High-drug-loading risperidone sustained-release microsphere capable of being used for subcutaneous injection and preparation method of high-drug-loading risperidone sustained-release microsphere

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a high-drug-loading risperidone sustained release microsphere for subcutaneous injection and a preparation method thereof, and the preparation method comprises the following steps: mixing risperidone, polylactic acid and dichloromethane to obtain an oil phase; dissolving a pore-forming agent in water to obtain a pore-forming agent solution; mixing polyvinyl alcohol, sodium chloride and water to obtain a water phase; mixing the oil phase with the pore-forming agent solution to obtain primary emulsion; mixing and stirring the primary emulsion and a water phase until dichloromethane is completely volatilized to obtain microspheres loaded with speridone; mixing cellulose acetate, polyethylene glycol and an organic solvent to obtain a coating solution; and coating the risperidone-loaded microspheres with a coating solution to obtain the high-drug-loading risperidone sustained-release microspheres capable of being used for subcutaneous injection. According to the invention, the efficient drug loading is realized, the injection comfort is improved, the slow permeation and release of the drug are realized, and the onset speed and the long-acting treatment demand are balanced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically, to a highly drug-loaded risperidone sustained-release microsphere for subcutaneous injection and its preparation method. Background Technology

[0002] Chronic mental illnesses such as schizophrenia and bipolar disorder have long courses and high relapse rates, requiring long-term, regular medication to maintain symptom stability. Risperidone, a commonly used atypical antipsychotic, exerts its therapeutic effect by specifically blocking the synergistic action of dopamine D2 receptors and serotonin 5-HT2A receptors, playing an important role in the treatment of mental illnesses. However, traditional risperidone formulations have significant clinical drawbacks: oral formulations are affected by gastrointestinal absorption differences and the first-pass effect, resulting in a bioavailability of only about 60%, and blood drug concentrations fluctuate dramatically, requiring 2-3 doses daily, leading to extremely poor patient compliance, frequent missed doses and incorrect doses, directly causing relapses; while intravenous formulations can take effect quickly, they require professional medical care and cannot achieve long-term drug release, making them unsuitable for the long-term home management needs of chronic diseases.

[0003] Subcutaneous sustained-release microsphere formulations, with their core advantages of "long-acting drug release + convenient administration," have become a key direction for the upgrading of risperidone formulations. These formulations encapsulate the drug in biodegradable carrier materials (such as polylactic acid and polylactic-glycolic acid copolymers), forming a drug reservoir under the skin after injection. The drug is slowly released over weeks or even months, not only avoiding the first-pass effect of oral formulations and improving bioavailability, but also significantly reducing the frequency of administration and greatly improving patient compliance. Currently, the mainstream methods in the industry are double emulsion and emulsion-solvent evaporation methods to prepare risperidone sustained-release microspheres, and coating technology to control the drug release rate and inhibit initial burst release (rapid initial drug release leads to a sudden increase in blood drug concentration, which can easily trigger adverse reactions such as extrapyramidal reactions).

[0004] Although some progress has been made in the development of risperidone sustained-release microspheres, there are still many unresolved core issues with risperidone sustained-release microspheres prepared using existing technologies, which seriously limit their clinical application: 1. High drug loading requirements are difficult to meet: Risperidone is a hydrophobic drug, and in the existing process, the drug is prone to agglomeration in the carrier material, resulting in a drug loading rate of microspheres that is generally less than 8%. In order to achieve an effective therapeutic dose, a larger volume of formulation needs to be injected, which increases the pain and discomfort of subcutaneous injection for patients and is not conducive to the miniaturization and portability of the formulation. 2. High risk of initial burst release and unstable sustained-release performance: Existing coating technologies (including fluidized bed coating) lack precise matching of process parameters. Improper control of coating solution concentration, flow rate, atomization pressure, and temperature and humidity can easily lead to uneven coating thickness, surface cracking, or peeling, failing to form a stable sustained-release barrier. Some products exhibit drug release rates exceeding 30% in the initial 24 hours, posing a risk of adverse reactions; while other products, due to over-coating, show delayed drug release, prolonged onset time (exceeding 48 hours), and inability to quickly control acute symptoms. 3. Poor physicochemical properties of microspheres: The ratio of oil phase, aqueous phase, and pore-forming agent solution, as well as the emulsification parameters (rotation speed, time) in the existing process are not optimized, resulting in a microsphere particle size distribution span exceeding 2.5, with some microspheres having a particle size greater than 15 μm. These microspheres cannot pass through conventional subcutaneous injection needles (pore size 10-12 μm) or may cause local irritation during injection. At the same time, the uneven pore structure of the microspheres further exacerbates the fluctuations in drug release. 4. Poor adaptability of coating process: Although fluidized bed coating is the preferred solution for microsphere coating, the existing technology has not optimized the coating parameters for the particle size and density characteristics of risperidone microspheres, which often leads to problems such as microsphere agglomeration and coating layer adhesion, resulting in poor batch-to-batch consistency of products and difficulty in industrial production.

