Degradable slow-release local anesthetic microsphere as well as preparation method and application thereof
By designing the inner and outer layer structures of modified PLGA microspheres and preparing them using an emulsion-solvent evaporation method, the problems of low drug encapsulation efficiency and sustained-release characteristics of local anesthetic microspheres were solved, achieving efficient and stable drug release, meeting the needs of long-term surgery or postoperative analgesia, and reducing adverse reactions and production costs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 南昌大学第一附属医院
- Filing Date
- 2026-03-12
- Publication Date
- 2026-05-19
AI Technical Summary
Existing local anesthetic microspheres suffer from problems such as low drug encapsulation rate, difficulty in achieving sustained-release properties, complex preparation process, and insufficient biocompatibility, resulting in low drug utilization, numerous adverse reactions, and high production costs, making it difficult to meet the needs of long-term surgery or postoperative analgesia.
Modified PLGA was used as the carrier material. Microspheres were prepared by combining an inner diffusion regulation region and an outer release blocking region through a series structure design and an emulsion-solvent evaporation method. The inner layer was composed of hydrophobic biodegradable polymers, and the outer layer was composed of hydrophilic biodegradable polymers and water-soluble sustained-release regulating substances, forming a continuous coverage structure to achieve graded release control of the drug.
It significantly improves drug encapsulation efficiency and drug loading, avoids initial burst release of drugs, achieves stable and sustained drug release, prolongs anesthesia and analgesia time, reduces the risk of adverse reactions, simplifies the preparation process and reduces production costs, and is suitable for industrial production.
Smart Images
Figure CN122056852A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to, but is not limited to, the field of pharmaceutical technology, and particularly relates to a biodegradable sustained-release local anesthetic microsphere, its preparation method, and its application. Background Technology
[0002] Local anesthetics, as fundamental drugs used clinically to block nerve conduction and relieve pain, play an important role in various medical scenarios such as surgery, dental treatment, and postpartum analgesia. Traditional local anesthetics, such as lidocaine and bupivacaine, inhibit nerve conduction by blocking sodium ion channels. They have a rapid onset of action but a short duration of action, with a single dose typically only lasting a few hours. This makes it difficult to meet the needs of prolonged surgery or continuous postoperative analgesia, significantly limiting their clinical application.
[0003] To prolong the duration of anesthesia or analgesia, repeated administration or combined use of epinephrine is often employed in clinical practice. However, repeated injections not only increase the workload of medical staff but also potentially increase the risk of local tissue damage and infection, and pose a risk of systemic poisoning due to drug accumulation, leading to serious adverse reactions such as cardiovascular depression and central nervous system disorders. Furthermore, repeated administration places a significant burden on patients' experience, hindering rapid recovery and discharge. Addressing these shortcomings, developing a continuous, safe, and long-acting local anesthetic delivery system has become an urgent problem to be solved in both clinical and pharmaceutical fields.
[0004] In recent years, sustained-release microsphere drug delivery systems have attracted widespread attention as a novel strategy for local anesthetic drug delivery. Microspheres encapsulate drugs into micron-sized particles using suitable carrier materials, enabling slow and stable drug release in vivo through material degradation or diffusion. Compared to conventional injections, microspheres can significantly prolong the residence time of local anesthetics at the site of action, reduce the frequency of administration, thereby improving anesthetic efficacy and pain management.
[0005] Among various carrier materials, biodegradable polymers stand out, with polylactic-co-glycolic acid copolymer (PLGA) being one of the most widely studied microsphere carriers due to its excellent biocompatibility, controllable degradation rate, and the fact that its degradation products, lactic acid and glycolic acid, can be metabolized and absorbed by the body without residual toxicity. PLGA-based microspheres for local anesthetics not only allow for long-acting drug release but also allow for the regulation of drug release behavior by altering polymer composition, molecular weight, and preparation processes, resulting in a more sustained and stable analgesic effect. Existing studies have shown that PLGA microsphere carriers can significantly prolong the duration of local anesthesia with bupivacaine in vivo and reduce peak plasma drug concentrations, thus contributing to improved drug safety.
