Methylene blue-ropivacaine PLGA double drug time sequence sustained-release injection, preparation method and application

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a methylene blue-ropivacaine PLGA double-drug time sequence sustained-release injection, a preparation method and analgesic application after anorectal surgery. The injection comprises drug-loaded PLGA microspheres and a sterile injection solvent; raw materials of the drug-loaded microspheres are PLGA, ropivacaine, methylene blue, phosphatidylcholine and mannitol. The microspheres adopt a differential spatial distribution structure, and a part of the ropivacaine is distributed on the near-surface of the microspheres to form a rapid release component, and the methylene blue is embedded in the interior of the microspheres to realize slow release. The W / O / W multiple emulsion-solvent evaporation method is adopted to prepare the drug-loaded microspheres through solidification, washing and freeze-drying, and the microspheres and the solvent can be respectively stored in a double-cavity pre-filled syringe and mixed before use. The application realizes differential time sequence release of the two drugs through structural design, is specially adapted to long-acting analgesia of the perianal region after anorectal surgery such as hemorrhoids, anal fistula, anal fissure and perianal abscess, avoids the drawbacks of traditional manual drug preparation, and improves the convenience of preparation use and the standardization degree of batches.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically referring to a methylene blue-ropivacaine PLGA dual-drug-loaded time-release injection, its preparation method, and its application for postoperative analgesia in anorectal surgery. Background Technology

[0002] Following colorectal surgery, patients often experience significant postoperative pain due to the dense distribution of sensory nerve endings in the perianal area and the open wounds created by some procedures. Postoperative pain not only affects sleep and bowel movements but may also increase the need for analgesics and the risk of related complications. With over 2 million colorectal surgeries performed annually nationwide, persistent and severe postoperative pain for 3-7 days remains a core challenge hindering patient recovery and severely impeding the implementation of Enhanced Recovery After Surgery (ERAS) in colorectal surgery.

[0003] Currently, local analgesia in clinical practice typically involves infiltration or spot injection of local anesthetics, and sometimes different drugs are temporarily combined for use. The drugs in these aqueous solutions mainly rely on free diffusion for release, easily leading to high local instantaneous concentrations after injection. Furthermore, different drugs, due to differences in pharmacological effects, onset of action, and duration of action, cannot achieve continuous analgesia. Clinically, methylene blue injection combined with ropivacaine injection is routinely prepared manually for perianal injection analgesia during surgery. However, this method constitutes off-label subcutaneous administration of methylene blue, posing significant medical compliance risks. Manual on-site preparation cannot precisely control osmotic pressure, pH, and drug concentration, resulting in an adverse reaction rate of 5%-10%. Furthermore, the timing mismatch between ropivacaine and methylene blue creates a 4-6 hour analgesic window, leading to severe pain on the postoperative night and requiring large doses of opioid analgesics for remedial treatment.

[0004] Ropivacaine, in particular, is a local anesthetic with a relatively rapid onset of action, but its duration of effectiveness is affected by factors such as dosage, administration site, and local tissue environment. Methylene blue, when used for local nerve blocks, exhibits different characteristics from local anesthetics. Therefore, using a simple mixed injection method for these two free drugs makes it difficult to independently control the local release process of each drug.

[0005] Existing sustained-release formulation technologies typically employ a single drug to form microspheres with PLGA, achieving sustained release through the hydrolysis and degradation of the PLGA matrix and drug diffusion. However, for methylene blue and ropivacaine, which have different physicochemical properties and pharmacological effects, simply encapsulating both drugs in the same homogeneous structure makes it difficult to effectively establish a clear sequential release relationship.

[0006] In addition, existing local drug preparation methods have problems such as numerous on-site preparation steps, difficulty in controlling drug concentration consistency, and insufficient ease of use. Summary of the Invention

[0007] To address the challenge of controlling the release rate in traditional free drug mixtures, this invention provides a methylene blue-ropivacaine PLGA dual-drug-loaded time-release injection, its preparation method, and its application. By constructing PLGA drug-loaded microspheres with differentiated drug spatial distribution, ropivacaine forms a relatively rapid early release fraction, while methylene blue forms a relatively slow, sustained release fraction, thus creating a dual-drug time-release system. Specifically targeting postoperative analgesia in anorectal surgery, it fills the analgesic gap in traditional formulations, avoids the risks of off-label use of methylene blue via subcutaneous injection, and reduces adverse reactions such as local tissue irritation and abnormal perianal numbness. Furthermore, it provides emulsification, curing, washing, and lyophilization processes suitable for preparing the aforementioned dual-drug-loaded microspheres, improving the structural stability and batch consistency of the drug-loaded microspheres. Finally, it provides a formulation for isolating the drug-loaded microspheres from the sterile injection solvent for storage, reducing the stability impact caused by direct contact between the drug and the solvent during long-term storage.

