Probucol sustained-release capsule capable of reducing blood fat level and preparation method of probucol sustained-release capsule

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and provides a probucol sustained-release capsule for reducing the blood fat level and a preparation method thereof, and the probucol sustained-release capsule is prepared by filling a capsule shell with sustained-release pellets, the sustained-release pellet comprises a blank pellet core, a medicine carrying layer, an isolating layer and a sustained-release layer from inside to outside, wherein the medicine carrying layer comprises probucol and an adhesive in a mass ratio of (200-250): (8-12); the slow-release layer is prepared from eudragit RL PO, a plasticizer, a pore-foaming agent and an anti-sticking agent according to the mass ratio of (250 to 300) to (20 to 25) to (20 to 22) to (10 to 18); the pore-foaming agent is prepared from polyethylene glycol 400 and PVP K25 in a mass ratio of (8-12): (3-5). The probucol sustained-release capsule provided by the invention not only has an excellent sustained-release effect, but also enables drug absorption to be less affected by gastric emptying, reduces stimulation to gastrointestinal tracts, and can improve patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and relates to a probucol sustained-release capsule for lowering blood lipid levels and its preparation method. Background Technology

[0002] Hyperlipidemia is a systemic disorder of lipid metabolism. Patients with hyperlipidemia have excessively high levels of cholesterol, triglycerides, and / or low-density lipoprotein in their serum and / or excessively low levels of high-density lipoprotein in their serum.

[0003] Currently, medications for treating hyperlipidemia include statins, fibrates, niacin and its derivatives, bile acid sequestrants, cholesterol absorption inhibitors, and some traditional Chinese medicine lipid-regulating drugs. Commonly used ones include atorvastatin, rosuvastatin, fenofibrate, bezafibrate, and probucol.

[0004] Probucol has a good effect on regulating blood lipid levels. Its chemical structure differs from known lipid-regulating drugs; its molecule contains two easily oxidized phenolic hydroxyl groups, which have a strong ability to capture oxygen ions. These phenolic hydroxyl groups combine with oxygen ions to form stable phenolic oxygen groups. Simultaneously, the phenolic hydroxyl groups are lipid-soluble, and after oral absorption, they accumulate in low-density lipoprotein, exhibiting a good anti-atherosclerotic effect.

[0005] Probucol is a lipid-soluble drug with low solubility in water, making it difficult to formulate into liquid preparations. Clinically, oral tablets are used. Probucol's absorption in the gastrointestinal tract is limited and irregular, with only 2-8% absorbed. Therefore, tablet dosages are relatively large, resulting in significant waste of raw materials and poor patient compliance. Some research has been conducted in the field of probucol sustained-release capsule formulations. For example, Chinese patent CN 102973537 A discloses a probucol sustained-release capsule for treating hypercholesterolemia and its manufacturing method. This formulation uses a sucrose blank core, sequentially coated with a drug-coating layer, an isolation layer, a sustained-release layer, and a film coating layer. The sustained-release layer uses ethyl cellulose aqueous dispersion as the main sustained-release material. However, research has shown that this technical solution still has the following risks: high gastric release, posing a potential irritation risk; it may cause irritation to some patients with sensitive gastrointestinal tracts.

[0006] Therefore, optimizing probucol sustained-release capsules to minimize the impact of gastric emptying on drug absorption and improve patient compliance is of great significance. Summary of the Invention

[0007] This invention proposes a probucol sustained-release capsule for lowering blood lipid levels and its preparation method. The probucol sustained-release capsule provided by this invention not only has excellent sustained-release effect, but also makes drug absorption less affected by gastric emptying, reduces gastrointestinal irritation, and improves patient compliance.

[0008] The technical solution of this invention is implemented as follows: Technical Topic 1 A probucol sustained-release capsule for lowering blood lipid levels is made by filling a capsule shell with sustained-release microspheres; the sustained-release microspheres include, from the inside out, a blank core, a drug-loaded layer, an isolation layer, and a sustained-release layer; wherein, the drug-loaded layer includes probucol and a binder in a mass ratio of 200-250:8-12. The sustained-release layer is composed of Utec RL PO, plasticizer, pore-forming agent, and anti-sticking agent in a mass ratio of 250-300:20-25:20-22:10-18; the pore-forming agent is polyethylene glycol 400 and PVP K25 in a mass ratio of 8-12:3-5.

[0009] Preferably, the pore-forming agent is polyethylene glycol 400 and PVP K25 in a mass ratio of 9-12:4.

