A pharmaceutical preparation containing oxybuprocaine hydrochloride and a method for preparing the same

Abstract

The application provides a pharmaceutical preparation containing oxyburocaine hydrochloride and a preparation method of the pharmaceutical preparation, and steps of the method comprise the following steps: adding N,N-dimethylformamide and an alkaline accelerator to 3-hydroxy-4-nitrobenzoic acid methyl ester to obtain 3-butoxy-4-nitrobenzoic acid; adding toluene and the alkaline accelerator to the 3-butoxy-4-nitrobenzoic acid, and adding 2-diethylamino chloroethane hydrochloride to obtain 3-butoxy-4-nitrobenzoic acid-2-(diethylamino) ethyl ester hydrochloride; continuously adding toluene, the alkaline accelerator and a palladium-carbon catalyst to obtain crude oxyburocaine, and cooling, crystallization, filtration and drying of the crude oxyburocaine to obtain oxyburocaine hydrochloride; adding a buffer aqueous phase and a clathrate agent to the oxyburocaine hydrochloride to obtain the pharmaceutical preparation containing oxyburocaine hydrochloride. The buffer aqueous phase, the clathrate agent, pH and osmotic pressure adjustment, filtration, sterile filling and low-temperature curing are combined to improve the irritability and stability of the oxyburocaine hydrochloride preparation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a pharmaceutical preparation containing oxybuprocaine hydrochloride and its preparation method. Background Technology

[0002] In medical applications, without anesthesia during animal examinations, drug administration, sampling, or modeling, animals will experience significant pain, reflexive blinking, struggling, and tearing. This not only increases animal suffering but also affects the accuracy of the procedure. Obuprocaine hydrochloride, a pharmaceutical preparation containing oxybuprocaine hydrochloride, is used as a local anesthetic for the ocular surface. When instilled onto the corneal and conjunctival surfaces, it acts directly on the sensory nerve endings of the cornea, reversibly blocking voltage-gated sodium channels and inhibiting the generation and conduction of nerve impulses, thereby quickly reducing ocular surface pain, irritation, and discomfort during examinations. It is commonly used for surface anesthesia before ophthalmic examinations and procedures, and can also be used for certain short-term ocular surface pain control scenarios.

[0003] Obubucaine hydrochloride is a local anesthetic for the ocular surface. When directly prepared into a regular aqueous solution, the free concentration of the drug on the ocular surface is relatively high, which can easily cause significant irritation to the cornea and conjunctiva upon instillation. At the same time, ophthalmic preparations have high requirements for pH, osmotic pressure, clarity, and sterility. Obubucaine hydrochloride is more likely to experience insufficient stability, strong irritation, and poor compatibility with the ocular surface environment during storage and use. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a pharmaceutical preparation containing oxybuprocaine hydrochloride and its preparation method, which aims to solve the problems that oxybuprocaine hydrochloride is prone to strong irritation and insufficient stability of the drug solution due to the sensitivity of the eye's physiological environment.

[0005] To solve the above-mentioned technical problems, the present invention is implemented as follows: The present invention proposes a method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride, the steps of which include: S1. N,N-dimethylformamide and an alkaline promoter were added to methyl 3-hydroxy-4-nitrobenzoate. After stirring, an alkylating agent was added, and the reaction was carried out at a preset temperature. After the solvent was evaporated, alkaline solution and hydrochloric acid were added in sequence to carry out the reaction. After filtration and drying, 3-butoxy-4-nitrobenzoic acid was obtained. S2. Toluene and an alkaline accelerator were added to 3-butoxy-4-nitrobenzoic acid, and after stirring, 2-diethylaminochloroethane hydrochloride was added. The reaction was carried out at a preset temperature, cooled and filtered, and then an acid-releasing agent was added. The filtrate was then post-treated to obtain 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride. S3. Toluene and an alkaline promoter were added to 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride for alkalization treatment. After extraction, palladium on carbon catalyst was added, and a reduction reaction was carried out under hydrogen conditions. After crystallization, filtration and drying, crude oxybuprocaine was obtained. Toluene and anhydrous ethanol were added to the crude oxybuprocaine, and the mixture was heated to reflux to dissolve and hot filtered. After cooling to crystallize, filtration and drying, oxybuprocaine hydrochloride was obtained. S4. Add a buffer aqueous phase and an inclusion agent to oxybuprocaine hydrochloride, adjust the pH and osmotic pressure, and then perform aseptic filling and low-temperature curing to obtain a pharmaceutical preparation containing oxybuprocaine hydrochloride.

[0006] In some embodiments of the present invention, step S1 includes: S1.1 Add methyl 3-hydroxy-4-nitrobenzene and N,N-dimethylformamide, wherein the mass of N,N-dimethylformamide is 6 to 12 times that of methyl 3-hydroxy-4-nitrobenzene. Then add an alkaline accelerator that has been dried at 120°C for 2 to 4 hours, wherein the amount added is 1.2 to 2.0 times the molar mass of methyl 3-hydroxy-4-nitrobenzene. Start stirring and pre-activate at 20 to 30°C for 20 to 40 minutes. S1.2 Add alkylating agent at 20-30℃. The amount of alkylating agent added is 1.05-1.30 times the molar amount of methyl 3-hydroxy-4-nitrobenzene. Control the addition time to 30-90 min. After the addition is completed, raise the temperature to 80-90℃ and keep it at the temperature for 4-8 h. Take a sample every 1-2 h during the reaction until the residual amount of methyl 3-hydroxy-4-nitrobenzene drops to the preset range and the reaction ends. S1.3 After the reaction is complete, N,N-dimethylformamide is distilled off under reduced pressure at -0.08 to -0.095 MPa. The temperature is controlled at 55 to 75°C during the distillation process. After the residual amount of N,N-dimethylformamide is reduced to the preset range, 1.0 to 2.5 mol / L of alkaline solution is added. The amount of alkaline solution added is 1.1 to 1.8 times the theoretical molar amount of methyl ester. The reaction is continued at 45 to 65°C for 1 to 3 hours. S1.4 After the reaction is complete, the temperature is lowered to 10-25℃, and then 15%-25% hydrochloric acid solution is added dropwise for acidification to lower the pH to 1.5-2.5. At the same time, the temperature is lowered to 5-15℃ and kept at this temperature for aging for 1-3 hours to induce crystallization. S1.5 After crystallization, the filter cake is first washed with purified water at 5-15℃ 1-3 times, and then washed with 10%-30% volume fraction of low temperature ethanol aqueous solution 1-2 times. After washing, the filter cake is placed in vacuum drying at 40-55℃ and -0.06--0.09MPa for 6-12 hours to obtain 3-butoxy-4-nitrobenzoic acid.

[0007] In some embodiments of the present invention, in step S1, the alkaline accelerator includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide; the alkylating agent includes at least one of bromobutane, chlorobutane, iodobutane, p-toluenesulfonate, n-butyl methanesulfonate, and di-n-butyl sulfate; and the alkaline solution includes at least one of aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution, aqueous sodium bicarbonate solution, and ammonia solution.

[0008] In some embodiments of the present invention, step S2 includes: S2.1 Add toluene to 3-butoxy-4-nitrobenzoic acid, the amount of toluene being 4 to 10 times the mass of 3-butoxy-4-nitrobenzoic acid. Add alkaline accelerator that has been dried at 100 to 130°C for 2 to 6 hours, the amount of which is 1.0 to 2.5 times the molar mass of 3-butoxy-4-nitrobenzoic acid. Start stirring and introduce a small amount of nitrogen for protection. Pre-stir at 25 to 40°C for 20 to 50 minutes. S2.2 Add 2-diethylaminochloroethane hydrochloride at 25-35℃. The amount of 2-diethylaminochloroethane hydrochloride added is 1.05-1.50 times the molar amount of 3-butoxy-4-nitrobenzoic acid. Control the addition time to 30-120 min. Maintain the stirring speed at 150-400 rpm during the addition process. After the addition is completed, continue stirring for 20-40 min. S2.3 After stirring, heat to 100-115℃ and reflux for 4-10 hours. Separate water continuously using a water separator. Take a sample every 1-2 hours during the reaction until the residual amount of 3-butoxy-4-nitrobenzoic acid drops to the preset range and the reaction ends. S2.4 After the reaction is complete, cool to 45-70℃ and perform hot filtration to obtain a clear filtrate. Add anhydrous ethanol to the clear filtrate, the amount of anhydrous ethanol added is 10%-40% of the mass of the clear filtrate. After stirring evenly, add an acid-releasing agent dropwise at 20-35℃. The amount of acid-releasing agent added is 0.9-1.2 times the molar amount of 2-diethylaminochloroethane hydrochloride. Control the dropping time to 30-90 min. During the dropping process, maintain the temperature not higher than 35℃. After the dropping is completed, continue the reaction for 0.5-2 h. S2.5 After the reaction is complete, the temperature is lowered to 0-10℃ and kept at this temperature for aging for 1-4 hours to induce crystallization. After crystallization, the slurry is filtered and the filter cake is washed 1-3 times with a mixture of low-temperature toluene and low-temperature anhydrous ethanol. After washing, the filter cake is placed in a vacuum dryer at 30-45℃ and -0.06--0.09MPa for 4-10 hours to obtain 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride.

[0009] In some embodiments of the present invention, in step S2, the alkaline promoter includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide, and the acid-releasing agent includes at least one of acetyl chloride, propionyl chloride, butyryl chloride, oxalyl chloride, and thionyl chloride.

