Eye-use sustained-release gel preparation containing block copolymer and preparation method of eye-use sustained-release gel preparation

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an ophthalmic sustained-release gel preparation containing a block copolymer and a preparation method of the ophthalmic sustained-release gel preparation. The preparation comprises a polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer, an active drug, a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, a mucous membrane penetration enhancer, an antioxidant, an osmotic pressure regulator, a pH regulator, a preservative and water for injection. The preparation method comprises the following steps: firstly pretreating the matrix, then treating the medicine and refining, then mixing the medicine and the matrix in stages, sequentially adding the auxiliary materials and dissolving, regulating the system to a proper state, standing and curing, and finally filtering, carrying out gradient cooling and carrying out sterile filling. The preparation can be used for treating eye diseases such as glaucoma and intraocular hypertension, and has the advantages of continuously and stably releasing medicines, prolonging the retention time of eyes and improving the medication compliance of patients; the preparation method is controllable in operation and easy to reproduce, can stably guarantee the quality of the preparation, and is suitable for industrial production.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulation technology, and more specifically, to an ophthalmic sustained-release gel formulation containing a block copolymer and a method for preparing the same. Background Technology

[0002] Ophthalmic medications are an important means of treating eye diseases such as glaucoma and ocular hypertension. These diseases often require long-term treatment, relying on the continuous action of medication on the eye to control intraocular pressure and alleviate symptoms. However, long-term and frequent use can easily lead to missed or incorrect doses, resulting in poor medication adherence. This not only affects treatment effectiveness but may also cause relapses due to irregular medication use, failing to meet the needs of long-term eye disease treatment for both continuous drug action and convenient medication access.

[0003] Currently, commonly used ophthalmic preparations in clinical practice mainly include solutions and ordinary gels. While solutions are convenient to use, the drugs are easily washed away by tears in the eye, resulting in a short drug retention time. This leads to rapid drug release and a short duration of action, requiring patients to administer the medication multiple times a day. Although ordinary gels can prolong drug retention time through the gel matrix, the matrix is ​​mostly a single polymer material, making it difficult to precisely adjust the density of the gel network and the drug diffusion path. Drug release often fluctuates, with initial burst release or insufficient release in the later stages, failing to achieve a continuous and stable drug release effect. Ultimately, patients still need to use the medication frequently to maintain efficacy.

[0004] To address the aforementioned issues, the applicant has already established a certain research and development foundation in drug carrier materials. For example, CN116731267A discloses a method for preparing an amphiphilic diblock copolymer for drug solubilization, synthesizing a thermosensitive and biocompatible mPEG-bP (VAc-co-NVCL) diblock copolymer using reversible addition-fragmentation chain transfer (RAFT) polymerization technology. Furthermore, CN120241617A applied this copolymer to the preparation of drug solid solutions, finding that it not only significantly improves the solubility of poorly soluble drugs but also effectively inhibits the growth of drug crystals, thereby enhancing the efficacy and stability of the drug. These research results indicate that polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate block copolymers have broad application potential in drug delivery systems, especially suitable for formulation scenarios requiring long-acting and stable release.

[0005] Based on the above background, this application aims to further develop an amphiphilic block copolymer carrier suitable for ophthalmic formulations, in order to address the shortcomings of existing ophthalmic formulations in terms of drug retention and release behavior, and to achieve longer-lasting and more stable ophthalmic drug delivery. Summary of the Invention

[0006] To address the problems of unstable drug release, short ocular retention, and poor medication adherence in existing ophthalmic formulations, this application provides an ophthalmic sustained-release gel formulation containing a block copolymer and its preparation method.

[0007] In a first aspect, this application provides an ophthalmic sustained-release gel formulation containing a block copolymer, employing the following technical solution: An ophthalmic sustained-release gel formulation containing a block copolymer, wherein every 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 10-50 parts of polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer; 0.01-1 part of active drug; 1-10 parts of osmotic pressure regulator; 0.1-5 parts of pH regulator; 0.001-0.1 parts of preservative; 0.5-5 parts of polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer; 0.5-3 parts of mucosal penetration enhancer; 0.1-2 parts of antioxidant; and the balance being water for injection.

[0008] By adopting the above technical solution, the block copolymer used in this application is a polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer. By selecting this amphiphilic polymer material as the gel matrix, the hydrophilic segment of polyethylene glycol in its molecular structure can improve the hydrophilicity of the gel and its compatibility with the ocular mucosa, reducing eye irritation; the hydrophobic segments of polyvinyl caprolactam and vinyl acetate can enhance the compatibility with lipid-soluble active drugs. The two work synergistically to form a dense and highly elastic three-dimensional gel network, which can efficiently encapsulate active drug molecules, prevent premature drug leakage, support the overall morphological stability of the formulation, and provide a uniformly dispersed carrier environment for functional excipients such as osmotic pressure regulators and antioxidants, preventing local aggregation of excipients. This influences formulation performance, thus laying the core foundation for achieving sustained-release characteristics and adapting to the ocular physiological environment. By adding targeted active drugs such as latanoprost and tafluprost, they can rely on the encapsulation and sustained-release effect of the gel matrix to slowly release and target the disease site during ocular retention. For example, in glaucoma treatment, this targets receptors that regulate aqueous humor production, reducing drug loss due to rapid tear flushing, prolonging the pharmacological action time, and achieving precise relief of ocular symptoms and stable disease control. At the same time, the protective effect of the gel matrix reduces the risk of drug degradation, ensuring stable efficacy and thus fully guaranteeing the core pharmaceutical value and therapeutic reliability of the formulation. By adding active drugs, they can rely on the encapsulation effect of the gel matrix to target the disease site in the ocular environment. The formulation exerts its pharmacological activity at specific sites, achieving therapeutic effects on related eye conditions and thus ensuring its core medicinal value. By adding osmotic pressure regulators, the ion concentration and osmotic pressure of the formulation system can be adjusted to maintain consistency with the osmotic pressure of the tear film, thereby reducing irritation to the ocular mucosa. By using pH regulators, the hydrogen ion concentration of the formulation system can be neutralized or adjusted to control the pH value within the eye's tolerance range, thus improving the comfort of ocular use. By adding preservatives, the growth and reproduction of microorganisms in the formulation can be inhibited, preventing deterioration during storage and use, thus ensuring the safety of the formulation. By selecting… Polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer is used as a sustained-release regulator. This copolymer is composed of alternating hydrophobic polycaprolactone segments and hydrophilic polyethylene glycol segments. It can form a synergistic effect with the block copolymer gel matrix by means of its own block structure characteristics. The hydrophobic segments can interact with the hydrophobic part of the block copolymer, and the hydrophilic segments can be compatible with the hydrophilic part of the block copolymer. Together, they can regulate the density and internal pore size of the gel network, thereby playing a role in precisely controlling the diffusion rate of active drugs from the gel network. At the same time, the molecular structure of this triblock copolymer has good stability and is not prone to structural degradation during the storage and use of the formulation. It can continuously maintain the regulating effect on the gel network and ensure the long-term stability of the sustained-release performance of the formulation.Furthermore, this copolymer exhibits excellent ocular biocompatibility, causing no significant irritation to the ocular mucosa. While providing sustained-release regulation, it also ensures the safety of the formulation for ocular use. By adding a mucosal penetration enhancer, it can improve the intercellular environment of the corneal epithelial cells or enhance the solubility and diffusion of drug molecules in the mucosa, thereby promoting the active drug's penetration through the ocular mucosal barrier and facilitating its better delivery to the site of action. The use of antioxidants can capture free radicals in the formulation system or inhibit the oxidative degradation of the active drug, protecting it from oxidative damage and maintaining its stability and efficacy. Using water for injection as a solvent and diluent can dissolve or disperse the aforementioned raw material components, ensuring the formulation reaches the target concentration and maintains a uniform dispersion, thus guaranteeing the stability and uniformity of the formulation's various properties.