[0006] Despite this, current microsphere technology for local anesthetics still faces significant challenges: First, the drug encapsulation rate is low. Small molecule local anesthetics easily diffuse from the aqueous phase to the external phase during preparation, resulting in most of the drug not being effectively encapsulated, reducing drug utilization and formulation efficacy. Second, sustained-release characteristics are difficult to achieve ideally. Some microspheres exhibit significant initial burst release, posing a risk of excessively high local drug concentrations in a short period; while the later release rate may be too slow to maintain sufficient analgesic concentrations. ([American Chemical Society Publications][6]) Third, the preparation process is complex and lacks reproducibility. Commonly used methods such as emulsion-solvent evaporation and two-emulsion methods have high requirements for process conditions and are easily affected by interfacial tension, shear force, and solvent residue, increasing production difficulty and cost, and hindering large-scale industrial production. In addition, insufficient matching between the degradation rate of the carrier material and the drug release rate can also affect the stability and controllability of the sustained-release effect, making it difficult to predict and optimize the analgesic time and intensity.
[0007] Therefore, developing a biodegradable sustained-release microsphere formulation of local anesthetic with high drug encapsulation efficiency, good sustained-release effect, simple preparation process and excellent biocompatibility is of great practical significance and has broad application prospects for improving the clinical local anesthesia and postoperative analgesia effects, reducing adverse reactions and optimizing the postoperative recovery pathway of patients. Summary of the Invention
[0008] To address the problems existing in the prior art, this invention provides a biodegradable sustained-release local anesthetic microsphere, its preparation method, and its application.
[0009] This invention is achieved by providing a biodegradable sustained-release local anesthetic microsphere, comprising a drug core and a carrier shell covering the drug core. The carrier shell includes an inner diffusion control region and an outer release blocking region formed radially. The inner diffusion control region reduces the rate of drug diffusion from the drug core outwards, and the outer release blocking region reduces the rate of drug release from the carrier shell to the outside. The inner diffusion control region and the outer release blocking region constitute a series diffusion resistance structure, thereby enabling graded control of the drug release process.
[0010] Furthermore, the inner diffusion control region is composed of hydrophobic biodegradable polymers, and the outer release blocking region is composed of hydrophilic biodegradable polymers and water-soluble slow-release control substances.
[0011] Furthermore, the outer layer release blocking region forms a continuous covering structure on the surface of the microsphere.
[0012] Furthermore, the drug release pathway must sequentially pass through the inner diffusion regulation region and the outer release inhibition region.
[0013] The present invention also provides a biodegradable sustained-release local anesthetic microsphere, which includes a drug core and a carrier shell encapsulating the drug core. The drug core is a local anesthetic, and the carrier shell is a composite material of modified polylactic acid-glycolic acid copolymer (PLGA) and biocompatible excipients.
[0014] Furthermore, the local anesthetic is selected from one or more of lidocaine, bupivacaine, ropivacaine, and mepivacaine.
[0015] Furthermore, the modified PLGA is obtained by linking PLGA and polyethylene glycol PEG through ester bonds, wherein the molar ratio of lactic acid units to glycolic acid units of PLGA is 50:50~85:15, and the molecular weight is 10000~50000 Da; the molecular weight of PEG is 2000~8000 Da, and the mass fraction of PEG in the modified PLGA is 5%~20%.
[0016] Furthermore, the biocompatible excipient is selected from one or more of mannitol, lactose, povidone (PVP), and sodium carboxymethyl cellulose, and the mass fraction of the excipient in the carrier shell is 2% to 8%.
[0017] Furthermore, the microspheres have a particle size of 1~10 μm, a drug encapsulation efficiency of ≥85%, and a drug loading of 10%~30%.