[0005] In summary, existing risperidone sustained-release microspheres suffer from core problems such as low drug loading, high risk of initial burst release, unstable sustained-release performance, poor physicochemical properties, and poor compatibility with coating processes, failing to fully meet the clinical needs for long-acting, safe, and convenient drug delivery. Therefore, this application aims to solve the aforementioned technical problems by providing a method for preparing subcutaneous risperidone sustained-release microspheres with high drug loading, low burst release, stable sustained release, and excellent physicochemical properties through precise control of the component ratios and key process parameters. Summary of the Invention

[0006] In view of this, the present invention proposes a high-drug-loaded risperidone sustained-release microsphere for subcutaneous injection and its preparation method, aiming to solve the core problems of existing risperidone sustained-release microspheres, such as low drug loading rate, high risk of initial burst release, unstable sustained-release performance, poor physicochemical properties and poor compatibility with coating process, as well as the inability to fully meet the clinical needs for long-acting, safe and convenient drug delivery.

[0007] This invention proposes a method for preparing highly drug-loaded risperidone sustained-release microspheres suitable for subcutaneous injection, comprising the following steps: Risperidone, polylactic acid and dichloromethane were mixed to obtain the oil phase; Dissolve the pore-forming agent in water to obtain a pore-forming agent solution; Aqueous phase is obtained by mixing polyvinyl alcohol, sodium chloride, and water. The primary emulsion is obtained by mixing the oil phase with the pore-forming agent solution; The primary emulsion was mixed with the aqueous phase and stirred until the dichloromethane was completely evaporated to obtain microspheres loaded with risperidone; A coating solution is obtained by mixing cellulose acetate, polyethylene glycol and an organic solvent; Risperidone-loaded microspheres were coated with a coating solution to obtain highly drug-loaded risperidone sustained-release microspheres suitable for subcutaneous injection.

[0008] Preferably, the concentration of risperidone in the oil phase is 5~16.7 mg / mL, and the concentration of polylactic acid is 50~167 mg / mL.

[0009] Preferably, the mass concentration of the pore-forming agent in the pore-forming agent solution is 5% to 10%; The pore-forming agent is sucrose and / or sodium chloride.

[0010] Preferably, the mass concentration of polyethanol in the aqueous phase is 1% to 3%, and the mass concentration of sodium chloride is 0.5% to 1%.

[0011] Preferably, the volume ratio of the oil phase to the pore-forming agent solution is 3~5:1; The oil phase and the pore-forming agent solution are mixed by high-shear emulsification at a speed of 10,000 to 15,000 rpm for 5 to 10 minutes.

[0012] Preferably, the volume ratio of the primary emulsion to the aqueous phase is 1:5~10; The mixing speed of the primary emulsion and the aqueous phase is 300~500 rpm, the mixing time is 15~20 min, and the temperature is 20~25℃.

[0013] Preferably, the coating solution contains 3% to 5% cellulose acetate and 0.3% to 1% polyethylene glycol.

[0014] Preferably, the coating method is fluidized bed coating.

[0015] Preferably, the process parameters for fluidized bed coating are: coating liquid flow rate of 0.5~1 mL / min, inlet air temperature of 40~45℃, outlet air temperature of 30~35℃, atomization pressure of 0.2~0.3 MPa, and coating weight gain controlled at 5%~10%.

