Preparation method of complex sustained-release preparation with synchronous sustained release and synergy

Abstract

The application discloses a compound sustained-release preparation synchronous sustained-release synergistic preparation method, which comprises the following steps: step 1, preparing the component components of the compound sustained-release preparation according to the mass fraction; step 2, raw material pretreatment; step 3, mixing; step 4, granulation; step 5, drying; step 6, whole granulation; step 7, total mixing; step 8, tabletting or capsule filling; the polydopamine-quercetin copolymer has the synergistic effects of sustained release and antioxidation, the polylactic acid-hydroxyacetic acid-chitosan graft copolymer improves the biocompatibility and degradability of the sustained-release system, and the glucose-responsive polymethyl methacrylate-beta-hydroxyethyl ester microsphere realizes responsive sustained release; the synergistic effects of the three can solve the problem of single sustained-release performance of traditional auxiliary materials; the synergistic regulation of the three innovative components can accurately match the release requirements of different therapeutic active ingredients, realizes the synchronous sustained release of multiple components, avoids blood drug concentration fluctuation, improves the treatment effect and drug safety, and has excellent synchronous sustained-release effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically a method for the simultaneous sustained-release and synergistic preparation of compound sustained-release and controlled-release formulations. Background Technology

[0002] Sustained-release and controlled-release formulations maintain stable blood drug concentrations by controlling the drug release rate, reducing the frequency of dosing, improving patient adherence, and lowering the risk of adverse reactions caused by fluctuations in blood drug concentrations. They offer significant advantages in the treatment of chronic diseases. Compound sustained-release and controlled-release formulations further achieve comprehensive treatment of complex diseases through the synergistic effects of multiple drug components. Compared to single-component formulations, they feature enhanced synergistic efficacy and a broader range of indications.

[0003] However, the research and development and preparation of existing compound sustained-release formulations still face many technical bottlenecks: Firstly, the physicochemical properties (such as solubility, molecular weight, stability, etc.) of different drug components vary greatly, making it difficult to achieve simultaneous sustained release. This often results in a rapid release of one component leading to a sudden increase in blood drug concentration, while the release of another component is too slow to take effect in time. Secondly, the sustained-release excipients used in existing formulations are mostly traditional polymer materials, such as ethyl cellulose and hydroxypropyl methylcellulose. Their sustained-release properties are singular, making it difficult to precisely control the release according to the release requirements of different drug components, and they lack synergistic effects with drug components. Third, existing preparation processes mostly involve step-by-step preparation followed by mixing and molding, which can easily lead to uneven component distribution, affecting the uniformity and stability of formulation release. At the same time, the process steps are cumbersome and the production cost is high.

[0004] Based on this, a method for the simultaneous sustained-release and synergistic preparation of compound sustained-release formulations was designed. Summary of the Invention

[0005] In view of the above situation and to overcome the defects of the prior art, the present invention provides a method for the simultaneous sustained-release and synergistic preparation of compound sustained-release formulations, which effectively solves the problems mentioned in the background.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a method for the simultaneous sustained-release and synergistic preparation of compound sustained-release formulations, comprising the following steps: Step 1: Prepare the components of the compound sustained-release formulation according to the specified weight proportions: Therapeutic active ingredient: 20-40 parts; Polydopamine-quercetin copolymer: 6-12 parts; Polylactic acid-glycolic acid-chitosan graft copolymer: 3-9 parts; Glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres: 1.5-6 parts; Filler: 25-45 parts; Adhesive: 3-8 parts; Lubricant: 1-3 parts; Step 2, Raw material pretreatment: Grind the therapeutic active ingredients, polydopamine-quercetin copolymer, polylactic acid-glycolic acid-chitosan graft copolymer, glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and fillers through a 100-120 mesh sieve for later use; Step 3, Mixing: Weigh out 20-40 parts of the pretreated therapeutic active ingredient, 6-12 parts of polydopamine-quercetin copolymer, 3-9 parts of polylactic acid-glycolic acid-chitosan graft copolymer, 1.5-6 parts of glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and 25-45 parts of filler according to the following mass proportions. Add them to a three-dimensional mixer and mix for 15-25 minutes at a speed of 20-30 rpm to obtain a mixed powder. Step 4, Granulation: Gradually add 3-8 parts of binder to the mixed powder while stirring at a speed of 100-150 rpm to form a suitable soft material. Then, granulate the material by extrusion through a 16-20 mesh sieve to obtain wet granules. Step 5, Drying: Place the wet granules into a fluidized bed dryer and dry for 2-3 hours under the conditions of inlet air temperature 50-60℃, outlet air temperature 30-40℃, and air velocity 1.0-1.5 m / s. After drying, the moisture content of the granules should be controlled at 2%-4%. Step 6, Granulation: Granulate the dried granules using a 14-16 mesh sieve to remove oversized particles and fine powder; Step 7, General Mixing: Add 1-3 parts of lubricant to the granulated particles, put them into a three-dimensional mixer, and mix for 5-10 minutes at a speed of 15-25 rpm. Step 8: Tableting or Capsule Filling: Compress the total mixed granules into tablets at a pressure of 8-12 kN, with the tablet weight difference controlled within ±3%; or directly fill them into capsules to obtain a compound sustained-release formulation.