[0010] Preferably, the isolation layer is composed of hydroxypropyl methylcellulose E5 and glyceryl monostearate in a mass ratio of 40-45:4-6. The function of the isolation layer is to form a stable film outside the drug-loaded layer, completely isolating the drug from the subsequent organic coating process, ensuring that the sustained-release layer can be formed on a complete and stable basis. This invention investigated this through accelerated stability testing, finding that if the isolation layer uses hydroxypropyl methylcellulose E5 and glyceryl monostearate in a mass ratio of 40-45:4-6, the sustained-release microparticles can achieve a release of <2% within 2 hours in a simulated gastric acid (pH 1.2) environment after 0, 1, 3, and 6 months of storage. If glyceryl monostearate is omitted from the isolation layer, the release after 6 months of storage will exceed 2%.

[0011] Preferably, the mass ratio of the blank pellet core, probucol, hydroxypropyl methylcellulose E5, and eutectic RL PO is 350-450: 200-250: 40-45: 250-300.

[0012] Preferably, the anti-adhesion agent is magnesium stearate, talc, or colloidal silica.

[0013] Preferably, the anti-adhesion agent is talc.

[0014] Preferably, the plasticizer is tributyl citrate, triethyl acetylglucosate, or triethyl citrate.

[0015] Preferably, the blank pellet core is a sucrose pellet core, a mannitol pellet core, a starch pellet core, a lactose pellet core, or a microcrystalline cellulose pellet core.

[0016] Preferably, the adhesive is selected from one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose.

[0017] Preferably, the adhesive is polyvinylpyrrolidone; more preferably, the adhesive is polyvinylpyrrolidone K30.

[0018] Preferably, the blank pellet core is a microcrystalline cellulose pellet core.

[0019] Technical Theme Two This invention also provides a method for preparing the probucol sustained-release capsules for lowering blood lipid levels as described in Technical Subject 1, comprising the following steps: S1. Mix the binder and solvent, then add probucol and stir to prepare a drug-loaded coating solution; add blank pellet cores to the bottom spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores to apply the drug, thus obtaining drug-loaded pellet cores; S2. Add hydroxypropyl methylcellulose E5 to purified water and stir at 50-60℃; add glyceryl monostearate and stir to prepare an isolation coating solution; add the drug-loaded pellet core obtained in step S1 to the bottom spray fluidized bed and use the isolation coating solution to perform fluidized bed coating to obtain isolated drug-loaded microparticles. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent and solvent, add anti-adhesion agent, stir to prepare sustained-release coating solution; add the isolated drug-loaded microparticles obtained in step S2 to bottom spray fluidized bed, use sustained-release coating solution to fluidize bed coating, and prepare sustained-release drug-loaded microparticles. S4. The sustained-release drug-loaded microspheres obtained in step S3 are loaded into empty capsule shells to obtain sustained-release capsules.

[0020] Preferably, the solvent in step S1 is purified water or a mixture of purified water and ethanol.

[0021] Preferably, the solvent in step S1 is a mixture of purified water and ethanol.

[0022] Preferably, the solvent in step S1 is a mixture of purified water and ethanol in a weight ratio of 7:3.

[0023] Preferably, the fluidized bed process parameters in step S1 are: inlet air temperature 50-60℃, air volume 20-25m³ / h, atomization pressure 1.4-1.6bar, and spraying speed 8-10 g / min.

[0024] Preferably, the amount of purified water used in step S2 is 10-20 times that of hydroxypropyl methylcellulose E5.

[0025] Preferably, the fluidized bed process parameters in step S2 are: inlet air temperature 35-40℃, air volume 22-28 m³ / h, atomization pressure 1.5-2.0 bar, and spray rate 1-5 g / min. Preferably, the spray rate is 1-3 g / min.

[0026] Preferably, the solvent in step S3 is selected from one or more of ethanol, acetone, and dichloromethane, with ethanol being the most preferred.

[0027] Preferably, the fluidized bed process parameters in step S3 are: inlet air temperature 30-35℃, air volume 25-30m³ / h, atomization pressure 1.4-1.7bar, and spraying speed 10-12g / min.

[0028] The beneficial effects of the present invention using the above technical solution are as follows: 1. The probucol sustained-release capsules provided by this invention have excellent sustained-release properties. The in vitro dissolution curve shows that very little drug is released in the gastric acid environment (<2%), which reduces gastric irritation. The drug is continuously released in the intestine for more than 24 hours, supporting once-daily dosing and improving patient compliance.

[0029] 2. This invention ensures stable drug release by optimizing the composition of the sustained-release layer and the isolation layer, especially the selection of the pore-forming agent (a combination of polyethylene glycol 400 and PVPK25) and the anti-adhesion agent.