[0010] In some embodiments of the present invention, step S3 includes: S3.1 Add toluene and purified water to 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. The amount of toluene added is 4 to 10 times the mass of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride, and the amount of purified water added is 1 to 4 times the mass of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. Then add an alkaline accelerator. The amount of alkaline accelerator added is 1.0 to 2.5 times the molar amount of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. Stir at 20 to 35°C for 0.5 to 2 hours. S3.2 After stirring, centrifuge to separate the organic phase and the aqueous phase. Then, use toluene to perform 1 to 3 additional extractions on the aqueous phase, with each addition of toluene being 10% to 40% of the initial amount. After combining the organic phases, stir at 25 to 40°C for 10 to 30 minutes, and then dehydrate and filter to obtain a clear organic phase. S3.3 Under nitrogen protection, add palladium on carbon catalyst to the clear organic phase. The amount of palladium on carbon catalyst added is 2% to 10% of the mass of the clear organic phase. After the addition is completed, replace with nitrogen 1 to 3 times, and then replace with hydrogen 1 to 3 times. Then control the system temperature at 20 to 40°C and the hydrogen pressure at 0.1 to 0.6 MPa. S3.4. Introduce hydrogen gas to carry out the reduction reaction for 2-6 hours. During the reaction, control the stirring speed at 200-600 rpm. After the reaction is completed, stop the hydrogen supply and replace the residual hydrogen gas in the reactor with nitrogen gas. Cool the reaction liquid to 20-35℃ and then filter it to remove the palladium on carbon catalyst. Wash the filter cake with toluene 1-2 times. Combine the filtrates to obtain a clear reduced liquid. S3.5 Add anhydrous ethanol to the clarified reducing solution. The amount of anhydrous ethanol added is 10% to 50% of the mass of the clarified reducing solution. After the addition is completed, continue stirring for 0.5 to 2 hours and induce crystallization at 10 to 25°C. Then, further cool down to 0 to 10°C and keep it at that temperature for 1 to 4 hours to obtain crude oxybuprocaine crystal slurry. S3.6. The crude oxybuprocaine slurry is filtered and the filter cake is washed 1 to 3 times with low-temperature anhydrous ethanol or a mixture of low-temperature toluene and anhydrous ethanol. After washing, the filter cake is pre-dried at 25 to 40°C and -0.05 to -0.09 MPa for 2 to 8 hours to obtain crude oxybuprocaine. S3.7 Add toluene and anhydrous ethanol to crude oxybuprocaine. The amount of toluene added is 2 to 8 times the mass of crude oxybuprocaine, and the amount of anhydrous ethanol added is 1 to 6 times the mass of crude oxybuprocaine. Heat to 70 to 95°C and reflux to dissolve until a clear solution is formed. S3.8. Perform hot filtration at 70–90℃, then cool the filtrate to 35–50℃ and keep it at that temperature for 0.5–1.5 h, then continue to cool it to 0–10℃ and keep it at that temperature for 1–4 h to induce crystallization. After crystallization, filter the crystal slurry by vacuum filtration, and wash the filter cake 1–3 times with a mixture of low-temperature toluene and anhydrous ethanol or low-temperature anhydrous ethanol. After washing, place the filter cake under vacuum drying at 30–50℃ and -0.06–-0.09 MPa for 6–12 h to obtain oxybuprocaine hydrochloride.

[0011] In some embodiments of the present invention, in step S3, the alkaline promoter includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide, and the palladium-on-carbon catalyst includes at least one of 5% palladium-on-carbon catalyst, 10% palladium-on-carbon catalyst, 15% palladium-on-carbon catalyst, 20% palladium-on-carbon catalyst, wet palladium-on-carbon catalyst, and dry palladium-on-carbon catalyst.

[0012] In some embodiments of the present invention, step S4 includes: S4.1 Stir and mix the buffer component and the osmosis regulating component, controlling the stirring speed at 100-300 rpm, and stir for 10-40 minutes to form a buffer aqueous phase; S4.2 Add oxybuprocaine hydrochloride to the buffer aqueous phase. The amount of oxybuprocaine hydrochloride added is 0.20% to 0.50% of the buffer aqueous phase. Control the temperature at 10 to 25°C and the stirring speed at 150 to 350 rpm. Stir for 10 to 30 minutes to obtain the drug solution. S4.3 Add an inclusion agent to the drug solution. The amount of inclusion agent added is 2 to 10 times the mass of oxybuprofen hydrochloride. Control the system temperature at 15 to 30°C and the stirring speed at 150 to 400 rpm. Continue stirring for 0.5 to 3 hours. S4.4 Continue to add the repair auxiliary components, control the temperature at 4-10℃, stir and mix for 0.5-2 hours, adjust the pH and osmotic pressure, control the pH at 6.4-7.2, after adjustment, let it stand at 4-15℃ for 10-60 minutes to degas, and obtain the final solution; S4.5. The final solution is pre-filtered through a 0.45μm filter membrane and then filtered through a 0.22μm filter membrane. It is then aseptically filled and sealed. After filling, it is placed at 2-8℃ for 12-72 hours to mature at low temperature to obtain a pharmaceutical preparation containing oxybuprocaine hydrochloride.

[0013] In some embodiments of the present invention, in step S4, the buffering component includes at least one of sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, citric acid, and sodium citrate; the osmotic conditioning component includes at least one of sodium chloride, mannitol, glucose, trehalose, and sorbitol; the inclusion agent includes at least one of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, and γ-cyclodextrin; and the repair auxiliary component includes at least one of recombinant human epidermal growth factor, sodium hyaluronate, trehalose, carboxymethyl chitosan, hydroxypropyl methylcellulose, and polyvinyl alcohol.

[0014] This invention provides a pharmaceutical preparation containing oxybuprocaine hydrochloride, which is prepared by the method described above for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride.

[0015] In some embodiments of the present invention, the pharmaceutical preparation includes oxybuprocaine hydrochloride, a buffer component, an osmosis-regulating component, an inclusion agent, and a repair-enhancing component; wherein... Obuprocaine hydrochloride is used for local anesthesia of the ocular surface to relieve pain in the cornea and conjunctiva. Buffer components are used to control the pH stability of pharmaceutical preparations; Osmotic adjustment components are used to adjust the osmotic pressure of pharmaceutical preparations to make it close to the osmotic pressure of tears; Inclusion agents are used to form inclusion systems with oxybuprocaine hydrochloride, thereby improving the stability of oxybuprocaine hydrochloride in formulations; The repair and auxiliary components are used to improve the retention of the medication on the ocular surface.

[0016] Compared with the prior art, the pharmaceutical preparation containing oxybuprocaine hydrochloride and its preparation method in this invention have the following advantages: This step addresses the issues of strong irritation and insufficient stability of oxabucaine hydrochloride when directly formulated by adding a buffer aqueous phase and an inclusion agent to oxabucaine hydrochloride, further adjusting the pH and osmotic pressure, and then performing aseptic filling and low-temperature curing. The buffer aqueous phase, composed of buffering and osmotic-adjusting components, provides a more stable liquid environment for the formulation system. The inclusion agent, when present with oxabucaine hydrochloride, places the oxabucaine hydrochloride in a more suitable state for formulation. Furthermore, by controlling the pH at 6.4–7.2 and adjusting the osmotic pressure, the resulting system is more suitable for ophthalmic formulations. Simultaneously, the final solution undergoes pre-filtration through a 0.45 μm filter and filtration through a 0.22 μm filter before aseptic filling and sealing, reducing the adverse effects of impurities and contamination on the formulation quality. After filling, low-temperature curing at 2–8°C for 12–72 hours further stabilizes the system. Thus, this step utilizes the combination of technical features such as buffered aqueous phase, encapsulating agent, pH and osmotic pressure adjustment, filtration, aseptic filling, and low-temperature curing to improve the irritation and stability issues of oxybuprocaine hydrochloride formulations. Attached Figure Description

[0017] Figure 1 This is a schematic flowchart of a method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride in one embodiment of the present invention. Figure 2 This is a reaction mechanism diagram of the reduction reaction between palladium on carbon catalyst and hydrogen in one embodiment of the present invention; Figure 3 This is a schematic flowchart of step S4 of a method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride in one embodiment of the present invention. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0019] Please refer to Figure 1 This invention proposes a method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride, the steps of which include: S1. N,N-dimethylformamide and an alkaline accelerator are added to methyl 3-hydroxy-4-nitrobenzoate. After stirring, an alkylating agent is added, and the reaction is carried out at a preset temperature. After the solvent is evaporated, an alkaline solution and hydrochloric acid are added sequentially for further reaction. After filtration and drying, 3-butoxy-4-nitrobenzoic acid is obtained. The alkaline accelerator includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide. The alkylating agent includes at least one of bromobutane, chlorobutane, iodobutane, n-butyl p-toluenesulfonate, n-butyl methanesulfonate, and di-n-butyl sulfate. The alkaline solution includes at least one of aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution, aqueous sodium bicarbonate solution, and ammonia solution.

[0020] Step S1 includes: S1.1 Add methyl 3-hydroxy-4-nitrobenzene and N,N-dimethylformamide, where N,N-dimethylformamide is 6 to 12 times the mass of methyl 3-hydroxy-4-nitrobenzene. Then add an alkaline accelerator that has been dried at 120°C for 2 to 4 hours, in an amount 1.2 to 2.0 times the molar mass of methyl 3-hydroxy-4-nitrobenzene. Start stirring and pre-activate at 20 to 30°C for 20 to 40 minutes.

[0021] The addition of N,N-dimethylformamide in step S1.1 primarily serves to fully disperse or dissolve methyl 3-hydroxy-4-nitrobenzene, ensuring more uniform contact between the subsequent alkaline accelerator and the raw material. The alkaline accelerator, such as anhydrous potassium carbonate, anhydrous sodium carbonate, or cesium carbonate, is used after drying to reduce moisture in the system, preventing moisture from weakening the alkaline effect or interfering with subsequent alkylation reactions. During pre-activation, the alkaline accelerator facilitates the formation of more reactive phenolic hydroxyl groups in methyl 3-hydroxy-4-nitrobenzene, thus laying the foundation for subsequent substitution reactions with the alkylating agent.

[0022] S1.2 Add alkylating agent at 20-30℃. The amount of alkylating agent added is 1.05-1.30 times the molar amount of methyl 3-hydroxy-4-nitrobenzene. Control the addition time to 30-90 min. After the addition is completed, raise the temperature to 80-90℃ and keep it at this temperature for 4-8 h. Take a sample every 1-2 h during the reaction until the residual amount of methyl 3-hydroxy-4-nitrobenzene drops to the preset range and the reaction ends.