[0018] Furthermore, the method for preparing the biodegradable sustained-release local anesthetic microspheres employs an emulsification-solvent evaporation method, with the following specific steps: S1: Oil phase preparation: Modified PLGA, biocompatible excipients and local anesthetics are added to an organic solvent, ultrasonically dissolved and mixed evenly to obtain an oil phase; wherein, the mass ratio of local anesthetics to modified PLGA is 1:3 to 1:10, and the amount of organic solvent is 5 to 10 times the total mass of the oil phase. S2: Aqueous phase preparation: The emulsifier is added to deionized water and stirred to dissolve, thus obtaining the aqueous phase; wherein, the mass concentration of the emulsifier is 0.5%~2%; S3: Preparation of colostrum: The oil phase is slowly added dropwise to the aqueous phase and emulsified under high-speed stirring at a stirring rate of 8000~15000 r / min for 5~15 min to obtain a W / O type colostrum. S4: Preparation of double emulsion: The primary emulsion is slowly added dropwise to the above aqueous phase, and secondary emulsification is carried out under medium speed stirring. The stirring rate is 2000~5000 r / min, and the emulsification time is 10~30 min to obtain W / O / W type double emulsion. S5: Solvent evaporation. Place the double emulsion in a constant temperature water bath at 30~45℃ and evaporate the organic solvent under magnetic stirring. The stirring rate is 300~600 r / min and the evaporation time is 2~6 h. S6: Post-processing: After the solvent has evaporated, the reaction solution is centrifuged at a speed of 8000~12000 r / min for 10~20 min. The precipitate is collected, washed 3~5 times with deionized water, and then freeze-dried to obtain biodegradable sustained-release local anesthetic microspheres.
[0019] Furthermore, the organic solvent in S1 is selected from one or more of dichloromethane, chloroform, and ethyl acetate; the emulsifier in S2 is selected from one or more of polyvinyl alcohol (PVA), polysorbate 80, and sodium dodecyl sulfate (SDS).
[0020] Furthermore, the freeze-drying conditions described in S6 are as follows: pre-freezing temperature is -40~-60℃, pre-freezing time is 2~4 h, sublimation drying temperature is -20~0℃, sublimation drying time is 12~24 h, desorption drying temperature is 10~30℃, and desorption drying time is 4~8 h.
[0021] Furthermore, the application of the aforementioned biodegradable sustained-release local anesthetic microspheres in the preparation of local anesthetic drugs or postoperative analgesics.
[0022] Furthermore, the microspheres can be administered via subcutaneous injection or local infiltration injection, and are suitable for the treatment of surgical procedures, dental procedures, postpartum analgesia, or chronic pain.
[0023] Based on the above technical solutions and the technical problems solved, the advantages and positive effects of the technical solution to be protected by this invention are as follows: This invention uses modified PLGA as a carrier material. PEG modification improves the hydrophilicity and drug compatibility of the carrier, significantly increasing the encapsulation rate (≥85%) and drug loading (10%~30%) of local anesthetics, reducing drug waste, and improving drug utilization. The microspheres of this invention have good sustained-release properties, which can avoid the initial burst release of drugs and achieve a stable and continuous release of drugs, prolonging the anesthesia and analgesia time to 24-72 hours. This can meet the needs of long-term surgery and continuous postoperative analgesia, reduce the number of administrations, and reduce the risk of drug overdose poisoning. The carrier material is a biodegradable modified PLGA with good biocompatibility. The degradation products can be metabolized and absorbed by the human body without residual toxicity. At the same time, the added biocompatible excipients further improve the biosafety of the microspheres and reduce local tissue irritation. The preparation method of this invention adopts the emulsification-solvent evaporation method, which is simple, convenient to operate, has low production cost, and is easy to realize industrial production. The microspheres of this invention have a moderate particle size (1~10 μm), which facilitates drug administration by injection and allows them to remain in local tissues for a long time, thereby increasing local drug concentration, enhancing anesthetic and analgesic effects, and reducing the occurrence of systemic adverse reactions. Attached Figure Description
[0024] Figure 1 This is a schematic diagram of the biodegradable sustained-release local anesthetic microspheres provided in an embodiment of the present invention; Figure 2 This is a schematic diagram illustrating the types of biocompatible excipients provided in the embodiments of the present invention; Figure 3 This is a flowchart of the preparation method of biodegradable sustained-release local anesthetic microspheres provided in the embodiments of the present invention; Figure 4 This is a schematic diagram illustrating the implementation effect provided by an embodiment of the present invention; In the diagram: 1. Drug core; 2. Carrier shell. Detailed Implementation
[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0026] like Figure 1 As shown, this embodiment of the invention provides a biodegradable sustained-release local anesthetic microsphere. The local anesthetic microsphere includes a drug core 1 and a carrier shell 2 that wraps around the drug core. The drug core 1 is a local anesthetic, and the carrier shell 2 is a composite material of modified polylactic acid-glycolic acid copolymer (PLGA) and biocompatible excipients.
