A naphthomostat mesylate lyophilized composition and a method for preparing the same

Abstract

The application belongs to the field of pharmaceutical preparations, and particularly relates to a nafamostat mesylate pharmaceutical composition and a preparation method thereof. Cyclodextrin is introduced as a nafamostat mesylate freeze-drying protective agent. The unique structure of the external hydrophilic and internal hydrophobic structure can capture the active ingredient in the cavity to form an inclusion compound, thereby inhibiting the hydrolysis of the active ingredient, reducing the degradation of the active ingredient by light, heat, oxygen and the like, and improving the drug stability. The increase of the related substances of the freeze-dried preparation obtained in the application is significantly lower than that of the positive control after being placed under high-temperature and light conditions for 30 days. In addition, the results of special safety tests (including hemolytic, vascular irritation and allergic tests) of the freeze-dried preparation in the application show that the product is good in safety.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a lyophilized composition of naphthostat mesylate and its preparation method. Background Technology

[0002] Naphthostat mesylate is a synthetic protease inhibitor with strong selective inhibitory effects on trypsin, fibrinogen, plasminogen, kallikrein (vasodilator), and trypsin-like serine proteases such as C1r and C1S. It is used to treat acute pancreatitis, acute exacerbation of chronic pancreatitis, postoperative pancreatitis, and can also be used for anticoagulation during open-heart surgery and extracorporeal blood circulation, early treatment of DIC, shock, and treatment of autoimmune diseases.

[0003] Naphastox mesylate is a white crystalline powder that is readily soluble in water. However, due to its ester structure, it has poor stability in water (especially hot water), alkaline media, and strong acidic conditions, and is prone to degradation reactions that produce impurities. Currently, only injectable naphastox mesylate is available for clinical use.

[0004] Torii Pharmaceutical Co., Ltd. of Japan first developed its lyophilized powder injection and launched it in Japan in 1986. Patent ZL200610161308.X discloses a method for preparing lyophilized powder injection of naphthostat mesylate, which uses citrate buffer as a pH adjuster. Citrate has a certain degree of deliquescence, which is not conducive to the stable preservation of the drug.

[0005] Patent application CN 201110404953.0 describes the addition of metal ion salts, excipients, and pH adjusters, along with other pharmaceutical excipients, during the preparation of naphalosporin mesylate lyophilized powder for injection. Through specific preparation steps such as dissolution, filtration, filling, and freeze-drying, the stability and quality of the drug are improved. However, the presence of metal ions raises concerns about drug safety.

[0006] Patent application CN 201210101793.7 discloses a lyophilized powder injection of naphamostat mesylate. By combining naphamostat mesylate with mannitol as an excipient and pH adjuster, and through steps such as formulation, pyrogen removal, sterilization, and filling, the moisture content is controlled to be <2% during the freeze-drying process to form a stable formulation. However, this invention has not verified the stability of the drug, and whether it can improve the stability of the lyophilized naphamostat mesylate formulation remains to be considered.

[0007] Patent ZL 201510775602.9 discloses a naphthostat mesylate composition and its preparation method. It uses a combination of amino acids and a pH adjuster as a stabilizer, and succinic acid as a pH adjuster to control the solution pH within the range of 2-4. Combined with excipients and antioxidants, naphthostat mesylate is stabilized through a specific preparation sequence and conditions (such as temperature control) to prepare an injectable naphthostat mesylate composition. The ratio of naphthostat mesylate to succinic acid in the formulation is 1:0.1. According to the product's instructions (when used for in vitro anticoagulation, naphthostat mesylate is dissolved in 5% glucose injection, and then continuously injected at a rate of 20-50 mg per hour through an anticoagulant infusion tube), the maximum daily dose is 50 mg × 24 h = 1200 mg (based on naphthostat mesylate), corresponding to 120 mg of succinic acid. This far exceeds the maximum daily dose of succinic acid (38 mg) published in the FDA's inactive database. As a human immune metabolite, abnormal changes in the concentration of succinic acid may trigger an inflammatory response in the body. Summary of the Invention

[0008] Through extensive experimental research, the inventors of this invention have obtained a lyophilized formulation of naphthostat mesylate with better stability and safety, while simplifying the production process and making it more suitable for industrial production.

[0009] The first objective of this application is to provide a naphthostat mesylate composition, said composition being a lyophilized formulation, said composition containing naphthostat mesylate, cyclodextrin, tartaric acid and water for injection, wherein the mass ratio of naphthostat mesylate to cyclodextrin is 1:0.5 to 1:4.