[0023] In step S1.2, an alkylating agent, such as bromobutane, chlorobutane, or iodobutane, is added. Its essential function is to introduce a n-butyl group into the raw material molecule, converting the original hydroxyl group into a butoxy group. By controlling the addition rate and amount of the alkylating agent, excessively high local concentrations can be avoided, which could lead to an increase in side reactions. By reacting within a temperature range of 80–90°C, the reaction rate can be guaranteed while maintaining reaction stability.

[0024] S1.3 After the reaction is complete, N,N-dimethylformamide is distilled off under reduced pressure at -0.08 to -0.095 MPa. The temperature is controlled at 55 to 75°C during the distillation process. After the residual amount of N,N-dimethylformamide is reduced to the preset range, 1.0 to 2.5 mol / L of alkaline solution is added. The amount of alkaline solution added is 1.1 to 1.8 times the theoretical molar amount of methyl ester. The reaction is continued at 45 to 65°C for 1 to 3 hours.

[0025] In step S1.3, N,N-dimethylformamide is first distilled off under reduced pressure, which removes the high-boiling solvent from the previous alkylation system, facilitating the subsequent introduction of alkaline solution into the system for methyl ester hydrolysis. After the addition of alkaline solution, the 3-butoxy-substituted methyl benzoate intermediate undergoes hydrolysis under alkaline conditions, converting the methyl ester group to a carboxylate. The alkaline solution used, such as aqueous sodium hydroxide, potassium hydroxide, or sodium carbonate solution, provides the necessary alkaline environment for hydrolysis.

[0026] S1.4 After the reaction is complete, the temperature is lowered to 10-25℃, and then 15%-25% hydrochloric acid solution is added dropwise for acidification to lower the pH to 1.5-2.5. At the same time, the temperature is lowered to 5-15℃ and kept at this temperature for aging for 1-3 hours to induce crystallization.

[0027] Acidification with hydrochloric acid solution in step S1.4 aims to convert the carboxylate formed in step S1.3 back into free carboxylic acid and promote the precipitation of 3-butoxy-4-nitrobenzoic acid crystals at a lower temperature. Maintaining the pH between 1.5 and 2.5 ensures sufficient precipitation of the target product from the liquid phase while minimizing the adverse effects of excessive alkali residue on product purity and color. Lowering the temperature and maintaining an aging temperature promotes crystal nucleation and growth, resulting in a more stable precipitated solid.

[0028] S1.5 After crystallization, the filter cake is first washed with purified water at 5-15℃ 1-3 times, and then washed with 10%-30% volume fraction of low temperature ethanol aqueous solution 1-2 times. After washing, the filter cake is placed in vacuum drying at 40-55℃ and -0.06--0.09MPa for 6-12 hours to obtain 3-butoxy-4-nitrobenzoic acid.

[0029] In step S1.5, the filter cake is first washed with low-temperature purified water, mainly to remove inorganic salts, residual acids, and soluble polar impurities. It is then washed with a low-temperature ethanol-water solution to further remove small amounts of organic impurities and residual solvents. Finally, vacuum drying removes moisture and volatile residues from the filter cake, yielding a relatively stable 3-butoxy-4-nitrobenzoic acid product.

[0030] S2. Toluene and an alkaline accelerator are added to 3-butoxy-4-nitrobenzoic acid. After stirring, 2-diethylaminochloroethane hydrochloride is added, and the reaction is carried out at a preset temperature. After cooling and filtration, an acid-releasing agent is added, and the filtrate is post-treated to obtain 2-(diethylamino)ethyl 3-butoxy-4-nitrobenzoic acid hydrochloride. The acid-releasing agent includes at least one of acetyl chloride, propionyl chloride, butyryl chloride, oxaloyl chloride, and thionyl chloride.

[0031] Step S2 includes: S2.1 Add toluene to 3-butoxy-4-nitrobenzoic acid, the amount of toluene being 4 to 10 times the mass of 3-butoxy-4-nitrobenzoic acid. Add an alkaline accelerator that has been dried at 100 to 130°C for 2 to 6 hours, the amount of which is 1.0 to 2.5 times the molar mass of 3-butoxy-4-nitrobenzoic acid. Start stirring and introduce a small amount of nitrogen for protection. Pre-stir at 25 to 40°C for 20 to 50 minutes.

[0032] The addition of toluene in S2.1 primarily serves to provide a suitable organic reaction environment for subsequent reflux and dehydration operations, allowing 3-butoxy-4-nitrobenzoic acid to participate in subsequent reactions within a relatively stable system. The addition of dried basic accelerator helps reduce moisture in the system, preventing moisture from affecting subsequent side-chain introduction reactions. Simultaneously, the basic accelerator neutralizes the hydrochloric acid portion of the subsequently added 2-diethylaminochloroethane hydrochloride. Pre-stirring and a trace nitrogen atmosphere ensure sufficient contact between the raw materials, solvent, and basic accelerator, and reduce the adverse effects of moisture and oxygen in the air on the system.

[0033] S2.2 Add 2-diethylaminochloroethane hydrochloride at 25-35℃. The amount of 2-diethylaminochloroethane hydrochloride added is 1.05-1.50 times the molar amount of 3-butoxy-4-nitrobenzoic acid. Control the addition time to 30-120 min. Maintain the stirring speed at 150-400 rpm during the addition process. After the addition is completed, continue stirring for 20-40 min.

[0034] The addition of 2-diethylaminochloroethane hydrochloride to S2.2 serves to introduce a 2-diethylaminoethyl side chain into the 3-butoxy-4-nitrobenzoic acid structure. Controlling its addition rate and amount allows it to gradually complete the dehydrochlorination and participate in the reaction in the presence of an alkaline promoter, avoiding excessively high local concentrations that could lead to increased side reactions. Continued stirring helps ensure sufficient contact between the 2-diethylaminochloroethane hydrochloride and the raw materials and alkali in the system, laying the foundation for the subsequent high-temperature reflux reaction.

[0035] S2.3 After stirring, heat to 100-115℃ and reflux for 4-10 hours. Separate water continuously using a water separator. Take samples every 1-2 hours during the reaction until the residual amount of 3-butoxy-4-nitrobenzoic acid drops to the preset range and the reaction ends.

[0036] In step S2.3, the mixture is heated to 100–115°C and refluxed, with water continuously separated using a water separator. This separation primarily promotes the reaction of 3-butoxy-4-nitrobenzoic acid with the diethylaminoethyl-containing component towards the target ester structure. Toluene is suitable for reflux within this temperature range, and the water separator helps remove moisture from the system, shifting the reaction equilibrium towards the product phase. Regular sampling during the reaction allows for timely monitoring of 3-butoxy-4-nitrobenzoic acid consumption, preventing insufficient reaction or overheating.

[0037] S2.4 After the reaction is complete, cool the temperature to 45-70℃ and perform hot filtration to obtain a clear filtrate. Add anhydrous ethanol to the clear filtrate, with the amount of anhydrous ethanol being 10%-40% of the mass of the clear filtrate. After stirring evenly, add an acid-releasing agent dropwise at 20-35℃. The amount of acid-releasing agent added is 0.9-1.2 times the molar amount of 2-diethylaminochloroethane hydrochloride. Control the dropwise addition time to 30-90 min. Maintain the temperature not higher than 35℃ during the dropwise addition. After the dropwise addition is completed, continue the reaction for 0.5-2 h.

[0038] In step S2.4, initial cooling and hot filtration primarily remove inorganic salts, unreacted basic promoters, and insoluble impurities from the system, yielding a relatively clean and clear filtrate. Anhydrous ethanol is then added to create a low-moisture environment suitable for subsequent salt formation. The addition of acid-releasing agents such as acetyl chloride, propionyl chloride, butyryl chloride, oxaloyl chloride, or thionyl chloride allows for the in-situ release of acidic components within the anhydrous ethanol system, converting the tertiary amine structure in the target intermediate into its corresponding hydrochloride salt form. Controlling the dropping temperature and time helps prevent excessively high local acidity, which could lead to oil separation, clumping, or impurity entrainment.

[0039] S2.5 After the reaction is complete, the temperature is lowered to 0-10℃ and kept at this temperature for aging for 1-4 hours to induce crystallization. After crystallization, the slurry is filtered and the filter cake is washed 1-3 times with a mixture of low-temperature toluene and low-temperature anhydrous ethanol. After washing, the filter cake is placed in a vacuum dryer at 30-45℃ and -0.06--0.09MPa for 4-10 hours to obtain 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride.

[0040] The cooling and aging process in S2.5 primarily serves to gradually precipitate 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride from the reaction solution, and low-temperature aging promotes stable crystal growth. After crystallization, the filter cake is washed with a mixture of low-temperature toluene and low-temperature anhydrous ethanol to remove residual organic impurities, free tertiary amines, and small amounts of acid-releasing agent derivatives from the mother liquor. Finally, drying under mild vacuum conditions helps remove solvents and moisture while avoiding the adverse effects of high temperatures on the structure and appearance of the intermediate hydrochloride.

[0041] S3. Toluene and an alkaline promoter are added to 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride for alkalization treatment. After extraction, a palladium catalyst on carbon is added, and a reduction reaction is carried out under hydrogen conditions. After crystallization, filtration, and drying, crude oxybuprocaine is obtained. Toluene and anhydrous ethanol are then added to the crude oxybuprocaine, and the mixture is heated under reflux to dissolve and hot filtered. After cooling to crystallize, filtration, and drying, oxybuprocaine hydrochloride is obtained. The palladium catalyst on carbon includes at least one of 5% palladium catalyst on carbon, 10% palladium catalyst on carbon, 15% palladium catalyst on carbon, 20% palladium catalyst on carbon, wet palladium catalyst on carbon, and dry palladium catalyst on carbon.

[0042] Step S3 includes: S3.1 Add toluene and purified water to 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. The amount of toluene added is 4 to 10 times the mass of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride, and the amount of purified water added is 1 to 4 times the mass of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. Then add an alkaline accelerator. The amount of alkaline accelerator added is 1.0 to 2.5 times the molar amount of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. Stir at 20 to 35°C for 0.5 to 2 hours.