[0030] 3. Stability tests show that the dissolution curve of the capsules of the present invention remains stable after long-term storage, and the characteristic of reduced release under gastric acid environment is maintained, ensuring the reliability of the product. Attached Figure Description

[0031] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0032] Figure 1 This is a dissolution curve of the drug of the present invention. Detailed Implementation

[0033] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0034] The probucol sustained-release capsule provided by the present invention is made by filling sustained-release microspheres into a capsule shell; The sustained-release microsphere structure comprises, from the inside out, a blank pellet core, a drug-loaded layer, an isolation layer, and a sustained-release layer; specifically as follows: Blank pellet core: dosage 350-450mg, the type of which is selected from sucrose pellet core, mannitol pellet core, starch pellet core, lactose pellet core or microcrystalline cellulose pellet core, with microcrystalline cellulose pellet core being more preferred, the particle size of the microcrystalline cellulose pellet core being 600-800 µm. Drug-carrying layer: 200-250mg probucol; 8-12 mg of adhesive; the adhesive is selected from one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose, preferably polyvinylpyrrolidone; more preferably, the adhesive is polyvinylpyrrolidone K30; Isolation layer: 40-45mg hydroxypropyl methylcellulose E5; 4-6 mg glyceryl monostearate; Sustained-release layer: 250-300mg Eucerin RL PO; 20-25 mg plasticizer; the plasticizer is tributyl citrate, triethyl acetylglucosyl citrate, or triethyl citrate; 20-22 mg of porogen; the porogen is polyethylene glycol 400 and PVP K25 in a mass ratio of 8-12:3-5; 10-18 mg of anti-adhesion agent; the anti-adhesion agent is magnesium stearate, talc, or colloidal silica; preferably talc.

[0035] The preparation method of the above-mentioned probucol sustained-release capsules for lowering blood lipid levels includes the following steps: S1. Mix the adhesive with 50-60 times its weight of solvent, then add probucol and stir to obtain a drug-loaded coating solution; add blank pellet cores to a bottom-spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores for drug loading. After drug loading, maintain the fluidized state and continue drying for 10-12 min to obtain drug-loaded pellet cores; the solvent in step S1 is purified water or a mixture of purified water and ethanol; preferably, the solvent in step S1 is a mixture of purified water and ethanol; more preferably, the solvent in step S1 is a mixture of purified water and ethanol with a weight ratio of 7:3; the fluidized bed process parameters in step S1 are: inlet air temperature 50-60℃, air volume 20-25 m³ / h, atomization pressure 1.4-1.6 bar, and spraying speed 8-10 g / min; S2. Add hydroxypropyl methylcellulose E5 to purified water and stir at 50-60℃ and 300-500 rpm to obtain an E5 mixture. Heat glyceryl monostearate to 60-65℃, then slowly add the E5 mixture and stir for 20-30 minutes at 500-600 rpm. Reduce the temperature to 35℃ to prepare an isolation coating solution. Add the drug-loaded pellet core obtained in step S1 to a bottom-spray fluidized bed and use the isolation coating solution for fluidized bed coating. After coating, continue fluidized drying for 12-15 minutes to obtain isolated drug-loaded microspheres. The amount of purified water used is 10-20 times that of hydroxypropyl methylcellulose E5. The fluidized bed process parameters in step S2 are: inlet air temperature 35-40℃, air volume 22-28 m³ / h, atomization pressure 1.5-2.0 bar, and spray rate 1-5 g / min. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent, and solvent, add anti-adhesion agent, and stir to obtain a sustained-release coating solution; add the isolated drug-loaded microcapsules obtained in step S2 to a bottom-spray fluidized bed, and use the sustained-release coating solution for fluidized bed coating. After coating, continue fluidized drying for 25–30 min to obtain sustained-release drug-loaded microcapsules; the amount of solvent used is 10–15 times that of Eutrich RL PO; the solvent in step S3 is selected from one or more of ethanol, acetone, and dichloromethane, preferably ethanol; the fluidized bed process parameters in step S3 are: inlet air temperature 30–35℃, air volume 25–30 m³ / h, atomization pressure 1.4–1.7 bar, and spraying speed 10–12 g / min; S4. The sustained-release drug-loaded microspheres obtained in step S3 are filled into gelatin empty capsule shells to obtain sustained-release capsules.