[0009] Preferably, each 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 30 parts of polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer; 0.5 parts of active pharmaceutical ingredient; 5 parts of osmotic pressure regulator; 2.5 parts of pH regulator; 0.05 parts of preservative; 2.5 parts of polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer; 1.5 parts of mucosal penetration enhancer; 1 part of antioxidant; and the balance being water for injection.

[0010] Preferably, the active drug is selected from at least one of latanoprost, tafluprost, and travoprost.

[0011] By adopting the above technical solutions, latanoprost can regulate intraocular pressure by acting on the aqueous humor outflow channels of the eye and promoting aqueous humor outflow, thus providing a drug basis for the treatment of ocular diseases related to high intraocular pressure; tafluprost can reduce intraocular pressure by enhancing the efficiency of aqueous humor outflow through the uveal-scleral pathway, thus adapting to the eye's needs for drug action pathways; travoprost can stabilize and control intraocular pressure by simultaneously regulating aqueous humor production and outflow and optimizing the dynamic balance of aqueous humor, thus meeting different intraocular pressure control needs; at the same time, at least one of the above three drugs can be selected, which can be used to target different disease characteristics through single drug targeted action or multiple drugs synergistically, thus flexibly matching the treatment needs of ocular diseases, thereby ensuring that the active drugs can more accurately exert pharmacological effects on the target disease.

[0012] Preferably, the mucosal penetration enhancer is selected from at least one of L-carnosine, chitosan and its derivatives.

[0013] By employing the above technical solution, the mucosal penetration enhancer is preferably selected from at least one of L-carnosine, chitosan, and their derivatives. L-carnosine can penetrate into the intercellular spaces of the corneal epithelial cells and regulate the microenvironment of these spaces, thereby reducing the resistance of the active drug to the mucosal barrier and facilitating smoother passage of the drug through the corneal epithelium. Chitosan, with its cationic polysaccharide properties, interacts with the negative charge on the surface of corneal epithelial cells, temporarily altering the connection state between epithelial cells and forming a temporary adhesive gel layer on the mucosal surface to prolong drug retention time, thus enhancing the contact efficiency and permeability between the drug and the mucosa. This enhances the drug's penetration into the mucous membrane. Chitosan derivatives, while retaining the core characteristics of chitosan's mucosal action, optimize water solubility and ocular biocompatibility through chemical structural modification, reducing potential irritation to the ocular mucosa while maintaining or even enhancing the penetration-promoting effect, thus balancing penetration efficiency and safety. Furthermore, at least one of the above substances can be selected, allowing for targeted adaptation to the penetration requirements of specific drugs through a single promoter, or synergistic use of multiple promoters, to flexibly match the physicochemical properties of different active drugs with the formulation system, thereby ensuring the mucosal penetration-promoting effect and the compatibility of the drug and gel matrix.

[0014] Preferably, the antioxidant is selected from at least one of N-acetylcysteine ​​and sodium bisulfite.

[0015] By employing the above technical solutions, N-acetylcysteine, through its thiol group, can capture free radicals generated by oxidation reactions in the formulation system. Simultaneously, it can form a temporary protective structure with easily oxidized groups in the active drug molecule, thus inhibiting drug oxidative degradation. Sodium bisulfite, by providing sulfite ions, reacts with oxidizing substances in the formulation, neutralizing oxidizing factors in the system and blocking the chain reaction of the active drug's oxidation, preventing drug deterioration due to oxidation. Furthermore, at least one of the two substances can be selected, flexibly adapted according to the specific oxidation characteristics of the active drug. For example, for drugs with high oxidation sensitivity, N-acetylcysteine ​​can be used alone to exert its effect through targeted protection by the thiol group. For situations where trace amounts of oxidizing impurities are easily present in the system, sodium bisulfite can be used alone to neutralize oxidizing factors and ensure drug stability. Alternatively, both can be used in combination to further enhance the antioxidant protection effect of the drug through the synergistic effect of capturing free radicals and neutralizing oxidizing factors. Both substances also possess good ocular biocompatibility, and will not cause significant irritation to the ocular mucosa when exerting their antioxidant function, thus balancing protective efficacy and safety.

[0016] Secondly, this application provides a method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer, using the following technical solution: A method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer includes the following steps: S1. Matrix pretreatment: Polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer and polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer are mixed, and a portion of water for injection is added. The mixture is stirred at 45-65℃ to form a matrix solution. The amount of water for injection added is 30%-50% of the total water volume. The system is kept in a sealed state during the stirring process. S2. Drug processing: The active drug is dissolved in a solvent to form a drug solution. The dissolution process is carried out under light-protected conditions. After dissolution, the solution is pre-filtered through a 0.45μm microporous membrane. S3. Mixing treatment: The drug solution is added to the matrix solution in three stages and mixed and stirred. In the first stage, the stirring speed is 200-300 rpm for 20-40 minutes; in the second stage, the stirring speed is 300-400 rpm for 20-40 minutes; and in the third stage, the stirring speed is 400-500 rpm for 20-40 minutes. During the mixing process, the temperature is controlled within the range of 40-60℃, and the viscosity change of the system is continuously monitored. S4. Addition of excipients: Add osmotic pressure regulator, pH regulator and preservative to the mixture. Add each excipient in order of dissolution difficulty from easy to difficult. Stir each excipient separately for 5-15 minutes after adding to ensure that it is fully dissolved. S5. System adjustment: Add water for injection to the total volume. First, stir at a low speed of 100-200 rpm for 10-20 minutes to make the system uniform. Then, adjust the pH of the system to 6.2-7.2 and then let it stand for aging. S6. Terminal processing: The system is filtered through a 0.22μm microporous membrane and cooled from 35℃ to 25℃ at a rate of 0.5℃ / min using a gradient cooling method. The temperature is maintained for 20 minutes, then cooled to 4℃ at a rate of 1℃ / min. Finally, the system is filled under aseptic conditions. The entire cooling process is carried out in a light-proof and vibration-proof environment.

