preparation method, application number CN202010991597.6. This existing technology uses 70%-75% SMZ, 14%-15% TMP, starch, hydroxypropyl cellulose, sodium carboxymethyl starch, and magnesium stearate as the main components. Currently available capsules disintegrate and release upon contact with gastric juice. SMZ has a strong chemical irritant effect on the gastric mucosa, easily causing gastrointestinal adverse reactions such as nausea, vomiting, and burning pain in the stomach. This leads some patients to discontinue treatment due to intolerance. Furthermore, SMZ has low solubility in the acidic environment of the stomach, easily crystallizing and forming crystalluria in the urinary tract, with the risk significantly increasing, especially in acidic urine environments. Summary of the Invention

[0003] This invention provides a compound sulfamethoxazole enteric-coated capsule and its preparation method, which can effectively solve the problems mentioned in the background art, such as the current capsules disintegrating and releasing upon initial exposure to gastric juice, the strong chemical irritation of SMZ to the gastric mucosa, which easily causes gastrointestinal adverse reactions such as nausea, vomiting, and burning stomach pain, leading some patients to discontinue treatment due to intolerance, and the low solubility of SMZ in the acidic environment of the stomach, which easily crystallizes and forms crystalluria in the urinary tract, especially with a significantly increased risk in an acidic urine environment.

[0004] To achieve the above objectives, the present invention provides the following technical solution: a compound sulfamethoxazole enteric-coated capsule, the capsule being composed of drug-containing microspheres and empty hard capsules, wherein the drug-containing microspheres include a core and a drug-containing layer, an isolation layer, a sustained-release layer and an enteric coating layer sequentially coated from the inside out; One portion of the drug-containing microspheres is coated with a sustained-release layer to form sustained-release microspheres, while the remaining portion of the drug-containing microspheres is not coated with a sustained-release layer to form immediate-release microspheres. The mass ratio of sustained-release microspheres to immediate-release microspheres is 50:50-70:30. Sustained-release and immediate-release microcapsules are mixed in a certain mass ratio and then coated with an enteric coating. Finally, they are filled into empty hard capsules. Each empty hard capsule contains sulfamethoxazole and trimethoprim, with 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

[0005] According to the above technical solution, the core is a sucrose core or a microcrystalline cellulose core, with a particle size of 0.50-0.71 mm and a dosage of 80-100 mg per core; The drug-containing layer is composed of hydroxypropyl methylcellulose E5, povidone K30, microcrystalline cellulose PH101 and active ingredients, with hydroxypropyl methylcellulose E5 at a dosage of 12-18 mg, povidone K30 at a dosage of 4-8 mg, and microcrystalline cellulose PH101 at a dosage of 6-10 mg.

[0006] According to the above technical solution, the isolation layer is composed of hydroxypropyl methylcellulose E15 and talc, with 8-12 mg of hydroxypropyl methylcellulose E15 and 4-6 mg of talc. The sustained-release layer is composed of ethyl cellulose, polyethylene glycol 400, hydroxypropyl methylcellulose E5 and talc, with ethyl cellulose accounting for 14-22 mg, polyethylene glycol 400 accounting for 2-4 mg, hydroxypropyl methylcellulose E5 accounting for 1.5-3 mg and talc accounting for 2-3 mg.

[0007] According to the above technical solution, the enteric coating is composed of a copolymer of methacrylic acid and ethyl acrylate, polyethylene glycol 6000, triethyl citrate and talc. The amount of methacrylic acid and ethyl acrylate copolymer is 35-50 mg, the amount of polyethylene glycol 6000 is 3-6 mg, the amount of triethyl citrate is 1.5-3 mg, and the amount of talc is 4-7 mg.

[0008] A method for preparing compound sulfamethoxazole enteric-coated capsules includes the following steps: Step S1: Drying and sieving of raw and auxiliary materials; Step S2: Preparation of drug-containing coating solution and preparation of drug-containing microspheres; Step S3: Prepare the coating solution and the isolation layer for coating; Step S4: Selective coating of the sustained-release layer; Step S5: Prepare the enteric coating solution and fully coat the product with the enteric coating layer; Step S6: Drying, sieving, and intermediate inspection; Step S7: Capsule filling, packaging, and finished product inspection.

