A paeonol-6-o'-benzenesulfonic acid ester fat emulsion injection of a specific complex carrier and a preparation method thereof

Abstract

This invention relates to the pharmaceutical field, specifically to a paeoniflorin-6-O'-benzenesulfonate fat emulsion injection with a specific compound carrier and its preparation method. The formulation of this invention comprises the following components in the indicated mass ratios: 1.5%–5.5% solid dispersion, 10%–30% oil phase solvent, 3%–10% isotonic adjuster, 0.1%–1% pH adjuster, and the balance being water for injection; the solid dispersion is formed by mixing paeoniflorin-6-O'-benzenesulfonate with a compound carrier. This invention first prepares paeoniflorin-6-O'-benzenesulfonate into a solid dispersion, and then prepares a fat emulsion to increase the lipid solubility of paeoniflorin-6-O'-benzenesulfonate, thus solving the problem that paeoniflorin-6-O'-benzenesulfonate is insoluble in the oil phase and cannot be used to prepare fat emulsion injections. It also improves the stability and membrane permeability of easily degradable paeoniflorin-6-O'-benzenesulfonate, reducing the dosage. The prepared particles are smaller, more stable, have higher drug loading, and higher encapsulation efficiency. Furthermore, it solves the problem of slow absorption in the gastrointestinal tract, and by using injection, it significantly improves bioavailability.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to a paeoniflorin-6-O'-benzenesulfonate fat emulsion injection with a specific compound carrier and its preparation method. Background Technology

[0002] Paeoniflorin is one of the main pharmacologically active components of total paeoniflorin, possessing various pharmacological activities and currently used in the clinical treatment of rheumatoid arthritis. However, due to its weak lipophilicity, even after entering the bloodstream, it is difficult for paeoniflorin to cross biological membranes and distribute to diseased tissues to exert its therapeutic effect. Studies have reported that the reaction of paeoniflorin as a lead compound with benzenesulfonyl chloride to prepare paeoniflorin-6-O'-benzenesulfonate not only significantly improves its lipophilicity but also retains the anti-inflammatory and immunomodulatory activities of paeoniflorin. Patent number [201910010987.8] indicates that paeoniflorin-6-O'-benzenesulfonate can exert a strong immunomodulatory effect, inhibiting angiogenesis mediated by tumor-associated macrophages (TAMs), thereby inhibiting the occurrence and development of gliomas. Compared with paeoniflorin, paeoniflorin-6-O'-benzenesulfonate has better drug absorption, exhibiting slower drug clearance, longer retention time, and higher bioavailability. Therefore, paeoniflorin-6-O'-benzenesulfonate has great potential for drug development.

[0003] The physicochemical properties of paeoniflorin-6-O'-benzenesulfonate were examined, revealing its strong hygroscopicity, resulting in a viscous consistency after absorbing moisture. When paeoniflorin-6-O'-benzenesulfonate was prepared into conventional tablets and administered orally to mice, most of the active ingredient was excreted in the feces, resulting in low blood concentrations. This is likely due to the drug's high viscosity in the gastrointestinal tract, leading to encapsulation with excipients and hindering effective absorption. Furthermore, paeoniflorin-6-O'-benzenesulfonate is poorly soluble in water and almost insoluble in oils, but readily soluble in highly polar organic solvents such as ethanol and methanol. It exhibits poor stability and is easily degraded at high temperatures by reacting with hydroxyl-containing organic solvents. Therefore, selecting an appropriate dosage form is crucial for maximizing the efficacy of paeoniflorin-6-O'-benzenesulfonate.

[0004] Conventional oral formulations are not conducive to the absorption of paeoniflorin-6-O'-benzenesulfonate, resulting in low bioavailability. Therefore, developing an enteral administration route has become a viable option for the formulation of paeoniflorin-6-O'-benzenesulfonate. Intravenous injection not only ensures 100% bioavailability but also allows the drug to enter the bloodstream unchanged to exert its therapeutic effect. However, the unique solubility of paeoniflorin-6-O'-benzenesulfonate makes it impossible to prepare it into an injectable solution using a suitable solvent. Fat emulsions, as drug delivery carriers, can solve the problem of poorly soluble drug administration because the oil droplets in the emulsion can be massively phagocytosed by macrophages and selectively accumulated at sites of inflammation. This not only helps improve the bioavailability and cell penetration of drugs with low water solubility but also reduces drug concentrations in other tissues, minimizing adverse drug reactions and improving efficacy. However, because paeoniflorin-6-O'-benzenesulfonate is almost insoluble in the oil phase, and its conventional good solvents all contain hydroxyl groups, which are detrimental to its stability, it is impossible to directly prepare paeoniflorin-6-O'-benzenesulfonate into a fat emulsion injection using conventional methods. Currently, there are no technical reports on injectable paeoniflorin-6-O'-benzenesulfonate formulations. Summary of the Invention

[0005] The main objective of this invention is to disclose a paeoniflorin-6-O'-benzenesulfonate fat emulsion injection and its preparation method. Addressing the unique physicochemical properties of paeoniflorin-6-O'-benzenesulfonate and the shortcomings of conventional formulations and processes, this invention aims to solve the technical problem of selecting a suitable formulation and preparation process to prepare a fat emulsion injection of paeoniflorin-6-O'-benzenesulfonate with small particle size, high drug loading and encapsulation efficiency, and good stability.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] A paeoniflorin-6-O'-benzenesulfonate fat emulsion injection with a specific compound carrier comprises the following components in the following mass ratio: 1.5% to 5.5% solid dispersion, 10% to 30% oil phase solvent, 3% to 10% isotonic adjuster, 0.1% to 1% pH adjuster, and the balance being water for injection; wherein the solid dispersion is formed by paeoniflorin-6-O'-benzenesulfonate and carrier material.