[0008] To achieve the above functions, the technical solution adopted by the present invention is as follows: a methylene blue-ropivacaine PLGA dual-drug-loaded sustained-release injection, comprising drug-loaded PLGA microspheres and a sterile injection solvent for reconstituted or suspended the drug-loaded PLGA microspheres to form an injectable formulation.

[0009] The drug-loaded PLGA microspheres comprise, by weight: 80-90 parts PLGA; 3-8 parts ropivacaine; 0.5-2 parts methylene blue; 2-5 parts phosphatidylcholine; and 2-5 parts mannitol.

[0010] The PLGA is a lactic acid-glycolic acid copolymer, preferably with a mass ratio of lactic acid to glycolic acid of 75:25, and the weight-average molecular weight of the PLGA is 12,000 to 20,000.

[0011] The preferred particle size of the drug-loaded PLGA microspheres is 10–50 μm.

[0012] The drug-loaded PLGA microspheres have a differentiated drug-loaded structure, wherein ropivacaine is at least partially distributed in the region near the outer surface of the drug-loaded PLGA microspheres, and methylene blue is at least partially embedded inside the drug-loaded PLGA microspheres.

[0013] Through the aforementioned spatial distribution structure of the drug, ropivacaine has a relatively short drug diffusion path, resulting in a relatively rapid release component; methylene blue, on the other hand, has a relatively long diffusion path, and, combined with the gradual hydrolysis and degradation of the PLGA matrix, forms a relatively slow release component; after injection, ropivacaine takes effect rapidly within 10-15 minutes, while methylene blue continues to be released slowly for 7-14 days as the PLGA matrix degrades, achieving reversible long-term blockade of peripheral nerves at the anal end, and meeting the need for seamless analgesia throughout the entire cycle from 0 to 14 days after anorectal surgery.

[0014] Furthermore, the sterile injection solvent includes an isotonic sodium chloride aqueous solution and sodium carboxymethyl cellulose.

[0015] Preferably, the mass concentration of sodium carboxymethyl cellulose in the sterile injection solvent is 0.3-0.8%.

[0016] The drug-loaded PLGA microspheres and sterile injectable solvent are isolated from each other in the storage state and are mixed to form a drug-loaded microsphere suspension before use.

[0017] Preferably, the drug-loaded PLGA microspheres and the sterile injection solvent are respectively sealed and stored in two independent chambers of a dual-chamber pre-filled syringe, with a destructible isolation diaphragm between the two chambers.

[0018] In use, the isolation diaphragm is broken by the push rod, allowing the sterile injection solvent to enter the chamber containing the drug-loaded PLGA microspheres. The lyophilized drug-loaded PLGA microspheres are then redispersed in the injection solvent by pushing and oscillating, forming a uniform drug-loaded microsphere suspension. This suspension can be directly used for subcutaneous injection into the perianal wound after anorectal surgery, eliminating the need for manual temporary drug preparation in the operating room.

[0019] A method for preparing a methylene blue-ropivacaine PLGA dual-load sustained-release injection specifically includes the following steps:

[0020] S1. Preparation of PLGA organic phase: Weigh PLGA and phosphatidylcholine, add them to an organic solvent, and dissolve PLGA completely under stirring conditions to form a PLGA organic phase; the organic solvent is preferably dichloromethane; then add ropivacaine to the PLGA organic phase to form an organic drug-loaded phase containing ropivacaine;

[0021] S2. Preparation of aqueous methylene blue phase: Add methylene blue and mannitol to deionized water and dissolve or uniformly disperse them under stirring to form an aqueous methylene blue phase.

[0022] S3. First emulsification: The methylene blue aqueous phase is slowly added to the ropivacaine-containing organic drug-loaded phase, and a W / O primary emulsion is formed by high-speed homogenization; by controlling the addition rate of the inner aqueous phase, the homogenization speed and the homogenization time, the methylene blue aqueous phase is dispersed in the PLGA organic phase in the form of tiny droplets.

