A method for preparing lidocaine microspheres

Abstract

The application provides a preparation method of lidocaine microspheres and relates to the technical field of drug microspheres. The preparation method comprises the following steps: dissolving lidocaine and PLGA in an organic solvent to obtain an oil phase; dissolving polyvinyl alcohol in water for injection to obtain an external water phase; adding ethylene glycol dropwise into the oil phase to obtain a pre-phase separation mixed phase; mixing the pre-phase separation mixed phase and the external water phase and performing emulsification to obtain an O / W emulsion; continuously stirring the O / W emulsion, collecting wet microspheres, adding a freeze-drying protective solution, and performing freeze-drying to obtain the lidocaine microspheres. In the application, water-soluble non-solvent ethylene glycol is introduced into the oil phase to induce the system to enter the metastable region of pre-phase change, realize controllable liquid-liquid phase separation, make lidocaine synchronously enrich with PLGA to form liquid drops, and form a polymer skin layer with a barrier function on the surface of the liquid drops. The polymer skin layer reduces drug loss, avoids local aggregation and precipitation of the drug, greatly improves the drug loading capacity and the encapsulation efficiency of the microspheres, and reduces the initial burst release.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical microsphere technology and relates to a method for preparing lidocaine microspheres. Background Technology

[0002] Lidocaine is a commonly used amide-type local anesthetic in clinical practice, possessing both analgesic and antiarrhythmic effects, with a definite anesthetic effect and rapid onset. However, lidocaine injection has a short biological half-life, resulting in a limited duration of action and large fluctuations in blood drug concentration after a single dose, easily leading to insufficient efficacy; repeated administration can cause local irritation. Microsphere sustained-release formulations are commonly used clinically to improve these administration defects, achieving slow drug release, prolonged duration of action, and reduced dosing frequency and toxic side effects. Formulation studies have shown that the drug loading of lidocaine microspheres is a key indicator determining the formulation's efficacy, sustained-release performance, and clinical application results.

[0003] Currently, lidocaine microspheres are mostly prepared using an emulsification-solvent evaporation method. However, as a small molecule drug, lidocaine is prone to diffusion and loss into the aqueous phase during emulsification and solidification, resulting in low drug loading and unstable encapsulation efficiency. To improve drug loading, Chinese patent CN101961316A discloses a LID-PEG-PLGA sustained-release nanosphere and its preparation method. This method involves dispersing lidocaine in a matrix solution to prepare an oil phase, followed by ultrasonic emulsification to prepare a W / O type primary emulsion, further emulsification to a W / O / W type secondary emulsion, and finally solidification by vacuum evaporation at room temperature to obtain nanospheres. This method increases the lidocaine loading in sustained-release microspheres to 15-22%, achieves an encapsulation efficiency of 68-78%, and extends the half-life to 3-4 days. However, the ultrasonic emulsification and secondary emulsification steps in this method are highly sensitive to emulsification power, time, and operating temperature, the process is cumbersome, and the consistency of microsphere particle size distribution and drug loading between batches is difficult to control stably.

[0004] Therefore, it is necessary to further optimize the existing methods for preparing lidocaine microspheres. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for preparing lidocaine microspheres.

[0006] The technical solution of the present invention is as follows: A method for preparing lidocaine microspheres, comprising the following steps: Lidocaine and PLGA were dissolved in an organic solvent to obtain an oil phase; Polyvinyl alcohol was dissolved in water for injection to obtain the external aqueous phase; Ethylene glycol was added dropwise to the oil phase to obtain a prephase-separated mixed phase; The prephase separation mixed phase and the external aqueous phase are mixed and emulsified to obtain an O / W emulsion; The O / W emulsion was continuously stirred, the wet microspheres were collected and a freeze-drying protective solution was added. The microspheres were then freeze-dried to obtain lidocaine microspheres.

[0007] Preferably, the mass ratio of lidocaine, PLGA and organic solvent in the oil phase is 1.5:3:6-3:3:6.

[0008] Preferably, the weight-average molecular weight of the PLGA is 15,000-30,000 Da.