[0027] The local anesthetic is selected from one or more of lidocaine, bupivacaine, ropivacaine, and mepivacaine.
[0028] The modified PLGA is obtained by linking PLGA and polyethylene glycol (PEG) through ester bonds. The molar ratio of lactic acid units to glycolic acid units in PLGA is 50:50 to 85:15, and the molecular weight is 10,000 to 50,000 Da. The molecular weight of PEG is 2,000 to 8,000 Da, and the mass fraction of PEG in the modified PLGA is 5% to 20%.
[0029] like Figure 2 As shown, the biocompatible excipient is selected from one or more of mannitol, lactose, povidone (PVP), and sodium carboxymethyl cellulose, and the mass fraction of the excipient in the carrier shell is 2% to 8%.
[0030] The microspheres have a particle size of 1~10 μm, a drug encapsulation efficiency of ≥85%, and a drug loading of 10%~30%.
[0031] like Figure 3 As shown, the method for preparing the biodegradable sustained-release local anesthetic microspheres employs an emulsification-solvent evaporation method, and the specific steps are as follows: S1: Oil phase preparation: Modified PLGA, biocompatible excipients and local anesthetics are added to an organic solvent, ultrasonically dissolved and mixed evenly to obtain an oil phase; wherein, the mass ratio of local anesthetics to modified PLGA is 1:3 to 1:10, and the amount of organic solvent is 5 to 10 times the total mass of the oil phase. S2: Aqueous phase preparation: The emulsifier is added to deionized water and stirred to dissolve, thus obtaining the aqueous phase; wherein, the mass concentration of the emulsifier is 0.5%~2%; S3: Preparation of colostrum: The oil phase is slowly added dropwise to the aqueous phase and emulsified under high-speed stirring at a stirring rate of 8000~15000 r / min for 5~15 min to obtain a W / O type colostrum. S4: Preparation of double emulsion: The primary emulsion is slowly added dropwise to the above aqueous phase, and secondary emulsification is carried out under medium speed stirring. The stirring rate is 2000~5000 r / min, and the emulsification time is 10~30 min to obtain W / O / W type double emulsion. S5: Solvent evaporation. Place the double emulsion in a constant temperature water bath at 30~45℃ and evaporate the organic solvent under magnetic stirring. The stirring rate is 300~600 r / min and the evaporation time is 2~6 h. S6: Post-processing: After the solvent has evaporated, the reaction solution is centrifuged at a speed of 8000~12000 r / min for 10~20 min. The precipitate is collected, washed 3~5 times with deionized water, and then freeze-dried to obtain biodegradable sustained-release local anesthetic microspheres.
[0032] The organic solvent in S1 is selected from one or more of dichloromethane, chloroform, and ethyl acetate; the emulsifier in S2 is selected from one or more of polyvinyl alcohol (PVA), polysorbate 80, and sodium dodecyl sulfate (SDS).
[0033] The freeze-drying conditions described in S6 are as follows: pre-freezing temperature is -40~-60℃, pre-freezing time is 2~4 h, sublimation drying temperature is -20~0℃, sublimation drying time is 12~24 h, desorption drying temperature is 10~30℃, and desorption drying time is 4~8 h.
[0034] The application of the aforementioned biodegradable sustained-release local anesthetic microspheres in the preparation of local anesthetic drugs or postoperative analgesics.
[0035] The microspheres are administered via subcutaneous injection or local infiltration injection and are suitable for the treatment of surgical procedures, dental procedures, postpartum analgesia, or chronic pain.
[0036] Sustained-release performance test: like Figure 4 As shown, 0.1 g of the prepared ropivacaine microspheres were placed in 50 mL of phosphate buffer (pH=7.4) and subjected to in vitro release experiments in a constant temperature shaker at 37℃ and 100 r / min. Samples of 5 mL were taken at 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h, and 5 mL of fresh phosphate buffer was added simultaneously. The concentration of ropivacaine in the samples was determined by high performance liquid chromatography (HPLC), and the cumulative release rate was calculated.