[0036] Example 1 A probucol sustained-release capsule for lowering blood lipid levels is made by filling a capsule shell with sustained-release microspheres; The sustained-release micro-pellet formulation of the single capsule is shown in the table below: The preparation method of the above-mentioned probucol sustained-release capsules for lowering blood lipid levels, based on a prescription dosage of 10,000 capsules, includes the following steps: S1. Mix the adhesive with 55 times its weight of solvent, then add probucol and stir to obtain a drug-loaded coating solution; add blank pellet cores to a bottom-spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores for drug loading. After drug loading is completed, maintain the fluidized state and continue drying for 11 min to obtain drug-loaded pellet cores; the solvent in step S1 is a mixed solvent of purified water and ethanol with a weight ratio of 7:3; the fluidized bed process parameters in step S1 are: inlet air temperature 55℃, air volume 22m³ / h, atomization pressure 1.5bar, and spraying speed 9 g / min.

[0037] S2. Hydroxypropyl methylcellulose E5 is added to purified water and stirred at 55°C and 400 rpm to obtain an E5 mixture. Glyceryl monostearate is heated to 60-65°C and then slowly added to the E5 mixture. The mixture is stirred at 550 rpm for 25 minutes and then cooled to 35°C to prepare an isolation coating solution. The drug-loaded pellet cores obtained in step S1 are added to a bottom-spray fluidized bed and coated using the isolation coating solution. After coating, fluidized bed drying is continued for 13 minutes to obtain isolated drug-loaded microparticles. The amount of solvent used is 15 times that of hydroxypropyl methylcellulose E5. The fluidized bed process parameters in step S2 are: inlet air temperature 38°C, air volume 25 m³ / h, atomization pressure 1.8 bar, and spray rate 2 g / min. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent and solvent, add anti-adhesion agent, stir to prepare sustained-release coating solution; add the isolated drug-loaded microparticles obtained in step S2 to the bottom spray fluidized bed, use sustained-release coating solution for fluidized bed coating, after coating, continue fluidized drying for 26 min to obtain sustained-release drug-loaded microparticles; the amount of solvent used is 12 times that of Eutrich RL PO; the solvent in step S3 is ethanol; the fluidized bed process parameters in step S3 are: inlet air temperature 32℃, air volume 26m³ / h, atomization pressure 1.6bar, spraying speed 11g / min.

[0038] S4. The sustained-release drug-loaded microspheres obtained in step S3 are filled into gelatin empty capsule shells to obtain sustained-release capsules.

[0039] Example 2 A probucol sustained-release capsule for lowering blood lipid levels is made by filling a capsule shell with sustained-release microspheres; The sustained-release micro-pellet formulation of the single capsule is shown in the table below: The preparation method of the above-mentioned probucol sustained-release capsules for lowering blood lipid levels, based on a prescription dosage of 10,000 capsules, includes the following steps: S1. Mix the adhesive with 50 times its weight of solvent, then add probucol and stir to obtain a drug-loaded coating solution; add blank pellet cores to a bottom-spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores for drug loading. After drug loading is completed, maintain the fluidized state and continue drying for 12 min to obtain drug-loaded pellet cores; the solvent in step S1 is a mixed solvent of purified water and ethanol with a weight ratio of 7:3; the fluidized bed process parameters in step S1 are: inlet air temperature 50℃, air volume 25m³ / h, atomization pressure 1.4bar, and spraying speed 10 g / min.

[0040] S2. Hydroxypropyl methylcellulose E5 is added to purified water and stirred at 50°C (500 rpm) to obtain an E5 mixture. Glyceryl monostearate is heated to 60-65°C, and then slowly added to the E5 mixture. The mixture is stirred (500 rpm) for 30 min and then cooled to 35°C to prepare an isolation coating solution. The drug-loaded pellet cores obtained in step S1 are added to a bottom-spray fluidized bed and coated using the isolation coating solution. After coating, fluidized bed drying is continued for 12 min to obtain isolated drug-loaded microparticles. The amount of solvent used is 20 times that of hydroxypropyl methylcellulose E5. The fluidized bed process parameters in step S2 are: inlet air temperature 35°C, air volume 28 m³ / h, atomization pressure 1.5 bar, and spray rate 3 g / min. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent and solvent, add anti-adhesion agent, stir to prepare sustained-release coating solution; add the isolated drug-loaded microparticles obtained in step S2 to the bottom spray fluidized bed, use sustained-release coating solution for fluidized bed coating, after coating, continue fluidized drying for 25 min to obtain sustained-release drug-loaded microparticles; the amount of solvent used is 15 times that of Eutrich RL PO; the solvent in step S3 is ethanol; the fluidized bed process parameters in step S3 are: inlet air temperature 30℃, air volume 30m³ / h, atomization pressure 1.4bar, spraying speed 12g / min.