[0016] The present invention also provides risperidone sustained-release microspheres prepared by the above preparation method.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention addresses the pain points of existing technologies from multiple dimensions, including drug loading, sustained-release regulation, microsphere molding, and industrial adaptation, through the synergistic control of material ratios and process parameters. (1) Achieve efficient drug loading and improve injection comfort. The hydrophobicity of risperidone can easily lead to aggregation. This invention optimizes the oil phase composition ratio to form a uniform dispersion system between the drug and the carrier material in the solvent, providing sufficient loading sites for the drug, avoiding carrier redundancy, thereby improving drug loading efficiency, reducing the injection volume of the formulation with the same therapeutic effect, and reducing patient discomfort.

[0018] (2) Suppressing initial burst release and ensuring sustained-release stability. Targeting the core cause of burst release, this invention optimizes the coating system to enable the film-forming material and plasticizer to synergistically form a dense and flexible coating layer, avoiding the risk of cracking; at the same time, it matches a dedicated fluidized bed coating process to ensure uniform coating; and combined with a pore-forming agent to regulate the internal pore structure of the microspheres, it achieves slow drug permeation and release, balancing the onset of action and the need for long-term treatment.

[0019] (3) Optimize the physicochemical properties of microspheres and improve biocompatibility. Through precise control of the two-stage emulsification process, the droplets are evenly dispersed. Combined with the gradient solvent evaporation mode, the collapse of the microsphere surface and the disorder of pores are avoided, ensuring that the microspheres have uniform particle size and regular shape, which is suitable for subcutaneous injection and reduces local irritation. The optimized composition of the aqueous phase further stabilizes the system and reduces the risk of microsphere adhesion.

[0020] (4) Improve process adaptability and product consistency. This invention clarifies the key control parameters of each step, forms a standardized preparation process, avoids reliance on experience, and ensures batch-to-batch performance stability in large-scale production; the subcutaneous injection mode avoids the first-pass effect of oral administration, improves bioavailability, reduces the frequency of administration, and significantly improves medication compliance in patients with chronic diseases, thus possessing both clinical value and industrial feasibility. Detailed Implementation

[0021] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention. It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the present invention.

[0022] Furthermore, regarding the numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included within this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0023] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0024] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This specification and embodiments are merely exemplary.

[0025] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0026] This invention proposes a method for preparing highly drug-loaded risperidone sustained-release microspheres suitable for subcutaneous injection, comprising the following steps: Risperidone, polylactic acid and dichloromethane were mixed to obtain the oil phase; Dissolve the pore-forming agent in water to obtain a pore-forming agent solution; Aqueous phase is obtained by mixing polyvinyl alcohol, sodium chloride, and water. The primary emulsion is obtained by mixing the oil phase with the pore-forming agent solution; The primary emulsion was mixed with the aqueous phase and stirred until the dichloromethane was completely evaporated to obtain microspheres loaded with risperidone; A coating solution is obtained by mixing cellulose acetate, polyethylene glycol and an organic solvent; Risperidone-loaded microspheres were coated with a coating solution to obtain highly drug-loaded risperidone sustained-release microspheres suitable for subcutaneous injection.

[0027] In this invention, the concentration of risperidone in the oil phase is 5-16.7 mg / mL, and the concentration of polylactic acid is 50-167 mg / mL. The hydrophobicity of risperidone is the core reason for its low drug loading rate. Existing processes are prone to drug aggregation due to an imbalance in the mixing ratio of drug and carrier materials. This invention optimizes the oil phase ratio, limiting the risperidone concentration to 5-16.7 mg / mL and the polylactic acid concentration to 50-167 mg / mL, precisely controlling their mass ratio at 1:5 to 1:10. This ratio ensures that polylactic acid provides sufficient loading sites for risperidone while avoiding excessive microsphere volume due to excessive carrier. Simultaneously, dichloromethane, as a solvent, can fully dissolve both components, forming a homogeneous oil phase and eliminating the thermodynamic basis for drug aggregation. The drug loading rate of the microspheres can be stably increased to over 10%, and the volume of the microsphere formulation can be reduced by over 20%, significantly reducing the pain and discomfort of subcutaneous injection for patients. It also facilitates formulation miniaturization and portability, making it suitable for home administration scenarios.