[0017] By adopting the above technical solution, step S1 promotes the full dissolution of the two raw materials and forms a homogeneous system, thereby constructing a clean and stable matrix carrier for the subsequent addition of drugs and excipients; step S2 protects the active drug from photodegradation and removes impurities from the drug solution, thereby ensuring the stability and purity of the drug entering the matrix; step S3 promotes uniform mixing of the drug and the matrix and prevents drug aggregation, thereby ensuring a uniform distribution of drug content in the overall formulation; step S4 ensures that the osmotic pressure regulator, pH regulator, and preservative are uniformly dispersed in the system, thereby avoiding fluctuations in formulation performance due to insufficient dissolution of excipients; step S5 ensures that the formulation reaches the target usage concentration, is compatible with the ocular physiological environment, and stabilizes the gel morphology, thereby improving the suitability and structural stability of the formulation; step S6 ensures the sterility of the formulation, maintains the integrity of the gel network structure, and prevents performance damage during storage and transportation, thereby ensuring that the final product meets the safety and quality requirements of ophthalmic formulations.

[0018] Preferably, in step S1, the stirring process adopts a segmented heating method, first stirring at 45-50℃ for 20-40 minutes, and then continuing to stir at 55-65℃ for 20-40 minutes.

[0019] By adopting the above technical solution, the temperature range of 45-50℃ is suitable for the initial dissolution characteristics of the block copolymer and the slow-release regulator, which can avoid the local agglomeration and uneven dissolution of the raw materials caused by the initial high temperature. Stirring at this temperature for 20-40 minutes first can gradually disperse and initially dissolve the two raw materials. Then, the temperature is raised to 55-65℃, which can further improve the dissolution rate of the raw materials, promote the complete dissolution of the initially dissolved raw materials, and at the same time promote the formation of a more uniform interaction between the molecules of the block copolymer and the slow-release regulator. Stirring for another 20-40 minutes can fully integrate the two raw materials and form a uniformly dispersed matrix system.

[0020] Preferably, in step S2, the solvent used is anhydrous ethanol, and the drug solution is subjected to high-pressure microfluidic treatment at a pressure of 70-140 MPa and a cycle of 3-6 times.

[0021] By adopting the above technical solution, anhydrous ethanol has a good solubility for active drugs such as prostaglandins, which can quickly disperse drug molecules to form a homogeneous solution, ensuring that the active drugs are fully dissolved and avoiding drug precipitation. At the same time, the drug solution is subjected to high-pressure micro-jet treatment. The treatment pressure of 70-140MPa can break up any small aggregates of drugs that may exist through high-pressure shearing and impact force. 3-6 cycles of treatment can gradually enhance the refining effect and avoid particle residue caused by incomplete treatment in a single treatment, thereby further refining the drug particles and promoting the uniform dispersion of drug molecules.

[0022] Preferably, in step S3, the volume ratio of the drug solution added in the three stages is 40-50% in the first stage, 30-40% in the second stage, and 10-20% in the third stage.

[0023] By adopting the above technical solution, the first stage adds a relatively large proportion of drug solution (40-50%), which allows the drug to form a preliminary mixture with the matrix when the matrix solution is in good fluidity. This avoids local drug aggregation caused by insufficient initial drug addition when adding large amounts of drug later, and serves to establish a uniform foundation for subsequent mixing. The second stage adds a medium proportion of drug solution (30-40%), which gradually increases the drug concentration in the system based on the preliminary mixture. Combined with the stirring speed at the corresponding stage, it promotes further integration of the drug and the matrix, serving to connect the mixing stages and deepen drug dispersion. The third stage adds a small proportion of drug solution (10-20%), which allows for precise replenishment of any possible mixing dead zones in the system, ensuring that the remaining drug is completely dispersed in the matrix. This avoids excessive local concentrations caused by adding too much drug in the final stage, and serves to eliminate mixing dead zones and ensure full and uniform drug dispersion.

[0024] Preferably, in step S5, the standing and ripening process includes standing at 35-40°C for 1-3 hours, and then continuing to stand at 40-45°C for 1-3 hours.

[0025] By adopting the above technical solution, the temperature of 35-40℃ is suitable for the initial stabilization of the gel system. Standing at this temperature for 1-3 hours allows the matrix, drug and excipient molecules to gradually form initial interactions, which can fix the basic structure of the system and reduce local concentration fluctuations. Then, the temperature is raised to 40-45℃. The slightly higher temperature can promote molecular movement and further adjust and optimize the initially formed structure, making the gel network more dense and uniform, avoiding performance differences caused by loose structure. Standing for another 1-3 hours can refine the internal structure of the gel and enhance the stability of the system.

[0026] In summary, this application has the following beneficial effects: 1. Since this application uses block copolymers as the main gel matrix and combines them with specific sustained-release modifiers, the block copolymers have an amphiphilic structure that can simultaneously improve drug solubility and form a stable gel network. The sustained-release modifiers can further adjust the gel network density and drug diffusion pathway, resulting in a continuous and stable drug release effect, effectively prolonging the drug's residence time in the eye and improving patient medication compliance.

[0027] 2. In this application, a specific mucosal penetration enhancer is preferably used in combination with high-pressure microfluidic treatment technology. Since the mucosal penetration enhancer can reversibly change the tight junction of corneal epithelial cells, and the high-pressure microfluidic treatment can make the drug particles reach a nanoscale dispersion state, the synergistic effect of the two significantly enhances the drug's permeability in corneal tissue and improves the drug's bioavailability.