[0008] Paeoniflorin-6-O'-benzenesulfonate is almost insoluble in the oil phase, has poor thermal stability, and conventional good solvents contain hydroxyl groups, which are detrimental to its stability. Therefore, it is impossible to directly prepare paeoniflorin-6-O'-benzenesulfonate into a fat emulsion injection using conventional methods. Solid dispersions are dispersion systems formed by highly dispersed and uniformly dispersed drugs within carrier molecules. They not only increase the affinity of the drug for carrier molecules and the oil phase but also improve the stability and membrane permeability of easily degradable compounds, significantly enhancing bioavailability.

[0009] Preferably, the preparation of the solid dispersion includes: dissolving paeoniflorin-6-O'-benzenesulfonate and the compounded carrier in a good solvent, then adding it to a poor solvent and stirring to mix evenly, removing the good solvent, and then further drying to obtain the solid dispersion.

[0010] Conventional methods for preparing solid dispersions, such as melt processing, solvent extraction, and grinding, involve relatively harsh reaction conditions that significantly impact the stability of the active ingredient. This invention first employs an antisolvent co-precipitation method to prepare a paeoniflorin-6-O'-benzenesulfonate solid dispersion. This method uses mild reaction conditions, avoiding degradation of paeoniflorin-6-O'-benzenesulfonate due to high heat. Furthermore, the good solvent used in the preparation process is self-volatile and easily removed, reducing solvent residue in the dispersion. The obtained solid dispersion is then further prepared into a paeoniflorin-6-O'-benzenesulfonate fat emulsion injection.

[0011] Preferably, in the solid dispersion, the mass ratio of paeoniflorin-6-O'-benzenesulfonate to the composite carrier is 1:(1-9); the concentration of paeoniflorin-6-O'-benzenesulfonate in the good solvent is 0-0.5 g / mL; the concentration of the composite carrier in the good solvent is 2-6 g / mL; the ratio of the good solvent to the poor solvent is 1:2-5; the stirring is carried out at room temperature, the stirring speed is 800 rpm-1200 rpm, and the stirring time is 0.5-2 hours; the good solvent is removed by vacuum drying; and the further drying method is freeze drying.

[0012] Preferably, the compound carrier comprises multiples of copovidone, polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer, caprylic / capric acid PEG-glycerol ester, polyglycerol fatty acid ester, and vitamin E PEG-succinate; the good solvent comprises one or more of methanol, ethanol, and isopropanol; the poor solvent comprises water; the oil phase solvent comprises one or more of long-chain triglycerides and medium-chain triglycerides, the long-chain triglycerides comprising one or more of soybean oil, olive oil, and fish oil for injection, and the medium-chain triglycerides comprising triglycerides of medium-chain fatty acids having 6 to 14 carbon atoms or mixtures thereof; the osmotic pressure regulator comprises one or more of glucose, sucrose, lactose, trehalose, mannitol, and sorbitol; and the pH regulator comprises one or more of sodium hydroxide, sodium bicarbonate, and sodium carbonate.

[0013] Preferably, the compound carrier comprises a composite of octanoic acid, caprylic acid, decanoic acid, polyethylene glycol glycerol ester, and other carriers; the good solvent is ethanol; the long-chain triglyceride is soybean oil for injection; the medium-chain triglyceride comprises triglycerides composed of caprylic acid and caprylic acid, or mixtures thereof; the osmotic pressure regulator is sucrose; and the pH regulator is sodium hydroxide.

[0014] Preferably, the other carriers include one or more of vitamin E polyethylene glycol succinate, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate graft copolymer, and polyglycerol fatty acid ester; the oil phase solvent includes long-chain triglycerides and medium-chain triglycerides compounded in a mass ratio of 0.5 to 1:1.

[0015] Preferably, the other carrier includes vitamin E polyethylene glycol succinate; the compound carrier includes the polyethylene glycol glyceride caprylate and the vitamin E polyethylene glycol succinate compounded in a mass ratio of 0.5 to 2:1.

[0016] Carrier materials are an important component of solid dispersions. They maintain the stability of solid dispersions by reducing intermolecular migration, increasing drug-carrier interactions, and reducing the aggregation of active molecules. Polymer carrier materials possess good resistance to shock, stability, and storage properties. Considering the unique physicochemical properties of paeoniflorin-6-O'-benzenesulfonate, fat emulsion injections prepared by forming solid dispersions with a polymer carrier material exhibit smaller particle sizes and more stable coefficients. Using a single carrier material has significant limitations. For example, povidone's high viscosity can hinder dissolution, and excessive use of polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer can form a gel layer that impedes drug release. Combining carriers, especially a combination of polyethylene glycol glycerol octanoate and polyethylene glycol succinate at a mass ratio of 0.5–2:1, can effectively regulate drug dissolution rates, reduce drug hygroscopicity, and achieve extremely high encapsulation efficiency and drug content.