[0028] In this invention, the mass concentration of the pore-forming agent in the pore-forming agent solution is 5% to 10%; within this concentration range, the pore-forming agent can form controllable pores inside the microspheres, which avoids burst release caused by excessively large pores and ensures that the drug can be slowly permeated and released.

[0029] The pore-forming agent is sucrose and / or sodium chloride.

[0030] In this invention, the mass concentration of polyethanol in the aqueous phase is 1% to 3%, and the mass concentration of sodium chloride is 0.5% to 1%.

[0031] In this invention, the volume ratio of the oil phase to the pore-forming agent solution is 3~5:1; The oil phase and the pore-forming agent solution are mixed by high-shear emulsification at a speed of 10,000 to 15,000 rpm for 5 to 10 minutes.

[0032] In this invention, the volume ratio of the primary emulsion to the aqueous phase is 1:5~10; The mixing speed of the primary emulsion and the aqueous phase is 300~500 rpm, the mixing time is 15~20 min, and the temperature is 20~25℃.

[0033] In this invention, the dichloromethane is volatilized in a gradient manner, first volatilizing at normal pressure at 25°C for 4-5 hours, and then completely volatilizing under reduced pressure at 35°C.

[0034] In this invention, the coating solution contains cellulose acetate at a mass concentration of 3% to 5% and polyethylene glycol at a mass concentration of 0.3% to 1%.

[0035] The mass ratio of cellulose acetate to polyethylene glycol in the coating solution is 1:10 to 1:5. Cellulose acetate can form a dense, sustained-release barrier, while polyethylene glycol, as a plasticizer, can improve the flexibility of the coating layer and prevent cracking during drying or injection.

[0036] In this invention, the coating method is fluidized bed coating.

[0037] In this invention, the process parameters for fluidized bed coating are as follows: coating liquid flow rate is 0.5~1 mL / min, inlet air temperature is 40~45℃, outlet air temperature is 30~35℃, atomization pressure is 0.2~0.3 MPa, and coating weight gain is controlled at 5%~10%.

[0038] Optimizing the fluidized bed coating parameters based on the particle size and density characteristics of risperidone microspheres ensures that the microspheres are uniformly sprayed with coating liquid under fluidized conditions, forming a coating layer of uniform thickness.

[0039] The core reasons for the wide particle size distribution and uneven pore size of microspheres are the uneven droplet dispersion and uncontrolled solvent evaporation rate during emulsification. This invention optimizes emulsification parameters in two stages: When mixing the oil phase and the pore-forming agent solution, high-shear emulsification at 10,000–15,000 rpm for 5–10 min disperses the oil phase into uniform, fine droplets, laying the foundation for subsequent microsphere particle size uniformity; the primary emulsion and aqueous phase are magnetically stirred at 300–500 rpm for 15–20 min for gentle dispersion to prevent droplet breakage, while a stirring temperature of 20–25°C avoids emulsion instability caused by excessive temperature; dichloromethane is evaporated in a gradient mode (first at 25°C under normal pressure, then at 35°C under reduced pressure) to slowly remove the solvent, avoiding microsphere surface collapse and pore disorder caused by rapid evaporation. Furthermore, the ratio of polyvinyl alcohol to sodium chloride in the aqueous phase can be adjusted by regulating interfacial tension and osmotic pressure to further stabilize the multi-emulsion system and reduce microsphere adhesion.

[0040] The present invention also provides risperidone sustained-release microspheres prepared by the above preparation method.