[0023] S4. Secondary emulsification: The obtained W / O pre-emulsion is slowly added to the external aqueous phase containing polyvinyl alcohol, and W / O / W double emulsion is formed by high-speed homogenization. During the formation of the double emulsion, the internal aqueous phase containing methylene blue is coated inside the PLGA organic phase and further dispersed in the external aqueous phase, thus providing a structural basis for the embedding of methylene blue inside the PLGA microspheres.

[0024] S5. Solvent evaporation and microsphere curing: The obtained W / O / W double emulsion was placed under stirring conditions to allow the organic solvent to gradually evaporate. As the organic solvent evaporated, the PLGA concentration gradually increased and solidified to form drug-loaded microspheres. By controlling the solvent evaporation rate and stirring conditions, the drug-loaded microspheres formed a stable spherical structure, and the methylene blue was mainly located inside the microspheres, while the ropivacaine formed a drug-loaded area relatively close to the outer surface of the microspheres.

[0025] S6. Microsphere separation and washing: The solidified drug-loaded microsphere suspension is centrifuged, the supernatant is discarded, and the microspheres are washed with deionized water. It is preferable to wash 2 to 4 times to remove residual polyvinyl alcohol, free drug and other water-soluble impurities. After each washing, the microspheres are centrifuged to obtain purified drug-loaded PLGA microspheres.

[0026] S7. Lyophilization: The washed drug-loaded PLGA microspheres are redispersed in a protective solution containing mannitol, pre-frozen, and then vacuum lyophilized to obtain drug-loaded PLGA lyophilized microspheres; the mannitol serves as both a formulation component and a lyophilization protection system during the lyophilization process to improve the redispersibility of the lyophilized microspheres.

[0027] S8. Dispensing and Dual-Cavity Assembly: Under the condition of meeting the requirements for sterile preparation production, drug-loaded PLGA lyophilized microspheres and sterile injection solvent are respectively filled into the two independent chambers of a dual-chamber pre-filled syringe; wherein, the drug-loaded PLGA lyophilized microspheres are filled into the dry powder chamber, and the sterile injection solvent is filled into the liquid chamber, and the two chambers are isolated by an isolation diaphragm; after assembly, the syringe is sealed and packaged to obtain the dual-drug-loaded time-release injection.

[0028] Preferably, in step S3, the first emulsification is performed using a high-speed homogenization process at 8000-15000 rpm for 1-5 minutes.

[0029] Preferably, in step S4, the second emulsification is performed using a high-speed homogenization process at 8000–15000 rpm for 3–8 min; the mass concentration of polyvinyl alcohol in the external aqueous phase is 0.5–2.0%.

[0030] Preferably, in step S5, the W / O / W re-emulsion is stirred at 20-30°C, the stirring speed is 300-800 rpm, and the stirring time is 3-6 hours.

[0031] Preferably, in step S6, the drug-loaded microspheres are washed with deionized water 2 to 4 times, and centrifuged at 7000 to 9000 rpm for 8 to 12 minutes after each wash.

[0032] Preferably, in step S7, the drug-loaded microspheres are pre-frozen and then vacuum freeze-dried for 20-30 hours.

[0033] The particle size of the obtained drug-loaded PLGA microspheres can be adjusted by changing the homogenization speed, homogenization time, and PLGA concentration during the first and second emulsification processes.

[0034] Compared with the prior art, the present invention achieves the following beneficial effects by adopting the above solution:

[0035] 1. By constructing dual-drug-loaded sustained-release microspheres using PLGA, ropivacaine and methylene blue are placed in a drug-loaded structure with differentiated spatial distribution, allowing the two drugs to have different release pathways, thus enabling sequential release; specifically adapted for analgesia after anorectal surgery, ropivacaine has a rapid onset of action to eliminate severe pain in the early postoperative period, while the internally embedded methylene blue slowly releases to achieve mid- to long-term peripheral nerve block at the analgesic end, eliminating the analgesic window period of traditional aqueous preparations and achieving continuous seamless analgesia from 0 to 14 days;

[0036] 2. Ropivacaine is distributed close to the surface of the microspheres, which can form a relatively fast early release component. Methylene blue is mainly embedded inside the PLGA microspheres. As the PLGA absorbs water, degrades, and the drug diffuses, it is gradually released, thus forming a relatively continuous release process.