[0009] Preferably, the organic solvent is selected from one or a combination of two or more of dichloromethane, chloroform, and ethyl acetate.

[0010] Preferably, the concentration of polyvinyl alcohol in the external aqueous phase is 0.5-1 wt%.

[0011] Preferably, the mass ratio of ethylene glycol to oil phase in the prephase separation mixed phase is 0.5:1 to 1.5:1; Preferably, the mass ratio of the ethylene glycol to the oil phase is 1.1:1.

[0012] Preferably, the dropping rate of the ethylene glycol is 1-10 mL / min; Preferably, the dropping rate of the ethylene glycol is 4 mL / min.

[0013] Preferably, the mass ratio of the prephase-separated mixed phase to the external aqueous phase in the O / W emulsion is 1:100-1:300.

[0014] Preferably, the freeze-drying protective solution contains mannitol.

[0015] The beneficial effects of this invention are: (1) This invention introduces water-soluble non-solvent ethylene glycol into the oil phase. Relying on the bidirectional mass transfer effect between ethylene glycol and organic solvent, the organic solvent continuously diffuses and migrates from the oil phase to the ethylene glycol phase, inducing the system to enter the metastable region of pre-phase change, thus achieving controllable liquid-liquid phase separation. PLGA and lidocaine in the oil phase are continuously enriched and concentrated, forming viscous droplets; the PLGA polymer on the surface of the droplets preferentially aggregates, forming a relatively dense polymer skin layer. This polymer skin layer can act as a physical barrier, hindering the diffusion and leakage of internal lidocaine to the external aqueous phase during subsequent emulsification and solidification stages, reducing drug loss; at the same time, it ensures the uniform dispersion of lidocaine within the polymer matrix, avoiding local drug aggregation and precipitation, thereby significantly improving the drug loading and encapsulation efficiency of the microspheres, and effectively reducing the burst release of microspheres in the early stage of in vitro release, improving the efficacy and safety of drug administration.

[0016] (2) The polymer skin layer formed by the present invention has self-stabilizing properties, which can effectively inhibit the aggregation and adhesion between droplets during subsequent emulsification and solvent evaporation, thereby ensuring the uniformity of microsphere size and morphological integrity.

[0017] (3) The method of the present invention is controllable, has stable parameters and good repeatability. It does not require special expensive equipment or scarce auxiliary materials. It is suitable for laboratory pilot-scale research and development as well as large-scale industrial production and has great industrialization promotion value. Attached Figure Description

[0018] Figure 1 This is the ternary phase diagram of the PLGA-organic solvent (taking dichloromethane as an example)-ethylene glycol system in this invention; Figure 2 Here are SEM images of lidocaine microspheres obtained in Example 1; Figure 3 The in vitro cumulative drug release curve of lidocaine microspheres obtained in Example 1; Figure 4 SEM images of lidocaine microspheres obtained in Comparative Example 1; Figure 5 The image shows a SEM image of lidocaine microspheres obtained in Comparative Example 2. Detailed Implementation

[0019] The technical solution of the present invention will be further explained and described below through specific embodiments.

[0020] This invention proposes a method for preparing lidocaine microspheres, comprising the following steps: Lidocaine and PLGA were dissolved in an organic solvent to obtain an oil phase; Polyvinyl alcohol was dissolved in water for injection to obtain the external aqueous phase; Ethylene glycol was added dropwise to the oil phase to obtain a prephase separated mixed phase; The prephase-separated mixed phase and the external aqueous phase are mixed and emulsified to obtain an O / W emulsion; The O / W emulsion was continuously stirred, the wet microspheres were collected, and a freeze-drying protective solution was added. The microspheres were then freeze-dried to obtain lidocaine microspheres.