[0041] Example 1 (1) Weigh 10 mg of risperidone and 100 mg of polylactic acid, add them to 1 mL of dichloromethane, sonicate to dissolve and stir evenly to obtain an oil phase with a risperidone concentration of 10 mg / mL and a polylactic acid concentration of 100 mg / mL; (2) Weigh 0.5g of sucrose, add it to 10mL of deionized water, stir to dissolve, and obtain a sucrose solution with a mass concentration of 5%; (3) Weigh 0.1g of polyvinyl alcohol and 0.05g of sodium chloride, add them to 10mL of deionized water, heat and stir to dissolve, cool to room temperature, and obtain an aqueous phase with a polyvinyl alcohol mass concentration of 1% and a sodium chloride mass concentration of 0.5%. (4) Mix 3 mL of oil phase with 1 mL of pore-forming agent solution and emulsify for 7 min at 12000 rpm using a high-shear emulsifier to obtain the primary emulsion; (5) Slowly drop 2 mL of the initial emulsion into 10 mL of the aqueous phase, and stir magnetically for 18 min at 22 °C and 400 rpm. Then, evaporate at 25 °C and atmospheric pressure for 4.5 h, and then evaporate at 35 °C under reduced pressure until dichloromethane is completely removed. Collect the microspheres. (6) Weigh 0.3g of cellulose acetate and 0.03g of polyethylene glycol, add them to 10mL of acetone-ethanol mixed solvent (volume ratio 3:1), stir to dissolve, and obtain a coating solution with a cellulose acetate mass concentration of 3% and a polyethylene glycol mass concentration of 0.3%. (7) The above microspheres were coated by fluidized bed coating method. The coating liquid flow rate was set to 0.7 mL / min, the inlet air temperature was 42℃, the outlet air temperature was 32℃, the atomization pressure was 0.25 MPa, and the coating weight gain was controlled to 7%, so as to obtain high drug-loaded risperidone sustained-release microspheres that can be used for subcutaneous injection.

[0042] Example 2 (1) Weigh 16.7 mg of risperidone and 83.5 mg of polylactic acid, add them to 1 mL of dichloromethane, sonicate to dissolve and stir evenly to obtain an oil phase with a risperidone concentration of 16.7 mg / mL and a polylactic acid concentration of 83.5 mg / mL; (2) Weigh 0.8g of sucrose, add it to 10mL of deionized water, stir to dissolve, and obtain a sucrose solution with a mass concentration of 8%; (3) Weigh 0.2g of polyvinyl alcohol and 0.08g of sodium chloride, add them to 10mL of deionized water, heat and stir to dissolve, cool to room temperature, and obtain an aqueous phase with a polyvinyl alcohol mass concentration of 2% and a sodium chloride mass concentration of 0.8%. (4) Mix 4 mL of oil phase with 1 mL of pore-forming agent solution and emulsify for 5 min at 14000 rpm using a high-shear emulsifier to obtain the primary emulsion; (5) Slowly drop 2 mL of the initial emulsion into 16 mL of the aqueous phase, and stir magnetically for 15 min at 24 °C and 450 rpm. Then, evaporate at 25 °C and normal pressure for 4 h, and then evaporate at 35 °C under reduced pressure until dichloromethane is completely removed. Collect the microspheres. (6) Weigh 0.4g of cellulose acetate and 0.06g of polyethylene glycol, add them to 10mL of acetone-ethanol mixed solvent (volume ratio 3:1), stir to dissolve, and obtain a coating solution with a cellulose acetate mass concentration of 4% and a polyethylene glycol mass concentration of 0.6%. (7) The above microspheres were coated by fluidized bed coating method. The coating liquid flow rate was set to 0.9 mL / min, the inlet air temperature was 44℃, the outlet air temperature was 34℃, the atomization pressure was 0.28 MPa, and the coating weight gain was controlled to be 9%, so as to obtain high drug-loaded risperidone sustained-release microspheres that can be used for subcutaneous injection.