[0009] According to the above technical solution, in step S1, sulfamethoxazole and trimethoprim are respectively placed in a vacuum drying oven for drying treatment; Subsequently, the dried sulfamethoxazole and trimethoprim were passed through a 100-mesh sieve for later use, while the sucrose pellet cores were passed through an 18-25-mesh sieve for later use.

[0010] According to the above technical solution, in step S2, when preparing the drug-containing coating solution, hydroxypropyl methylcellulose E5 is first added to purified water and stirred to swell. Then, povidone K30 is added and stirred to dissolve to form a clear aqueous solution. Then, sulfamethoxazole, trimethoprim, and microcrystalline cellulose PH101 are added and stirred at high speed to form a suspension of solid materials in the solution. The suspension is then passed through a 60-mesh sieve twice and then degassed under vacuum for 30 minutes to obtain the drug-containing coating solution for later use. In the preparation of drug-containing microcapsules, sucrose pellet cores are put into a fluidized bed coating machine, the air intake is adjusted, and the air intake temperature is set to 50±2℃, the air outlet temperature to 38-42℃, and the atomization pressure to 2.0-2.5 bar. After starting the spray gun, spray the drug-containing coating solution onto the surface of the sucrose pellet core. The entire spraying process lasts for 90-120 minutes. Continue fluidized drying for 15 minutes to dry the surface of the drug-containing microspheres and obtain drug-containing microspheres. The weight gain of the drug-containing microcapsules is 100% of the initial sucrose core, the drug content is 65%-70%, the particle size is controlled between 0.71-1.18 mm, and qualified drug-containing microcapsules are collected after sieving. In step S3, during the preparation of the coating solution, hydroxypropyl methylcellulose E15 is added to purified water, stirred and dissolved, and then talc is added. The solution is homogenized at high speed for 30 minutes to obtain an aqueous coating solution. During the isolation layer coating process, drug-containing microspheres are placed into a fluidized bed, maintaining an inlet air temperature of 50°C, an atomization pressure of 2.0 bar, and a spray rate of 5-8 ml / min. The coating solution is continuously sprayed for 40 minutes, followed by fluidization for another 10 minutes to complete film formation, thus obtaining isolation layer coated microspheres.

[0011] According to the above technical solution, in step S4, the isolation layer is coated with microspheres in a mass ratio of 6:4, with part A being 60% and part B being 40%. A portion of micro-pellets was placed into a fluidized bed and sprayed with a slow-release coating solution containing 7 cps of ethyl cellulose, polyethylene glycol 400, hydroxypropyl methylcellulose E5 and talc as solvent. The process parameters for the sustained-release coating were set as follows: inlet air temperature 45±2℃, outlet air temperature 32-36℃, atomization pressure 1.8-2.2 bar, spray rate 3-6 ml / min, material temperature controlled between 30-34℃, spraying process lasting 60 minutes, followed by fluidized drying to obtain sustained-release microspheres; The B-component microcapsules will not be coated with a sustained-release layer and will be used directly as immediate-release microcapsules. In step S5, when preparing the enteric coating solution, Eudragit L30D-55 aqueous dispersion is first slowly stirred, polyethylene glycol 6000 and triethyl citrate are dissolved in a small amount of purified water by heating and then slowly added to the Eudragit dispersion by stirring, talc powder is added and homogenized at high speed, and after sieving, the enteric coating solution is obtained. During the enteric coating process, the obtained sustained-release microspheres and immediate-release microspheres were added to a fluidized bed at a mass ratio of 60:40. The enteric coating solution was sprayed on, and the process parameters were as follows: inlet air temperature 35±2℃, outlet air temperature 28-32℃, atomization pressure 1.8 bar, spray rate 4-6 ml / min, and material temperature 26-30℃. The spraying process was carried out for 80-100 minutes, followed by continued fluidization to complete the curing.

[0012] According to the above technical solution, in step S6, the enteric-coated microspheres are placed in a vacuum drying oven to dry them so that the moisture content is controlled below 3.0%. After passing through a 14-mesh sieve and a 30-mesh sieve in sequence, samples are taken and sent for testing. The test items include content, release rate and moisture content. After the intermediate passes the test, it enters the next filling process.