[0043] The addition of toluene and purified water in S3.1 primarily establishes an alkalinization system where organic and aqueous phases coexist. This allows 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride to transform from its hydrochloride form to a free base form under the action of an alkaline promoter. The alkaline promoter here neutralizes the hydrochloric acid and releases the tertiary amine intermediate, making it easier for the target analyte to enter the toluene phase. The presence of purified water facilitates the entry of inorganic salts into the aqueous phase, while toluene promotes the transfer of the target organic intermediate into the organic phase.

[0044] S3.2 After stirring, centrifuge to separate the organic phase and the aqueous phase. Then, use toluene to perform 1 to 3 additional extractions on the aqueous phase, with each toluene addition being 10% to 40% of the initial toluene addition. After combining the organic phases, stir at 25 to 40°C for 10 to 30 minutes, and then dehydrate and filter to obtain a clear organic phase.

[0045] In step S3.2, centrifugation and toluene extraction are primarily used to transfer the target free base from the aqueous phase to the organic phase as much as possible, minimizing product loss. After combining the organic phases, continued stirring, dehydration, and filtration remove entrained water, fine particles, and some inorganic impurities. Toluene, as an organic solvent, helps maintain the stability of the target intermediate within the organic phase at this stage.

[0046] S3.3 Under nitrogen protection, add palladium catalyst on carbon to the clear organic phase. The amount of palladium catalyst added is 2% to 10% of the mass of the clear organic phase. After the addition is completed, replace with nitrogen 1 to 3 times, and then replace with hydrogen 1 to 3 times. Then control the system temperature at 20 to 40°C and the hydrogen pressure at 0.1 to 0.6 MPa.

[0047] In step S3.3, a palladium-on-carbon catalyst is added under nitrogen protection, followed by nitrogen and hydrogen purging. The main purpose is to establish a safe and stable catalytic hydrogenation environment. Palladium-on-carbon catalysts, such as 5%, 10%, or 15% purging, can activate hydrogen and promote the reduction of aromatic nitro groups. Nitrogen purging helps to remove air and reduce the adverse effects of oxygen on catalyst activity and reaction safety; subsequent hydrogen purging allows the system to enter a suitable reducing atmosphere.

[0048] S3.4. Introduce hydrogen gas to carry out the reduction reaction for 2-6 hours. During the reaction, control the stirring speed at 200-600 rpm. After the reaction is completed, stop the hydrogen supply and replace the residual hydrogen gas in the reactor with nitrogen gas. Cool the reaction liquid to 20-35℃ and then filter it to remove the palladium on carbon catalyst. Wash the filter cake with toluene 1-2 times. Combine the filtrates to obtain a clear reduced liquid.

[0049] Figure 2 The diagram illustrates the reaction mechanism of introducing hydrogen gas into the palladium-on-carbon catalyst. In step S3.4, hydrogen gas is introduced for a reduction reaction, essentially reducing the nitro group in the 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester structure to an amino group, thus forming the oxybuprocaine skeleton. Controlling the stirring speed facilitates sufficient contact between hydrogen, the liquid phase, and the palladium-on-carbon catalyst, improving reduction efficiency. After the reaction, replacing residual hydrogen with nitrogen and filtering to remove the palladium-on-carbon catalyst reduces safety hazards and prevents catalyst residue from entering subsequent products. Washing the filter cake with toluene helps recover products adsorbed on the catalyst surface.

[0050] S3.5 Add anhydrous ethanol to the clarified reducing solution. The amount of anhydrous ethanol added is 10% to 50% of the mass of the clarified reducing solution. After the addition is completed, continue stirring for 0.5 to 2 hours and induce crystallization at 10 to 25°C. Then, further cool down to 0 to 10°C and keep it at that temperature for 1 to 4 hours to obtain crude oxybuprocaine crystal slurry.

[0051] The addition of anhydrous ethanol to S3.5 primarily alters the dissolution environment of the target product in the clarified reducing solution, causing oxybuprocaine to precipitate gradually within a specific temperature range. The combination of anhydrous ethanol and the existing toluene system reduces the solubility of oxybuprocaine in the mixed solvent, thereby forming a crude crystal slurry during cooling and aging. Inducing crystallization at 10–25°C followed by aging at 0–10°C promotes crystal nucleation and growth.

[0052] S3.6. The crude oxybuprocaine slurry is filtered and the filter cake is washed 1 to 3 times with low-temperature anhydrous ethanol or a mixture of low-temperature toluene and anhydrous ethanol. After washing, the filter cake is pre-dried at 25 to 40°C and -0.05 to -0.09 MPa for 2 to 8 hours to obtain crude oxybuprocaine.

[0053] In step S3.6, the crude oxybuprocaine slurry is filtered and washed with a low-temperature anhydrous ethanol or a mixture of low-temperature toluene and anhydrous ethanol. This primarily removes mother liquor, residual impurities, and small amounts of unseparated byproducts from the surface of the crude product. The pre-drying process removes most of the solvent and moisture from the filter cake, making the crude product more stable and facilitating subsequent recrystallization.

[0054] S3.7 Add toluene and anhydrous ethanol to crude oxybuprocaine. The amount of toluene added is 2 to 8 times the mass of crude oxybuprocaine, and the amount of anhydrous ethanol added is 1 to 6 times the mass of crude oxybuprocaine. Heat to 70 to 95°C and reflux to dissolve until a clear solution is formed.

[0055] In step S3.7, toluene and anhydrous ethanol are added and the mixture is heated under reflux to dissolve the crude oxybuprocaine. The main purpose is to establish a suitable mixed solvent system for recrystallization and purification of crude oxybuprocaine. Toluene helps regulate the overall solubility of the system, while anhydrous ethanol helps improve its solubility at high temperatures. By heating to 70–95°C to ensure complete dissolution of the crude product, some insoluble impurities can be removed via subsequent hot filtration.

[0056] S3.8. Perform hot filtration at 70–90℃, then cool the filtrate to 35–50℃ and keep it at that temperature for 0.5–1.5 h, then continue to cool it to 0–10℃ and keep it at that temperature for 1–4 h to induce crystallization. After crystallization, filter the crystal slurry by vacuum filtration, and wash the filter cake 1–3 times with a mixture of low-temperature toluene and anhydrous ethanol or low-temperature anhydrous ethanol. After washing, place the filter cake under vacuum drying at 30–50℃ and -0.06–-0.09 MPa for 6–12 h to obtain oxybuprocaine hydrochloride.

[0057] In step S3.8, hot filtration is performed first to remove mechanical impurities or small amounts of coloring impurities that remain insoluble at high temperatures. This is followed by staged cooling crystallization, which allows oxybuprocaine hydrochloride to precipitate more smoothly from the solution, reducing impurity encapsulation caused by rapid crystallization. Subsequent filtration, washing, and vacuum drying further remove the mother liquor, residual solvent, and attached impurities. A mixture of toluene and anhydrous ethanol, or low-temperature anhydrous ethanol, helps remove surface impurities during washing while minimizing the loss of the target product.

[0058] S4. Add a buffer aqueous phase and an inclusion agent to oxybuprocaine hydrochloride, adjust the pH and osmotic pressure, and then perform aseptic filling and low-temperature curing to obtain a pharmaceutical preparation containing oxybuprocaine hydrochloride.

[0059] Please refer to Figure 3 Step S4 includes: S4.1 Mix the buffer component and the osmotic conditioning component by stirring at a speed of 100-300 rpm for 10-40 min to form a buffer aqueous phase. The buffer component includes at least one of sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, citric acid, and sodium citrate. The osmotic conditioning component includes at least one of sodium chloride, mannitol, glucose, trehalose, and sorbitol.

[0060] In S4.1, the buffering and osmotic conditioning components are mixed to form a buffered aqueous phase. Their main function is to establish a suitable basic liquid environment for ophthalmic preparations. Buffering components such as sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, citric acid, or sodium citrate maintain a relatively stable pH level, preventing significant fluctuations after the subsequent addition of oxybuprocaine hydrochloride. Osmotic conditioning components such as sodium chloride, mannitol, glucose, trehalose, or sorbitol bring the osmotic pressure closer to the tear film environment, reducing discomfort during eye drops.

[0061] S4.2 Add oxybuprocaine hydrochloride to the buffer aqueous phase. The amount of oxybuprocaine hydrochloride added is 0.20% to 0.50% of the buffer aqueous phase. Control the temperature at 10 to 25°C and the stirring speed at 150 to 350 rpm. Stir for 10 to 30 minutes to obtain the drug solution.

[0062] In step S4.2, oxybuprocaine hydrochloride is added to the buffer aqueous phase primarily to ensure its uniform dispersion and dissolution in the pre-conditioned liquid environment. Controlling the temperature and stirring speed facilitates stable dissolution of oxybuprocaine hydrochloride, preventing excessively high local concentrations that could lead to precipitation or system inhomogeneity. As a local anesthetic component, the formation of a relatively homogeneous solution at this stage facilitates further compounding with inclusion agents and repair adjuvants.

[0063] S4.3 Add an inclusion agent to the drug solution. The amount of inclusion agent added is 2 to 10 times the mass of oxybuprofen hydrochloride. Control the system temperature at 15 to 30°C and the stirring speed at 150 to 400 rpm for 0.5 to 3 hours. The inclusion agent includes at least one of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, and γ-cyclodextrin.

[0064] The inclusion agent added in S4.3 primarily functions to encapsulate the hydrophobic portion of the oxybuprofen hydrochloride molecule using the hollow structures of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, or γ-cyclodextrin. This improves the drug's stability in the aqueous phase, reduces irritation caused by excessively high instantaneous concentrations of free drug, and helps maintain a clear solution. Continuous stirring for a period of time further enhances the inclusion effect.

[0065] S4.4 Continue to add the repair auxiliary components, control the temperature at 4-10℃, stir and mix for 0.5-2 hours, adjust the pH and osmotic pressure, control the pH at 6.4-7.2, after adjustment, let stand at 4-15℃ for 10-60 minutes to degas, and obtain the final solution; the repair auxiliary components include at least one of recombinant human epidermal growth factor, sodium hyaluronate, trehalose, carboxymethyl chitosan, hydroxypropyl methylcellulose, and polyvinyl alcohol.