[0017] Preferably, the other carrier is a polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer or a polyglycerol fatty acid ester; the compound carrier includes the polyethylene glycol glycerol ester of caprylic / capric acid and the other carrier compounded in a mass ratio of 1:1.

[0018] In the experiment, it was found that the combined use of polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer or polyglycerol fatty acid ester and octanoic acid-capric acid-polyethylene glycol glycerol ester, especially when combined in a mass ratio of 1:1, can also achieve high encapsulation efficiency and drug content, and can regulate the drug dissolution rate and reduce the drug's hygroscopicity to a certain extent.

[0019] A method for preparing the above-mentioned paeoniflorin-6-O'-benzenesulfonate fat emulsion injection includes the following steps:

[0020] A. Add the solid dispersion to the oil phase solvent in proportion, heat and stir until completely dissolved to form an oil phase;

[0021] B. Mix the isotonicity regulator, the pH regulator and an appropriate amount of water for injection in proportion, and heat until completely dissolved to form an aqueous phase;

[0022] C. Slowly add the oil phase to the aqueous phase, shear it, and then add the remaining water for injection to obtain the colostrum;

[0023] D. Homogenize the colostrum to obtain the final milk;

[0024] E. The final emulsion is filtered and sterilized, bottled, filled with nitrogen, and sealed to obtain the paeoniflorin-6-O'-benzenesulfonate fat emulsion injection.

[0025] Preferably, in step A, the heating temperature is 50-60℃; in step B, the heating temperature is 50-60℃; in step C, the shearing speed is 8000-15000 rpm, the shearing time is 8-20 min, and the shearing temperature is 50-60℃; in step D, the homogenization temperature is 50-60℃, and the cycle is performed 1-4 times at a pressure of 200-600 bar, and 4-8 times at a pressure of 800-1000 bar.

[0026] Preferably, in step B, the amount of water for injection accounts for 30% to 50% of the total amount of water for injection by mass; in step C, the amount of water for injection accounts for 50% to 70% of the total amount of water for injection by mass.

[0027] Compared with the prior art, implementing the present invention has the following beneficial effects:

[0028] (1) The present invention first prepares paeoniflorin-6-O'-benzenesulfonate into a solid dispersion, and then prepares fat emulsion, which increases the affinity of the drug with the compound carrier and with the oil phase, and solves the problem that paeoniflorin-6-O'-benzenesulfonate is insoluble in the oil phase and cannot be used to prepare fat emulsion injection.

[0029] (2) This method improves the stability and membrane permeability of easily degradable paeoniflorin-6-O'-benzenesulfonate, and reduces the dosage.

[0030] (3) This method produces smaller particle size, higher stability and encapsulation efficiency than the method using a cosolvent.

[0031] (4) The good solvent used in this method is self-volatile and easy to remove, which can reduce solvent residue in the dispersion and improve the safety of clinical drug use.

[0032] (5) It solves the problem of low and slow absorption due to gastrointestinal tract, and adopts injection administration, which significantly improves bioavailability. Attached Figure Description

[0033] Figure 1The effect of different carrier materials on the dissolution rate of paeoniflorin-6-O'-benzenesulfonate solid dispersion;

[0034] Figure 2 Emulsification index of carrier materials with different proportions;

[0035] Figure 3 The effect of different carrier material ratios on the dissolution rate of paeoniflorin-6-O'-benzenesulfonate solid dispersion;

[0036] Figure 4 Effect of different carrier material dosages on the dissolution rate of paeoniflorin-6-O'-benzenesulfonate solid dispersion. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0038] Example 1

[0039] Screening of carrier materials

[0040] Excellent solid dispersion carrier materials can improve drug stability and have strong dispersing ability by interacting with drugs and reducing molecular migration. 2g of copovidone for injection, polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer, caprylic / capric acid PEG-glycerol, polyglycerol fatty acid ester, vitamin E PEG-succinate, and 1g of paeoniflorin-6-O'-benzenesulfonate were dissolved in 1mL of ethanol and added to 3mL of water, stirred for 2 hours. The uniformly mixed paeoniflorin-6-O'-benzenesulfonate, caprylic / capric acid PEG-glycerol, and vitamin E PEG-succinate solution was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dissolution rate of the obtained sample was then determined.

[0041] The results are as follows Figure 1 As shown, there are significant differences in the dissolution rates of paeoniflorin-6-O'-benzenesulfonate solid dispersions prepared with different carrier materials. Among them, the cumulative dissolution rates of the solid dispersions of octanoic acid-capric acid-polyethylene glycol glycerol ester and vitamin E-polyethylene glycol succinate group are almost 100% after 60 minutes, while the cumulative dissolution rates of the solid dispersions of polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate graft copolymer and polyglycerol fatty acid ester group are higher than 80% after 60 minutes.