[0041] S4. The sustained-release drug-loaded microspheres obtained in step S3 are filled into gelatin empty capsule shells to obtain sustained-release capsules.

[0042] Example 3 A probucol sustained-release capsule for lowering blood lipid levels is made by filling a capsule shell with sustained-release microspheres; The sustained-release micro-pellet formulation of the single capsule is shown in the table below: The preparation method of the above-mentioned probucol sustained-release capsules for lowering blood lipid levels, based on a prescription dosage of 10,000 capsules, includes the following steps: S1. Mix the adhesive with 60 times its weight of solvent, then add probucol and stir to obtain a drug-loaded coating solution; add blank pellet cores to a bottom-spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores for drug loading. After drug loading is completed, maintain the fluidized state and continue drying for 10 minutes to obtain drug-loaded pellet cores; the solvent in step S1 is a mixed solvent of purified water and ethanol with a weight ratio of 7:3; the fluidized bed process parameters in step S1 are: inlet air temperature 60℃, air volume 20m³ / h, atomization pressure 1.6bar, and spraying speed 8g / min.

[0043] S2. Hydroxypropyl methylcellulose E5 is added to purified water and stirred at 60°C (300 rpm) to obtain an E5 mixture. Glyceryl monostearate is heated to 60-65°C, and then slowly added to the E5 mixture. The mixture is stirred (600 rpm) for 20 min and then cooled to 35°C to prepare an isolation coating solution. The drug-loaded pellet cores obtained in step S1 are added to a bottom-spray fluidized bed and coated using the isolation coating solution. After coating, the mixture is further fluidized and dried for 15 min to obtain isolated drug-loaded microparticles. The amount of solvent used is 10 times that of hydroxypropyl methylcellulose E5. The fluidized bed process parameters in step S2 are: inlet air temperature 40°C, air volume 22 m³ / h, atomization pressure 2.0 bar, and spray rate 1 g / min. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent and solvent, add anti-adhesion agent, stir to prepare sustained-release coating solution; add the isolated drug-loaded microparticles obtained in step S2 to the bottom spray fluidized bed, use sustained-release coating solution for fluidized bed coating, after coating, continue fluidized drying for 30 min to obtain sustained-release drug-loaded microparticles; the amount of solvent used is 10 times that of Eutrich RL PO; the solvent in step S3 is ethanol; the fluidized bed process parameters in step S3 are: inlet air temperature 35℃, air volume 25m³ / h, atomization pressure 1.7bar, spraying speed 10g / min.

[0044] S4. The sustained-release drug-loaded microspheres obtained in step S3 are filled into gelatin empty capsule shells to obtain sustained-release capsules.

[0045] Example 4 A probucol sustained-release capsule for lowering blood lipid levels is made by filling a capsule shell with sustained-release microspheres; The sustained-release micro-pellet formulation of the single capsule is shown in the table below: The preparation method of the above-mentioned probucol sustained-release capsules for lowering blood lipid levels, based on a prescription dosage of 10,000 capsules, includes the following steps: S1. Mix the adhesive with 55 times its weight of solvent, then add probucol and stir to obtain a drug-loaded coating solution; add blank pellet cores to a bottom-spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores for drug loading. After drug loading is completed, maintain the fluidized state and continue drying for 10 min to obtain drug-loaded pellet cores; the solvent in step S1 is a mixed solvent of purified water and ethanol with a weight ratio of 7:3; the fluidized bed process parameters in step S1 are: inlet air temperature 55℃, air volume 22m³ / h, atomization pressure 1.5bar, and spraying speed 9 g / min.

[0046] S2. Hydroxypropyl methylcellulose E5 is added to purified water and stirred at 50°C and 400 rpm to obtain an E5 mixture. Glyceryl monostearate is heated to 60-65°C and then slowly added to the E5 mixture. The mixture is stirred at 550 rpm for 25 minutes and then cooled to 35°C to prepare an isolation coating solution. The drug-loaded pellet cores obtained in step S1 are added to a bottom-spray fluidized bed and coated using the isolation coating solution. After coating, fluidized bed drying is continued for 13 minutes to obtain isolated drug-loaded microparticles. The amount of solvent used is 15 times that of hydroxypropyl methylcellulose E5. The fluidized bed process parameters in step S2 are: inlet air temperature 38°C, air volume 25 m³ / h, atomization pressure 1.8 bar, and spray rate 2 g / min. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent and solvent, add anti-adhesion agent, stir to prepare sustained-release coating solution; add the isolated drug-loaded microparticles obtained in step S2 to the bottom spray fluidized bed, use sustained-release coating solution for fluidized bed coating, after coating, continue fluidized drying for 26 min to obtain sustained-release drug-loaded microparticles; the amount of solvent used is 12 times that of Eutrich RL PO; the solvent in step S3 is ethanol; the fluidized bed process parameters in step S3 are: inlet air temperature 32℃, air volume 26m³ / h, atomization pressure 1.6bar, spraying speed 10g / min.