[0013] According to the above technical solution, in step S7, during the capsule filling process, a fully automatic capsule filling machine is used to fill enteric-coated microcapsules into empty hard capsules at a filling amount of 0.62 grams per capsule. During the filling process, samples are taken every 15 minutes to check the difference in filling amount, and unqualified capsules are removed at the same time. During the packaging process, an aluminum-plastic blister packaging machine is used for packaging, with 12 capsules per blister pack and 2 blister packs per box; During finished product inspection, each batch is fully inspected according to the prescribed quality standards, and those that pass the inspection are stored in the warehouse.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention uses an enteric coating to keep the drug intact and prevent its release in gastric juice. After entering the duodenum and jejunum, the drug rapidly disintegrates when the pH of the intestinal juice rises to above 6.0, significantly reducing the chemical irritation of SMZ on the gastric mucosa, eliminating gastrointestinal adverse reactions such as nausea, vomiting, and burning stomach, and reducing the risk of urinary tract crystallization caused by SMZ crystallization in gastric acid. Meanwhile, by dividing the microcapsules into sustained-release and immediate-release portions and combining them in a 60:40 ratio, the capsules achieve biphasic drug release characteristics. The immediate-release portion rapidly disintegrates and releases the drug after entering the intestine, allowing the blood drug concentration to reach an effective therapeutic concentration in a short time. The sustained-release portion slowly and continuously releases the drug through the ethyl cellulose membrane, significantly prolonging the duration of effective blood drug concentration. This significantly improves patient medication compliance, enhances drug efficacy, and avoids medication interruption. Attached Figure Description

[0015] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof.

[0016] In the attached diagram: Figure 1 This is a flowchart of the steps in preparing the capsule of the present invention. Detailed Implementation

[0017] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0018] Example: The present invention provides a technical solution, a compound sulfamethoxazole enteric-coated capsule, which is composed of drug-containing microspheres and empty hard capsules. The drug-containing microspheres include a core and a drug-containing layer, an isolation layer, a sustained-release layer and an enteric coating layer, which are sequentially coated from the inside out. One portion of the drug-containing microspheres is coated with a sustained-release layer to form sustained-release microspheres, while the remaining portion of the drug-containing microspheres is not coated with a sustained-release layer to form immediate-release microspheres. The mass ratio of sustained-release microspheres to immediate-release microspheres is 60:40. Sustained-release microcapsules and immediate-release microcapsules are mixed in a certain mass ratio and then coated with an enteric coating. Finally, they are filled into empty hard capsules according to the required filling amount. The empty hard capsules are made of No. 0 gelatin and each empty hard capsule contains 0.62 grams. Each empty hard capsule contains the active ingredients sulfamethoxazole and trimethoprim, with 400 mg of sulfamethoxazole and 80 mg of trimethoprim in a mass ratio of 5:1, which is the optimal ratio for antibacterial effect.

[0019] Based on the above technical solution, the core of the pellet is sucrose, with a particle size of 0.62 mm and a dosage of 90 mg per pellet; The drug-containing layer is composed of hydroxypropyl methylcellulose E5, povidone K30, microcrystalline cellulose PH101 and active ingredients. Among them, 15 mg of hydroxypropyl methylcellulose E5 is used as a binder, 6 mg of povidone K30 is used as an adhesive aid, and 8 mg of microcrystalline cellulose PH101 is used as a diluent and anti-adhesion agent to adhere SMZ and TMP to the surface of the pellet core.

[0020] Based on the above technical solution, the isolation layer is composed of hydroxypropyl methylcellulose E15 and talc, wherein 10 mg of hydroxypropyl methylcellulose E15 is used as the main film-forming agent, and 5 mg of talc is used as an anti-adhesion agent to prevent the active ingredients from migrating to the sustained-release layer and enteric layer. The sustained-release layer is composed of ethyl cellulose, polyethylene glycol 400, hydroxypropyl methylcellulose E5 and talc. Ethyl cellulose is used in an amount of 18 mg as the main material for sustained-release film formation, polyethylene glycol 400 is used in an amount of 3 mg as a plasticizer, hydroxypropyl methylcellulose E5 is used in an amount of 2 mg as a pore-forming agent, and talc is used in an amount of 2.5 mg as an anti-adhesion agent.