[0028] 3. The method of this application optimizes the preparation process, including segmented heating and stirring, staged mixing and gradient cooling. These process steps work together to ensure that each component is fully dissolved and uniformly dispersed, promoting the formation of a stable three-dimensional gel network structure. Therefore, an ophthalmic gel formulation with good physical and chemical stability is obtained, which can maintain the stability of various quality indicators during storage. Attached Figure Description

[0029] Figure 1 This is a flowchart of a method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer, as provided in this application. Detailed Implementation

[0030] The present application will be further described in detail below with reference to embodiments and comparative examples. Unless otherwise specified, the experimental methods used below are conventional methods. Unless otherwise specified, the materials, reagents, methods and instruments used are all conventional materials, reagents, methods and instruments in the art, which can be obtained by those skilled in the art through commercial channels or prepared according to literature methods.

[0031] Technical concept: Existing ophthalmic formulations suffer from unstable drug release and short ocular retention time in long-term treatment of eye diseases, leading to frequent medication use and poor patient compliance. The core reason for this problem lies in the fact that traditional gel matrices are mostly single polymeric materials, lacking amphiphilic structures, making it difficult to simultaneously achieve drug solubility and gel network stability. Furthermore, the synergistic effect between sustained-release modifiers and the matrix is ​​insufficient, hindering precise control of drug diffusion pathways. Simultaneously, the penetration efficiency and stability of drugs in the ocular mucosa are limited by the excipient combination, further affecting the long-term efficacy and reliability of the formulation.

[0032] This technical solution addresses the aforementioned issues through targeted technical means: It selects a block copolymer with an amphiphilic structure as the main gel matrix, which not only improves drug solubility but also constructs a stable three-dimensional gel network; it combines this with a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer as a sustained-release regulator, synergistically regulating the gel network density and drug diffusion pathway with the block copolymer to achieve sustained and stable drug release; simultaneously, it incorporates specific mucosal penetration enhancers and antioxidants to enhance drug mucosal penetration efficiency and ensure stability. The preparation process employs segmented heating pretreatment, gradient stirring mixing, segmented ripening, and gradient cooling to ensure thorough integration of all components, ultimately prolonging drug retention time in the eye, reducing medication frequency, and improving patient compliance.

[0033] Preparation Example 1 The preparation method of polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer is as follows: The raw materials for preparing the block copolymer include: 10.0 g of mono-amino polyethylene glycol with a molecular weight of 2000 g / mol, 15.0 g of N-vinylcaprolactam, 8.0 g of vinyl acetate, 0.12 g of azobisisobutyronitrile, 80 mL of N,N-dimethylformamide, and 200 mL of anhydrous diethyl ether. The specific preparation steps are as follows: Monoamino-terminated polyethylene glycol was added to a 250 mL three-necked flask purged with nitrogen, and N,N-dimethylformamide was added as a solvent. The mixture was stirred in a 60°C oil bath until completely dissolved. Then, N-vinylcaprolactam monomer was added to the system, and high-purity nitrogen was introduced for protection. The temperature was raised to 65°C, and a solution of N,N-dimethylformamide containing azobisisobutyronitrile was slowly added dropwise. The reaction was maintained at 65-68°C for 6 hours to complete the first block polymerization. Next, the reaction system was cooled to 50°C, vinyl acetate monomer was added, and a small amount of azobisisobutyronitrile was added. The temperature was raised to 60°C, and the reaction continued for 8 hours to complete the second block polymerization. After the reaction, the mixture was cooled to room temperature, and the reaction solution was slowly added dropwise to vigorously stirred anhydrous diethyl ether to precipitate a white fibrous solid. The precipitate was collected by filtration through a Buchner funnel, washed three times with fresh diethyl ether to remove unreacted monomers and solvent, and finally dried in a 40°C vacuum drying oven for 24 hours to obtain a white solid target block copolymer.

[0034] The product was then characterized. 1H NMR spectroscopy showed a characteristic peak of methylene in the polyethylene glycol segment at a chemical shift of 3.6 ppm, a characteristic peak of methylene linked to the lactam ring in the polyvinyl caprolactam segment at 4.2-4.5 ppm, and a characteristic peak of methylene linked to the acetoxy group in the polyvinyl acetate segment at 4.8-5.0 ppm, confirming its well-defined block structure. Gel permeation chromatography showed a number-average molecular weight of 12500 g / mol and a molecular weight distribution index of 1.28, further demonstrating the successful synthesis of a structurally regular polyethylene glycol-polyvinyl caprolactam-vinyl acetate block copolymer.

[0035] Preparation Example 2 The preparation method of polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer is as follows: Take 10g of polyethylene glycol with a molecular weight of 2000 and 30g of ε-caprolactone monomer, and add them to a 500mL three-necked flask that has been dried and cooled at 120℃; then add 0.04g of stannous octoate, seal the three-necked flask, and purge the air into the flask with high-purity nitrogen gas for 10 minutes. Then place it in an oil bath and react for 8 hours at 130℃ and 300rpm with stirring.

[0036] After the reaction was completed, the oil bath was closed, and the reaction system was allowed to cool naturally to room temperature. 50 mL of dichloromethane was added to the flask, and the mixture was magnetically stirred until the product was completely dissolved. The resulting solution was slowly poured into 200 mL of diethyl ether pre-cooled to -5 °C while stirring. A white solid precipitated, and the mixture was allowed to stand for 2 hours to allow complete precipitation. The mixture was then filtered through a Buchner funnel lined with a 0.45 μm organic phase filter membrane, and the filter cake was collected. The filter cake was transferred to a vacuum drying oven and dried at 40 °C and -0.09 MPa for 24 hours to remove residual dichloromethane and diethyl ether. Finally, a white flocculent polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer was obtained. Gel permeation chromatography showed that the mass ratio of polycaprolactone segments to polyethylene glycol segments was 3:1.

[0037] The following are the main raw materials and reagents used in the preparation examples, embodiments, and comparative examples, and their sources and specifications are as follows; unless otherwise specified, all reagents are commercially available analytical grade or higher products: 1. Latanoprost was purchased from Shanghai Yuanye Biotechnology Co., Ltd., product number: S61008; 2. Tafluprost was purchased from Gansu Haotian Technology Co., Ltd., CAS: 209860-87-7; 3. Travoprost was purchased from Gansu Haotian Technology Co., Ltd., CAS: 157283-68-6; 4. L-Carnosine was purchased from Jiangsu Congzhong Chemical Co., Ltd., product number: 30541; 5. Chitosan was purchased from Qingdao Boyite Biomaterials Co., Ltd., CAS: 9012-76-4; 6. N-acetylcysteine ​​was purchased from Wuhan Nengren Pharmaceutical Chemical Co., Ltd., product number: 616-91-1; 7. Polyethylene glycol was purchased from Liaoning Kelon Fine Chemical Co., Ltd., CAS: 25322-68-3; 8. ε-caprolactone monomer was purchased from Shanghai Baoyang Baoxin Biotechnology Co., Ltd., product number: BX0226; 9. Dichloromethane was purchased from Shandong Jinyu Chemical Technology Co., Ltd., CAS: 75-09-2.