[0042] Example 2

[0043] Investigation of the optimal ratio of composite carrier materials

[0044] Polyethylene glycol glycerol caprylate and polyethylene glycol succinate (PEG) were dissolved and uniformly dispersed in pure water to prepare 1 mg / mL solutions of PEG and PEG. Mixed solutions were prepared by mixing the two in different mass ratios (PEG:PEG = 4:1, 2:1, 1:1, 1:2, 1:4), and thoroughly mixed. 2 mL of each mixed solution, along with the PEG:PEG solution and the PEG:PEG solution, were placed in test tubes. Soybean oil was added to each test tube at an oil-to-water ratio of 1:1. The mixtures were shaken and allowed to stand at room temperature. The emulsification activity was characterized by the emulsification index. Emulsification index = emulsion height / total liquid height.

[0045] The results are as follows Figure 2 As shown, the emulsification index of polyethylene glycol glycerol caprylate or polyethylene glycol succinate alone is relatively low, while the emulsification index of the mixture of the two is significantly improved, indicating that polyethylene glycol glycerol caprylate and polyethylene glycol succinate have a good synergistic emulsification effect.

[0046] A fixed mass ratio of paeoniflorin-6-O'-benzenesulfonate to total carrier materials (polyethylene glycol glycerol octanoate and polyethylene glycol succinate of vitamin E) of 1:2 was used. Solid dispersions were prepared with carrier material mass ratios of 4:1, 2:1, 1:1, 1:2, and 1:4, and the dissolution rate was determined. The results are as follows: Figure 3 As shown, when the mass ratio of PEGylated caprylic / capric acid to PEGylated vitamin E is 2:1, 1:1, and 1:2, the dissolution of the solid dispersion is higher, with a dissolution rate of over 90% after 60 minutes. Therefore, the mass ratio of PEGylated caprylic / capric acid to PEGylated vitamin E is selected as (0.5–2):1.

[0047] Example 3

[0048] Concentration study of paeoniflorin-6-O'-benzenesulfonate in good solvents

[0049] 0.1, 0.3, 0.5, 0.7, and 0.9 g of paeoniflorin-6-O'-benzenesulfonate, 3 g of PEG-3-octanoic acid-capric acid, and 3 g of PEG-3-vitamin E succinate were dissolved in 1 mL of ethanol, and then added to 3 mL of water and stirred for 2 h. The well-mixed solutions of paeoniflorin-6-O'-benzenesulfonate, PEG-3-octanoic acid-capric acid, and PEG-3-vitamin E succinate were vacuum dried to remove the ethanol, and then freeze-dried to obtain paeoniflorin-6-O'-benzenesulfonate solid dispersions. The equilibrium solubility of the solid dispersions in water for each group was determined.

[0050] Table 1. Equilibrium solubility of paeoniflorin-6-O'-benzenesulfonate solid dispersions with different formulations

[0051]

[0052] The results are shown in Table 1. Compared with the equilibrium solubility of paeoniflorin-6-O'-benzenesulfonate in Group 6 without a carrier, the solubility of paeoniflorin-6-O'-benzenesulfonate significantly increased after being prepared into solid dispersions with PEG-3 (Groups 1-3) containing PEG-3-octanoic acid, PEG-3-caprylic acid, and PEG-3-vitamin E. However, when the amount of paeoniflorin-6-O'-benzenesulfonate exceeded 0.5 mg / mL (Groups 4 and 5), the drug precipitated and could not be prepared into a solid dispersion. Therefore, the concentration of paeoniflorin-6-O'-benzenesulfonate in a good solvent should be below 0.5 g / mL.

[0053] Example 4

[0054] Concentration study of carrier material in good solvent

[0055] Since the amount of carrier material directly affects the solubility and other properties of paeoniflorin-6-O'-benzenesulfonate, the mass ratio of caprylic / capric acid polyethylene glycol glyceride and vitamin E polyethylene glycol succinate was fixed at 1:1, and the concentration of paeoniflorin-6-O'-benzenesulfonate in ethanol was fixed at 0.2 g / mL. The total concentrations of caprylic / capric acid polyethylene glycol glyceride and vitamin E polyethylene glycol succinate in ethanol were set at 0–10 g / mL to prepare solid dispersions, and the dissolution rate of the prepared samples was determined.

[0056] The results are as follows Figure 4 As shown, preparing a solid dispersion of paeoniflorin-6-O'-benzenesulfonate with polyethylene glycol glycerol ester (PEG) and vitamin E PEG succinate significantly improved the dissolution rate of paeoniflorin-6-O'-benzenesulfonate. This is due to the improved drug dispersion and increased specific surface area. However, it was observed that if the amount of carrier material was too large, the dissolution rate decreased. This may be because a large amount of carrier material forms a diffusion layer, significantly enhancing the encapsulation ability of paeoniflorin-6-O'-benzenesulfonate, while slowing the release of the drug from the solid dispersion, affecting the stability of the solid dispersion, and thus relatively reducing its dissolution rate. Therefore, based on the effect of different amounts of carrier material on the dissolution rate of paeoniflorin-6-O'-benzenesulfonate solid dispersions, the total concentration of the carrier material in a good solvent was selected to be 2–6 g / mL.