[0021] Based on the above technical solution, the enteric coating is composed of Eudragit L30D-55, a copolymer of methacrylic acid and ethyl acrylate, polyethylene glycol 6000, triethyl citrate, and talc. The amount of methacrylic acid and ethyl acrylate copolymer is 40 mg as a pH-responsive enteric material. Polyethylene glycol 6000 and triethyl citrate work together as plasticizers. The amount of polyethylene glycol 6000 is 4 mg, triethyl citrate is 2 mg, and talc is 5 mg as an anti-sticking agent. Furthermore, the enteric coating uses a copolymer of methacrylic acid and ethyl acrylate as a pH-responsive enteric material, which dissolves in an environment with a pH of 5.5 or higher.

[0022] like Figure 1 As shown, a method for preparing compound sulfamethoxazole enteric-coated capsules includes the following steps: Step S1: Drying and sieving of raw and auxiliary materials; Step S2: Preparation of drug-containing coating solution and preparation of drug-containing microspheres; Step S3: Prepare the coating solution and the isolation layer for coating; Step S4: Selective coating of the sustained-release layer; Step S5: Prepare the enteric coating solution and fully coat the product with the enteric coating layer; Step S6: Drying, sieving, and intermediate inspection; Step S7: Capsule filling, packaging, and finished product inspection; The drug-containing layer, isolation layer, sustained-release layer, and enteric coating layer are all applied sequentially using a fluidized bed bottom spray coating process. After each coating layer is completed, the microcapsules are sieved and dried before proceeding to the next coating layer. Finally, the enteric-coated microcapsules are filled into empty hard capsules according to the specified dosage. The drug-containing layer, isolation layer, sustained-release layer, and enteric coating layer are all applied using the same fluidized bed equipment, and are completed sequentially by changing the spraying liquid.

[0023] Based on the above technical solution, S1, sulfamethoxazole and trimethoprim are placed in a vacuum drying oven at 50°C for drying treatment, and the drying time is controlled at 4 hours until the moisture content of sulfamethoxazole and trimethoprim is dried to below 0.3%. Subsequently, the dried sulfamethoxazole and trimethoprim were passed through a 100-mesh sieve to remove lumps and impurities and were set aside for later use. At the same time, the sucrose pellet cores were passed through a 20-mesh sieve to remove excessively fine powder and excessively large particles, retaining the pellet core carrier with a concentrated particle size and set aside for later use.

[0024] Based on the above technical solution, in S2, when preparing the drug-containing coating solution, hydroxypropyl methylcellulose E5 is first added to purified water and stirred until it is completely dissolved after 30 minutes of swelling. Then, povidone K30 is added and stirred to form a clear aqueous solution. Then, sieving and prepared sulfamethoxazole, trimethoprim, and microcrystalline cellulose PH101 are added and stirred at 3000 rpm for 45 minutes to form a uniformly dispersed suspension of solid materials in the solution. The suspension is passed through a 60-mesh sieve twice to remove any aggregated particles. After vacuum degassing for 30 minutes, a drug-containing coating solution with a solid content of 28% is obtained for later use. In the preparation of drug-containing microcapsules, sucrose pellet cores are put into a fluidized bed coating machine, and the air inlet is adjusted to make the sucrose pellet cores present a good fluidized state. The air inlet temperature is set to 50±2℃, the air outlet temperature is set to 40℃, and the atomization pressure is set to 2.2 bar. After starting the spray gun, the drug-containing coating solution is continuously sprayed onto the surface of the sucrose pellet core at a rate of 2 ml / min initially and gradually increased to 10 ml / min. The entire spraying process lasts for 110 minutes until all the drug-containing coating solution is sprayed. Then, fluidized drying is continued for 15 minutes to fully dry the surface of the drug-containing pellets. Finally, the material is discharged to obtain the drug-containing pellets. The weight gain of the drug-containing microcapsules is 100% of the initial sucrose core, the drug content is 68%, the particle size is controlled between 0.9 mm, and excessively large particles are removed by passing through a 14-mesh sieve and fine powder is removed by passing through a 24-mesh sieve. Qualified drug-containing microcapsules are collected. S3, when preparing the coating solution, add hydroxypropyl methylcellulose E15 to purified water, stir to dissolve, then add talc powder, homogenize at high speed for 30 minutes to obtain an aqueous coating solution with a solid content of 8%. During the isolation layer coating process, drug-containing microspheres are placed into a fluidized bed, maintaining an inlet air temperature of 50°C, an atomization pressure of 2.0 bar, and a spray rate of 7 ml / min. The coating liquid is continuously sprayed for 40 minutes until all the coating liquid is sprayed out. Fluidization is then continued for 10 minutes to complete film formation, resulting in isolation layer-coated microspheres.