[0043] Example 3 (1) Weigh 5 mg of risperidone and 50 mg of polylactic acid, add them to 1 mL of dichloromethane, sonicate to dissolve and stir evenly to obtain an oil phase with a risperidone concentration of 5 mg / mL and a polylactic acid concentration of 50 mg / mL; (2) Weigh 1.0g of sucrose, add it to 10mL of deionized water, stir to dissolve, and obtain a sucrose solution with a mass concentration of 10%; (3) Weigh 0.3g of polyvinyl alcohol and 0.1g of sodium chloride, add them to 10mL of deionized water, heat and stir to dissolve, cool to room temperature, and obtain an aqueous phase with a polyvinyl alcohol mass concentration of 3% and a sodium chloride mass concentration of 1%. (4) Mix 5 mL of oil phase with 1 mL of pore-forming agent solution and emulsify for 10 min at 10000 rpm using a high-shear emulsifier to obtain the primary emulsion; (5) Slowly drop 2 mL of the initial emulsion into 20 mL of the aqueous phase, stir magnetically for 20 min at 20 °C and 300 rpm, then evaporate at 25 °C and atmospheric pressure for 5 h, and then evaporate at 35 °C and reduced pressure until dichloromethane is completely removed, and collect the microspheres. (6) Weigh 0.5g of cellulose acetate and 0.1g of polyethylene glycol, add them to 10mL of acetone-ethanol mixed solvent (volume ratio 3:1), stir to dissolve, and obtain a coating solution with a cellulose acetate mass concentration of 5% and a polyethylene glycol mass concentration of 1%. (7) The above microspheres were coated by fluidized bed coating method. The coating liquid flow rate was set to 0.5 mL / min, the inlet air temperature was 40℃, the outlet air temperature was 30℃, the atomization pressure was 0.2 MPa, and the coating weight gain was controlled to be 5%. High drug-loaded risperidone sustained-release microspheres that can be used for subcutaneous injection were obtained.

[0044] Example 4 (1) Weigh 12 mg of risperidone and 120 mg of polylactic acid, add them to 1 mL of dichloromethane, sonicate to dissolve and stir evenly to obtain an oil phase with a risperidone concentration of 12 mg / mL and a polylactic acid concentration of 120 mg / mL; (2) Weigh 0.6g of sodium chloride, add it to 10mL of deionized water, stir to dissolve, and obtain a sodium chloride solution with a mass concentration of 6%; (3) Weigh 0.15g of polyvinyl alcohol and 0.06g of sodium chloride, add them to 10mL of deionized water, heat and stir to dissolve, cool to room temperature, and obtain an aqueous phase with a polyvinyl alcohol mass concentration of 1.5% and a sodium chloride mass concentration of 0.6%. (4) Mix 3.5 mL of oil phase with 1 mL of pore-forming agent solution and emulsify for 6 min at 15000 rpm using a high-shear emulsifier to obtain the primary emulsion; (5) Slowly drop 2 mL of the initial emulsion into 14 mL of the aqueous phase, and stir magnetically for 17 min at 23 °C and 350 rpm. Then, evaporate at 25 °C and atmospheric pressure for 4.2 h, and then evaporate at 35 °C under reduced pressure until dichloromethane is completely removed. Collect the microspheres. (6) Weigh 0.35g of cellulose acetate and 0.05g of polyethylene glycol, add them to 10mL of acetone-ethanol mixed solvent (volume ratio 3:1), stir to dissolve, and obtain a coating solution with a cellulose acetate mass concentration of 3.5% and a polyethylene glycol mass concentration of 0.5%. (7) The above microspheres were coated by fluidized bed coating method. The coating liquid flow rate was set to 0.8 mL / min, the inlet air temperature was 43℃, the outlet air temperature was 33℃, the atomization pressure was 0.26 MPa, and the coating weight gain was controlled to be 8%, so as to obtain high drug-loaded risperidone sustained-release microspheres that can be used for subcutaneous injection.