[0007] Preferably, the therapeutic active ingredient in step 1 is selected from two or three combinations of ibuprofen, metformin hydrochloride, and nifedipine.

[0008] Preferably, the filler in step 1 is a mixture of microcrystalline cellulose and lactose in a mass ratio of 1:0.5-2.

[0009] Preferably, the adhesive in step 1 is an ethanol solution of povidone K30 with a concentration of 5%-10%.

[0010] Preferably, the lubricant in step 1 is a mixture of magnesium stearate and talc in a mass ratio of 1:0.5-1.

[0011] Preferably, the preparation method of the polydopamine-quercetin copolymer in step 1 is as follows: Step A1: Add 5-10 parts of dopamine hydrochloride and 2-5 parts of quercetin to 100-200 parts of deionized water, stir to dissolve, and obtain a mixed solution; Step A2: Add tris(hydroxymethyl)aminomethane buffer to the mixed solution to adjust the pH to 8.0-8.5, then add 0.5-1.5 parts of ammonium persulfate as an initiator, and stir the reaction at 200-300 rpm for 4-6 hours at 25-35℃. Step A3: After the reaction is complete, centrifuge the reaction solution at a speed of 8000-10000 rpm for 10-15 minutes and collect the precipitate. Step A4: Wash the precipitate alternately with deionized water and anhydrous ethanol 3-5 times, centrifuge after each wash, and then dry it in a vacuum drying oven at 40-50℃ for 8-12 hours. Grind it through an 80-100 mesh sieve to obtain polydopamine-quercetin copolymer.

[0012] Preferably, the preparation method of the polylactic acid-glycolic acid-chitosan graft copolymer in step 1 is as follows: Step B1: Add 10-15 parts of polylactic acid-glycolic acid copolymer to 50-80 parts of dichloromethane, stir to dissolve, and obtain PLGA solution; wherein the molar ratio of lactic acid to glycolic acid is 50:50. Step B2: Add 2-4 parts of 1,6-hexamethylene diisocyanate to the PLGA solution, and stir the mixture at 150-250 rpm for 2-3 hours at 40-50℃ to obtain the modified PLGA solution. Step B3: Add 3-6 parts of chitosan to 20-40 parts of acetic acid solution with a mass fraction of 1%-2%, stir to dissolve, and obtain chitosan solution; Step B4: Slowly add the modified PLGA solution dropwise to the chitosan solution at a rate of 1-2 mL / min. After the addition is complete, stir the mixture at 200-300 rpm for 6-8 hours at 50-60°C. Step B5: After the reaction is complete, add sodium hydroxide solution to the reaction solution to adjust the pH value to 7.0-7.5, precipitate the precipitate, and centrifuge at 6000-8000 rpm for 8-12 minutes. Step B6: Wash the precipitate with deionized water until neutral, dry it in a vacuum drying oven at 50-60℃ for 12-16 hours, grind it through an 80-100 mesh sieve to obtain polylactic acid-hydroxyacetic acid-chitosan graft copolymer.

[0013] Preferably, the preparation method of the glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres in step 1 is as follows: Step C1: Add 8-12 parts of β-hydroxyethyl methacrylate, 2-4 parts of 3-acrylamidophenylboronic acid, and 1-2 parts of N,N-methylenebisacrylamide to 60-100 parts of deionized water, stir and mix evenly to obtain a monomer mixture. Step C2: Add 0.5-1.0 parts of sodium dodecyl sulfate as an emulsifier to the monomer mixture, and ultrasonically disperse for 15-25 minutes at an ultrasonic power of 200-300 watts to obtain an emulsion; Step C3: Heat the emulsion to 60-70℃, add 0.3-0.6 parts of potassium persulfate as an initiator, and stir the mixture at 250-350 rpm for 5-7 hours under nitrogen protection. Step C4: After the reaction is complete, cool the reaction solution to room temperature, centrifuge at 10,000-12,000 rpm for 15-20 minutes, and collect the precipitate. Step C5: Wash the precipitate with deionized water 3-4 times, and dry it in a vacuum drying oven at 45-55℃ for 10-14 hours to obtain glucose-responsive polymethyl methacrylate-β-hydroxyethyl ester microspheres.

[0014] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention designs three innovative sustained-release synergistic components: polydopamine-quercetin copolymer has both sustained-release and antioxidant synergistic effects; polylactic acid-glycolic acid-chitosan graft copolymer improves the biocompatibility and degradability of the sustained-release system; and glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres achieve responsive sustained release. The synergistic effect of the three components solves the problem of the single sustained-release performance of traditional excipients. 2. This invention, through the synergistic regulation of three innovative components, can precisely match the release requirements of different therapeutic active ingredients, achieve simultaneous sustained release of multiple components, avoid fluctuations in blood drug concentration, improve therapeutic efficacy and medication safety, and has excellent simultaneous sustained release effect; 3. This invention has good biocompatibility. All three innovative components are prepared using materials with excellent biocompatibility and are biodegradable, avoiding the biosafety issues that may arise from traditional excipients, and are suitable for long-term use. 4. This invention has a wide range of applications and can be adapted to combinations of various therapeutic active ingredients. It is especially suitable for the treatment of chronic diseases such as diabetes, hypertension, and arthritis, and has broad clinical application prospects. Detailed Implementation

[0015] The technical solution of the present invention will be clearly and completely described below with reference to specific 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 skilled in the art without creative effort are within the scope of protection of the present invention.