[0025] Based on the above technical solution, in step S4, the isolation layer is coated with micro-granules in a mass ratio of 6:4, with part A being 60% and part B being 40%. A portion of micro-pellets was placed into a fluidized bed and sprayed with a slow-release coating solution containing 7 cps of ethyl cellulose, polyethylene glycol 400, hydroxypropyl methylcellulose E5 and talc as solvent. The process parameters for the sustained-release coating were set as follows: inlet air temperature 45±2℃, outlet air temperature 34℃, atomization pressure 2.0 bar, spray rate 4 ml / min, material temperature controlled at 32℃, spraying process lasting 60 minutes until all coating liquid was sprayed, and then fluidized drying for 10 minutes to obtain sustained-release microspheres. The B-component microcapsules will not be coated with a sustained-release layer and will be used directly as immediate-release microcapsules. S5. When preparing the enteric coating solution, first slowly stir the Eudragit L30D-55 aqueous dispersion for 10 minutes to make it uniform. Dissolve polyethylene glycol 6000 and triethyl citrate in a small amount of purified water by heating to 60°C and then slowly add them to the Eudragit dispersion and stir for 15 minutes. Then add talc powder and homogenize at high speed for 20 minutes. After passing through a 60-mesh sieve, the enteric coating solution with a solid content of 19% is obtained. During the enteric coating process, the obtained sustained-release microspheres and immediate-release microspheres were mixed evenly at a mass ratio of 60:40 and then fed into a fluidized bed. The enteric coating solution was sprayed on, and the process parameters were as follows: inlet air temperature 35±2℃, outlet air temperature 30℃, atomization pressure 1.8 bar, spray rate 5 ml / min, and material temperature 28℃. This was to avoid excessive temperature causing Eudragit emulsion demulsification. The spraying process was continued for 90 minutes until all the enteric coating solution was sprayed. Then, the fluidization was continued for 20 minutes to complete the curing. The curing temperature was maintained at 40℃ to ensure that the polymer segments in the enteric coating film were fully arranged and stable, thus preventing the release curve from drifting during storage.

[0026] Based on the above technical solution, S6, the enteric-coated microspheres are placed in a vacuum drying oven at 40°C and dried for 6 hours to control the moisture content to below 3.0%. After passing through a 14-mesh sieve to remove large particles and a 30-mesh sieve to remove fine powder, samples are taken and sent for testing. The test items include content, release rate and moisture content. The release rate is qualified as follows: the release rate in 0.1 mol / L hydrochloric acid medium is no more than 10% after 2 hours to verify the integrity of the enteric coating; the release rate in pH 6.8 phosphate buffer is no less than 70% after 2 hours to verify the drug release performance in the intestinal environment. After the intermediate is qualified, it will proceed to the next filling process.

[0027] Based on the above technical solution, S7, during the capsule filling process, a fully automatic capsule filling machine is used to fill enteric-coated microcapsules into No. 0 hollow hard capsules at a filling amount of 0.62 grams per capsule. During the filling process, samples are taken every 15 minutes to check the filling amount difference and control the filling amount difference within ±5%. At the same time, capsules with unqualified appearance, such as cap separation, shriveled head, or contamination, are rejected. During the packaging process, an aluminum-plastic blister packaging machine is used for packaging. The packaging materials are polyvinyl chloride rigid sheets and aluminum foil. Each blister pack contains 12 capsules, and each box contains 2 blister packs. After packaging, a vacuum leak test is performed, which is maintained at a vacuum of -0.06 MPa for 1 minute to ensure that there is no air leakage. During finished product inspection, each batch is fully inspected according to the prescribed quality standards. The inspection items include appearance, fill weight variation, disintegration time, release rate, content, moisture, and microbial limits. The content of SMZ and TMP is determined by high performance liquid chromatography to ensure that all indicators meet the relevant regulations. After passing the inspection, the products are stored in the warehouse.