[0057] Example 5

[0058] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0059] 10g of paeoniflorin-6-O'-benzenesulfonate, 22.5g of octanoic acid-capric acid-capric acid-polyethylene glycol glycerol ester, and 22.5g of vitamin E-polyethylene glycol succinate were dissolved in 50mL of ethanol and added to 100mL of water, then stirred for 2 hours. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, octanoic acid-capric acid-capric acid-polyethylene glycol glycerol ester, and vitamin E-polyethylene glycol succinate was vacuum dried to remove the ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve as the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and heated under nitrogen protection. The mixture was stirred at 60°C to dissolve the oil phase, which was then used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60°C, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C–50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0060]

[0061] Example 6

[0062] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0063] 10g of paeoniflorin-6-O'-benzenesulfonate, 15g of PEG-30 g of vitamin E succinate, and 30g of vitamin E succinate were dissolved in 20mL of ethanol and added to 60mL of water, then stirred for 2 hours. The homogeneous mixture of paeoniflorin-6-O'-benzenesulfonate, PEG-30 g of PEG-30 g of vitamin E succinate was vacuum dried to remove the ethanol, and then freeze-dried to obtain a solid dispersion of paeoniflorin-6-O'-benzenesulfonate. The dried solid dispersion was added to 100g of medium-chain triglyceride oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve, forming the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and heated to 60℃ under nitrogen protection, then stirred. The oil phase was dissolved and used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at a temperature of 60°C, a rotation speed of 12000 rpm, and a shearing time of 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C to 50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0064]

[0065] Example 7

[0066] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0067] 10g of paeoniflorin-6-O'-benzenesulfonate, 27g of PEG-3-caprylate and 18g of PEG-3-vitamin E succinate were dissolved in 20mL of ethanol and added to 60mL of water, then stirred for 2 hours. The homogeneous mixture of paeoniflorin-6-O'-benzenesulfonate, PEG-3-caprylate, and PEG-3-vitamin E succinate was vacuum dried to remove the ethanol, and then freeze-dried to obtain a solid dispersion of paeoniflorin-6-O'-benzenesulfonate. The dried solid dispersion was added to 100g of medium-chain triglyceride oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve, forming the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and heated to 60℃ under nitrogen protection, then stirred. The oil phase was dissolved and used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at a temperature of 60°C, a rotation speed of 12000 rpm, and a shearing time of 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C to 50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0068]

[0069] Example 8

[0070] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0071] 5g of paeoniflorin-6-O'-benzenesulfonate, 5g of caprylic / capric decanoic acid polyethylene glycol glycerol ester, and 5g of vitamin E polyethylene glycol succinate were dissolved in 20mL of ethanol and added to 60mL of water, stirring for 1 hour. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, caprylic / capric decanoic acid polyethylene glycol glycerol ester, and vitamin E polyethylene glycol succinate was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve as the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, heated to 60℃ under nitrogen protection, and stirred. The oil phase was dissolved and used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at a temperature of 60°C, a rotation speed of 12000 rpm, and a shearing time of 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C to 50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0072]

[0073] Example 9

[0074] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0075] 5g of paeoniflorin-6-O'-benzenesulfonate, 10g of PEG-3-caprylate, and 10g of PEG-3-vitamin E succinate were dissolved in 20mL of ethanol and added to 60mL of water, then stirred for 1 hour. The homogeneous mixture of paeoniflorin-6-O'-benzenesulfonate, PEG-3-caprylate, and PEG-3-vitamin E succinate was vacuum dried to remove the ethanol, and then freeze-dried to obtain a solid dispersion of paeoniflorin-6-O'-benzenesulfonate. The dried solid dispersion was added to 100g of medium-chain triglyceride oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve, forming the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and heated to 60℃ under nitrogen protection, then stirred. The oil phase was dissolved and used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at a temperature of 60°C, a rotation speed of 12000 rpm, and a shearing time of 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C to 50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0076]

[0077] Example 10

[0078] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0079] 5g of paeoniflorin-6-O'-benzenesulfonate, 15g of PEG-3-caprylate and PEG-3-caprylate, and 15g of PEG-3-vitamin E succinate were dissolved in 20mL of ethanol and added to 60mL of water, then stirred for 1 hour. The homogeneous mixture of paeoniflorin-6-O'-benzenesulfonate, PEG-3-caprylate, and PEG-3-vitamin E succinate was vacuum dried to remove the ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried solid dispersion was added to 100g of medium-chain triglyceride oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve, forming the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and heated to 60℃ under nitrogen protection, then stirred. The oil phase was dissolved and used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at a temperature of 60°C, a rotation speed of 12000 rpm, and a shearing time of 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C to 50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0080]

[0081]

[0082] Example 11

[0083] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0084] 5g of paeoniflorin-6-O'-benzenesulfonate, 20g of octanoic acid-capric acid-decanoic acid polyethylene glycol glycerol ester, and 20g of vitamin E polyethylene glycol succinate were dissolved in 20mL of ethanol and added to 60mL of water, stirring for 1 hour. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, octanoic acid-capric acid-decanoic acid-decanoic acid ester, and vitamin E polyethylene glycol succinate was vacuum dried to remove ethanol, and then freeze-dried to obtain a solid dispersion of paeoniflorin-6-O'-benzenesulfonate. The dried solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred under nitrogen protection to dissolve as the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, heated to 60℃ under nitrogen protection, and stirred. The oil phase was dissolved and used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at a temperature of 60°C, a rotation speed of 12000 rpm, and a shearing time of 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C to 50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0085]