[0016] This invention provides a method for the simultaneous sustained-release and synergistic preparation of compound sustained-release formulations, comprising the following steps: Step 1: Prepare the components of the compound sustained-release formulation according to the specified weight proportions: Therapeutic active ingredient: 20-40 parts; Polydopamine-quercetin copolymer: 6-12 parts; Polylactic acid-glycolic acid-chitosan graft copolymer: 3-9 parts; Glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres: 1.5-6 parts; Filler: 25-45 parts; Adhesive: 3-8 parts; Lubricant: 1-3 parts; Step 2, Raw material pretreatment: Grind the therapeutic active ingredients, polydopamine-quercetin copolymer, polylactic acid-glycolic acid-chitosan graft copolymer, glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and fillers through a 100-120 mesh sieve for later use; Step 3, Mixing: Weigh out 20-40 parts of the pretreated therapeutic active ingredient, 6-12 parts of polydopamine-quercetin copolymer, 3-9 parts of polylactic acid-glycolic acid-chitosan graft copolymer, 1.5-6 parts of glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and 25-45 parts of filler according to the following mass proportions. Add them to a three-dimensional mixer and mix for 15-25 minutes at a speed of 20-30 rpm to obtain a mixed powder. Step 4, Granulation: Gradually add 3-8 parts of binder to the mixed powder while stirring at a speed of 100-150 rpm to form a suitable soft material. Then, granulate the material by extrusion through a 16-20 mesh sieve to obtain wet granules. Step 5, Drying: Place the wet granules into a fluidized bed dryer and dry for 2-3 hours under the conditions of inlet air temperature 50-60℃, outlet air temperature 30-40℃, and air velocity 1.0-1.5 m / s. After drying, the moisture content of the granules should be controlled at 2%-4%. Step 6, Granulation: Granulate the dried granules using a 14-16 mesh sieve to remove oversized particles and fine powder; Step 7, General Mixing: Add 1-3 parts of lubricant to the granulated particles, put them into a three-dimensional mixer, and mix for 5-10 minutes at a speed of 15-25 rpm. Step 8: Tableting or Capsule Filling: Compress the total mixed granules into tablets at a pressure of 8-12 kN, with the tablet weight difference controlled within ±3%; or directly fill them into capsules to obtain a compound sustained-release formulation.

[0017] The therapeutic active ingredient in this embodiment is selected from two or three combinations of ibuprofen, metformin hydrochloride, and nifedipine.

[0018] The filler in this embodiment is a mixture of microcrystalline cellulose and lactose in a mass ratio of 1:0.5-2.

[0019] In this embodiment, the adhesive is an ethanol solution of povidone K30 with a concentration of 5%-10%.

[0020] The lubricant in this embodiment is a mixture of magnesium stearate and talc powder in a mass ratio of 1:0.5-1.

[0021] The preparation method of the polydopamine-quercetin copolymer in this embodiment is as follows: Step A1: Add 5-10 parts of dopamine hydrochloride and 2-5 parts of quercetin to 100-200 parts of deionized water, stir to dissolve, and obtain a mixed solution; Step A2: Add tris(hydroxymethyl)aminomethane buffer to the mixed solution to adjust the pH to 8.0-8.5, then add 0.5-1.5 parts of ammonium persulfate as an initiator, and stir the reaction at 200-300 rpm for 4-6 hours at 25-35℃. Step A3: After the reaction is complete, centrifuge the reaction solution at a speed of 8000-10000 rpm for 10-15 minutes and collect the precipitate. Step A4: Wash the precipitate alternately with deionized water and anhydrous ethanol 3-5 times, centrifuge after each wash, and then dry it in a vacuum drying oven at 40-50℃ for 8-12 hours. Grind it through an 80-100 mesh sieve to obtain polydopamine-quercetin copolymer.