[0047] S4. The sustained-release drug-loaded microspheres obtained in step S3 are filled into gelatin empty capsule shells to obtain sustained-release capsules.

[0048] Example 5 A probucol sustained-release capsule for lowering blood lipid levels is made by filling a capsule shell with sustained-release microspheres; The sustained-release micro-pellet formulation of the single capsule is shown in the table below: The preparation method of the above-mentioned probucol sustained-release capsules for lowering blood lipid levels, based on a prescription dosage of 10,000 capsules, includes the following steps: S1. Mix the adhesive with 50 times its weight of solvent, then add probucol and stir to obtain a drug-loaded coating solution; add blank pellet cores to a bottom-spray fluidized bed, fluidize, and spray the drug-loaded coating solution onto the blank pellet cores for drug loading. After drug loading is completed, maintain the fluidized state and continue drying for 12 min to obtain drug-loaded pellet cores; the solvent in step S1 is a mixed solvent of purified water and ethanol with a weight ratio of 7:3; the fluidized bed process parameters in step S1 are: inlet air temperature 50℃, air volume 22m³ / h, atomization pressure 1.5bar, and spraying speed 9 g / min.

[0049] S2. Hydroxypropyl methylcellulose E5 is added to purified water and stirred at 55°C and 400 rpm to obtain an E5 mixture. Glyceryl monostearate is heated to 60-65°C and then slowly added to the E5 mixture. The mixture is stirred at 550 rpm for 20 min, then cooled to 35°C to prepare an isolation coating solution. The drug-loaded pellet cores obtained in step S1 are added to a bottom-spray fluidized bed and coated using the isolation coating solution. After coating, fluidized bed drying is continued for 13 min to obtain isolated drug-loaded microparticles. The amount of solvent used is 15 times that of hydroxypropyl methylcellulose E5. The fluidized bed process parameters in step S2 are: inlet air temperature 38°C, air volume 25 m³ / h, atomization pressure 1.8 bar, and spray rate 2 g / min. S3. Mix Eutrich RL PO, plasticizer, pore-forming agent and solvent, add anti-adhesion agent, stir to prepare sustained-release coating solution; add the isolated drug-loaded microparticles obtained in step S2 to the bottom spray fluidized bed, use sustained-release coating solution for fluidized bed coating, after coating, continue fluidized drying for 25 min to obtain sustained-release drug-loaded microparticles; the amount of solvent used is 12 times that of Eutrich RL PO; the solvent in step S3 is ethanol; the fluidized bed process parameters in step S3 are: inlet air temperature 32℃, air volume 26m³ / h, atomization pressure 1.6bar, spraying speed 10g / min.

[0050] S4. The sustained-release drug-loaded microspheres obtained in step S3 are filled into gelatin empty capsule shells to obtain sustained-release capsules.

[0051] Comparative Example 1 Compared to Example 1, the only difference is that the pore-forming agent used is only polyethylene glycol 400. The sustained-release microsphere formulation of the single capsule is shown in the table below: Comparative Example 2 Compared to Example 1, the only difference is that only PVP K25 is used as the pore-forming agent. The sustained-release microsphere formulation of the single capsule is shown in the table below: Comparative Example 3 Compared to Example 1, the only difference is that the pore-forming agent is polyethylene glycol 400 and PVP K25 in a mass ratio of 20:4. The sustained-release microsphere formulation of the single capsule is shown in the table below: Comparative Example 4 Compared to Example 1, the only difference is that the pore-forming agent is polyethylene glycol 400 and PVP K25 in a mass ratio of 4:4. The sustained-release microsphere formulation of the single capsule is shown in the table below: Comparative Example 5 Sustained-release capsules were prepared using the formulation and method described in Example 1 of CN102973537B. The formulation composition is as follows: The production method is as follows: (1) Pass probucol through a 100-mesh sieve and set aside; then put the prescribed amount of water into a container and stir, add probucol, continue stirring for 60 minutes, then add the prescribed amount of gastric-soluble Opadry and continue stirring for 45 minutes to obtain the drug coating solution and set aside; then adjust the temperature in the fluidized bed to 40℃, put in blank pellet cores, adjust the air pressure and air intake to make the pellet cores completely boil; adjust the spray rate of the coating solution to 2-5g / min, spray coating, and after the drug coating solution is completely sprayed, continue boiling and drying for 30 minutes; pass the drug pellets through a 30-mesh sieve to remove broken pellets and obtain the drug pellets and set aside.