[0086] Example 12

[0087] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0088] 10g of paeoniflorin-6-O'-benzenesulfonate, 22.5g of polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer, and 22.5g of caprylic / capric acid glycerol ester were dissolved in 50mL of ethanol and added to 100mL of water, then stirred for 2 hours. The uniformly mixed solution of paeoniflorin-6-O'-benzenesulfonate, caprylic / capric acid glycerol ester, and polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred until dissolved under nitrogen protection to form the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and then dissolved under nitrogen protection. Under nitrogen protection, the mixture was heated to 60°C and stirred to dissolve the oil phase, which was then used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60°C, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30°C–50°C. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22 μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0089]

[0090] Example 13

[0091] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0092] 10g of paeoniflorin-6-O'-benzenesulfonate, 22.5g of octanoic acid-capric acid-decaloic acid polyethylene glycol glycerol ester, and 22.5g of polyglycerol fatty acid ester were dissolved in 50mL of ethanol and added to 100mL of water, then stirred for 2 hours. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, octanoic acid-capric acid-decaloic acid ester, and polyglycerol fatty acid ester was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred until dissolved under nitrogen protection to form the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and heated to 60℃ under nitrogen protection. The solution was dissolved by stirring at ℃, forming the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60℃, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the promulgation. Under nitrogen protection, the homogenization temperature was controlled at 30℃~50℃. The promulgation was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was sterilized by passing it through a 0.22μm filter membrane, protected with nitrogen, and sealed to obtain the finished product.

[0093]

[0094]

[0095] Comparative Example 1

[0096] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion not prepared as a solid dispersion

[0097] 5g of paeoniflorin-6-O'-benzenesulfonate, 100g of medium-chain triglycerides, and 100g of soybean oil were heated to 60°C and stirred until dissolved, forming the oil phase. 22.5g of PEGylated caprylic / capric acid and 22.5g of PEGylated vitamin E succinate, 50g of sucrose, and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection and heated to 60°C under nitrogen protection, stirring until dissolved, forming the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60°C, 12000rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000mL. After shearing and standing, the drug precipitated and separated into layers, making further preparation impossible. This demonstrates that without pre-prepared solid dispersion, drug precipitation and emulsion separation occur during the shearing step, preventing the preparation of a fat emulsion injection product.

[0098] Comparative Example 2

[0099] Preparation of Paeoniflorin-6-O'-benzenesulfonate Fat Emulsion Using Natural Emulsifiers

[0100] 5g of paeoniflorin-6-O'-benzenesulfonate and 45g of egg yolk lecithin were dissolved in 20mL of ethanol and added to 60mL of water, stirring for 2 hours. The well-mixed paeoniflorin-6-O'-benzenesulfonate and egg yolk lecithin solution was vacuum dried to remove the ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred until dissolved under nitrogen protection to form the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water for injection, and stirred under nitrogen protection. Under nitrogen protection, the oil phase was heated to 60℃ and stirred to dissolve the oil, which became the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60℃, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the primary emulsion. Under nitrogen protection, the homogenization temperature was controlled between 30℃ and 50℃. The primary emulsion was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion could not be sterilized by a 0.22 μm filter membrane. The physicochemical parameters before filtration are shown in the table below. It can be seen that using lecithin as a natural emulsifier for the preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion resulted in large-particle-size and unevenly dispersed emulsions with precipitation.

[0101]

[0102] Comparative Example 3

[0103] Preparation of Paeoniflorin-6-O'-benzenesulfonate Fat Emulsion with a High Vitamin E Polyethylene Glycol Succinate Ratio

[0104] 5g of paeoniflorin-6-O'-benzenesulfonate, 10g of octanoic acid-capric acid-decanoic acid polyethylene glycol glycerol ester, and 35g of vitamin E polyethylene glycol succinate were dissolved in 20mL of ethanol and added to 60mL of water, stirring for 2 hours. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, octanoic acid-capric acid-decanoic acid-decanoic acid ester, and vitamin E polyethylene glycol succinate was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred until dissolved under nitrogen protection to form the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of... In water for injection, under nitrogen protection, the mixture was heated to 60°C and stirred to dissolve the oil phase, which was then used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60°C, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL, yielding the promulgated emulsion. Under nitrogen protection, the homogenization temperature was controlled between 30°C and 50°C. The promulgated emulsion was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion became clear after being filtered through a 0.22 μm filter membrane for sterilization. The physicochemical parameters before filtration are shown in the table below. It can be seen that selecting a high vitamin E polyethylene glycol succinate ratio for the preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion resulted in emulsions with larger particle sizes and uneven dispersion.

[0105]

[0106] Comparative Example 4

[0107] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion with a high ratio of caprylic / capric acid / polyethylene glycol glycerol ester

[0108] 5g of paeoniflorin-6-O'-benzenesulfonate, 35g of octanoic acid-capric acid-decanoic acid polyethylene glycol glycerol ester, and 10g of vitamin E polyethylene glycol succinate were dissolved in 20mL of ethanol and added to 60mL of water, stirring for 2 hours. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, octanoic acid-capric acid-decanoic acid-polyethylene glycol glycerol ester, and vitamin E polyethylene glycol succinate was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred until dissolved under nitrogen protection to form the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water... In water for injection, under nitrogen protection, the mixture was heated to 60°C and stirred to dissolve the oil phase, which was then used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60°C, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the primary emulsion. Under nitrogen protection, the homogenization temperature was controlled between 30°C and 50°C. The primary emulsion was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion became clear after being filtered through a 0.22 μm filter membrane for sterilization. The physicochemical parameters before filtration are shown in the table below. It can be seen that selecting the ratio of caprylic / capric acid to polyethylene glycol glycerol for the preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion resulted in a larger particle size and uneven dispersion of the emulsion.