[0037] 3. Compared with direct mixing and injection of two free drugs, this invention uses a PLGA carrier to reduce the local concentration peak caused by the instantaneous release of the drug, which helps to reduce the risk of adverse reactions such as perianal local irritation, abnormal numbness, and distending discomfort, and reduces postoperative complications of anorectal surgery such as urinary retention and delayed wound healing; at the same time, it avoids the compliance risks of subcutaneous administration of methylene blue under the instructions of the instructions due to manual mixing during clinical operation.

[0038] 4. By storing the lyophilized drug-loaded microspheres and sterile injectable solvent in separate cavities, the stability of drugs in a long-term aqueous environment can be reduced, and the convenience of formulation storage and clinical use can be improved. The finished product is pre-filled in a dual-cavity pre-filled syringe, eliminating the need for on-site drug preparation in clinical practice, reducing the risk of drug contamination and incorrect mixing, and shortening the operation time, which is in line with the ERAS (Enhanced Recovery After Surgery) comfort medical concept in anorectal surgery.

[0039] 5. Controlling the drug ratio, microsphere size, and drug loading structure through standardized preparation processes helps improve batch-to-batch consistency of formulations. Detailed Implementation

[0040] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] Example 1: Preparation of dual-drug-loaded PLGA microspheres with preferred formulation

[0042] A methylene blue-ropivacaine PLGA dual-loaded sustained-release injection, weighed in the following proportions by weight: PLGA 85 parts; ropivacaine 5 parts; methylene blue 1 part; phosphatidylcholine 3 parts; mannitol 3 parts. This formulation is an optimal ratio for routine anorectal surgery and is suitable for long-acting perianal analgesia after surgery for common mixed hemorrhoids and anal fissures.

[0043] A method for preparing a methylene blue-ropivacaine PLGA dual-load sustained-release injection specifically includes the following steps:

[0044] S1. Preparation of PLGA organic phase: PLGA and phosphatidylcholine are added to dichloromethane and stirred until PLGA is fully dissolved to form a homogeneous PLGA organic phase; then ropivacaine is added and stirring is continued to disperse or dissolve ropivacaine uniformly in the PLGA organic phase, thus obtaining an organic drug-loaded phase containing ropivacaine.

[0045] S2. Preparation of methylene blue aqueous phase: Add methylene blue and mannitol to deionized water and dissolve them completely under stirring to form methylene blue aqueous phase;

[0046] S3. First emulsification: The methylene blue aqueous phase is slowly added to the organic drug-loaded phase containing ropivacaine, and homogenized at 10,000 to 12,000 rpm for 2 to 4 minutes to form a W / O promulgation;

[0047] S4. Second emulsification: The obtained W / O primary emulsion is slowly added to the external aqueous phase containing polyvinyl alcohol, and homogenized at 10,000 to 15,000 rpm for 4 to 6 minutes to form a W / O / W double emulsion.

[0048] S5. Solvent evaporation and curing: The obtained W / O / W double emulsion is placed at 20-30℃ and stirred continuously at 300-600 rpm for 3-5 hours to allow dichloromethane to gradually evaporate and PLGA to solidify into drug-loaded microspheres.

[0049] S6. Separation and washing: The solidified drug-loaded microspheres are centrifuged, the supernatant is discarded, and the microspheres are washed with deionized water for a total of 3 times. After each washing, centrifugation is performed to remove residual polyvinyl alcohol, free drug and other water-soluble impurities.

[0050] S7. Lyophilization: The washed drug-loaded microspheres are redispersed in a protective solution containing mannitol, pre-frozen, and then vacuum freeze-dried for 20-26 hours to obtain drug-loaded PLGA lyophilized microspheres.

[0051] S8. Assembly of the dual-chamber pre-filled syringe: The obtained drug-loaded PLGA lyophilized microspheres are loaded into the dry powder chamber of the dual-chamber pre-filled syringe, the sterile isotonic injection solvent is loaded into the liquid chamber, and the two chambers are isolated by an isolation diaphragm.

[0052] During use, the isolation diaphragm is ruptured by the push rod, allowing the sterile injection solvent to enter the dry powder chamber. By pushing the push rod and coordinating with vibration, the drug-loaded PLGA lyophilized microspheres are redispersed in the sterile injection solvent, forming a drug-loaded microsphere suspension, which is used for perianal subcutaneous injection after anorectal surgery.