[0021] This invention, prior to emulsification, regulates the distribution of organic solvents by adding water-soluble non-solvent ethylene glycol to the oil phase, inducing the system to enter a metastable region of pre-phase change. This achieves controllable liquid-liquid phase separation, allowing lidocaine to accumulate synchronously with PLGA within the droplets, forming a polymer skin layer with barrier function on the droplet surface. This polymer skin layer reduces drug loss while preventing local drug aggregation and precipitation, thereby significantly increasing the drug loading and encapsulation efficiency of the microspheres and reducing the initial burst release effect. The thermodynamic changes throughout the process can be visualized using a ternary phase diagram (see...). Figure 1 The explanation is divided into three stages: (1) Single-phase dissolution stage: PLGA polymer and lipid-soluble lidocaine are completely dissolved in organic solvent, and the oil phase system is uniformly distributed, presenting a stable single-phase state.

[0022] (2) Homogeneous stable stage: When a small amount of ethylene glycol is added to the above oil phase system, the four components of PLGA, lidocaine, organic solvent and ethylene glycol are completely miscible and the system still maintains a uniform and stable homogeneous state. Corresponding to region ① of the ternary phase diagram, no phase separation or precipitation occurs.

[0023] (3) Controllable prephase separation stage: As the amount of ethylene glycol gradually increases, when the ratio of ethylene glycol to oil phase exceeds the critical value, the system enters the ternary phase diagram region ②. At this time, there is a concentration difference between the organic solvent in the oil phase and the ethylene glycol phase, forming a two-way mass transfer driving force, breaking the original thermodynamic equilibrium, and causing the system to enter a thermodynamically unstable state: the organic solvent continues to diffuse and migrate from the oil phase to the ethylene glycol phase, and PLGA and lidocaine in the oil phase are continuously enriched and concentrated, spontaneously causing liquid-liquid phase separation, forming highly concentrated PLGA-lidocaine viscous droplets. Since the process of organic solvent redistribution is to advance layer by layer from the droplet surface to the interior, the PLGA polymer on the droplet surface preferentially aggregates, forming a relatively dense polymer skin layer on the surface of the viscous droplet; at the same time, the lipid-soluble lidocaine has a higher solubility in the polymer-rich phase and can be simultaneously embedded in the droplet, completing the initial loading of the drug.

[0024] In some embodiments, the mass ratio of lidocaine, PLGA, and organic solvent in the oil phase is 1.5:3:6 to 3:3:6. The mass ratio of lidocaine, PLGA, and organic solvent in the oil phase can be any value or any value between 1.5:3:6, 1.6:3:6, 1.7:3:6, 1.8:3:6, 1.9:3:6, 2:3:6, 2.1:3:6, 2.2:3:6, 2.3:3:6, 2.4:3:6, 2.5:3:6, 2.6:3:6, 2.7:3:6, 2.8:3:6, 2.9:3:6, and 3:3:6, without any particular limitation.

[0025] In some embodiments, the weight-average molecular weight of PLGA is 15,000-30,000 Da. For example, the weight-average molecular weight of PLGA can be any value or any value between 15,000 Da, 16,000 Da, 17,000 Da, 18,000 Da, 19,000 Da, 20,000 Da, 21,000 Da, 22,000 Da, 23,000 Da, 24,000 Da, 25,000 Da, 26,000 Da, 27,000 Da, 28,000 Da, 29,000 Da, and 30,000 Da, without any particular limitation. There is no particular limitation on the molar ratio of LA to GA in PLGA, which can be 50:50-75:25.

[0026] In some embodiments, the organic solvent is selected from one or a combination of two or more of dichloromethane, chloroform, and ethyl acetate. The organic solvents selected in this invention exhibit good solubility for both lidocaine and PLGA, which is beneficial for constructing a homogeneous and stable oil-phase system, providing a foundation for subsequent controllable prephase separation. Furthermore, they are moderately miscible with ethylene glycol, enabling bidirectional mass transfer and driving stable prephase separation. If the miscibility between the organic solvent and ethylene glycol is too high, the mass transfer rate will be too fast, leading to excessively rapid precipitation and aggregation of PLGA. This will prevent the formation of a dense polymer skin layer and cause a large amount of lidocaine to migrate and be lost with the organic solvent before it can be encapsulated, resulting in a significant decrease in the drug loading and encapsulation efficiency of the microspheres. Simultaneously, the rapid precipitation and aggregation of PLGA also prevents the formation of regular droplets, resulting in irregular microsphere morphology and a wide particle size distribution.