[0028] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are 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 compound sulfamethoxazole enteric-coated capsule, characterized in that: The capsule consists of drug-containing microcapsules and empty hard capsules. The drug-containing microcapsules include a core and a drug-containing layer, an isolation layer, a sustained-release layer and an enteric coating layer, which are wrapped from the inside out. The drug-containing microspheres are coated with a sustained-release layer to form sustained-release microspheres, while the drug-containing microspheres are not coated with a sustained-release layer to form immediate-release microspheres. The mass ratio of sustained-release microspheres to immediate-release microspheres is 50:50-70:

30. Sustained-release and immediate-release microcapsules are mixed in a certain mass ratio and then coated with an enteric coating. Finally, they are filled into empty hard capsules. Each empty hard capsule contains sulfamethoxazole and trimethoprim, with 400 mg of sulfamethoxazole and 80 mg of trimethoprim.

2. The compound sulfamethoxazole enteric-coated capsule according to claim 1, characterized in that: The pellet core is a sucrose pellet core or a microcrystalline cellulose pellet core, with a particle size of 0.50-0.71 mm and a dosage of 80-100 mg per pellet; The drug-containing layer is composed of hydroxypropyl methylcellulose E5, povidone K30, microcrystalline cellulose PH101 and active ingredients, with hydroxypropyl methylcellulose E5 at a dosage of 12-18 mg, povidone K30 at a dosage of 4-8 mg, and microcrystalline cellulose PH101 at a dosage of 6-10 mg.

3. The compound sulfamethoxazole enteric-coated capsule according to claim 1, characterized in that: The insulating layer is composed of hydroxypropyl methylcellulose E15 and talc, with 8-12 mg of hydroxypropyl methylcellulose E15 and 4-6 mg of talc. The sustained-release layer is composed of ethyl cellulose, polyethylene glycol 400, hydroxypropyl methylcellulose E5 and talc, with ethyl cellulose accounting for 14-22 mg, polyethylene glycol 400 accounting for 2-4 mg, hydroxypropyl methylcellulose E5 accounting for 1.5-3 mg and talc accounting for 2-3 mg.

4. The compound sulfamethoxazole enteric-coated capsule according to claim 1, characterized in that: The enteric coating is composed of a copolymer of methacrylic acid and ethyl acrylate, polyethylene glycol 6000, triethyl citrate, and talc. The amount of methacrylic acid and ethyl acrylate copolymer is 35-50 mg, the amount of polyethylene glycol 6000 is 3-6 mg, the amount of triethyl citrate is 1.5-3 mg, and the amount of talc is 4-7 mg.

5. A method for preparing compound sulfamethoxazole enteric-coated capsules, used to prepare the compound sulfamethoxazole enteric-coated capsules according to any one of claims 1-4, characterized in that: Includes the following steps: Step S1: Drying and sieving of raw and auxiliary materials; Step S2: Preparation of drug-containing coating solution and preparation of drug-containing microspheres; Step S3: Prepare the coating solution and the isolation layer for coating; Step S4: Selective coating of the sustained-release layer; Step S5: Prepare the enteric coating solution and fully coat the product with the enteric coating layer; Step S6: Drying, sieving, and intermediate inspection; Step S7: Capsule filling, packaging, and finished product inspection.

6. The method for preparing compound sulfamethoxazole enteric-coated capsules according to claim 5, characterized in that: In step S1, sulfamethoxazole and trimethoprim are respectively placed in a vacuum drying oven for drying treatment; Subsequently, the dried sulfamethoxazole and trimethoprim were passed through a 100-mesh sieve for later use, while the sucrose pellet cores were passed through an 18-25-mesh sieve for later use.