[0052] (2) Place the prescribed amount of water in a container and stir. Add stomach-soluble Opadry and stir for 45 minutes to obtain the isolation layer coating solution for later use. Then adjust the temperature in the fluidized bed to 40°C, put in the drug pellets, and adjust the air pressure and air volume to make the drug pellets boil completely. Adjust the spray rate of the coating solution to 2-5 g / min and spray coating. After the isolation layer coating solution is completely sprayed, continue boiling and drying for 30 minutes. Pass the isolation layer pellets through a 30-mesh sieve to remove broken pellets and obtain the isolation layer pellets for later use.

[0053] (3) Place the prescribed amount of water in a container and stir. Add the prescribed amount of ethyl cellulose aqueous dispersion and enteric-coated Opadry respectively. Continue stirring for 45 minutes to obtain a sustained-release coating solution for later use. Then adjust the temperature in the fluidized bed to 40°C, put in the isolation layer pellets, and adjust the air pressure and air volume to make the isolation layer pellets completely boil. Adjust the spray rate of the coating solution to 2-5 g / min, spray to coat the sustained-release film, and when the weight gain reaches 12%, stop the coating and continue boiling and drying for 30 minutes. Pass the coated pellets through a 30-mesh sieve to remove broken pellets and obtain probucol sustained-release pellets.

[0054] (4) Place the prescribed amount of water in a container and stir. Add the gastric-soluble red Opadry and stir for 45 minutes to obtain a film coating solution for later use. Then adjust the temperature in the fluidized bed to 40°C, put in the sustained-release pellets, and adjust the air pressure and air volume to make the sustained-release pellets boil completely. Then adjust the spray rate of the coating solution to 2-5 g / min and spray coating. After the film coating solution is completely sprayed, continue boiling and drying for 30 minutes. Pass the coated pellets through a 25-mesh sieve to remove broken pellets and obtain film-coated probucol sustained-release pellets for later use.

[0055] (5) The probucol sustained-release pellets prepared above are filled into capsules according to the dosage to obtain probucol sustained-release capsules.

[0056] Test case 1. 24-hour sustained-release performance test Take at least 6 capsules of this product, carefully open the capsule shell, and transfer the contents (sustained-release microspheres) intact into a dissolution vessel as the test sample. Take care to avoid damaging the microspheres. Then, perform an in vitro dissolution curve determination of the sustained-release characteristics over 24 hours. The determination method is based on Method II (paddle method) of the General Chapter IV of the Chinese Pharmacopoeia 2025, using the following conditions: Initial 2 hours: 900 mL of 0.1 mol / L hydrochloric acid solution (pH 1.2) to simulate the gastric environment; Subsequent 22 hours: After 2 hours, add 250 mL of 0.2 mol / L sodium phosphate solution preheated to 37±0.5°C to adjust the pH to 6.8 (simulating the intestinal environment), for a total volume of 1150 mL. Temperature: 37±0.5°C; Rotation speed: 50 rpm (simulating intestinal peristalsis); Sampling time points: 0.5, 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours. At each time point, 5 mL of sample was taken (with an equal volume of fresh medium added at the same temperature), filtered, and the concentration of probucol was determined by HPLC. The cumulative release rate (%) was calculated, and the results are shown in Table 1 below.

[0057] Table 1 As can be seen from the dissolution curves of Examples 1-5, the sustained-release microparticles of the present invention release very low levels (<2%) within 2 hours in a simulated gastric acid (pH 1.2) environment, which can effectively reduce irritation to the stomach; and can be continuously released for more than 24 hours in a simulated intestinal fluid (pH 6.8).

[0058] 2. To determine the long-term stability of probucol sustained-release capsules, especially their ability to maintain dissolution profiles and release behavior under gastric acid conditions after storage, accelerated stability tests and long-term stability tests were conducted.

[0059] Test conditions: Accelerated stability: 40±2°C / 75±5% RH, storage for 0, 1, 3, and 6 months.

[0060] Long-term stability: 25±2°C / 60±5% RH, stored for 0, 3, 6, 9, and 12 months.