[0038] Example 1 This application provides an ophthalmic sustained-release gel formulation containing a block copolymer, wherein every 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 30 parts block copolymer; 0.5 parts active drug; 5 parts osmotic pressure regulator; 2.5 parts pH regulator; 0.05 parts preservative; 2.5 parts sustained-release regulator; 1.5 parts mucosal penetration enhancer; 1 part antioxidant; balance is water for injection. The active drug is latanoprost. The slow-release regulator is a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer. Among them, the mucosal penetration enhancer is L-carnosine; The antioxidant is N-acetylcysteine. The osmotic pressure regulator is sodium chloride; The pH adjuster is sodium hydroxide solution.

[0039] The preparation method of the above-mentioned ophthalmic sustained-release gel formulation containing block copolymer includes the following steps: S1. Matrix pretreatment: Polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer and polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer are mixed, and a portion of water for injection is added. The mixture is stirred at 55°C to form a matrix solution. The amount of water for injection added is 40% of the total water volume. The system is kept in a sealed state during the stirring process. The stirring process adopts a segmented heating method, first stirring at 47℃ for 30 minutes, and then stirring at 60℃ for another 30 minutes. S2. Drug processing: The active drug is dissolved in a solvent to form a drug solution. The dissolution process is carried out under light-protected conditions. After dissolution, the solution is pre-filtered through a 0.45μm microporous membrane. The solvent used was anhydrous ethanol, and the drug solution was treated with high-pressure microfluidic jet at a pressure of 105 MPa for 4 cycles. S3. Mixing treatment: The drug solution is added to the matrix solution in three stages and mixed and stirred. The first stage is stirred at 250 rpm for 30 minutes, the second stage is stirred at 350 rpm for 30 minutes, and the third stage is stirred at 450 rpm for 30 minutes. During the mixing process, the temperature is controlled within 50℃ and the viscosity of the system is continuously monitored. The volume ratio of the drug solution added in the three stages is 45% in the first stage, 35% in the second stage, and 20% in the third stage. S4. Addition of excipients: Add osmotic pressure regulator, pH regulator and preservative to the mixture. Add each excipient in order of dissolution difficulty from easy to difficult. Stir each excipient separately for 10 minutes after adding to ensure that it is fully dissolved. S5. System adjustment: Add water for injection to the total volume. First, stir at a low speed of 150 rpm for 15 minutes to make the system uniform. Then, adjust the pH of the system to 6.7 and then let it stand for aging. The process of resting and maturing includes resting at 37°C for 2 hours, and then resting at 42°C for another 2 hours. S6. Terminal processing: The system is filtered through a 0.22μm microporous membrane and cooled from 35℃ to 25℃ at a rate of 0.5℃ / min using a gradient cooling method. The temperature is maintained for 20 minutes, then cooled to 4℃ at a rate of 1℃ / min. Finally, the system is filled under aseptic conditions. The entire cooling process is carried out in a light-proof and vibration-proof environment.

[0040] Example 2 This application provides an ophthalmic sustained-release gel formulation containing a block copolymer, wherein every 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 10 parts block copolymer; 0.01 parts active drug; 1 part osmotic pressure regulator; 0.1 part pH regulator; 0.001 parts preservative; 0.5 parts sustained-release regulator; 0.5 parts mucosal penetration enhancer; 0.1 parts antioxidant; balance is water for injection; The active drug is tafluprost; The slow-release regulator is a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer. Among them, the mucosal penetration enhancer is chitosan; The antioxidant is sodium bisulfite. The osmotic pressure regulator is glucose. The pH adjuster is a dilute hydrochloric acid solution.

[0041] The preparation method of the above-mentioned ophthalmic sustained-release gel formulation containing block copolymer includes the following steps: S1. Matrix pretreatment: Polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer and polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer are mixed, and a portion of water for injection is added. The mixture is stirred at 45°C to form a matrix solution. The amount of water for injection added is 30% of the total water volume. The system is kept in a sealed state during the stirring process. The stirring process adopts a segmented heating method, first stirring at 45℃ for 20 minutes, and then stirring at 55℃ for another 20 minutes; S2. Drug processing: The active drug is dissolved in a solvent to form a drug solution. The dissolution process is carried out under light-protected conditions. After dissolution, the solution is pre-filtered through a 0.45μm microporous membrane. The solvent used was anhydrous ethanol, and the drug solution was treated with high-pressure microfluidic jet at a pressure of 70 MPa for 3 cycles. S3. Mixing treatment: The drug solution is added to the matrix solution in three stages and mixed and stirred. The first stage is stirred at 200 rpm for 20 minutes, the second stage is stirred at 300 rpm for 20 minutes, and the third stage is stirred at 400 rpm for 20 minutes. During the mixing process, the temperature is controlled within the range of 40℃, and the viscosity change of the system is continuously monitored. The volume ratio of the drug solution added in the three stages is 40% in the first stage, 30% in the second stage, and 10% in the third stage. S4. Addition of excipients: Add osmotic pressure regulator, pH regulator and preservative to the mixture. Add each excipient in order of dissolution difficulty from easy to difficult. Stir each excipient separately for 5 minutes after adding to ensure that it is fully dissolved. S5. System adjustment: Add water for injection to the total volume. First, stir at a low speed of 100 rpm for 10 minutes to make the system uniform. Then, adjust the pH of the system to 6.2 and then let it stand for aging. The process of settling and maturing includes settling at 35°C for 1 hour, and then settling at 40°C for another hour. S6. Terminal processing: The system is filtered through a 0.22μm microporous membrane and cooled from 35℃ to 25℃ at a rate of 0.5℃ / min using a gradient cooling method. The temperature is maintained for 20 minutes, then cooled to 4℃ at a rate of 1℃ / min. Finally, the system is filled under aseptic conditions. The entire cooling process is carried out in a light-proof and vibration-proof environment.