[0022] The preparation method of the polylactic acid-glycolic acid-chitosan graft copolymer in this embodiment is as follows: Step B1: Add 10-15 parts of polylactic acid-glycolic acid copolymer to 50-80 parts of dichloromethane, stir to dissolve, and obtain PLGA solution; wherein the molar ratio of lactic acid to glycolic acid is 50:50. Step B2: Add 2-4 parts of 1,6-hexamethylene diisocyanate to the PLGA solution, and stir the mixture at 150-250 rpm for 2-3 hours at 40-50℃ to obtain the modified PLGA solution. Step B3: Add 3-6 parts of chitosan to 20-40 parts of acetic acid solution with a mass fraction of 1%-2%, stir to dissolve, and obtain chitosan solution; Step B4: Slowly add the modified PLGA solution dropwise to the chitosan solution at a rate of 1-2 mL / min. After the addition is complete, stir the mixture at 200-300 rpm for 6-8 hours at 50-60°C. Step B5: After the reaction is complete, add sodium hydroxide solution to the reaction solution to adjust the pH value to 7.0-7.5, precipitate the precipitate, and centrifuge at 6000-8000 rpm for 8-12 minutes. Step B6: Wash the precipitate with deionized water until neutral, dry it in a vacuum drying oven at 50-60℃ for 12-16 hours, grind it through an 80-100 mesh sieve to obtain polylactic acid-hydroxyacetic acid-chitosan graft copolymer.

[0023] The preparation method of glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres in this embodiment is as follows: Step C1: Add 8-12 parts of β-hydroxyethyl methacrylate, 2-4 parts of 3-acrylamidophenylboronic acid, and 1-2 parts of N,N-methylenebisacrylamide to 60-100 parts of deionized water, stir and mix evenly to obtain a monomer mixture. Step C2: Add 0.5-1.0 parts of sodium dodecyl sulfate as an emulsifier to the monomer mixture, and ultrasonically disperse for 15-25 minutes at an ultrasonic power of 200-300 watts to obtain an emulsion; Step C3: Heat the emulsion to 60-70℃, add 0.3-0.6 parts of potassium persulfate as an initiator, and stir the mixture at 250-350 rpm for 5-7 hours under nitrogen protection. Step C4: After the reaction is complete, cool the reaction solution to room temperature, centrifuge at 10,000-12,000 rpm for 15-20 minutes, and collect the precipitate. Step C5: Wash the precipitate with deionized water 3-4 times, and dry it in a vacuum drying oven at 45-55℃ for 10-14 hours to obtain glucose-responsive polymethyl methacrylate-β-hydroxyethyl ester microspheres.

[0024] Example 1: A method for preparing compound sustained-release and controlled-release formulations with simultaneous sustained-release and synergistic effects includes the following steps: Step 1, Raw material pretreatment: Grind the therapeutic active ingredients (15 parts ibuprofen + 15 parts metformin hydrochloride), 8 parts polydopamine-quercetin copolymer, 6 parts polylactic acid-glycolic acid-chitosan graft copolymer, 3 parts glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and filler (15 parts microcrystalline cellulose + 10 parts lactose) through a 110-mesh sieve for later use; Step 2, Mixing: Weigh each pretreated component according to the above mass proportions, add them to a three-dimensional mixer, and mix for 20 minutes at a speed of 25 rpm to obtain a mixed powder; Step 3, Granulation: Gradually add binder (5 parts of 5% povidone K30 ethanol solution) to the mixed powder while stirring at a speed of 120 rpm to form a suitable soft material. Then, granulate the material by extrusion through an 18-mesh sieve to obtain wet granules. Step 4, Drying: Place the wet granules into a fluidized bed dryer and dry for 2.5 hours under the conditions of inlet air temperature 55℃, outlet air temperature 35℃, and air velocity 1.2 m / s. After drying, the moisture content of the granules should be controlled at 3%. Step 5, Granulation: Granulate the dried granules using a 15-mesh sieve to remove oversized particles and fine powder; Step 6, General Mixing: Add lubricant (1 part magnesium stearate + 0.5 parts talc) to the granulated particles, put them into a three-dimensional mixer, and mix for 8 minutes at a speed of 20 rpm; Step 7, tableting: Compress the mixed granules into tablets at a pressure of 10 kN, with the tablet weight difference controlled within ±3%, to obtain compound sustained-release tablets.

[0025] The preparation method of polydopamine-quercetin copolymer is as follows: Step A1: Add 7 parts of dopamine hydrochloride and 3 parts of quercetin to 150 parts of deionized water, stir to dissolve, and obtain a mixed solution; Step A2: Add tris(hydroxymethyl)aminomethane buffer to the mixed solution to adjust the pH to 8.2, then add 1.0 part of ammonium persulfate as an initiator, and stir the reaction at 250 rpm for 5 hours at 30°C. Step A3: After the reaction is complete, centrifuge the reaction solution at 9000 rpm for 12 minutes and collect the precipitate. Step A4: Wash the precipitate four times alternately with deionized water and anhydrous ethanol. After each washing, centrifuge the precipitate and then dry it in a vacuum drying oven at 45°C for 10 hours. Grind the precipitate through a 90-mesh sieve to obtain polydopamine-quercetin copolymer.