[0027] In some embodiments, the concentration of polyvinyl alcohol in the external aqueous phase is 0.5-1 wt%. The concentration of polyvinyl alcohol in the external aqueous phase can be any value from 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, or any value between these values, without particular limitation. For the preparation method of the external aqueous phase, polyvinyl alcohol can be dissolved in hot water for injection, cooled, and then filtered for sterilization.

[0028] In some embodiments, the mass ratio of ethylene glycol to oil phase in the prephase separation mixed phase is 0.5:1 to 1.5:1. When the mass ratio of ethylene glycol to oil phase is 0.5:1 to 1.5:1, the system is in the metastable region of controllable liquid-liquid phase separation, which is beneficial for obtaining microspheres with high drug loading and encapsulation efficiency and uniform particle size. For example, the mass ratio of ethylene glycol to oil phase in the prephase separation mixed phase can be any value or any value between 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, etc., without any particular limitation.

[0029] Furthermore, the mass ratio of ethylene glycol to the oil phase is 1.1:1.

[0030] In some embodiments, the dropping rate of ethylene glycol is 1-10 mL / min. The dropping rate of ethylene glycol should not be too high; otherwise, the mass transfer with the organic solvent will be too rapid, easily leading to a larger overall droplet size in the PLGA-lidocaine solution and reducing the density of the polymer skin layer, thus weakening its physical barrier effect. For example, the dropping rate of ethylene glycol can be any value or any value between 1 mL / min, 2 mL / min, 3 mL / min, 4 mL / min, 5 mL / min, 6 mL / min, 7 mL / min, 8 mL / min, 9 mL / min, and 10 mL / min, without particular limitation.

[0031] Furthermore, the dropping rate of ethylene glycol was 4 mL / min.

[0032] In some embodiments, the mass ratio of the prephase-separated mixed phase to the external aqueous phase in the O / W emulsion is 1:100 to 1:300. For example, the mass ratio of the prephase-separated mixed phase to the external aqueous phase in the O / W emulsion can be any value or any value between 1:100, 1:120, 1:140, 1:160, 1:180, 1:200, 1:220, 1:240, 1:260, 1:280, 1:300, etc., without any particular limitation.

[0033] In some embodiments, the lyophilization protectant contains mannitol. There is no particular limitation on the concentration of mannitol; it can be 5-10 wt%.

[0034] The technical solutions of the present invention will be further described and explained below with reference to various embodiments.

[0035] Example 1 2.0 g lidocaine and 3.0 g PLGA (weight average molecular weight 20000 Da) were dissolved in 6.0 g dichloromethane, filtered to remove bacteria, and the oil phase was obtained with a lidocaine concentration of 18.2 wt%. 24.0 g of polyvinyl alcohol was dissolved in water for injection heated to 90 °C, and the volume was adjusted to 4800 g. The solution was filtered to remove bacteria, and the external aqueous phase was obtained. The concentration of polyvinyl alcohol was 0.5 wt%. Under vigorous stirring, 12.1 g of ethylene glycol was slowly added dropwise to the oil phase at a mass ratio of 1.1:1, with the dropping rate of ethylene glycol controlled at 4 mL / min. After the addition was completed, the mixture was stirred vigorously for 5 min to obtain a prephase separated mixed phase. The prephase-separated mixed phase was added to 4620g of external aqueous phase and homogenized and emulsified to obtain an O / W emulsion. The O / W emulsion was continuously stirred at 200 rpm for 3 hours. The wet microspheres were collected and an appropriate amount of 10 wt% mannitol solution was added. The mixture was then freeze-dried to obtain lidocaine microspheres.

[0036] Comparative Example 1 This comparative example uses the emulsification-solvent evaporation method (O / W monoemulsion method) to prepare lidocaine microspheres.