[0061] Test parameters: Take at least 6 capsules of this product, carefully open the capsule shell, and transfer the contents (sustained-release microspheres) intact to a dissolution vessel as the test sample. Take care to avoid damaging the microspheres. Then, perform in vitro dissolution curve determination of sustained-release characteristics. The determination method is based on Method II (paddle method) of the General Chapter IV of the Chinese Pharmacopoeia 2025, using the following conditions: 900 mL of 0.1 mol / L hydrochloric acid solution (pH 1.2) to simulate the gastric environment; take 5 mL samples at 2 hours (simultaneously adding an equal volume of fresh medium at the same temperature); filter and determine the probucol concentration using HPLC; calculate the cumulative release rate (%).

[0062] Table 2 Accelerated stability results Table 3 Long-term stability results The results showed that, under accelerated and long-term stability conditions, the release rate of the sample in Example 1 remained below 2% after 2 hours in a gastric acid environment at pH 1.2, demonstrating that the characteristic of reduced release under gastric acid conditions was maintained.

[0063] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. 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 sustained release capsule of probucol for reducing blood lipid level, characterized in that, The sustained-release micro-pellets are filled in a capsule shell; the sustained-release micro-pellets comprise, from inside to outside, a blank core, a drug-loaded layer, a separation layer, and a sustained-release layer; wherein the drug-loaded layer comprises probucol and a binder in a mass ratio of 200-250:8-12; The sustained-release layer is composed of Utrige RL PO, a plasticizer, a pore-forming agent, and an anti-adhesion agent in a mass ratio of 250-300:20-25:20-22:10-18; the pore-forming agent is polyethylene glycol 400 and PVP K25 in a mass ratio of 8-12:3-5.

2. The probucol sustained release capsule for reducing blood lipid level according to claim 1, characterized in that, The separation layer is hydroxypropyl methylcellulose E5 and glyceryl monostearate in a mass ratio of 40-45:4-6.

3. The probucol sustained release capsule for reducing blood lipid level according to claim 2, characterized in that, The mass ratio of the blank core, probucol, hydroxypropyl methylcellulose E5, and Utrige RL PO is 350-450:200-250:40-45:250-300.

4. The probucol sustained release capsule for reducing blood lipid level according to claim 1, wherein the probucol is present in an amount of 500 mg. The anti-adhesion agent is magnesium stearate, talc, or colloidal silicon dioxide.

5. The probucol sustained release capsule for reducing blood lipid level according to claim 1, wherein the probucol is present in an amount of 500 mg. The blank core is a sucrose core, a mannitol core, a starch core, a lactose core, or a microcrystalline cellulose core.

6. The probucol sustained release capsule for reducing blood lipid level according to claim 1, wherein the probucol is present in an amount of 500 mg. The binder is selected from one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, and hydroxypropyl cellulose.

7. The probucol sustained release capsule for reducing blood lipid level according to claim 1, wherein the probucol is present in an amount of 500 mg. The plasticizer is tributyl citrate, acetyl triethyl citrate, or triethyl citrate.

8. The method for preparing probucol sustained-release capsules for lowering blood lipid levels as described in any one of claims 1-7, characterized in that, The method comprises the following steps: S1. Mix the binder with a solvent, then add probucol, stir, and prepare a drug-loaded coating liquid; add the blank core to a bottom-spray fluidized bed, fluidize, spray the drug-loaded coating liquid onto the blank core to load the drug, and obtain a drug-loaded core; S2. Mix hydroxypropyl methylcellulose E5 with purified water, stir at 50-60°C; add glyceryl monostearate, stir, and prepare a separation coating liquid; add the drug-loaded core prepared in step S1 to a bottom-spray fluidized bed, use the separation coating liquid for fluidized bed coating, and obtain a separation drug-loaded micro-pellet; S3. Mix Utrige RL PO, a plasticizer, a pore-forming agent, and a solvent, add an anti-adhesion agent, stir, and prepare a sustained-release coating liquid; add the separation drug-loaded micro-pellet prepared in step S2 to a bottom-spray fluidized bed, use the sustained-release coating liquid for fluidized bed coating, and obtain a sustained-release drug-loaded micro-pellet; S4. Fill the sustained-release drug-loaded micro-pellet prepared in step S3 into a hollow capsule shell, and prepare a sustained-release capsule.

9. The method for preparing a probucol sustained-release capsule for lowering blood lipid levels according to claim 8, characterized in that, The solvent in step S1 is purified water or a mixed solvent of purified water and ethanol.

10. The method of claim 8, wherein the probucol sustained release capsule is prepared by the following steps of: The solvent in step S3 is selected from one or more of ethanol, acetone, and dichloromethane. ​

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