[0026] The preparation method of polylactic acid-glycolic acid-chitosan graft copolymer is as follows: Step B1: Add 12 parts of polylactic acid-glycolic acid copolymer (PLGA, with a molar ratio of lactic acid to glycolic acid of 50:50) to 65 parts of dichloromethane, stir to dissolve, and obtain a PLGA solution; Step B2: Add 3 parts of 1,6-hexamethylene diisocyanate to the PLGA solution, and stir the mixture at 200 rpm for 2.5 hours at 45°C to obtain the modified PLGA solution. Step B3: Add 4 parts of chitosan to 30 parts of acetic acid solution with a mass fraction of 1.5%, stir to dissolve, and obtain chitosan solution; Step B4: Slowly add the modified PLGA solution to the chitosan solution at a rate of 1.5 mL / min. After the addition is complete, stir the mixture at 250 rpm for 7 hours at 55°C. Step B5: After the reaction is complete, add sodium hydroxide solution to the reaction solution to adjust the pH value to 7.2, precipitate out the precipitate, and centrifuge at 7000 rpm for 10 minutes. Step B6: Wash the precipitate with deionized water until neutral, dry it in a vacuum drying oven at 55°C for 14 hours, grind it through a 90-mesh sieve to obtain polylactic acid-hydroxyacetic acid-chitosan graft copolymer.

[0027] The preparation method of glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres is as follows: Step C1: Add 10 parts of β-hydroxyethyl methacrylate (HEMA), 3 parts of 3-acrylamidophenylboronic acid (PBA), and 1.5 parts of N,N-methylenebisacrylamide to 80 parts of deionized water, stir and mix evenly to obtain a monomer mixture. Step C2: Add 0.8 parts of sodium dodecyl sulfate as an emulsifier to the monomer mixture, and ultrasonically disperse for 20 minutes at an ultrasonic power of 250 watts to obtain an emulsion; Step C3: Heat the emulsion to 65°C, add 0.4 parts of potassium persulfate as an initiator, and stir the mixture at 300 rpm for 6 hours under nitrogen protection. Step C4: After the reaction is complete, cool the reaction solution to room temperature, centrifuge at 11,000 rpm for 18 minutes, and collect the precipitate. Step C5: Wash the precipitate four times with deionized water and dry it in a vacuum drying oven at 50°C for 12 hours to obtain glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres.

[0028] Example 2: A method for preparing compound sustained-release and controlled-release formulations with simultaneous sustained-release and synergistic effects includes the following steps: Step 1, Raw material pretreatment: Grind the therapeutic active ingredients (20 parts nifedipine + 20 parts metformin hydrochloride), 12 parts polydopamine-quercetin copolymer, 9 parts polylactic acid-glycolic acid-chitosan graft copolymer, 6 parts glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and filler (20 parts microcrystalline cellulose + 20 parts lactose) through a 120-mesh sieve for later use; Step 2, Mixing: Weigh each pretreated component according to the above mass proportions, add them to a three-dimensional mixer, and mix for 25 minutes at a speed of 30 rpm to obtain a mixed powder; Step 3, Granulation: Gradually add binder (8 parts of 10% povidone K30 ethanol solution) to the mixed powder while stirring at a speed of 150 rpm to form a suitable soft material. Then, granulate the material by extrusion through a 20-mesh sieve to obtain wet granules. Step 4, Drying: Place the wet granules into a fluidized bed dryer and dry for 3 hours at an inlet air temperature of 60℃, an outlet air temperature of 40℃, and an air velocity of 1.5 m / s. After drying, the moisture content of the granules should be controlled at 2%. Step 5, Granulation: Granulate the dried granules using a 16-mesh sieve to remove oversized particles and fine powder; Step 6, General Mixing: Add lubricant (1.5 parts magnesium stearate + 1.5 parts talc) to the granulated particles, put them into a three-dimensional mixer, and mix for 10 minutes at a speed of 25 rpm; Step 7, Capsule filling: The mixed granules are directly filled into capsules to obtain compound sustained-release capsules.

[0029] The preparation method of polydopamine-quercetin copolymer is as follows: Step A1: Add 10 parts of dopamine hydrochloride and 4 parts of quercetin to 180 parts of deionized water, stir to dissolve, and obtain a mixed solution; Step A2: Add tris(hydroxymethyl)aminomethane buffer to the mixed solution to adjust the pH to 8.4, then add 1.2 parts of ammonium persulfate as an initiator, and stir the reaction at 280 rpm for 5.5 hours at 32°C. Step A3: After the reaction is complete, centrifuge the reaction solution at 9500 rpm for 14 minutes and collect the precipitate. Step A4: Wash the precipitate five times alternately with deionized water and anhydrous ethanol. After each washing, centrifuge the precipitate and then dry it in a vacuum drying oven at 48°C for 11 hours. Grind the precipitate through a 95-mesh sieve to obtain polydopamine-quercetin copolymer.