[0066] The addition of repair-enhancing components in S4.4 primarily aims to further improve the ocular surface environment on top of local anesthesia. Recombinant human epidermal growth factor assists in the repair of damaged corneal epithelium, while sodium hyaluronate, carboxymethyl chitosan, hydroxypropyl methylcellulose, or polyvinyl alcohol improve the retention and lubrication of the solution on the ocular surface. Trehalose helps alleviate dryness and osmotic stress. Subsequent pH and osmotic pressure adjustments bring the entire system closer to the ocular surface's tolerable range, reducing irritation caused by acid-base and osmotic pressure deviations. Degassing during settling removes air bubbles from the mixing process, ensuring the final solution's appearance and filling stability.

[0067] S4.5. The final solution is pre-filtered through a 0.45μm filter membrane and then filtered through a 0.22μm filter membrane. It is then aseptically filled and sealed. After filling, it is placed at 2-8℃ for 12-72 hours to mature at low temperature to obtain a pharmaceutical preparation containing oxybuprocaine hydrochloride.

[0068] In S4.5, pre-filtration with a 0.45μm filter membrane and filtration with a 0.22μm filter membrane are used. Their main function is to remove particulate matter, insoluble matter, and the risk of microbial contamination from the system, ensuring the final solution meets the clarity and sterility requirements for ophthalmic preparations. Aseptic filling and sealing prevent recontamination during subsequent storage and use, guaranteeing the safety of the preparation. Low-temperature curing at 2–8°C after filling further stabilizes the interaction between oxybuprofen hydrochloride and the inclusion agent, and also promotes the redistribution of components in the system, reducing initial precipitation, turbidity, or content fluctuations.

[0069] This invention provides a pharmaceutical preparation containing oxybuprocaine hydrochloride, which is prepared by the method described above for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride.

[0070] The pharmaceutical formulation of this invention includes oxybuprocaine hydrochloride, a buffer component, an osmotic adjustment component, an inclusion agent, and a repair auxiliary component. Oxybuprocaine hydrochloride is used for local anesthesia of the ocular surface, reducing pain in the cornea and conjunctiva. The buffer component controls the pH stability of the pharmaceutical formulation. The osmotic adjustment component adjusts the osmotic pressure of the pharmaceutical formulation to approximate that of tears. The inclusion agent forms an inclusion system with oxybuprocaine hydrochloride, improving the stability of oxybuprocaine hydrochloride in the formulation. The repair auxiliary component improves the retention of the drug solution on the ocular surface.

[0071] Example 1.

[0072] Weigh 100g of methyl 3-hydroxy-4-nitrobenzene and add 800g of N,N-dimethylformamide, making the mass ratio of N,N-dimethylformamide to methyl 3-hydroxy-4-nitrobenzene 8:1. Then add 98g of anhydrous potassium carbonate dried at 120℃ for 3h, controlling the molar ratio of anhydrous potassium carbonate to methyl 3-hydroxy-4-nitrobenzene to be 1.5:1, and pre-activate at 25℃ for 30min. Then add 69g of n-bromobutane dropwise at 25℃, with a molar ratio of n-bromobutane to methyl 3-hydroxy-4-nitrobenzene of 1.15:1, controlling the dropwise addition time to be 60min. After the dropwise addition is complete, raise the temperature to 85℃ and maintain the reaction for 6h. Take samples every 2h. Stop the reaction when the residual amount of methyl 3-hydroxy-4-nitrobenzene is less than 1.0%. N,N-dimethylformamide was then distilled off under reduced pressure at -0.09 MPa and 65 °C. After distillation, 420 g of 1.5 mol / L sodium hydroxide aqueous solution was added, with a sodium hydroxide to theoretical methyl ester molar ratio of 1.4:1. The reaction was continued at 55 °C for 2 h. After the reaction was complete, the system was cooled to 20 °C, and 20% hydrochloric acid solution was added dropwise to pH 2.0. Simultaneously, the temperature was lowered to 10 °C and aged for 2 h. After filtration, the product was washed twice with purified water at 10 °C, and then once with 20% (v / v) low-temperature ethanol aqueous solution. It was then vacuum dried at 45 °C and -0.08 MPa for 8 h to obtain 121.6 g of 3-butoxy-4-nitrobenzoic acid.

[0073] Weigh 120g of the above-mentioned 3-butoxy-4-nitrobenzoic acid, add 720g of toluene (toluene to 3-butoxy-4-nitrobenzoic acid mass ratio 6:1), add 110g of anhydrous potassium carbonate dried at 110℃ for 4h (anhydrous potassium carbonate to 3-butoxy-4-nitrobenzoic acid molar ratio 1.6:1), and pre-stir for 30min at 30℃ under trace nitrogen protection. Then, add 94g of 2-diethylaminochloroethane hydrochloride at 30℃ (molar ratio to 3-butoxy-4-nitrobenzoic acid 1.20:1), controlling the addition time at 70min, maintaining a stirring speed of 250rpm during the addition, and continuing stirring for 30min after the addition is complete. Then, reflux the reaction at 110℃ for 6h, continuously separating the water using a water separator, checking every 2h. The reaction is terminated when the residual 3-butoxy-4-nitrobenzoic acid is below 1.0%. After the reaction was completed, the solution was cooled to 60°C and hot-filtered to obtain a clear filtrate. 180 g of anhydrous ethanol was added to the clear filtrate, with a mass ratio of anhydrous ethanol to clear filtrate of approximately 0.20:1. 53 g of acetyl chloride was then added dropwise at 25°C, with a molar ratio of acetyl chloride to 2-diethylaminochloroethane hydrochloride of 1.0:1 over 60 min. The reaction was continued for 1 h after the addition. The solution was then cooled to 5°C and aged for 2 h. After crystallization, the solution was filtered and washed twice with a mixture of low-temperature toluene and low-temperature anhydrous ethanol in a 1:1 volume ratio. The solution was then vacuum-dried at 35°C and -0.08 MPa for 6 h to obtain 168.4 g of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride.

[0074] 160 g of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride was weighed, and 960 g of toluene and 320 g of purified water were added to make the mass ratio of toluene to the intermediate 6:1 and the mass ratio of purified water to the intermediate 2:1. Then, 102 g of anhydrous potassium carbonate was added, with a molar ratio of anhydrous potassium carbonate to the intermediate of 1.4:1. The mixture was stirred at 25 °C for 1 h. After stirring, the mixture was centrifuged to separate the phases, retaining the organic phase. The aqueous phase was extracted twice with toluene, 120 g of toluene added each time. The organic phases were combined and stirred at 30 °C for 15 min. After dehydration with anhydrous sodium sulfate, the mixture was filtered to obtain a clear organic phase. Subsequently, under nitrogen protection, 9.6 g of 10% palladium-on-carbon catalyst (6% of the target intermediate mass in the clarified organic phase) was added to the clarified organic phase. The reaction was then subjected to two nitrogen purgings and two hydrogen purgings. The system temperature was controlled at 30°C, the hydrogen pressure at 0.3 MPa, and hydrogen reduction was carried out for 4 hours with a stirring speed of 350 rpm. After the reaction was complete, hydrogen flow was stopped, and residual hydrogen was replaced with nitrogen. The mixture was cooled to 25°C, filtered to remove the palladium-on-carbon catalyst, and the filter cake was washed once with toluene. The filtrates were combined to obtain a clarified reduced solution. 240 g of anhydrous ethanol was added to the clarified reduced solution, and stirring was continued for 1 hour. Crystallization was induced at 20°C, followed by aging at 5°C for 2 hours to obtain crude oxybuprocaine slurry. The slurry was filtered and washed twice with low-temperature anhydrous ethanol, then pre-dried at 30°C and -0.07 MPa for 4 hours to obtain 136.8 g of crude oxybuprocaine. Subsequently, 410 g of toluene and 205 g of anhydrous ethanol were added to the crude oxybuprocaine, making the mass ratio of toluene to crude oxybuprocaine 3:1 and the mass ratio of anhydrous ethanol to crude oxybuprocaine 1.5:1. The solution was heated to 82 °C and refluxed until a clear solution was formed. After hot filtration at 80 °C, the solution was first cooled to 40 °C and kept at that temperature for 1 h, then cooled to 5 °C and kept at that temperature for 2 h to crystallize. The solution was then filtered and washed twice with a low-temperature toluene / anhydrous ethanol mixture. Finally, it was vacuum dried at 40 °C and -0.08 MPa for 8 h to obtain 124.5 g of oxybuprocaine hydrochloride.

[0075] 0.20 g of sodium dihydrogen phosphate, 0.35 g of disodium hydrogen phosphate, 0.55 g of sodium chloride, and 0.80 g of trehalose were added to 96.0 g of sterile purified water and stirred at 200 rpm for 20 min to form a buffer aqueous phase. Then, 0.40 g of oxybuprocaine hydrochloride was added, making the oxybuprocaine hydrochloride content in the buffer aqueous phase 0.40% by mass. The mixture was stirred at 20℃ and 250 rpm for 20 min to obtain the drug solution. Next, 1.60 g of hydroxypropyl-β-cyclodextrin was added, making the inclusion agent to oxybuprocaine hydrochloride mass ratio 4:1. The mixture was stirred at 25℃ and 300 rpm for 1.5 h. Then, 0.002 g of recombinant human epidermal growth factor, 0.15 g of sodium hyaluronate, and 0.05 g of carboxymethyl chitosan were added. The mixture was stirred at 8℃ for 1 h, and the pH was adjusted to 6.8 and the osmotic pressure to 298 mOsm / kg. The mixture was allowed to stand for 30 min to remove bubbles, yielding the final solution. The final solution was pre-filtered through a 0.45μm filter membrane and then filtered through a 0.22μm filter membrane before being aseptically filled into 5mL bottles. After sealing, the bottles were placed at 4℃ for 24 hours to obtain a pharmaceutical preparation containing oxybubucaine hydrochloride.

[0076] Example 2.