[0053] Example 2: Low-methylene blue loading formulation

[0054] A methylene blue-ropivacaine PLGA dual-loaded sustained-release injection, weighed in the following proportions by weight: PLGA 88 parts; ropivacaine 6 parts; methylene blue 0.5 parts; phosphatidylcholine 3 parts; mannitol 2.5 parts. This embodiment reduces the amount of methylene blue, resulting in a milder formula suitable for elderly patients, women with sensitive pelvic floors, and those with weak bowel control after anorectal surgery, thus reducing the long-term risk of perianal numbness.

[0055] Drug-loaded PLGA microspheres were prepared according to the preparation method in Example 1.

[0056] This embodiment reduces the proportion of methylene blue in the formulation to form a relatively low methylene blue loading formulation, which can be used to study the effects of different methylene blue loading amounts on the structure and release behavior of drug-loaded microspheres.

[0057] Example 3: High-methylene blue loading formulation

[0058] A methylene blue-ropivacaine PLGA dual-load sustained-release injection is prepared by weight as follows: PLGA 82 parts; ropivacaine 4 parts; methylene blue 1.8 parts; phosphatidylcholine 4 parts; mannitol 3 parts. This embodiment increases the methylene blue loading, resulting in a stronger long-lasting analgesic effect, and is suitable for complex anorectal surgeries with large wounds, such as complex anal fistulas, severe perianal abscesses, and large-area mixed hemorrhoids.

[0059] Drug-loaded PLGA microspheres were prepared according to the preparation method in Example 1.

[0060] This embodiment increases the proportion of methylene blue in the formulation to form a relatively high methylene blue drug loading formulation, which can be used to study the effects of different methylene blue drug loading amounts on the structure and release behavior of drug-loaded microspheres.

[0061] Example 4: Control of microsphere particle size and preparation parameters

[0062] Based on the formulation described in Example 1, the particle size of the drug-loaded PLGA microspheres was adjusted by modifying the homogenization speed, homogenization time, and polyvinyl alcohol concentration in the external aqueous phase during the second emulsification process.

[0063] Increasing the homogenization speed or appropriately extending the homogenization time can change the size of the droplets formed during emulsification, thereby adjusting the final drug-loaded microsphere particle size. Furthermore, changing the PLGA concentration and the polyvinyl alcohol concentration in the external aqueous phase can further affect the stability of the emulsion system and the microsphere formation process.

[0064] Therefore, the above process parameters can be combined and adjusted according to the particle size range required by the formulation to control the particle size of the drug-loaded PLGA microspheres within a range suitable for forming a stable suspension.

[0065] This embodiment is used to illustrate the regulatory effect of emulsification process parameters on the particle size and structure formation process of drug-loaded PLGA microspheres, and does not limit the specific particle size results obtained without actual testing.

[0066] Example 5: Formulation of a dual-chamber pre-filled formulation

[0067] The drug-loaded PLGA lyophilized microspheres obtained in any of Examples 1 to 4 were loaded into the dry powder chamber of a dual-chamber pre-filled syringe.

[0068] Take another sterile injection solvent and fill it into the liquid chamber.

[0069] The dry powder chamber and the liquid chamber are sealed and isolated by an isolation diaphragm, so that the drug-loaded PLGA lyophilized microspheres are separated from the sterile injection solvent during storage.

[0070] During use, pushing the plunger ruptures the isolation diaphragm, allowing the sterile injection solvent in the liquid chamber to enter the dry powder chamber. Through the pusher's movement and agitation, the lyophilized drug-loaded microspheres are redispersed in the sterile injection solvent, forming a drug-loaded microsphere suspension that can be directly used for subcutaneous injection around the anus after anorectal surgery.

[0071] This embodiment illustrates the compartmentalized storage of drug-loaded PLGA lyophilized microspheres and sterile injectable solvent, as well as the mixing method before use.

[0072] Any equivalent substitutions or conventional adjustments made by those skilled in the art to the molecular weight of PLGA, the lactic acid / glycolic acid ratio, the drug loading, the emulsification parameters, the microsphere size, the lyophilization protectant, and the injection solvent without departing from the technical concept of this invention should be included within the scope of protection of this invention.