[0030] The preparation method of polylactic acid-glycolic acid-chitosan graft copolymer is as follows: Step B1: Add 15 parts of polylactic acid-glycolic acid copolymer (PLGA, with a molar ratio of lactic acid to glycolic acid of 50:50) to 75 parts of dichloromethane, stir to dissolve, and obtain a PLGA solution. Step B2: Add 4 parts of 1,6-hexamethylene diisocyanate to the PLGA solution, and stir the mixture at 240 rpm for 2.8 hours at 48°C to obtain the modified PLGA solution. Step B3: Add 6 parts of chitosan to 38 parts of acetic acid solution with a mass fraction of 1.8%, stir to dissolve, and obtain chitosan solution; Step B4: Slowly add the modified PLGA solution dropwise to the chitosan solution at a rate of 1.8 mL / min. After the addition is complete, stir the mixture at 280 rpm for 7.5 hours at 58°C. Step B5: After the reaction is complete, add sodium hydroxide solution to the reaction solution to adjust the pH value to 7.4, precipitate out the precipitate, and centrifuge at 7800 rpm for 11 minutes. Step B6: Wash the precipitate with deionized water until neutral, dry it in a vacuum drying oven at 58°C for 15 hours, grind it through a 95-mesh sieve to obtain polylactic acid-hydroxyacetic acid-chitosan graft copolymer.

[0031] The preparation method of glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres is as follows: Step C1: Add 12 parts of β-hydroxyethyl methacrylate (HEMA), 4 parts of 3-acrylamidophenylboronic acid (PBA) and 2 parts of N,N-methylenebisacrylamide to 95 parts of deionized water, stir and mix evenly to obtain a monomer mixture. Step C2: Add 1.0 part of sodium dodecyl sulfate as an emulsifier to the monomer mixture, and ultrasonically disperse for 24 minutes at an ultrasonic power of 280 watts to obtain an emulsion; Step C3: Heat the emulsion to 68°C, add 0.55 parts of potassium persulfate as an initiator, and stir the mixture at 340 rpm for 6.5 hours under nitrogen protection. Step C4: After the reaction is complete, cool the reaction solution to room temperature, centrifuge at 11,800 rpm for 19 minutes, and collect the precipitate. Step C5: Wash the precipitate four times with deionized water and dry it in a vacuum drying oven at 54°C for 13 hours to obtain glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres.

[0032] Example 3: A method for preparing compound sustained-release and controlled-release formulations with simultaneous sustained-release and synergistic effects includes the following steps: Step 1, Raw material pretreatment: Grind the therapeutic active ingredients (10 parts ibuprofen + 10 parts nifedipine + 10 parts metformin hydrochloride), 6 parts polydopamine-quercetin copolymer, 3 parts polylactic acid-glycolic acid-chitosan graft copolymer, 1.5 parts glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and filler (10 parts microcrystalline cellulose + 15 parts lactose) through a 100-mesh sieve for later use; Step 2, Mixing: Weigh each pretreated component according to the above mass proportions, add them to a three-dimensional mixer, and mix for 15 minutes at a speed of 20 rpm to obtain a mixed powder; Step 3, Granulation: Gradually add binder (3 parts of 7% povidone K30 ethanol solution) to the mixed powder while stirring at 100 rpm to form a suitable soft material. Then, granulate the material by extrusion through a 16-mesh sieve to obtain wet granules. Step 4, Drying: Place the wet granules into a fluidized bed dryer and dry for 2 hours under the conditions of inlet air temperature 50℃, outlet air temperature 30℃, and air velocity 1.0 m / s. After drying, the moisture content of the granules should be controlled at 4%. Step 5, Granulation: Granulate the dried granules using a 14-mesh sieve to remove oversized particles and fine powder; Step 6, General Mixing: Add lubricant (0.8 parts magnesium stearate + 0.4 parts talc) to the granulated particles, place them in a three-dimensional mixer, and mix for 5 minutes at a speed of 15 rpm; Step 7, tableting: Compress the mixed granules into tablets at a pressure of 8 kN, with the tablet weight difference controlled within ±3%, to obtain compound sustained-release tablets.

[0033] The preparation method of polydopamine-quercetin copolymer is as follows: Step A1: Add 5 parts of dopamine hydrochloride and 2 parts of quercetin to 100 parts of deionized water, stir to dissolve, and obtain a mixed solution; Step A2: Add tris(hydroxymethyl)aminomethane buffer to the mixed solution to adjust the pH to 8.0, then add 0.5 parts of ammonium persulfate as an initiator, and stir the mixture at 200 rpm for 4 hours at 25°C. Step A3: After the reaction is complete, centrifuge the reaction solution at 8000 rpm for 10 minutes and collect the precipitate. Step A4: Wash the precipitate three times alternately with deionized water and anhydrous ethanol. After each washing, centrifuge the precipitate and then dry it in a vacuum drying oven at 40°C for 8 hours. Grind the precipitate through an 80-mesh sieve to obtain polydopamine-quercetin copolymer.

[0034] The preparation method of polylactic acid-glycolic acid-chitosan graft copolymer is as follows: Step B1: Add 10 parts of polylactic acid-glycolic acid copolymer (PLGA, with a molar ratio of lactic acid to glycolic acid of 50:50) to 50 parts of dichloromethane, stir to dissolve, and obtain a PLGA solution; Step B2: Add 2 parts of 1,6-hexamethylene diisocyanate to the PLGA solution, and stir the mixture at 150 rpm for 2 hours at 40°C to obtain the modified PLGA solution. Step B3: Add 3 parts of chitosan to 20 parts of acetic acid solution with a mass fraction of 1%, stir to dissolve, and obtain chitosan solution; Step B4: Slowly add the modified PLGA solution to the chitosan solution at a rate of 1 mL / min. After the addition is complete, stir the mixture at 200 rpm for 6 hours at 50°C. Step B5: After the reaction is complete, add sodium hydroxide solution to the reaction solution to adjust the pH value to 7.0, precipitate out, and centrifuge at 6000 rpm for 8 minutes. Step B6: Wash the precipitate with deionized water until neutral, dry it in a vacuum drying oven at 50°C for 12 hours, and grind it through an 80-mesh sieve to obtain polylactic acid-hydroxyacetic acid-chitosan graft copolymer.