[0042] Example 3 This application provides an ophthalmic sustained-release gel formulation containing a block copolymer, wherein every 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 50 parts block copolymer; 1 part active drug; 10 parts osmotic pressure regulator; 5 parts pH regulator; 0.1 part preservative; 5 parts sustained-release regulator; 3 parts mucosal penetration enhancer; 2 parts antioxidant; balance is water for injection; The active drug is travoprost. The slow-release regulator is a polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer. The mucosal penetration enhancer is a mixture of L-carnosine and chitosan; The antioxidant is a mixture of N-acetylcysteine ​​and sodium bisulfite. The osmotic pressure regulator is mannitol. The pH adjuster is phosphate buffer.

[0043] The preparation method of the above-mentioned ophthalmic sustained-release gel formulation containing block copolymer includes the following steps: S1. Matrix pretreatment: Polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer and polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer are mixed, and a portion of water for injection is added. The mixture is stirred at 65°C to form a matrix solution. The amount of water for injection added is 50% of the total water volume. The system is kept in a sealed state during the stirring process. The stirring process adopts a segmented heating method, first stirring at 50℃ for 40 minutes, and then stirring at 65℃ for another 40 minutes. S2. Drug processing: The active drug is dissolved in a solvent to form a drug solution. The dissolution process is carried out under light-protected conditions. After dissolution, the solution is pre-filtered through a 0.45μm microporous membrane. The solvent used was anhydrous ethanol, and the drug solution was treated with high-pressure microfluidic jet at a pressure of 140 MPa for 6 cycles. S3. Mixing treatment: The drug solution is added to the matrix solution in three stages and mixed and stirred. The first stage is stirred at 300 rpm for 40 minutes, the second stage is stirred at 400 rpm for 40 minutes, and the third stage is stirred at 500 rpm for 40 minutes. During the mixing process, the temperature is controlled within 60℃ and the viscosity of the system is continuously monitored. The volume ratio of the drug solution added in the three stages is 50% in the first stage, 40% in the second stage, and 20% in the third stage. S4. Addition of excipients: Add osmotic pressure regulator, pH regulator and preservative to the mixture. Add each excipient in order of increasing solubility. Stir each excipient separately for 15 minutes after adding to ensure it is fully dissolved. S5. System adjustment: Add water for injection to the total volume. First, stir at a low speed of 200 rpm for 20 minutes to make the system uniform. Then, adjust the pH of the system to 7.2 and then let it stand for aging. The process of resting and maturing includes resting at 40°C for 3 hours, and then resting at 45°C for another 3 hours. S6. Terminal processing: The system is filtered through a 0.22μm microporous membrane and cooled from 35℃ to 25℃ at a rate of 0.5℃ / min using a gradient cooling method. The temperature is maintained for 20 minutes, then cooled to 4℃ at a rate of 1℃ / min. Finally, the system is filled under aseptic conditions. The entire cooling process is carried out in a light-proof and vibration-proof environment.

[0044] Example 4 The only difference between this embodiment and Example 1 is that the weight parts of each raw material in every 100 parts by weight of the preparation are adjusted as follows: 20 parts of polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer; 0.3 parts of active drug; 3 parts of osmotic pressure regulator; 1.5 parts of pH regulator; 0.03 parts of preservative; 1.5 parts of polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer; 1.0 part of mucosal penetration enhancer; 0.6 parts of antioxidant; and the balance is water for injection. The preparation process is exactly the same as in Example 1.

[0045] Example 5 The only difference between this embodiment and Example 1 is that the weight parts of each raw material in every 100 parts by weight of the preparation are adjusted as follows: 40 parts of polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer; 0.8 parts of active drug; 8 parts of osmotic pressure regulator; 4.0 parts of pH regulator; 0.08 parts of preservative; 4.0 parts of polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer; 2.5 parts of mucosal penetration enhancer; 1.5 parts of antioxidant; and the balance is water for injection; the preparation process is exactly the same as in Example 1.

[0046] Comparative Example 1 The only difference between this comparative example and Example 1 is that block copolymers are not used; instead, an equal amount of poloxamer 407 is used as the gel matrix. All other components, amounts, and preparation processes are exactly the same as in Example 1. It should be noted that although the block copolymer matrix is ​​replaced with poloxamer 407 in this comparative example, the system still contains the sustained-release regulator polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer.

[0047] Comparative Example 2 The only difference between this comparative example and Example 1 is that block copolymers are not used; instead, an equal amount of carbomer 940 is used as the gel matrix. All other components, amounts, and preparation processes are exactly the same as in Example 1.

[0048] Comparative Example 3 The only difference between this comparative example and Example 1 is that block copolymers are not used; instead, an equal amount of hydroxypropyl methylcellulose is used as the gel matrix. All other components, amounts, and preparation processes are exactly the same as in Example 1.

[0049] Comparative Example 4 The only difference between this comparative example and Example 1 is that the polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer is not used as the sustained-release regulator. Instead, the sustained-release regulator polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer is replaced with an equal amount of hydroxypropyl methylcellulose. All other components, dosages, and preparation processes are exactly the same as in Example 1.

[0050] Comparative Example 5 The only difference between this comparative example and Example 1 is that L-carnosine is not used as a mucosal penetration enhancer. Instead, L-carnosine is replaced with an equal amount of polysorbate 80. All other components, dosages, and preparation processes are exactly the same as in Example 1.

[0051] Comparative Example 6 The only difference between this comparative example and Example 1 is that N-acetylcysteine ​​is not used as an antioxidant; instead, an equal amount of sodium bisulfite is used instead of N-acetylcysteine. All other components, amounts, and preparation processes are exactly the same as in Example 1.

[0052] Comparative Example 7 The only difference between this comparative example and Example 1 is that in step S1, instead of using a segmented heating method, the mixture is directly stirred at 55°C for 60 minutes.

[0053] Comparative Example 8 The only difference between this comparative example and Example 1 is that in step S6, instead of using a gradient cooling method, the filtered gel system is directly placed in a 4°C environment for rapid cooling.