[0037] Test results showed that the cumulative release rate was 12.3% at 1 h, 25.6% at 4 h, 42.1% at 12 h, 65.8% at 24 h, 82.4% at 48 h, and 91.7% at 72 h. This indicates that the microspheres did not exhibit significant initial burst release, the drug release was stable, the sustained-release effect was significant, and the release could be maintained for 72 hours.
[0038] Biocompatibility testing: The prepared ropivacaine microspheres were subjected to in vitro cytotoxicity testing according to GB / T 16886.5-2017 standard. After co-culturing the microsphere extract with L929 cells for 24 h, 48 h, and 72 h, cell viability was determined using the MTT assay.
[0039] Test results showed that the cell survival rate at each time point was ≥90%, indicating that the microspheres had no obvious cytotoxicity and good biocompatibility.
[0040] In vivo anesthesia effect test: Thirty healthy SD rats were randomly divided into three groups of 10 rats each: experimental group (injected with ropivacaine microspheres prepared in Example 1 at a dose of 5 mg / kg), control group 1 (injected with commercially available ropivacaine injection at a dose of 5 mg / kg), and control group 2 (injected with physiological saline). The drugs were administered via tail infiltration injection, and the time for analgesia to disappear (onset of anesthesia) and the time for analgesia to return (duration of anesthesia) were observed and recorded.
[0041] The test results showed that the onset time of anesthesia in the experimental group was 3.5±0.8 min, and the duration of anesthesia was 68.2±5.3 h; the onset time of anesthesia in control group 1 was 2.8±0.6 min, and the duration of anesthesia was 4.5±1.2 h; control group 2 had no obvious anesthetic effect. This indicates that the microsphere anesthesia of the present invention has a rapid onset and a significantly prolonged duration, resulting in excellent anesthetic effect.
[0042] Example 1: Formation of a gradient hierarchical structure A local anesthetic and a hydrophobic biodegradable polymer are dissolved in an organic solvent to form a first dispersed phase. The first dispersed phase is then dispersed in an aqueous phase under high-speed shearing conditions to form a primary dispersion system. The primary dispersion system is then dispersed in a second aqueous phase under low-speed shearing conditions to form a secondary dispersion system. The organic solvent is removed under continuous stirring to solidify the polymer. The solidified particles are collected, washed, and dried.
[0043] Scanning electron microscopy and elemental distribution analysis of the obtained particles showed that there was a difference in composition between the inner and outer layers along the radial direction. Hydrophobic biodegradable polymers were mainly distributed inside the particles, while hydrophilic polymers and water-soluble regulatory substances were mainly distributed on the particle surface, forming a continuous outer layer structure.
[0044] Example 2: The Influence of Shear Strength Differences on Structural Distribution Keeping the formulation unchanged, the shear strength of the first dispersion process is set to be higher than that of the second dispersion process, so that smaller droplets are formed in the first dispersion process and the droplets remain stable without significant breakage in the second dispersion process.
[0045] Cross-sectional composition analysis of the obtained particles showed that hydrophobic polymers were concentrated in the interior to form a diffusion-regulating region, while hydrophilic components were concentrated in the exterior to form a release-restricting region, indicating that the difference in shear strength drove the formation of radial distribution.
[0046] Example 3: Formation of the outer continuous cover structure In the second dispersion stage, hydrophilic biodegradable polymers and water-soluble slow-release regulators are added, allowing them to participate in dispersion with the aqueous phase and preferentially accumulate at the interface during the solidification process.
[0047] Surface composition analysis revealed that a continuous hydrophilic layer was formed on the surface of the obtained particles, with a coverage of more than 90% of the particle surface area, and no obvious exposed hydrophobic areas were observed.
[0048] Example 4 Spatial Constraints on Drug Release Pathways The prepared particles were placed in a buffer solution for in vitro release testing, and samples were taken periodically to analyze the changes in drug concentration over time.
[0049] The release curve shows that the drug release process consists of two continuous stages: the initial release rate is controlled by the surface structure, while the release rate in the middle and later stages is controlled by the internal structure, indicating that the drug release pathway passes through the outer and inner structures sequentially.
[0050] Example 5: Inhibition of initial burst release by the outer layer blocking region Particles with an outer release-blocking structure were prepared and their release was compared with that of ordinary particles without an outer layer structure in a release experiment.