[0037] The oil phase and the external aqueous phase were prepared according to the steps of Example 1. The oil phase was added to the external aqueous phase and homogenized and emulsified to obtain an O / W emulsion. The O / W emulsion was continuously stirred at 200 rpm for 3 hours. The wet microspheres were collected and an appropriate amount of mannitol solution with a concentration of 10 wt% was added. The microspheres were then freeze-dried to obtain lidocaine microspheres.

[0038] Comparative Example 2 This comparative example uses an emulsification-solvent evaporation method (W / O / W double emulsion method) to prepare lidocaine microspheres.

[0039] Dissolve 2.0 g of lidocaine hydrochloride monohydrate in an appropriate amount of purified water, filter to remove bacteria, and obtain the inner aqueous phase W1; dissolve 3.0 g of PLGA in 6.0 g of dichloromethane, filter to remove bacteria, and obtain the oil phase O; the preparation of the outer aqueous phase W2 is the same as in Example 1; add the inner aqueous phase W1 to the oil phase, homogenize and emulsify to obtain a W1 / O emulsion; add the W1 / O emulsion to an appropriate amount of the outer aqueous phase W2, homogenize and emulsify to obtain a W1 / O / W2 emulsion; continuously stir the W1 / O / W2 emulsion at 200 rpm for 3 h, collect the wet microspheres and add an appropriate amount of 10 wt% mannitol solution, freeze dry, and obtain lidocaine microspheres.

[0040] Comparative Example 3 The main difference between this comparative example and Example 1 is that ethylene glycol is not added.

[0041] The oil phase and the external aqueous phase were prepared according to the steps of Example 1. The oil phase was stirred vigorously for 8 minutes and then added to the external aqueous phase. The mixture was homogenized and emulsified to obtain an O / W emulsion. The O / W emulsion was stirred continuously at 200 rpm for 3 hours. The wet microspheres were collected and an appropriate amount of mannitol solution with a concentration of 10 wt% was added. The mixture was then freeze-dried to obtain lidocaine microspheres.

[0042] The lidocaine microspheres prepared in Example 1 and Comparative Examples 1-3 were characterized, and the results are recorded in Table 1 and 2. Figure 2-5 .

[0043] Characterization of microspheres 1. Particle size determination: The lidocaine microspheres prepared in each example and comparative example were measured using a laser particle size analyzer. An appropriate amount of microsphere sample was accurately weighed, and a suitable amount of purified water was added and gently shaken to disperse the microspheres, preparing a microsphere suspension. The microsphere suspension was then placed in the laser particle size analyzer for measurement, and the particle size of the sample was recorded.

[0044] 2. Encapsulation efficiency and drug loading determination: A series of reference solutions with gradient concentrations were prepared. Referring to the detection method for lidocaine hydrochloride in the 2025 edition of the Pharmacopoeia, the solutions were filtered through a 0.22 μm microporous membrane and analyzed by HPLC. A standard curve was plotted with drug concentration as the x-axis and peak area as the y-axis to obtain the linear regression equation. Lidocaine microspheres prepared in each example and comparative example were accurately weighed, dissolved in methanol, and sonicated for 20 min to rupture the microspheres and release all the drug. After cooling to room temperature, the solution was diluted to volume. The supernatant was filtered through a 0.22 μm microporous membrane, and the peak area was determined by HPLC. The total drug content in the microspheres was calculated by substituting the peak area into the standard curve. Lidocaine microspheres prepared in each example and comparative example were accurately weighed, added to methanol solution, centrifuged, and the supernatant was filtered through a 0.22 μm microporous membrane. The peak area was determined by HPLC, and the free drug content was calculated by substituting the peak area into the standard curve. The following formula was used for calculation: Encapsulation efficiency % = [(Total drug content of microspheres - Free drug content) / Total drug content of microspheres] × 100% Drug loading % = (Total drug load of microspheres / Drug load) × 100%.