[0109]

[0110] Comparative Example 5

[0111] Preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion with a high proportion of carrier material

[0112] 5g of paeoniflorin-6-O'-benzenesulfonate, 25g of octanoic acid-capric acid-decanoic acid polyethylene glycol glycerol ester, and 25g of vitamin E polyethylene glycol succinate were dissolved in 20mL of ethanol and added to 60mL of water, stirring for 2 hours. The well-mixed solution of paeoniflorin-6-O'-benzenesulfonate, octanoic acid-capric acid-decanoic acid-decanoic acid ester, and vitamin E polyethylene glycol succinate was vacuum dried to remove ethanol, and then freeze-dried to obtain a paeoniflorin-6-O'-benzenesulfonate solid dispersion. The dried paeoniflorin-6-O'-benzenesulfonate solid dispersion was added to 100g of medium-chain oil and 100g of soybean oil, heated to 60℃, and stirred until dissolved under nitrogen protection to form the oil phase. 50g of sucrose and 1mL of sodium hydroxide (1mol / mL) were added to 600mL of water... In water for injection, the mixture was heated to 60°C under nitrogen protection and stirred to dissolve the oil phase, which was then used as the aqueous phase. Under nitrogen protection, the oil phase was added to the aqueous phase and sheared at 60°C, 12000 rpm for 12 minutes. After shearing, water for injection at the same temperature was added to bring the volume to 1000 mL to obtain the prothrombus. Under nitrogen protection, the homogenization temperature was controlled between 30°C and 50°C. The prothrombus was homogenized twice at 200 bar, twice at 600 bar, and finally six times at 800 bar to obtain the final emulsion. The final emulsion was viscous and could not be sterilized by a 0.22 μm filter membrane. The physicochemical parameters before filtration are shown in the table below. It can be seen that selecting a high proportion of carrier material in the preparation of paeoniflorin-6-O'-benzenesulfonate fat emulsion resulted in a large particle size and uneven dispersion of the emulsion.

[0113]

[0114] Example 1

[0115] HPLC method for determining the drug content and encapsulation efficiency of paeoniflorin-6-O'-benzenesulfonate fat emulsion

[0116] (1) Chromatographic conditions: A C18 column was used with acetonitrile-water (43:57) as the mobile phase, the detection wavelength was 272 nm, and the injection volume was 20 μl.

[0117] (2) Content determination: Take an appropriate amount of paeoniflorin-6-O'-benzenesulfonate fat emulsion into a 100 ml volumetric flask, add methanol to break the emulsion and dilute to the mark to prepare a solution containing approximately 25 μg per ml. Filter through a 0.22 μm microporous membrane, inject 20 μl of the filtrate into a high-performance liquid chromatograph, and determine the paeoniflorin-6-O'-benzenesulfonate content in the paeoniflorin-6-O'-benzenesulfonate fat emulsion using the external standard method.

[0118] (3) Encapsulation efficiency determination: The encapsulation efficiency of paeoniflorin-6-O'-benzenesulfonate fat emulsion was determined by ultrafiltration centrifugation. The total amount of drug in the fat emulsion and the drug content in the aqueous phase were determined separately, and the encapsulation efficiency was calculated by the following formula: Encapsulation efficiency = (1 - drug content in aqueous phase / total drug content in fat emulsion) * 100%

[0119] Determination of drug content in aqueous phase: Accurately pipette 1 ml of paeoniflorin-6-O'-benzenesulfonate fat emulsion into an ultrafiltration centrifuge tube with a molecular weight cutoff of 10000 mw, centrifuge at 4000 rpm for 10 min, add 2 ml of deionized water and centrifuge for another 10 min, transfer the filtrate to a 10 ml volumetric flask and dilute to the mark with mobile phase, inject 20 μL into the high performance liquid chromatograph, and determine the drug content in the aqueous phase of paeoniflorin-6-O'-benzenesulfonate fat emulsion by external standard method. The determination of total drug content in fat emulsion is the same as in "(2) Content Determination".

[0120] Table 2. Results of Paeoniflorin-6-O'-benzenesulfonate fat emulsion detection

[0121]

[0122]

[0123] The test results of paeoniflorin-6-O'-benzenesulfonate fat emulsion are shown in Table 2. Comparative Examples 2-5, although they could also prepare paeoniflorin-6-O'-benzenesulfonate fat emulsion injection products, still exhibited low encapsulation efficiency even at low drug concentrations, with large particle sizes and uneven particle size distribution, leading to drug precipitation and increasing the risk of clinical use. In contrast, Examples 5-13 yielded paeoniflorin-6-O'-benzenesulfonate fat emulsions with encapsulation efficiency exceeding 85% and drug concentrations as high as 10.0 mg / mL. In particular, the paeoniflorin-6-O'-benzenesulfonate fat emulsions using PEG-6-caprylate and PEG-6-vitamin E succinate as the compound carriers had smaller average particle sizes and more uniform particle size distribution. Furthermore, compared to Examples 12 and 13, the encapsulation efficiency of Examples 5-11 reached an astonishing 90% or more. Therefore, the paeoniflorin-6-O'-benzenesulfonate fat emulsion prepared according to the formulation and process of this invention is safe and stable, achieving unexpected results.