[0035] The preparation method of glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres is as follows: Step C1: Add 8 parts of β-hydroxyethyl methacrylate (HEMA), 2 parts of 3-acrylamidophenylboronic acid (PBA) and 1 part of N,N-methylenebisacrylamide to 60 parts of deionized water, stir and mix evenly to obtain a monomer mixture. Step C2: Add 0.5 parts of sodium dodecyl sulfate as an emulsifier to the monomer mixture, and ultrasonically disperse for 15 minutes at an ultrasonic power of 200 watts to obtain an emulsion; Step C3: Heat the emulsion to 60°C, add 0.3 parts of potassium persulfate as an initiator, and stir the mixture at 250 rpm for 5 hours under nitrogen protection. Step C4: After the reaction is complete, cool the reaction solution to room temperature, centrifuge at 10,000 rpm for 15 minutes, and collect the precipitate. Step C5: Wash the precipitate three times with deionized water and dry it in a vacuum drying oven at 45°C for 10 hours to obtain glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres.

[0036] Performance testing The compound sustained-release formulations prepared in Examples 1, 2, and 3 were subjected to in vitro release tests. The test conditions were uniform: the paddle method was used, the release medium was phosphate buffer solution with pH 7.4, the rotation speed was 50 rpm, and the temperature was 37°C. Samples were taken at 1, 2, 4, 6, 8, 12, and 24 hours to determine the cumulative release of each active ingredient.

[0037] The specific test results are as follows: Example 1 (Compound sustained-release tablets, active ingredients: 15 parts ibuprofen + 15 parts metformin hydrochloride): The cumulative release rate of ibuprofen over 24 hours was 92.3%, and the cumulative release rate of metformin hydrochloride over 24 hours was 91.8%. The difference in release rate between the two components at each time point was less than 5%, achieving a good simultaneous sustained-release effect.

[0038] Example 2 (Compound sustained-release capsules, active ingredients: 20 parts nifedipine + 20 parts metformin hydrochloride): The cumulative release rate of nifedipine over 24 hours was 90.8%, and the cumulative release rate of metformin hydrochloride over 24 hours was 91.2%. The difference in release rate between the two components at each time point was less than 4%, indicating excellent simultaneous sustained-release performance and good release stability of the capsule formulation.

[0039] Example 3 (Compound sustained-release tablets, active ingredients: 10 parts ibuprofen + 10 parts nifedipine + 10 parts metformin hydrochloride): The cumulative release rate of ibuprofen over 24 hours was 89.6%, the cumulative release rate of nifedipine over 24 hours was 89.2%, and the cumulative release rate of metformin hydrochloride over 24 hours was 90.1%. The difference in release rate of the three components at each time point was less than 5%, and the synergistic and simultaneous sustained-release effect of the multiple components met the target.

[0040] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0041] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing compound sustained-release and controlled-release formulations with simultaneous sustained-release and synergistic effects, characterized in that, Includes the following steps: Step 1: Prepare the components of the compound sustained-release formulation according to the specified weight proportions: Therapeutic active ingredient: 20-40 parts; Polydopamine-quercetin copolymer: 6-12 parts; Polylactic acid-glycolic acid-chitosan graft copolymer: 3-9 parts; Glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres: 1.5-6 parts; Filler: 25-45 parts; Adhesive: 3-8 parts; Lubricant: 1-3 parts; Step 2, Raw material pretreatment: Grind the therapeutic active ingredients, polydopamine-quercetin copolymer, polylactic acid-glycolic acid-chitosan graft copolymer, glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and fillers through a 100-120 mesh sieve for later use; Step 3, Mixing: Weigh out 20-40 parts of the pretreated therapeutic active ingredient, 6-12 parts of polydopamine-quercetin copolymer, 3-9 parts of polylactic acid-glycolic acid-chitosan graft copolymer, 1.5-6 parts of glucose-responsive polymethacrylate-β-hydroxyethyl ester microspheres, and 25-45 parts of filler according to the following mass proportions. Add them to a three-dimensional mixer and mix for 15-25 minutes at a speed of 20-30 rpm to obtain a mixed powder. Step 4, Granulation: Gradually add 3-8 parts of binder to the mixed powder while stirring at a speed of 100-150 rpm to form a suitable soft material. Then, granulate the material by extrusion through a 16-20 mesh sieve to obtain wet granules. Step 5, Drying: Place the wet granules into a fluidized bed dryer and dry for 2-3 hours under the conditions of inlet air temperature 50-60℃, outlet air temperature 30-40℃, and air velocity 1.0-1.5 m / s. After drying, the moisture content of the granules should be controlled at 2%-4%. Step 6, Granulation: Granulate the dried granules using a 14-16 mesh sieve to remove oversized particles and fine powder; Step 7, General Mixing: Add 1-3 parts of lubricant to the granulated particles, put them into a three-dimensional mixer, and mix for 5-10 minutes at a speed of 15-25 rpm. Step 8: Tableting or Capsule Filling: Compress the total mixed granules into tablets at a pressure of 8-12 kN, with the tablet weight difference controlled within ±3%; or directly fill them into capsules to obtain a compound sustained-release formulation.

2. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The therapeutic active ingredient mentioned in step 1 is selected from two or three combinations of ibuprofen, metformin hydrochloride, and nifedipine.

3. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The filler mentioned in step 1 is a mixture of microcrystalline cellulose and lactose in a mass ratio of 1:0.5-2.

4. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The adhesive mentioned in step 1 is an ethanol solution of povidone K30 with a concentration of 5%-10%.

5. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The lubricant mentioned in step 1 is a mixture of magnesium stearate and talc powder in a mass ratio of 1:0.5-1.

6. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The preparation method of the polydopamine-quercetin copolymer in step 1 is as follows: Step A1: Add 5-10 parts of dopamine hydrochloride and 2-5 parts of quercetin to 100-200 parts of deionized water, stir to dissolve, and obtain a mixed solution; Step A2: Add tris(hydroxymethyl)aminomethane buffer to the mixed solution to adjust the pH to 8.0-8.5, then add 0.5-1.5 parts of ammonium persulfate as an initiator, and stir the reaction at 200-300 rpm for 4-6 hours at 25-35℃. Step A3: After the reaction is complete, centrifuge the reaction solution at a speed of 8000-10000 rpm for 10-15 minutes and collect the precipitate. Step A4: Wash the precipitate alternately with deionized water and anhydrous ethanol 3-5 times, centrifuge after each wash, and then dry it in a vacuum drying oven at 40-50℃ for 8-12 hours. Grind it through an 80-100 mesh sieve to obtain polydopamine-quercetin copolymer.

7. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The preparation method of the polylactic acid-glycolic acid-chitosan graft copolymer in step 1 is as follows: Step B1: Add 10-15 parts of polylactic acid-glycolic acid copolymer to 50-80 parts of dichloromethane, stir to dissolve, and obtain PLGA solution; wherein the molar ratio of lactic acid to glycolic acid is 50:

50. Step B2: Add 2-4 parts of 1,6-hexamethylene diisocyanate to the PLGA solution, and stir the mixture at 150-250 rpm for 2-3 hours at 40-50℃ to obtain the modified PLGA solution. Step B3: Add 3-6 parts of chitosan to 20-40 parts of acetic acid solution with a mass fraction of 1%-2%, stir to dissolve, and obtain chitosan solution; Step B4: Slowly add the modified PLGA solution dropwise to the chitosan solution at a rate of 1-2 mL / min. After the addition is complete, stir the mixture at 200-300 rpm for 6-8 hours at 50-60°C. Step B5: After the reaction is complete, add sodium hydroxide solution to the reaction solution to adjust the pH value to 7.0-7.5, precipitate the precipitate, and centrifuge at 6000-8000 rpm for 8-12 minutes. Step B6: Wash the precipitate with deionized water until neutral, dry it in a vacuum drying oven at 50-60℃ for 12-16 hours, grind it through an 80-100 mesh sieve to obtain polylactic acid-hydroxyacetic acid-chitosan graft copolymer.

8. The method for simultaneous sustained-release and synergistic preparation of compound sustained-release formulations according to claim 1, characterized in that, The preparation method of the glucose-responsive poly(β-hydroxyethyl methacrylate) microspheres described in step 1 is as follows: Step C1: Add 8-12 parts of β-hydroxyethyl methacrylate, 2-4 parts of 3-acrylamidophenylboronic acid, and 1-2 parts of N,N-methylenebisacrylamide to 60-100 parts of deionized water, stir and mix evenly to obtain a monomer mixture. Step C2: Add 0.5-1.0 parts of sodium dodecyl sulfate as an emulsifier to the monomer mixture, and ultrasonically disperse for 15-25 minutes at an ultrasonic power of 200-300 watts to obtain an emulsion; Step C3: Heat the emulsion to 60-70℃, add 0.3-0.6 parts of potassium persulfate as an initiator, and stir the mixture at 250-350 rpm for 5-7 hours under nitrogen protection. Step C4: After the reaction is complete, cool the reaction solution to room temperature, centrifuge at 10,000-12,000 rpm for 15-20 minutes, and collect the precipitate. Step C5: Wash the precipitate with deionized water 3-4 times, and dry it in a vacuum drying oven at 45-55℃ for 10-14 hours to obtain glucose-responsive polymethyl methacrylate-β-hydroxyethyl ester microspheres.