[0045] 3. In vitro cumulative release determination: In vitro drug release tests were conducted using the paddle method, following the general standards for drug release testing. The test temperature was set at 37℃±0.5℃, the stirring speed at 50~100 rpm, and pH 7.4 phosphate buffer solution as the release medium. Samples were taken at different time points, and the sample solutions at each time point were filtered through a 0.22μm microporous membrane. The filtrate was used as the test solution. Following the method described in the 2025 edition of the Pharmacopoeia under the content determination section, the peak area of ​​lidocaine hydrochloride in the dissolution medium was determined by HPLC. The drug release concentration was calculated by substituting the peak area into the standard curve. The concentration was calculated using the following formula: Cumulative release percentage % = (total mass of drug released at each time point / total drug load in microspheres) × 100%.

[0046] Table 1

[0047] As shown in Table 1, Example 1 of the present invention, due to the addition of ethylene glycol to the oil phase for pre-phase separation, can pre-form a polymer skin layer and achieve uniform encapsulation of the drug in the polymer matrix, resulting in microspheres with high drug loading and encapsulation efficiency; Figure 2 As can be seen from the SEM images, the surface of the microspheres prepared in Example 1 is smooth and flat; Figure 3The in vitro cumulative drug release curves show that the microspheres of Example 1 have a low initial burst release and a stable cumulative drug release curve after 7 days, achieving a stable and long-lasting sustained-release effect. Compared with Example 1, Comparative Example 3, lacking ethylene glycol, cannot form a polymer epidermal barrier, resulting in a 49.7% decrease in drug loading, a 40.7% decrease in encapsulation efficiency, and a 394.1% increase in 30-minute cumulative release. Comparative Example 1 uses a conventional O / W single emulsion method, such as... Figure 4 As shown in the SEM images, obvious drug crystals are visible on the surface of the microspheres, indicating a significant burst release effect. Comparative Example 2 used a conventional double emulsion method; during solidification, the drug was lost along with the solvent migration, leaving numerous pores on the surface of the microspheres, as shown in the SEM images. Figure 5 As shown, this leads to a significant reduction in drug loading and encapsulation efficiency, and exacerbates the initial burst release.

[0048] Comparative Example 4 The main difference between this comparative example and Example 1 is that dichloromethane in Example 1 is replaced with an equal amount of acetone. The remaining steps remain unchanged.

[0049] Example 2 The main difference between this embodiment and Example 1 is that the amount of ethylene glycol used in Example 1 is replaced from 12.1g to 5.5g (i.e., the mass ratio of ethylene glycol to the oil phase is 0.5:1). The remaining steps remain unchanged.

[0050] Example 3 The main difference between this embodiment and Example 1 is that the amount of ethylene glycol used in Example 1 is replaced by 11g instead of 12.1g (i.e., the mass ratio of ethylene glycol to oil phase is 1:1). The remaining steps remain unchanged.

[0051] Example 4 The main difference between this embodiment and Example 1 is that the amount of ethylene glycol used in Example 1 is replaced from 12.1g to 16.5g (i.e., the mass ratio of ethylene glycol to oil phase is 1.5:1). The remaining steps remain unchanged.

[0052] Example 5 The main difference between this embodiment and Example 1 is that the dropping rate of ethylene glycol in Example 1 is adjusted from 4 mL / min to 1 mL / min. The remaining steps remain unchanged.

[0053] Example 6 The main difference between this embodiment and Example 1 is that the dropping rate of ethylene glycol in Example 1 is adjusted from 4 mL / min to 8 mL / min. The remaining steps remain unchanged.

[0054] Example 7 The main difference between this embodiment and Embodiment 1 is that the prescription amount in Embodiment 1 is scaled up by 10 times. The remaining steps remain unchanged.

[0055] The lidocaine microspheres prepared in Examples 1-7 and Comparative Example 4 were characterized, and the results are recorded in Table 2.

[0056] Characterization of microspheres 4. Determination of residual solvent: Accurately measure appropriate amounts of acetone and dichloromethane reference standards, and use dimethyl sulfoxide (DMSO) as the diluent to prepare a series of mixed reference standard gradient solutions containing acetone and dichloromethane. Place each gradient reference standard solution into a headspace vial, seal and compact, and determine by gas chromatography. Plot standard curves for acetone and dichloromethane with solvent concentration as the abscissa and corresponding peak area as the ordinate, respectively, to obtain the linear regression equation and the limits of detection and quantitation parameters.