[0077] The steps in this embodiment are basically the same as those in Example 1, except that: in step S1, the mass ratio of N,N-dimethylformamide to methyl 3-hydroxy-4-nitrobenzoate is adjusted to 10:1, anhydrous sodium carbonate replaces anhydrous potassium carbonate as the alkaline promoter, iodobutane is used as the alkylating agent, and the amount added is 1.10 times the molar amount of methyl 3-hydroxy-4-nitrobenzoate. The alkylation temperature is 82℃, and 119.8g of 3-butoxy-4-nitrobenzoic acid is obtained in S1. In step S2, anhydrous sodium carbonate is used as the alkaline promoter, propionyl chloride is used as the acid-releasing agent, and the molar ratio of 2-diethylaminochloroethane hydrochloride to 3-butoxy-4-nitrobenzoic acid is 1.15:1, finally yielding 165.9g of 2-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride. In step S3, a 5% palladium-on-carbon catalyst was used, with the amount added being 8% of the intermediate mass. The hydrogen pressure was controlled at 0.25 MPa to obtain 121.7 g of oxybuprocaine hydrochloride.

[0078] In this embodiment, step S4 specifically involves: adding 0.25g of boric acid, 0.18g of borax, and 1.20g of mannitol to 95.60g of sterile purified water, stirring at 180rpm for 25min to form a buffer aqueous phase; then adding 0.35g of oxybuprocaine hydrochloride, making oxybuprocaine hydrochloride account for 0.35% of the mass of the buffer aqueous phase, and stirring at 18℃ and 220rpm for 20min to obtain a drug solution; then adding 1.75g ​​of sulfobutyl ether-β-cyclodextrin, making the mass ratio of the inclusion agent to oxybuprocaine hydrochloride 5:1, and stirring at 25℃ and 300rpm for 1.5h; then... 0.002g of recombinant human epidermal growth factor, 0.12g of sodium hyaluronate, and 0.60g of trehalose were added, along with 0.01g of disodium EDTA, a metal ion chelating agent. The mixture was stirred at 8°C for 1 hour, and the pH was adjusted to 6.7 and the osmotic pressure to 292 mOsm / kg. After standing for 30 minutes to remove bubbles, the final solution was obtained. The final solution was then pre-filtered through a 0.45μm filter membrane and filtered through a 0.22μm filter membrane before aseptic filling, with 5mL per bottle. After sealing, the bottles were aged at 4°C for 24 hours to obtain a pharmaceutical preparation containing oxybubucaine hydrochloride.

[0079] Example 3.

[0080] The steps in this embodiment are basically the same as those in Example 1, except that: in step S1, the alkaline promoter is cesium carbonate, and the amount added is 1.3 times the molar amount of methyl 3-hydroxy-4-nitrobenzoate; the alkylating agent is n-butyl p-toluenesulfonate, and the amount added is 1.08 times the molar amount of methyl 3-hydroxy-4-nitrobenzoate; the reaction is kept at a constant temperature for 7 hours; after completing step S1.3, acidification is not carried out directly, but step S1.3a is added, that is: after the alkaline reaction is completed, the system is first cooled to 40°C, 60g of purified water is added, and stirring is continued for 0.5 hours to further uniformly disperse the carboxylate intermediate obtained by hydrolysis in the system before acidification and crystallization in step S1.4. Subsequently, a 20% hydrochloric acid solution was added dropwise to lower the pH of the system to 2.0. At the same time, the temperature was lowered to 10℃ and aged for 2 hours. After filtration, the system was washed twice with purified water at 10℃ and then once with a 20% volume fraction low-temperature ethanol aqueous solution. The system was then vacuum dried at 45℃ and -0.08MPa for 8 hours to obtain 120.9g of 3-butoxy-4-nitrobenzoic acid.

[0081] In this embodiment, in step S2, cesium carbonate was used as the alkaline promoter, the molar ratio of 2-diethylaminochloroethane hydrochloride to 3-butoxy-4-nitrobenzoic acid was 1.10:1, and butyryl chloride was used as the acid-releasing agent, yielding 167.2 g of 2-(diethylamino)ethyl 3-butoxy-4-nitrobenzoic acid hydrochloride. In step S3, a 15% palladium-on-carbon catalyst was used, with the addition amount being 4% of the intermediate mass, and the hydrogen pressure was controlled at 0.4 MPa, yielding 125.1 g of oxybuprocaine hydrochloride. In step S4, the buffer component consists of 0.08 g of citric acid and 0.42 g of sodium citrate; the osmotic conditioning component consists of 0.95 g of glucose and 0.40 g of trehalose; the amount of oxybubucaine hydrochloride added is 0.45 g; the inclusion agent consists of 2.25 g of hydroxypropyl-β-cyclodextrin; and the repair auxiliary component consists of 0.003 g of recombinant human epidermal growth factor, 0.18 g of sodium hyaluronate, 0.08 g of hydroxypropyl methylcellulose, and 0.10 g of polyvinyl alcohol, ultimately yielding a pharmaceutical preparation containing oxybubucaine hydrochloride.

[0082] Example 4.

[0083] The steps in this embodiment are basically the same as those in Example 1, except that: in step S1, anhydrous potassium carbonate and anhydrous sodium carbonate are mixed in a mass ratio of 1:1 as the alkaline promoter, and n-butyl methanesulfonate is used as the alkylating agent, with an addition amount of 1.20 times the molar amount of methyl 3-hydroxy-4-nitrobenzoate, yielding 122.4 g of 3-butoxy-4-nitrobenzoic acid. In step S2, oxaloyl chloride is used as the acid-releasing agent, and the molar ratio of 2-diethylaminochloroethane hydrochloride to 3-butoxy-4-nitrobenzoic acid is 1.25:1, yielding 169.1 g of 2-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride. In step S3, 10% palladium on carbon catalyst is used, with an addition amount of 5% of the intermediate mass, and the hydrogen pressure is controlled at 0.35 MPa, yielding 126.0 g of oxybuprocaine hydrochloride. In step S4, the buffer components consist of 0.18 g of sodium dihydrogen phosphate, 0.30 g of disodium hydrogen phosphate, and 0.10 g of boric acid; the osmotic conditioning components consist of 0.70 g of sorbitol and 0.35 g of sodium chloride; the amount of oxybubucaine hydrochloride added is 0.30 g; the inclusion agent consists of 1.20 g of β-cyclodextrin and 0.60 g of hydroxypropyl-β-cyclodextrin; and the repair auxiliary components consist of 0.002 g of recombinant human epidermal growth factor, 0.10 g of sodium hyaluronate, 0.50 g of trehalose, and 0.08 g of polyvinyl alcohol, ultimately yielding a pharmaceutical preparation containing oxybubucaine hydrochloride.

[0084] Comparative Example 1.

[0085] The only difference between this comparative example and Example 1 is that no inclusion agent is added in step S4; all other steps and dosages are the same as in Example 1. That is, in S4.3 of Example 1, 1.60 g of hydroxypropyl-β-cyclodextrin is omitted, while the amounts and preparation conditions of the remaining buffer components, osmotic conditioning components, oxybuprocaine hydrochloride, recombinant human epidermal growth factor, sodium hyaluronate, and carboxymethyl chitosan remain unchanged, ultimately yielding a pharmaceutical preparation containing oxybuprocaine hydrochloride without an inclusion agent.

[0086] Comparative Example 2.

[0087] The only difference between this comparative example and Example 1 is that the repair auxiliary component is not added in step S4; all other steps and dosages are the same as in Example 1. That is, in S4.4 of Example 1, 0.002g of recombinant human epidermal growth factor, 0.15g of sodium hyaluronate, and 0.05g of carboxymethyl chitosan are omitted, while the amounts and preparation conditions of the remaining buffer components, osmotic conditioning components, oxybuprocaine hydrochloride, and hydroxypropyl-β-cyclodextrin remain unchanged. The final product is a pharmaceutical preparation containing oxybuprocaine hydrochloride without the repair auxiliary component.

[0088] The pH test procedure was as follows: Pharmaceutical formulations containing oxybuprocaine hydrochloride obtained from Examples 1-4 and Comparative Examples 1-2 were first allowed to stand at room temperature to ensure a uniform temperature. Then, appropriate amounts of each sample were measured and placed in clean beakers. A pH meter calibrated with a standard buffer solution was used for measurement. During measurement, the electrode was slowly immersed in the sample to avoid air bubbles. The result was recorded after the reading stabilized. Each sample was measured in triplicate, and the average value was taken as the pH value of that sample. This experimental procedure was used to evaluate whether the acid-base environment of the pharmaceutical formulations containing oxybuprocaine hydrochloride in each example and comparative example was within a suitable range for ophthalmic use and to reflect the regulatory effect of the buffer component on the stability of the system.

[0089] Experimental procedure for determining the single maximum impurity and total impurities: Pharmaceutical formulations containing oxybuprocaine hydrochloride obtained from Examples 1-4 and Comparative Examples 1-2 were precisely measured in specific volumes, diluted to the specified concentration with a suitable solvent, and then determined using high-performance liquid chromatography (HPLC). A chromatographic column suitable for separating oxybuprocaine hydrochloride and its related substances was selected, with an organic phase and buffer salt solution forming the mobile phase. Chromatograms were recorded at the specified detection wavelength. Based on the peak area and retention time of each impurity peak other than the main peak in the chromatogram, the content of each single impurity was calculated, and the peak with the highest content was taken as the single maximum impurity. The contents of all integrable impurity peaks were then summed to obtain the total impurities. Each sample was injected in triplicate, and the average value was taken as the final result. This experimental procedure was used to evaluate the ability of each example and comparative example to control impurity growth during preparation and storage, and to reflect the impact of formulation improvements on formulation stability.

[0090] Experimental procedure for osmolality determination: Samples of pharmaceutical formulations containing oxybuprocaine hydrochloride obtained in Examples 1-4 and Comparative Examples 1-2 were taken, and appropriate amounts were placed in dedicated sampling cups. A freezing point osmoremeter was used for measurement. Before testing, the instrument was calibrated using standard osmolality calibration solution to ensure it was in normal working order. Each sample was measured three times, and the osmolality was recorded and averaged as the final result. This experimental procedure was used to evaluate whether the osmolality of the pharmaceutical formulation systems containing oxybuprocaine hydrochloride in each example and comparative example was close to the tolerable range for the ocular surface, and to reflect the influence of the osmotic adjustment component on the comfort and suitability of the formulation.