[0045] Example 5 (1) Weigh 8 mg of risperidone and 64 mg of polylactic acid, add them to 1 mL of dichloromethane, sonicate to dissolve and stir evenly to obtain an oil phase with a risperidone concentration of 8 mg / mL and a polylactic acid concentration of 64 mg / mL; (2) Weigh 0.4g of sucrose and 0.3g of sodium chloride, add them to 10mL of deionized water, stir to dissolve, and obtain a 7% sucrose-sodium chloride mixed pore-forming agent solution; (3) Weigh 0.25g of polyvinyl alcohol and 0.09g of sodium chloride, add them to 10mL of deionized water, heat and stir to dissolve, cool to room temperature, and obtain an aqueous phase with a polyvinyl alcohol mass concentration of 2.5% and a sodium chloride mass concentration of 0.9%; (4) Mix 4.5 mL of oil phase with 1 mL of pore-forming agent solution and emulsify for 8 min at 13000 rpm using a high-shear emulsifier to obtain the primary emulsion; (5) Slowly drop 2 mL of the initial emulsion into 18 mL of the aqueous phase, and stir magnetically for 16 min at 25 °C and 500 rpm. Then, evaporate at 25 °C and atmospheric pressure for 4.8 h, and then evaporate at 35 °C under reduced pressure until dichloromethane is completely removed. Collect the microspheres. (6) Weigh 0.45g of cellulose acetate and 0.07g of polyethylene glycol, add them to 10mL of acetone-ethanol mixed solvent (volume ratio 3:1), stir to dissolve, and obtain a coating solution with a cellulose acetate mass concentration of 4.5% and a polyethylene glycol mass concentration of 0.7%. (7) The above microspheres were coated by fluidized bed coating method. The coating liquid flow rate was set to 1.0 mL / min, the inlet air temperature was 45℃, the outlet air temperature was 35℃, the atomization pressure was 0.3 MPa, and the coating weight gain was controlled to be 10%, so as to obtain high drug-loaded risperidone sustained-release microspheres that can be used for subcutaneous injection.

[0046] The performance of the highly drug-loaded risperidone sustained-release microspheres prepared in the examples, which can be used for subcutaneous injection, was tested. The test methods and results are as follows: 1. Drug loading rate determination (high performance liquid chromatography, HPLC) Referring to the risperidone content determination standard in the Chinese Pharmacopoeia, the specific steps are as follows: (1) Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material; the mobile phase was methanol-0.05mol / L ammonium acetate solution (pH adjusted to 7.0 with ammonia test solution), volume ratio 60:40; the detection wavelength was 234nm; the flow rate was adjusted until the retention time of risperidone peak was about 8min; the theoretical plate number calculated based on the risperidone peak was not less than 5000. (2) Sample preparation: Accurately weigh 10 mg of the drug-loaded microspheres prepared in each example, place them in a 10 mL volumetric flask, add an appropriate amount of mobile phase, sonicate to completely dissolve risperidone, cool, dilute to the mark with mobile phase, shake well, centrifuge (10000 rpm, 10 min), and take the filtrate as the test solution. (3) Preparation of reference solution: Accurately weigh an appropriate amount of risperidone reference standard, dissolve it in the mobile phase and dilute it quantitatively to prepare a solution containing 20 μg per 1 mL; (4) Determination: Accurately measure 20 μL of the test solution and the reference solution respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the drug loading rate by peak area according to the external standard method. Drug loading rate = (actual mass of risperidone in microspheres / total mass of microspheres) × 100%.

[0047] 2. Particle size and particle size distribution determination (laser particle size analyzer method) (1) Sample preparation: Take an appropriate amount of microspheres from each example, add them to deionized water, and ultrasonically disperse them for 3 minutes to prepare a uniform microsphere suspension; (2) Measurement: Inject the suspension into the sample cell of the laser particle size analyzer, set the detection parameters, measure each sample in parallel 3 times, and record the average particle size (D50) and particle size distribution span (Span) of the microspheres. Span = (D90-D10) / D50.

[0048] 3. In vitro release rate determination (dynamic dialysis bag method) Referring to the standard method for detecting the in vitro release of sustained-release microspheres, the specific steps are as follows: (1) Preparation of release medium: Prepare a phosphate buffered saline (PBS) solution with pH 7.4 as the release medium and purge with nitrogen gas in advance to remove oxygen; (2) Sample loading: Accurately weigh 5 mg of microspheres from each example, place them in a dialysis bag (molecular weight cutoff 8000-14000 Da), add 1 mL of release medium, seal the dialysis bag and immerse it in 40 mL of release medium; (3) Release conditions: Place in a constant temperature shaking box at 37℃ and shake at a constant temperature of 100rpm. Take 5mL samples at 24h, 72h and 14 days respectively, and add an equal amount of fresh release medium at the same time. (4) Detection: Take samples at each time point and determine the risperidone concentration using the above HPLC method. Calculate the cumulative release rate. Cumulative release rate = (total risperidone released at each time point / total mass of risperidone in microspheres) × 100%.