[0124] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, any equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. A paeoniflorin-6-O'-benzenesulfonate fat emulsion injection with a specific compound carrier, characterized in that, The product comprises the following components in the indicated mass ratios: 1.5%–5.5% solid dispersion, 10%–30% oil phase solvent, 3%–10% isotonicity adjuster, 0.1%–1% pH adjuster, with the balance being water for injection; the solid dispersion is formed by mixing paeoniflorin-6-O'-benzenesulfonate with a compound carrier. The preparation of the solid dispersion includes: dissolving paeoniflorin-6-O'-benzenesulfonate and the compounded carrier in a good solvent, then adding it to a poor solvent and stirring to mix evenly, removing the good solvent, and then further drying to obtain the solid dispersion; In the solid dispersion, the mass ratio of paeoniflorin-6-O'-benzenesulfonate to the composite carrier is 1:(1~9); the concentration of paeoniflorin-6-O'-benzenesulfonate in the good solvent is 0~0.5 g / mL; the concentration of the composite carrier in the good solvent is 2~6 g / mL; the composite carrier is a composite of octanoic acid decanoic acid polyethylene glycol glycerol ester and other carriers; The other carrier is vitamin E polyethylene glycol succinate; the compound carrier is a composite of the caprylic / capric acid glyceride polyethylene glycol glyceride and the vitamin E polyethylene glycol succinate in a mass ratio of 0.5 to 2:

1. Alternatively, the other carrier may be a polyethylene glycol-polyvinylcaprolactam-polyvinyl acetate graft copolymer or a polyglycerol fatty acid ester; the composite carrier may be a compound of the octanoic acid-capric acid-polyethylene glycol glycerol ester and the other carrier in a mass ratio of 1:

1.

2. The paeoniflorin-6-O'-benzenesulfonate fat emulsion injection with the specific compound carrier according to claim 1, characterized in that, The volume ratio of the good solvent to the bad solvent is 1:2~5; the stirring is carried out at room temperature, the stirring speed is 800rpm~1200rpm, and the stirring time is 0.5~2 hours; the good solvent is removed by vacuum drying; the further drying method is freeze drying.

3. The paeoniflorin-6-O'-benzenesulfonate fat emulsion injection according to claim 1, characterized in that, The good solvent includes one or more of methanol, ethanol, and isopropanol; the poor solvent includes water; the oil phase solvent includes one or more of long-chain triglycerides and medium-chain triglycerides, the long-chain triglycerides include one or more of soybean oil, olive oil, and fish oil for injection, and the medium-chain triglycerides include triglycerides of medium-chain fatty acids having 6 to 14 carbon atoms or mixtures thereof; the isotonic adjuster includes one or more of glucose, sucrose, lactose, trehalose, mannitol, and sorbitol; the pH adjuster includes one or more of sodium hydroxide, sodium bicarbonate, and sodium carbonate.

4. The paeoniflorin-6-O'-benzenesulfonate fat emulsion injection according to claim 3, characterized in that, The good solvent is ethanol; the long-chain triglyceride is soybean oil for injection; the medium-chain triglyceride includes triglycerides composed of caprylic acid and capric acid or mixtures thereof; the isotonic adjuster is sucrose; and the pH adjuster is sodium hydroxide.

5. The paeoniflorin-6-O'-benzenesulfonate fat emulsion injection according to claim 4, characterized in that, The oil phase solvent comprises long-chain triglycerides and medium-chain triglycerides compounded in a mass ratio of 0.5 to 1:

1.

6. A method for preparing paeoniflorin-6-O'-benzenesulfonate fat emulsion injection according to claim 1, characterized in that, Includes the following steps: A. Add the solid dispersion to the oil phase solvent in proportion, heat and stir until completely dissolved to form an oil phase; B. Mix the isotonicity regulator, the pH regulator and an appropriate amount of water for injection in proportion, and heat until completely dissolved to form an aqueous phase; C. Slowly add the oil phase to the aqueous phase, shear it, and then add the remaining water for injection to obtain the colostrum; D. Homogenize the colostrum to obtain the final milk; E. The final emulsion is filtered and sterilized, bottled, filled with nitrogen, and sealed to obtain the paeoniflorin-6-O'-benzenesulfonate fat emulsion injection.

7. The method for preparing paeoniflorin-6-O'-benzenesulfonate fat emulsion injection with a specific compound carrier according to claim 6, characterized in that, In step A, the heating temperature is 50~60℃; in step B, the heating temperature is 50~60℃; in step C, the shearing speed is 8000~15000rpm, the shearing time is 8~20min, and the shearing temperature is 50~60℃; in step D, the homogenization temperature is 50~60℃, and the cycle is performed 1~4 times at a pressure of 200~600bar, and 4~8 times at a pressure of 800~1000bar; in step B, the mass percentage of water for injection is 30%~50% of the total water for injection; in step C, the mass percentage of water for injection is 50%~70% of the total water for injection.

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