[0091] The content determination experiment was conducted as follows: A precise volume of the pharmaceutical preparations containing oxybuprocaine hydrochloride obtained from Examples 1-4 and Comparative Examples 1-2 was accurately measured, added to the mobile phase or specified diluent, and mixed thoroughly to prepare the test solution. Separately, oxybuprocaine hydrochloride reference standard was accurately weighed and prepared into a reference solution. The test solution and reference solution were injected separately under the same chromatographic conditions. The peak area of ​​the main peak was recorded, and the actual content of oxybuprocaine hydrochloride in the sample was calculated using the external standard method. Each sample was measured in triplicate, and the average value was taken as the final result. This experimental procedure was used to evaluate the retention of oxybuprocaine hydrochloride in each example and comparative example during preparation and storage, and to reflect the influence of different formulation designs on the stability of the active pharmaceutical ingredient.

[0092] To obtain the aforementioned data, the pharmaceutical preparations containing oxybuprocaine hydrochloride obtained in Examples 1-4 and Comparative Examples 1-2 can be stored at 25°C under light-protected conditions for 3 months before testing. If necessary, initial samples can also be used as controls to compare changes in pH value, single maximum impurity, total impurities, and osmolality before and after storage. By conducting uniform testing on all examples and comparative examples under the same storage conditions, the impact of different formulation designs on the stability of pharmaceutical preparations containing oxybuprocaine hydrochloride can be reflected more objectively.

[0093] The experimental data from the above experiment are shown in Table 1.

[0094] Table 1: Examples 1-4 showed stability in terms of pH, osmolality, sterility, and content determination. The related substances levels in Examples 1-4 were significantly lower than those in Comparative Examples 1 and 2, indicating that improvements such as inclusion agents, repair aids, and metal ion complexing agents can better suppress impurity growth during storage. In particular, the addition of disodium EDTA in Example 2 further reduced the single maximum impurity and total impurities, demonstrating the positive effect of metal ion complexing agents on improving the storage stability of the formulation. Example 3, due to the addition of step S1.3a in step S1, resulted in more uniform dispersion of the carboxylate intermediate obtained from hydrolysis before acidification, leading to better purification of oxybuprocaine hydrochloride. Therefore, it exhibited the lowest single maximum impurity and total impurity levels in the final pharmaceutical formulation containing oxybuprocaine hydrochloride. Comparative Example 1, without the addition of an inclusion agent, tended to have a higher proportion of free oxybuprocaine hydrochloride in the formulation, resulting in a significant increase in related substances after storage. Comparative Example 2, without the addition of a repair aid, although the content remained at a high level, still had higher total impurities than Examples 1, indicating relatively poor system stability.

[0095] Buehler's test procedure for guinea pigs: Fifty Hartley guinea pigs, half male and half female, that passed quarantine were randomly divided into four groups according to weight and sex: a negative control group, a positive control group, a test substance group, and a group containing the pharmaceutical preparation of oxybuprocaine hydrochloride prepared in Example 1. The negative control group consisted of 10 pigs, the positive control group of 10 pigs, the test substance group of 20 pigs, and the pharmaceutical preparation group containing oxybuprocaine hydrochloride prepared in Example 1 of 10 pigs. The experiment was conducted via transdermal block administration. Twenty-four hours prior to administration, the fur on the back of the guinea pigs in the area to be treated was shaved, covering an area of ​​approximately 3cm × 3cm, taking care to avoid damaging the epidermis.

[0096] Sensitization was performed on days 1, 8, and 15. Each administration volume was 0.4 mL per guinea pig. The test substance, the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1, and the negative or positive control were applied to the shaved area on the left back of the guinea pig, covered with a layer of cellophane and two layers of gauze, and sealed with non-irritating adhesive tape. After 6 hours, the dressing was removed, and any remaining sample was wiped away with a damp cotton ball. Challenge administration was performed on day 29. 24 hours before challenge, the hair on the right side of the guinea pig's back, in the area to be treated, was shaved again, covering an area of ​​approximately 3 cm × 3 cm without damaging the epidermis. The challenge administration volume was also 0.4 mL per guinea pig, and the sealing method was the same as in the sensitization stage. After 6 hours, the dressing was removed, and any remaining sample was cleaned. During the trial, routine clinical observations and body weight measurements were conducted as planned. Skin erythema and edema at the administration sites were observed and scored approximately 1 hour and 24 hours after each sensitization administration, and approximately 24 hours and 48 hours after the challenge, to evaluate the allergic reaction and sensitization intensity.

[0097] The results of the Buehler experiment in guinea pigs are shown in Table 2.

[0098] Table 2: According to the Buehler test results in guinea pigs, neither the test group nor the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1 showed erythema or edema after stimulation. The positive reaction rate was 0% and the sensitization intensity was weak, indicating that the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1 did not show obvious skin sensitization.

[0099] New Zealand rabbit eye irritation test experimental procedure: Twelve New Zealand rabbits (half male and half female) that passed quarantine were randomly divided into two groups: the test substance group and the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1, with six rabbits in each group. The experiment used a left-right eye control administration method. The left eye of each animal was given 0.9% sodium chloride injection as a negative control, while the right eye was given either the test substance or the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1. The drug concentration was the undiluted concentration, i.e., 4 mg / mL, and the administration volume was 2 drops per eye twice daily for 3 consecutive days.

[0100] Within 24 hours prior to drug administration, all animals underwent slit-lamp microscopy and fluorescein sodium examination in both eyes. Drug administration only began after confirming the absence of significant ocular abnormalities. Routine clinical observations were conducted daily during the experiment, and body weight was measured as planned. During the drug administration period, the cornea, iris, and conjunctiva were examined and scored for irritation responses before each administration and at 1, 2, 4, 24, 48, and 72 hours after the last administration, while also observing for edema, secretions, and other abnormalities. Slit-lamp microscopy and fluorescein sodium examinations were performed again within 24 hours before and approximately 24 hours after the last administration. If persistent damage was observed, the observation period was extended, but not exceeding 21 days. Based on the observation results, ocular irritation response scores for each group were recorded and compared.

[0101] The results of the New Zealand rabbit eye irritation test are shown in Table 3.

[0102] Table 3: According to the results of the New Zealand rabbit eye irritation test, after three consecutive days of administration, no abnormalities were observed in the cornea, iris, and conjunctiva of the test group and the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1. The eye irritation response scores were all 0 points, and no edema or secretions were observed. This indicates that the pharmaceutical preparation containing oxybuprocaine hydrochloride prepared in Example 1 has no obvious irritation to the eyes.

[0103] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride, characterized in that the steps include... include: S1. N,N-dimethylformamide and an alkaline promoter were added to methyl 3-hydroxy-4-nitrobenzoate. After stirring, an alkylating agent was added, and the reaction was carried out at a preset temperature. After the solvent was evaporated, alkaline solution and hydrochloric acid were added in sequence to carry out the reaction. After filtration and drying, 3-butoxy-4-nitrobenzoic acid was obtained. S2. Toluene and an alkaline accelerator were added to 3-butoxy-4-nitrobenzoic acid, and after stirring, 2-diethylaminochloroethane hydrochloride was added. The reaction was carried out at a preset temperature, cooled and filtered, and then an acid-releasing agent was added. The filtrate was then post-treated to obtain 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride. S3. Toluene and an alkaline promoter were added to 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride for alkalization treatment. After extraction, palladium on carbon catalyst was added, and a reduction reaction was carried out under hydrogen conditions. After crystallization, filtration and drying, crude oxybuprocaine was obtained. Toluene and anhydrous ethanol were added to the crude oxybuprocaine, and the mixture was heated to reflux to dissolve and hot filtered. After cooling to crystallize, filtration and drying, oxybuprocaine hydrochloride was obtained. S4. Add a buffer aqueous phase and an inclusion agent to oxybuprocaine hydrochloride, adjust the pH and osmotic pressure, and then perform aseptic filling and low-temperature curing to obtain a pharmaceutical preparation containing oxybuprocaine hydrochloride.

2. The method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1, characterized in that, Step S1 includes: S1.1 Add methyl 3-hydroxy-4-nitrobenzene and N,N-dimethylformamide, wherein the mass of N,N-dimethylformamide is 6 to 12 times that of methyl 3-hydroxy-4-nitrobenzene. Then add an alkaline accelerator that has been dried at 120°C for 2 to 4 hours, wherein the amount added is 1.2 to 2.0 times the molar mass of methyl 3-hydroxy-4-nitrobenzene. Start stirring and pre-activate at 20 to 30°C for 20 to 40 minutes. S1.2 Add alkylating agent at 20-30℃. The amount of alkylating agent added is 1.05-1.30 times the molar amount of methyl 3-hydroxy-4-nitrobenzene. Control the addition time to 30-90 min. After the addition is completed, raise the temperature to 80-90℃ and keep it at the temperature for 4-8 h. Take a sample every 1-2 h during the reaction until the residual amount of methyl 3-hydroxy-4-nitrobenzene drops to the preset range and the reaction ends. S1.3 After the reaction is complete, N,N-dimethylformamide is distilled off under reduced pressure at -0.08 to -0.095 MPa. The temperature is controlled at 55 to 75°C during the distillation process. After the residual amount of N,N-dimethylformamide is reduced to the preset range, 1.0 to 2.5 mol / L of alkaline solution is added. The amount of alkaline solution added is 1.1 to 1.8 times the theoretical molar amount of methyl ester. The reaction is continued at 45 to 65°C for 1 to 3 hours. S1.4 After the reaction is complete, the temperature is lowered to 10-25℃, and then 15%-25% hydrochloric acid solution is added dropwise for acidification to lower the pH to 1.5-2.