[0057] Accurately weigh an appropriate amount of dried microsphere sample to constant weight and place it in a headspace vial. Accurately add a quantitative amount of diluent and seal the vial. Place the vial in a headspace sampler for constant temperature equilibration, allowing residual organic solvents inside the microspheres to fully evaporate into the headspace gas phase. After equilibration, automatically inject and detect the sample, recording the peak areas of characteristic acetone or dichloromethane. Substitute these values ​​into the corresponding standard curve to calculate the residual mass of the corresponding organic solvent in the sample.

[0058] The chromatographic conditions were as follows: a polar capillary column was used; the initial temperature was 30℃, maintained for 4 minutes, and then increased to 130℃ at a rate of 20℃ per minute, maintained for 3.5 minutes; the injection port temperature was 200℃, the detector temperature was 250℃, and the injection volume was 1μL.

[0059] Table 2

[0060] As shown in Examples 1-4, when the mass ratio of ethylene glycol to oil phase is controlled at 0.5-1.5:1, the drug loading of microspheres remains stable at 14.8-16.4%, and the release behavior is consistent. Examples 1 and 5-6 show that when the ethylene glycol dropping rate is 1-4 mL / min, it has little impact on the partial mass properties of the microspheres; as the ethylene glycol dropping rate increases, the migration of PLGA accelerates, resulting in an increase in the size of lidocaine-PLGA droplets formed in the thermodynamically unstable region, and consequently, a corresponding increase in the particle size of the final microspheres. Comparative Example 4 shows that when the oil phase solvent is replaced from dichloromethane to acetone, which is completely miscible with ethylene glycol, the migration rate from acetone to ethylene glycol is too fast. PLGA, due to the rapid increase in concentration, cannot disperse in time and quickly precipitates and solidifies, easily forming large-sized microspheres. Furthermore, the results of Example 7 indicate that the process scale-up has little impact on the mass properties of the microspheres, demonstrating the good feasibility of this method for scale-up.

[0061] As described above, the basic principles, main features, and advantages of the present invention have been shown and described. Those skilled in the art should understand that the present invention is not limited to the above embodiments, which are merely preferred embodiments and should not be construed as limiting the scope of the invention. All equivalent changes and modifications made in accordance with the scope of the patent and the description should still fall within the scope of the present invention. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing lidocaine microspheres, characterized in that the steps include... include: Lidocaine and PLGA were dissolved in an organic solvent to obtain an oil phase; Polyvinyl alcohol is dissolved in water for injection to obtain the external aqueous phase; Ethylene glycol was added dropwise to the oil phase to obtain a prephase-separated mixed phase; The prephase-separated mixed phase and the external aqueous phase are mixed and emulsified to obtain an O / W emulsion. The O / W emulsion was continuously stirred, the wet microspheres were collected, and a freeze-drying protective solution was added. The microspheres were then freeze-dried to obtain lidocaine microspheres.

2. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The mass ratio of lidocaine, PLGA, and organic solvent in the oil phase is 1.5:3:6 to 3:3:

6.

3. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The weight-average molecular weight of the PLGA is 15,000-30,000 Da.

4. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The organic solvent is selected from one or a combination of two or more of dichloromethane, chloroform and ethyl acetate.

5. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The concentration of polyvinyl alcohol in the external aqueous phase is 0.5-1 wt%.

6. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The mass ratio of ethylene glycol to oil phase in the prephase separation mixture is 0.5:1 to 1.5:1; Preferably, the mass ratio of the ethylene glycol to the oil phase is 1.1:

1.

7. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The dropping rate of the ethylene glycol is 1-10 mL / min; Preferably, the dropping rate of the ethylene glycol is 4 mL / min.

8. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The mass ratio of the prephase-separated mixed phase to the external aqueous phase in the O / W emulsion is 1:100-1:

300.

9. The method for preparing lidocaine microspheres according to claim 1, characterized in that, The freeze-drying protective solution contains mannitol.

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