Claims

1. A methylene blue-ropivacaine PLGA dual-loaded time-release injection, characterized in that, The product includes drug-loaded PLGA microspheres and a sterile injection solvent; the drug-loaded PLGA microspheres comprise, by weight: 80-90 parts of lactic acid-glycolic acid copolymer PLGA; 3-8 parts of ropivacaine; 0.5-2 parts of methylene blue; 2-5 parts of phosphatidylcholine; and 2-5 parts of mannitol. The ropivacaine is at least partially distributed in the region near the outer surface of the drug-loaded PLGA microspheres, forming a fast-release component of ropivacaine; the methylene blue is at least partially embedded inside the drug-loaded PLGA microspheres, forming a slow-release component of methylene blue, so that the drug-loaded PLGA microspheres have a dual-drug-loaded structure with different spatial distributions of ropivacaine and methylene blue; the injection is used for long-acting local subcutaneous analgesia in the perianal area after anorectal surgery.

2. The methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 1, characterized in that, The mass ratio of lactic acid to glycolic acid in the PLGA is 75:25, and the weight-average molecular weight of the PLGA is 12,000 to 20,000.

3. The methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 1, characterized in that, The particle size of the drug-loaded PLGA microspheres is 10–50 μm.

4. The methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 1, characterized in that, The weight ratio of PLGA, ropivacaine, methylene blue, phosphatidylcholine and mannitol in the drug-loaded PLGA microspheres is 85:5:1:3:

3.

5. The methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 1, characterized in that, The sterile injection solvent includes an isotonic sodium chloride aqueous solution and sodium carboxymethyl cellulose, wherein the mass concentration of sodium carboxymethyl cellulose is 0.3-0.8%.

6. The methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 1, characterized in that, The drug-loaded PLGA microspheres and the sterile injection solvent are respectively sealed and stored in two independent chambers of a dual-chamber pre-filled syringe. A ruptureable isolation diaphragm is provided between the two chambers. During use, the sterile injection solvent is allowed to enter the chamber containing the drug-loaded PLGA microspheres by breaking the isolation diaphragm, so as to form a drug-loaded microsphere suspension. The suspension is suitable for subcutaneous injection into the perianal area after anorectal surgery.

7. The method for preparing the methylene blue-ropivacaine PLGA dual-loaded time-release injection according to any one of claims 1 to 6, characterized in that, Includes the following steps: S1. Dissolve PLGA and phosphatidylcholine in an organic solvent to form an organic phase of PLGA, and add ropivacaine to form an organic drug-loaded phase containing ropivacaine. S2. Add methylene blue and mannitol to water to form an aqueous phase of methylene blue; S3. The methylene blue aqueous phase is added to the ropivacaine-containing organic drug-loaded phase for the first emulsification to form a W / O promulgated emulsion. The W / O promulgated emulsion is then added to the polyvinyl alcohol-containing external aqueous phase for the second emulsification to form a W / O / W double emulsion. S4. Stir the W / O / W double emulsion to evaporate the organic solvent and solidify the PLGA to form drug-loaded microspheres; S5. The drug-loaded microspheres are centrifuged and washed with deionized water. S6. The washed drug-loaded microspheres are freeze-dried to obtain drug-loaded PLGA freeze-dried microspheres. S7. The drug-loaded PLGA lyophilized microspheres and sterile injection solvent are respectively loaded into the two independent chambers of a dual-chamber pre-filled syringe and isolated and sealed by an isolation diaphragm.

8. The method for preparing the methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 7, characterized in that, In step S3, the first emulsification is performed by homogenization at 8000-15000 rpm for 1-5 min, and the second emulsification is performed by homogenization at 8000-15000 rpm for 3-8 min; the mass concentration of polyvinyl alcohol in the external aqueous phase is 0.5-2.0%.

9. The method for preparing the methylene blue-ropivacaine PLGA dual-loaded time-release injection according to claim 7, characterized in that, In step S4, the W / O / W double emulsion is stirred at 300-800 rpm for 3-6 hours at 20-30°C; in step S5, it is washed 2-4 times with deionized water, and centrifuged at 7000-9000 rpm for 8-12 minutes after each wash; in step S6, the drug-loaded microspheres are pre-frozen and then freeze-dried under vacuum for 20-30 hours.

10. The application of the methylene blue-ropivacaine PLGA dual-loaded time-release injection according to any one of claims 1 to 6, characterized in that, This preparation is used to develop a long-acting local analgesic for postoperative wound care in anorectal surgery. The formulation is pre-filled in a double-lumen pre-filled syringe and is suitable for local subcutaneous analgesia in the perianal area after radical treatment of mixed hemorrhoids, anal fistula, anal fissure, and perianal abscess.