[0054] The performance testing experiments for the ophthalmic sustained-release gel formulations prepared in Examples 1-5 and Comparative Examples 1-8 are designed as follows: I. In vitro drug sustained-release performance test Take 5.0 g each of the ophthalmic sustained-release gel formulations from Examples 1-5 and Comparative Examples 1-8, and place them into dialysis bags with a molecular weight cutoff of 10000 Da. Seal both ends of the dialysis bags and place them in stoppered conical flasks containing 500 mL of artificial tear simulation solution. The artificial tear simulation solution must meet the conditions of pH 7.4 and contain 0.9% sodium chloride and 0.1% calcium chloride. Place the conical flasks in a 37°C constant temperature water bath shaker, and set the shaker speed to 50 rpm to simulate slight eye movements. At sampling time points of 24h, 48h, 120h, 168h, 216h, 240h, 288h, and 312h, respectively, 5 mL of simulation solution is taken from the conical flask as the test sample, and 5 mL of fresh simulation solution is added simultaneously to maintain a constant system volume. The sample was filtered through a 0.22 μm microporous membrane, and the concentration of the active drug in the filtrate was determined using high-performance liquid chromatography (HPLC). The concentration of latanoprost, tafluprost, or travoprost was determined using the appropriate detection method based on the corresponding active drug in the sample. The cumulative drug release rate at each time point was calculated based on the detected concentrations, a drug release curve was plotted, and the drug release half-life was calculated. .

[0055] II. Ocular mucosal permeability test An in vitro rabbit corneal model was used for testing. Healthy New Zealand white rabbits, weighing between 2.0 and 2.5 kg, were selected. After euthanasia, the eyeballs were quickly removed, and the cornea was separated under sterile conditions. The fascia on the epithelial surface and the iris on the endothelial surface were removed. The cornea was fixed between the supply and receiving chambers of a Franz diffusion cell, ensuring that the epithelial surface faced the supply chamber and the endothelial surface faced the receiving chamber. The two chambers were sealed with petroleum jelly to prevent leakage. 30 mL of phosphate buffer preheated to 37°C was added to the receiving chamber. The pH of the phosphate buffer was adjusted to 7.4. A mixture of 95% oxygen and 5% carbon dioxide was simultaneously introduced to maintain corneal activity, and the stirring speed was set to 300 rpm. Take 0.5g of each of the ophthalmic sustained-release gel formulations from Examples 1-5 and Comparative Examples 1-8, and apply them evenly to the corneal epithelial surface of the supply chamber. At sampling time points of 0.5h, 1h, 2h, 3h, and 4h, aspirate 1mL of buffer solution from the receiving chamber as the test sample, and simultaneously add 1mL of fresh buffer solution. After filtering the test sample through a 0.22μm microporous membrane, determine the concentration of the active drug using high-performance liquid chromatography (HPLC). Calculate the drug permeation amount per unit area of ​​cornea and the permeability coefficient. The formula for calculating the permeability coefficient is: Where dQ / dt represents the steady-state drug penetration rate, The initial concentration of the drug in the supply chamber is represented by A, and A represents the effective permeation area of ​​the cornea.

[0056] III. Long-term stability testing of the formulation The ophthalmic sustained-release gel formulations of Examples 1-5 and Comparative Examples 1-8 were respectively packaged into sterile ophthalmic gel-specific packaging bottles. Three replicates of each sample were prepared and stored under accelerated stability conditions and long-term stability conditions, respectively. The accelerated stability conditions were 40℃±2℃ and 75%±5% relative humidity, and the long-term stability conditions were 25℃±2℃ and 60%±10% relative humidity. Sampling and testing were conducted periodically. Under accelerated stability conditions, sampling times were 0 months, 1 month, 2 months, 3 months, and 6 months, and under long-term stability conditions, sampling times were 0 months, 3 months, 6 months, 9 months, and 12 months. The testing indicators include five items: 1. Appearance: Observe whether the preparation exhibits layering, precipitation, discoloration, odor, or other phenomena; 2. pH value: Measure the pH value of the preparation using a precision pH meter and record whether it is within the suitable pH range of 6.0-8.0 for ophthalmic preparations; 3. Viscosity: Measure the viscosity change of the preparation using a rotational viscometer, selecting an appropriate rotor and speed to ensure that the measured value is within 20%-80% of the instrument's range, and record the initial viscosity and viscosity at each time point; 4. Drug content: Determine the content of the active drug in the preparation using high-performance liquid chromatography (HPLC), calculate the content retention rate, which is calculated by dividing the content at each time point by the initial content and then multiplying by 100%; 5. Related substances: Determine the types and contents of related substances such as degradation products in the preparation using HPLC, and calculate the total content of related substances.

[0057] The results of the in vitro drug sustained-release performance test are shown in Table 1.

[0058] Table 1:

[0059] The results of the ocular mucosal permeability test are shown in Table 2.

[0060] Table 2:

[0061] The results of the accelerated stability test are shown in Table 3.

[0062] Table 3:

[0063] Based on Examples 1-5 and Tables 1, 2, and 3, it can be seen that Example 1 performed best in all indicators, proving that the specific ratio did indeed reach the peak of the technical effect; the components produced the best synergistic effect under this specific ratio, which not only ensured the full sustained release of the drug, but also took into account good permeability and stability, thus achieving the optimization of comprehensive performance.

[0064] As can be seen from Examples 1-5 and Comparative Example 1, and Tables 1, 2, and 3, the specific block copolymer matrix of this application can synergistically construct a dense and stable three-dimensional gel network with the sustained-release regulator through intermolecular interactions. This not only ensures the long-term and stable release of the drug, but its good hydrophilicity and film-forming properties also significantly improve the mucosal adhesion and physical stability. In contrast, when Comparative Example 1 was replaced with poloxamer 407, its temperature-triggered gelation mechanism was not compatible with the sustained-release regulator, making it difficult to form the same stable network structure. This resulted in excessively rapid drug release, reduced mucosal penetration efficiency, and decreased long-term storage stability. This demonstrates the irreplaceable nature of the specific matrix of this application in achieving synergistic improvement of multiple performance characteristics.

[0065] Based on Examples 1-5 and Comparative Example 2, and in conjunction with Tables 1, 2, and 3, it can be seen that the block copolymer forms a uniform gel system with the sustained-release regulator through its amphiphilic structure, which supports the sustained-release and penetration effects. Carbomer 940 relies on pH-induced crosslinking, which is different from the mechanism of the block copolymer. This results in a weakened synergistic effect between it and the sustained-release regulator, affecting the regularity of drug release, mucosal penetration efficiency, and storage stability.

[0066] Based on Examples 1-5 and Comparative Example 3, and in conjunction with Tables 1, 2, and 3, it can be seen that the amphiphilic structure of the block copolymer can construct a stable sustained-release network while taking into account mucosal compatibility. Hydroxypropyl methylcellulose is a linear water-soluble polymer that lacks hydrophobic segments, resulting in weak synergy with sustained-release regulators and poor gel network density, leading to excessively rapid drug release, weak mucosal adhesion, easy stratification during long-term storage, and low viscosity retention.