7. The method for preparing compound sulfamethoxazole enteric-coated capsules according to claim 5, characterized in that: In step S2, when preparing the drug-coating solution, hydroxypropyl methylcellulose E5 is first added to purified water and stirred to swell. Then, povidone K30 is added and stirred to dissolve to form a clear aqueous solution. Then, sulfamethoxazole, trimethoprim, and microcrystalline cellulose PH101 are added and stirred at high speed to form a suspension of solid materials in the solution. The suspension is then passed through a 60-mesh sieve twice and degassed under vacuum for 30 minutes to obtain the drug-coating solution for later use. In the preparation of drug-containing microcapsules, sucrose pellet cores are put into a fluidized bed coating machine, the air intake is adjusted, and the air intake temperature is set to 50±2℃, the air outlet temperature to 38-42℃, and the atomization pressure to 2.0-2.5 bar. After starting the spray gun, spray the drug-containing coating solution onto the surface of the sucrose pellet core. The entire spraying process lasts for 90-120 minutes. Continue fluidized drying for 15 minutes to dry the surface of the drug-containing microspheres and obtain drug-containing microspheres. The weight gain of the drug-containing microcapsules is 100% of the initial sucrose core, the drug content is 65%-70%, the particle size is controlled between 0.71-1.18 mm, and qualified drug-containing microcapsules are collected after sieving. In step S3, during the preparation of the coating solution, hydroxypropyl methylcellulose E15 is added to purified water, stirred and dissolved, and then talc is added. The solution is homogenized at high speed for 30 minutes to obtain an aqueous coating solution. During the isolation layer coating process, drug-containing microspheres are placed into a fluidized bed, maintaining an inlet air temperature of 50°C, an atomization pressure of 2.0 bar, and a spray rate of 5-8 ml / min. The coating solution is continuously sprayed for 40 minutes, followed by fluidization for another 10 minutes to complete film formation, thus obtaining isolation layer coated microspheres.

8. The method for preparing compound sulfamethoxazole enteric-coated capsules according to claim 7, characterized in that: In step S4, the isolation layer is coated with microspheres in a mass ratio of 6:4, with part A being 60% and part B being 40%. A portion of micro-pellets was placed into a fluidized bed and sprayed with a slow-release coating solution containing 7 cps of ethyl cellulose, polyethylene glycol 400, hydroxypropyl methylcellulose E5 and talc as solvent. The process parameters for the sustained-release coating were set as follows: inlet air temperature 45±2℃, outlet air temperature 32-36℃, atomization pressure 1.8-2.2 bar, spray rate 3-6 ml / min, material temperature controlled between 30-34℃, spraying process lasting 60 minutes, followed by fluidized drying to obtain sustained-release microspheres; The B-component microcapsules will not be coated with a sustained-release layer and will be used directly as immediate-release microcapsules. In step S5, when preparing the enteric coating solution, Eudragit L30D-55 aqueous dispersion is first slowly stirred, polyethylene glycol 6000 and triethyl citrate are dissolved in a small amount of purified water by heating and then slowly added to the Eudragit dispersion by stirring, talc powder is added and homogenized at high speed, and after sieving, the enteric coating solution is obtained. During the enteric coating process, the obtained sustained-release microspheres and immediate-release microspheres were added to a fluidized bed at a mass ratio of 60:

40. The enteric coating solution was sprayed on, and the process parameters were as follows: inlet air temperature 35±2℃, outlet air temperature 28-32℃, atomization pressure 1.8 bar, spray rate 4-6 ml / min, and material temperature 26-30℃. The spraying process was carried out for 80-100 minutes, followed by continued fluidization to complete the curing.

9. The method for preparing a compound sulfamethoxazole enteric-coated capsule according to claim 8, characterized in that: In step S6, the enteric-coated microspheres are placed in a vacuum drying oven to dry them, so that the moisture content is controlled below 3.0%. After passing through a 14-mesh sieve and a 30-mesh sieve, samples are taken and sent for testing. The test items include content, release rate and moisture content. After the intermediate passes the test, it proceeds to the next filling process.

10. The method for preparing a compound sulfamethoxazole enteric-coated capsule according to claim 5, characterized in that: In step S7, during the capsule filling process, a fully automatic capsule filling machine is used to fill enteric-coated microcapsules into empty hard capsules at a dosage of 0.62 grams per capsule. During the filling process, samples are taken every 15 minutes to check for differences in the dosage, and unqualified capsules are removed. During the packaging process, an aluminum-plastic blister packaging machine is used for packaging, with 12 capsules per blister pack and 2 blister packs per box; During finished product inspection, each batch is fully inspected according to the prescribed quality standards, and those that pass the inspection are stored in the warehouse.

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