[0051] The results showed that the release rate of particles with outer layer structure was significantly lower than that of the control group in the early stage of drug administration, and the release curve was smooth and continuous with no obvious burst release peak.
[0052] Example 6: The effect of the inner diffusion control region on sustained release By adjusting the content of hydrophobic polymers to make the inner layer structure more compact, multiple batches of particles were prepared and medium- and long-term release tests were conducted.
[0053] The results showed that as the density of the inner layer increased, the release rate gradually decreased in the middle and late stages, while the release duration was significantly prolonged.
[0054] Example 7: Verification of Hierarchical Diffusion Control Behavior The release data were subjected to kinetic fitting analysis, and the fitting was compared using a single diffusion model and a staged diffusion model.
[0055] The results show that the hierarchical diffusion model fits the experimental data better than the single diffusion model, indicating that the release process is controlled by multiple diffusion resistance layers in a coordinated manner.
[0056] Example 8: Verification of Structural Stability and Batch Consistency Five batches of particles were prepared continuously under the same process conditions, and their particle size distribution, composition distribution and release curves were compared and analyzed.
[0057] The results showed that the particles from different batches had good consistency in radial structure distribution, release curve morphology and release cycle, indicating that the structure formation mechanism is stable and reproducible.
[0058] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions, and improvements made by those skilled in the art within the scope of the technology disclosed in the present invention, and within the spirit and principles of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A biodegradable sustained-release local anesthetic microsphere, characterized in that, The device includes a drug core and a carrier shell covering the drug core. The carrier shell includes an inner diffusion control region and an outer release blocking region formed in the radial direction. The inner diffusion control region is used to reduce the rate of drug diffusion from the drug core to the outside, and the outer release blocking region is used to reduce the rate of drug release from the carrier shell to the outside. The inner diffusion control region and the outer release blocking region form a series diffusion resistance structure, thereby enabling graded control of the drug release process.
2. The microspheres according to claim 1, characterized in that, The inner diffusion control region is composed of hydrophobic biodegradable polymers, and the outer release blocking region is composed of hydrophilic biodegradable polymers and water-soluble slow-release control substances.
3. The microspheres according to claim 1, characterized in that, The outer layer release blocking region forms a continuous covering structure on the surface of the microspheres.
4. The microspheres according to claim 1, characterized in that, The drug release pathway must pass sequentially through the inner diffusion regulation region and the outer release inhibition region.
5. A method for preparing the microspheres according to any one of claims 1 to 4, characterized in that, Includes the following steps: First, the drug and hydrophobic biodegradable polymer are dissolved to form a first dispersed phase. Then, the first dispersed phase is dispersed in an aqueous phase to form a primary dispersion system. Subsequently, the primary dispersion system is dispersed again in a second aqueous phase to form a secondary dispersion system. In the secondary dispersion system, the polymer is solidified by solvent removal. By controlling the difference in shear strength between the first and second dispersions, the hydrophobic biodegradable polymer preferentially aggregates to the inner layer, while the hydrophilic biodegradable polymer and water-soluble sustained-release regulator preferentially migrate to the outer layer, thereby forming a microsphere structure with an inner diffusion regulation region and an outer release retardation region.
6. The method according to claim 5, characterized in that, The shear strength of the first dispersion is higher than that of the second dispersion.
7. The method according to claim 5, characterized in that, During the polymer solidification process, the hydrophilic biodegradable polymer and the water-soluble slow-release regulating substance migrate outward along the radial direction of the microspheres.
8. A method for regulating the release of the microspheres according to any one of claims 1 to 4 in local drug delivery, characterized in that, The series diffusion resistance structure formed by the inner diffusion regulation region and the outer release retardation region makes the drug release process first controlled by the inner diffusion regulation region and then controlled by the outer release retardation region, thereby changing the drug release process from single diffusion control to hierarchical diffusion control.
9. The method according to claim 8, characterized in that, In the early stages of drug administration, drug release is mainly controlled by the outer layer release retardation zone, while in the middle and later stages of drug administration, drug release is mainly controlled by the inner layer diffusion regulation zone.
10. The method according to claim 8, characterized in that, The drug release pathway passes through the inner diffusion regulation region and the outer release inhibition region in sequence along the radial direction of the microsphere from the inside to the outside.