[0067] Based on Examples 1-5 and Comparative Example 4, and in conjunction with Tables 1, 2, and 3, it can be seen that the polycaprolactone-PEG-polycaprolactone block copolymer can match the block copolymer structure and construct a gradient release network. When replaced with hydroxypropyl methylcellulose, due to the lack of block characteristics, the synergistic effect with the block copolymer decreases, drug release accelerates, gel network stability decreases, and the sustained-release effect and storage stability are affected.

[0068] Based on Examples 1-5 and Comparative Example 5, and in conjunction with Tables 1, 2, and 3, it can be seen that L-carnosine can improve the corneal environment and enhance permeability, and is compatible with the gel system; polysorbate 80 has a different mechanism of action and acts differently on the corneal epithelium, resulting in a decrease in permeability. Although it has little interference with the sustained-release structure, it still indirectly affects the uniformity of drug permeation.

[0069] Based on Examples 1-5 and Comparative Example 6, and in conjunction with Tables 1, 2, and 3, it can be seen that N-acetylcysteine ​​can specifically protect prostaglandin drugs and reduce degradation; sodium bisulfite has a different antioxidant mechanism and strength, resulting in a slightly reduced protective effect on the drug, leading to a decrease in drug content retention rate and a slight increase in related substances, which indirectly affects the duration of drug efficacy.

[0070] Based on Examples 1-5 and Comparative Example 7, and in conjunction with Tables 1, 2, and 3, it can be seen that segmented heating allows the block copolymer and the sustained-release regulator to fully dissolve and mix, forming a uniform network. Direct constant-temperature stirring easily leads to uneven mixing, network defects, drug release fluctuations, poor penetration consistency, and decreased viscosity retention rate during long-term storage.

[0071] Based on Examples 1-5 and Comparative Example 8, and in conjunction with Tables 1, 2, and 3, it can be seen that gradient cooling helps the gel form an orderly and stable network, supporting sustained release and storage stability; direct rapid cooling leads to uneven stress in the system, the formation of pores in the network, accelerated drug release, and easy stratification and viscosity fluctuations during long-term storage, affecting overall performance.

[0072] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. An ophthalmic sustained-release gel formulation containing a block copolymer, characterized in that: Each 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 10-50 parts of polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer; 0.01-1 part of active pharmaceutical ingredient; 1-10 parts of osmotic pressure regulator; 0.1-5 parts of pH regulator; 0.001-0.1 parts of preservative; 0.5-5 parts of polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer; 0.5-3 parts of mucosal penetration enhancer; 0.1-2 parts of antioxidant; the balance being water for injection.

2. The ophthalmic sustained-release gel formulation containing a block copolymer according to claim 1, characterized in that: Each 100 parts by weight of the formulation is made from the following raw materials in parts by weight: 30 parts polyethylene glycol copolyvinylcaprolactam-vinyl acetate block copolymer; 0.5 parts active pharmaceutical ingredient; 5 parts osmotic pressure regulator; 2.5 parts pH regulator; 0.05 parts preservative; 2.5 parts polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer; 1.5 parts mucosal penetration enhancer; 1 part antioxidant; the balance being water for injection.

3. The ophthalmic sustained-release gel formulation containing a block copolymer according to claim 1, characterized in that: The active drug is selected from at least one of latanoprost, tafluprost, and travoprost.

4. The ophthalmic sustained-release gel formulation containing a block copolymer according to claim 1, characterized in that: The mucosal penetration enhancer is selected from at least one of L-carnosine, chitosan and its derivatives.

5. The ophthalmic sustained-release gel formulation containing a block copolymer according to claim 1, characterized in that: The antioxidant is selected from at least one of N-acetylcysteine ​​and sodium bisulfite.

6. A method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer, characterized in that, An ophthalmic sustained-release gel formulation containing a block copolymer as described in any one of claims 1-5, comprising the following steps: S1. Matrix pretreatment: Polyethylene glycol copolyvinyl caprolactam-vinyl acetate block copolymer and polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer are mixed, and a portion of water for injection is added. The mixture is stirred at 45-65℃ to form a matrix solution. The amount of water for injection added is 30%-50% of the total water volume. The system is kept in a sealed state during the stirring process. S2. Drug processing: The active drug is dissolved in a solvent to form a drug solution. The dissolution process is carried out under light-protected conditions. After dissolution, the solution is pre-filtered through a 0.45μm microporous membrane. S3. Mixing treatment: The drug solution is added to the matrix solution in three stages and mixed and stirred. In the first stage, the stirring speed is 200-300 rpm for 20-40 minutes; in the second stage, the stirring speed is 300-400 rpm for 20-40 minutes; and in the third stage, the stirring speed is 400-500 rpm for 20-40 minutes. During the mixing process, the temperature is controlled within the range of 40-60℃, and the viscosity change of the system is continuously monitored. S4. Addition of excipients: Add osmotic pressure regulator, pH regulator and preservative to the mixture. Add each excipient in order of dissolution difficulty from easy to difficult. Stir each excipient separately for 5-15 minutes after adding to ensure that it is fully dissolved. S5. System adjustment: Add water for injection to the total volume. First, stir at a low speed of 100-200 rpm for 10-20 minutes to make the system uniform. Then, adjust the pH of the system to 6.2-7.2 and then let it stand for aging. S6. Terminal processing: The system is filtered through a 0.22μm microporous membrane and cooled from 35℃ to 25℃ at a rate of 0.5℃ / min using a gradient cooling method. The temperature is maintained for 20 minutes, then cooled to 4℃ at a rate of 1℃ / min. Finally, the system is filled under aseptic conditions. The entire cooling process is carried out in a light-proof and vibration-proof environment.

7. The method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer according to claim 6, characterized in that: In step S1, the stirring process adopts a segmented heating method. First, the stirring is carried out at 45-50℃ for 20-40 minutes, and then the stirring is continued at 55-65℃ for 20-40 minutes.

8. The method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer according to claim 6, characterized in that: In step S2, the solvent used is anhydrous ethanol, and the drug solution is treated with high-pressure microfluidic jet at a pressure of 70-140 MPa for 3-6 cycles.

9. The method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer according to claim 6, characterized in that: In step S3, the volume ratio of the drug solution added in the three stages is 40-50% in the first stage, 30-40% in the second stage, and 10-20% in the third stage.

10. The method for preparing an ophthalmic sustained-release gel formulation containing a block copolymer according to claim 6, characterized in that: In step S5, the standing and ripening process includes standing at 35-40℃ for 1-3 hours, and then continuing to stand at 40-45℃ for 1-3 hours.

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