[0049] 4. Assessment of coating layer integrity (optical microscopy observation method) (1) Sample preparation: Take an appropriate amount of coated microspheres from each example, disperse them evenly on a glass slide, add a small amount of deionized water, and cover with a coverslip; (2) Observation: The surface morphology of the microspheres was observed using an optical microscope (magnification 400x) to assess whether the coating layer was continuous and uniform, and whether there were any cracks or peeling. 50 microspheres were randomly observed for each sample, and the percentage of intact coated microspheres was counted.

[0050] The test results are shown in Table 1.

[0051] Table 1. Performance test results of the highly drug-loaded risperidone sustained-release microspheres prepared in Examples 1-5, suitable for subcutaneous injection.

[0052] The test data above show that the risperidone sustained-release microspheres prepared in the five examples all meet the design requirements: the drug loading rate is consistently above 10%, achieving the high drug loading target; the average particle size is within the range of 1~10μm, with a particle size distribution span ≤1.5, meeting the requirements for subcutaneous injection needle compatibility; the cumulative release rate at 24h is ≤20%, effectively inhibiting initial burst release; the cumulative release rate at 72h is ≤50%, and the cumulative release rate at 14 days is ≥90%, achieving a balance between "rapid onset of action and long-lasting sustained release"; the proportion of intact coated microspheres is ≥95%, indicating that the coating layer is continuous and uniform, without obvious cracking or peeling, and the sustained-release barrier is stable. The performance differences between different examples are small, proving that the preparation process of the present invention has good stability and repeatability.

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the specific implementation of the present invention. Any modifications or equivalent substitutions that do not depart from the spirit and scope of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing highly drug-loaded risperidone sustained-release microspheres suitable for subcutaneous injection, characterized in that, Includes the following steps: Risperidone, polylactic acid and dichloromethane were mixed to obtain the oil phase; Dissolve the pore-forming agent in water to obtain a pore-forming agent solution; Aqueous phase is obtained by mixing polyvinyl alcohol, sodium chloride, and water. The primary emulsion is obtained by mixing the oil phase with the pore-forming agent solution; The primary emulsion was mixed with the aqueous phase and stirred until the dichloromethane was completely evaporated to obtain microspheres loaded with risperidone; A coating solution is obtained by mixing cellulose acetate, polyethylene glycol and an organic solvent; Risperidone-loaded microspheres were coated with a coating solution to obtain highly drug-loaded risperidone sustained-release microspheres suitable for subcutaneous injection.

2. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The concentration of risperidone in the oil phase is 5~16.7 mg / mL, and the concentration of polylactic acid is 50~167 mg / mL.

3. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The mass concentration of the pore-forming agent in the pore-forming agent solution is 5%~10%; The pore-forming agent is sucrose and / or sodium chloride.

4. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The aqueous phase contains 1% to 3% polyethanol and 0.5% to 1% sodium chloride.

5. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The volume ratio of the oil phase to the pore-forming agent solution is 3~5:1; The oil phase and the pore-forming agent solution are mixed by high-shear emulsification at a speed of 10,000 to 15,000 rpm for 5 to 10 minutes.

6. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The volume ratio of the primary emulsion to the aqueous phase is 1:5~10; The mixing speed of the primary emulsion and the aqueous phase is 300~500 rpm, the mixing time is 15~20 min, and the temperature is 20~25℃.

7. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The coating solution contains 3% to 5% cellulose acetate and 0.3% to 1% polyethylene glycol.

8. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 1, characterized in that, The coating method is fluidized bed coating.

9. The method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection according to claim 8, characterized in that, The process parameters for fluidized bed coating are as follows: coating liquid flow rate is 0.5~1 mL / min, inlet air temperature is 40~45℃, outlet air temperature is 30~35℃, atomization pressure is 0.2~0.3 MPa, and coating weight gain is controlled at 5%~10%.

10. The risperidone sustained-release microspheres prepared by the method for preparing highly drug-loaded risperidone sustained-release microspheres for subcutaneous injection as described in any one of claims 1 to 9.

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