5. At the same time, the temperature is lowered to 5-15℃ and kept at this temperature for aging for 1-3 hours to induce crystallization. S1.5 After crystallization, the filter cake is first washed with purified water at 5-15℃ 1-3 times, and then washed with 10%-30% volume fraction of low temperature ethanol aqueous solution 1-2 times. After washing, the filter cake is placed in vacuum drying at 40-55℃ and -0.06--0.09MPa for 6-12 hours to obtain 3-butoxy-4-nitrobenzoic acid.

3. A method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1 or 2, characterized in that, In step S1, the alkaline accelerator includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide; the alkylating agent includes at least one of bromobutane, chlorobutane, iodobutane, p-toluenesulfonate, methanesulfonate, and di-n-butyl sulfate; and the alkaline solution includes at least one of aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution, aqueous sodium bicarbonate solution, and ammonia solution.

4. The method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1, characterized in that, Step S2 includes: S2.1 Add toluene to 3-butoxy-4-nitrobenzoic acid, the amount of toluene being 4 to 10 times the mass of 3-butoxy-4-nitrobenzoic acid. Add alkaline accelerator that has been dried at 100 to 130°C for 2 to 6 hours, the amount of which is 1.0 to 2.5 times the molar mass of 3-butoxy-4-nitrobenzoic acid. Start stirring and introduce a small amount of nitrogen for protection. Pre-stir at 25 to 40°C for 20 to 50 minutes. S2.2 Add 2-diethylaminochloroethane hydrochloride at 25-35℃. The amount of 2-diethylaminochloroethane hydrochloride added is 1.05-1.50 times the molar amount of 3-butoxy-4-nitrobenzoic acid. Control the addition time to 30-120 min. Maintain the stirring speed at 150-400 rpm during the addition process. After the addition is completed, continue stirring for 20-40 min. S2.3 After stirring, heat to 100-115℃ and reflux for 4-10 hours. Separate water continuously using a water separator. Take a sample every 1-2 hours during the reaction until the residual amount of 3-butoxy-4-nitrobenzoic acid drops to the preset range and the reaction ends. S2.4 After the reaction is complete, cool to 45-70℃ and perform hot filtration to obtain a clear filtrate. Add anhydrous ethanol to the clear filtrate, the amount of anhydrous ethanol added is 10%-40% of the mass of the clear filtrate. After stirring evenly, add an acid-releasing agent dropwise at 20-35℃. The amount of acid-releasing agent added is 0.9-1.2 times the molar amount of 2-diethylaminochloroethane hydrochloride. Control the dropping time to 30-90 min. During the dropping process, maintain the temperature not higher than 35℃. After the dropping is completed, continue the reaction for 0.5-2 h. S2.5 After the reaction is complete, the temperature is lowered to 0-10℃ and kept at this temperature for aging for 1-4 hours to induce crystallization. After crystallization, the slurry is filtered and the filter cake is washed 1-3 times with a mixture of low-temperature toluene and low-temperature anhydrous ethanol. After washing, the filter cake is placed in a vacuum dryer at 30-45℃ and -0.06--0.09MPa for 4-10 hours to obtain 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl ester hydrochloride.

5. A method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1 or 4, characterized in that, In step S2, the alkaline promoter includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide, and the acid-releasing agent includes at least one of acetyl chloride, propionyl chloride, butyryl chloride, oxalyl chloride, and thionyl chloride.

6. The method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1, characterized in that, Step S3 includes: S3.1 Add toluene and purified water to 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. The amount of toluene added is 4 to 10 times the mass of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride, and the amount of purified water added is 1 to 4 times the mass of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. Then add an alkaline accelerator. The amount of alkaline accelerator added is 1.0 to 2.5 times the molar amount of 3-butoxy-4-nitrobenzoic acid-2-(diethylamino)ethyl hydrochloride. Stir at 20 to 35°C for 0.5 to 2 hours. S3.2 After stirring, centrifuge to separate the organic phase and the aqueous phase. Then, use toluene to perform 1 to 3 additional extractions on the aqueous phase, with each addition of toluene being 10% to 40% of the initial amount. After combining the organic phases, stir at 25 to 40°C for 10 to 30 minutes, and then dehydrate and filter to obtain a clear organic phase. S3.3 Under nitrogen protection, add palladium on carbon catalyst to the clear organic phase. The amount of palladium on carbon catalyst added is 2% to 10% of the mass of the clear organic phase. After the addition is completed, replace with nitrogen 1 to 3 times, and then replace with hydrogen 1 to 3 times. Then control the system temperature at 20 to 40°C and the hydrogen pressure at 0.1 to 0.6 MPa. S3.

4. Introduce hydrogen gas to carry out the reduction reaction for 2-6 hours. During the reaction, control the stirring speed at 200-600 rpm. After the reaction is completed, stop the hydrogen supply and replace the residual hydrogen gas in the reactor with nitrogen gas. Cool the reaction liquid to 20-35℃ and then filter it to remove the palladium on carbon catalyst. Wash the filter cake with toluene 1-2 times. Combine the filtrates to obtain a clear reduced liquid. S3.5 Add anhydrous ethanol to the clarified reducing solution. The amount of anhydrous ethanol added is 10% to 50% of the mass of the clarified reducing solution. After the addition is completed, continue stirring for 0.5 to 2 hours and induce crystallization at 10 to 25°C. Then, further cool down to 0 to 10°C and keep it at that temperature for 1 to 4 hours to obtain crude oxybuprocaine crystal slurry. S3.

6. The crude oxybuprocaine slurry is filtered and the filter cake is washed 1 to 3 times with low-temperature anhydrous ethanol or a mixture of low-temperature toluene and anhydrous ethanol. After washing, the filter cake is pre-dried at 25 to 40°C and -0.05 to -0.09 MPa for 2 to 8 hours to obtain crude oxybuprocaine. S3.7 Add toluene and anhydrous ethanol to crude oxybuprocaine. The amount of toluene added is 2 to 8 times the mass of crude oxybuprocaine, and the amount of anhydrous ethanol added is 1 to 6 times the mass of crude oxybuprocaine. Heat to 70 to 95°C and reflux to dissolve until a clear solution is formed. S3.

8. Perform hot filtration at 70–90℃, then cool the filtrate to 35–50℃ and keep it at that temperature for 0.5–1.5 h, then continue to cool it to 0–10℃ and keep it at that temperature for 1–4 h to induce crystallization. After crystallization, filter the crystal slurry by vacuum filtration, and wash the filter cake 1–3 times with a mixture of low-temperature toluene and anhydrous ethanol or low-temperature anhydrous ethanol. After washing, place the filter cake under vacuum drying at 30–50℃ and -0.06–-0.09 MPa for 6–12 h to obtain oxybuprocaine hydrochloride.

7. A method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1 or 6, characterized in that, In step S3, the alkaline promoter includes at least one of anhydrous potassium carbonate, anhydrous sodium carbonate, cesium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide, and the palladium-on-carbon catalyst includes at least one of 5% palladium-on-carbon catalyst, 10% palladium-on-carbon catalyst, 15% palladium-on-carbon catalyst, 20% palladium-on-carbon catalyst, wet palladium-on-carbon catalyst, and dry palladium-on-carbon catalyst.

8. The method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1, characterized in that, Step S4 includes: S4.1 Stir and mix the buffer component and the osmosis regulating component, controlling the stirring speed at 100-300 rpm, and stir for 10-40 minutes to form a buffer aqueous phase; S4.2 Add oxybuprocaine hydrochloride to the buffer aqueous phase. The amount of oxybuprocaine hydrochloride added is 0.20% to 0.50% of the buffer aqueous phase. Control the temperature at 10 to 25°C and the stirring speed at 150 to 350 rpm. Stir for 10 to 30 minutes to obtain the drug solution. S4.3 Add an inclusion agent to the drug solution. The amount of inclusion agent added is 2 to 10 times the mass of oxybuprofen hydrochloride. Control the system temperature at 15 to 30°C and the stirring speed at 150 to 400 rpm. Continue stirring for 0.5 to 3 hours. S4.4 Continue to add the repair auxiliary components, control the temperature at 4-10℃, stir and mix for 0.5-2 hours, adjust the pH and osmotic pressure, control the pH at 6.4-7.2, after adjustment, let it stand at 4-15℃ for 10-60 minutes to degas, and obtain the final solution; S4.

5. The final solution is pre-filtered through a 0.45μm filter membrane and then filtered through a 0.22μm filter membrane. It is then aseptically filled and sealed. After filling, it is placed at 2-8℃ for 12-72 hours to mature at low temperature to obtain a pharmaceutical preparation containing oxybuprocaine hydrochloride.

9. A method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 1 or 8, characterized in that, In step S4, the buffer component includes at least one of sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, citric acid, and sodium citrate; the osmotic conditioning component includes at least one of sodium chloride, mannitol, glucose, trehalose, and sorbitol; the inclusion agent includes at least one of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, methyl-β-cyclodextrin, and γ-cyclodextrin; and the repair auxiliary component includes at least one of recombinant human epidermal growth factor, sodium hyaluronate, trehalose, carboxymethyl chitosan, hydroxypropyl methylcellulose, and polyvinyl alcohol.

10. A pharmaceutical preparation containing oxybuprocaine hydrochloride, characterized in that, It is prepared by the method for preparing a pharmaceutical preparation containing oxybuprocaine hydrochloride as described in any one of claims 1-9.

11. A pharmaceutical preparation containing oxybuprocaine hydrochloride according to claim 10, characterized in that, The pharmaceutical preparation includes oxybuprocaine hydrochloride, buffer components, osmotic modifiers, inclusion agents, and repair adjuvants; among which, Obuprocaine hydrochloride is used for local anesthesia of the ocular surface to relieve pain in the cornea and conjunctiva. Buffer components are used to control the pH stability of pharmaceutical preparations; Osmotic adjustment components are used to adjust the osmotic pressure of pharmaceutical preparations to make it close to the osmotic pressure of tears; Inclusion agents are used to form inclusion systems with oxybuprocaine hydrochloride, thereby improving the stability of oxybuprocaine hydrochloride in formulations; The repair and auxiliary components are used to improve the retention of the medication on the ocular surface.

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