[0010] In some preferred embodiments of this application, the mass ratio of naphthostat mesylate to cyclodextrin is 1:0.5 to 1:2;

[0011] More preferably, the mass ratio of naphthostat mesylate to cyclodextrin is 1:2.

[0012] In some preferred embodiments of this application, the pH value of the composition is 2.7 to 3.1, and tartaric acid is used as a pH adjuster in the composition.

[0013] In some preferred embodiments of this application, the formulation of the composition is as follows:

[0014] Material Name Prescription quantity Naphthostat mesylate 50g Cyclodextrin 100g tartaric acid 4g Water for Injection 2L .

[0015] This invention unexpectedly discovered that the introduction of cyclodextrin as a lyophilization protectant in the injectable nafamostat mesylate formulation of this invention, with its unique structure of being hydrophilic on the outside and hydrophobic on the inside, can capture the active ingredient in its cavity to form an inclusion complex, thereby inhibiting the hydrolysis of the active ingredient, reducing the degradation of the active ingredient by light, heat, oxygen, etc., and improving drug stability; after being placed under high temperature and light conditions for 30 days, the growth of related substances in the lyophilized formulation obtained in this application was significantly lower than that in the positive control; in addition, the results of special safety tests (including hemolysis, vascular irritation, and allergy) of the lyophilized formulation of this application all showed that the product has good safety.

[0016] Another object of this application is to provide a method for preparing a naphthostat mesylate composition:

[0017] The method includes the following steps:

[0018] S1: Solution preparation: Dissolve the prescribed amount of cyclodextrin in water for injection, cool to room temperature (≤30℃), add nafamostat mesylate and stir until completely dissolved, then add tartaric acid to adjust the pH of the solution;

[0019] S2: Filtration and filling: Filter the liquid obtained in S1 and dispense it into containers;

[0020] S3: Freeze-drying: Place the sample obtained in S2 into a freeze dryer for freeze-drying. After the freeze-drying is completed, purge with nitrogen and perform full stoppering to obtain the freeze-dried formulation.

[0021] Furthermore, the pH value of the medicinal solution in S1 is 2.7 to 3.1.

[0022] Furthermore, the filtration conditions in S2 are sequential filtration through 0.45μm and 0.22μm polyethersulfone filter cartridges.

[0023] Furthermore, the freeze-drying conditions in S3 are: pre-freezing at -48℃ for 2 to 3 hours, and then drying at -10 to 50℃ for 20 to 28 hours.

[0024] More preferably, the method includes the following steps:

[0025] S1: Solution preparation: Dissolve the prescribed amount of cyclodextrin in water for injection, cool to room temperature (≤30℃), add nafamostat mesylate and stir until completely dissolved, then add tartaric acid to adjust the pH of the solution to 2.7-3.1;

[0026] S2: Filtration and filling: The medicine solution is filtered sequentially through 0.45μm and 0.22μm polyethersulfone filter cartridges and then filled into 4ml / vial.

[0027] S3: Freeze-drying: Place the sample obtained in S2 into a freeze dryer and pre-freeze it at -48℃ for 2-3 hours, then dry it at -10-50℃ for 20-28 hours to obtain the freeze-dried preparation.

[0028] This application introduces cyclodextrin into the lyophilized formulation of naphthostat, and the solution temperature is strictly controlled below 30°C. Samples prepared using the freeze-drying procedure specified in this application exhibit excellent product properties and high safety for clinical use. Detailed Implementation

[0029] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0030] General definitions and explanations:

[0031] The vacuum freeze dryer used in this embodiment is model SCIENTZ-12N.

[0032] All raw and auxiliary materials used in this application are commercially available products.

[0033] Example 1: Lyophilized Naphazoline Mesylate Composition for Injection (as per this application)

[0034] A lyophilized formulation of naphamostat mesylate for injection, comprising naphamostat mesylate, mannitol, sulfobutyl-β-cyclodextrin (hereinafter referred to as cyclodextrin) and tartaric acid, with the following formulation:

[0035] Table 1. Formulation of Naphthol Mesylate Lyophilized Composition in Example 1

[0036] Material Name Prescription quantity effect Naphthostat mesylate 50g Active ingredients Cyclodextrin 100g excipient tartaric acid 4g pH adjuster Water for Injection 2L solvent

[0037] Preparation method:

[0038] (1) Solution preparation: Dissolve the prescribed amount of cyclodextrin in water for injection, cool to room temperature (≤30℃), add naphthostat mesylate and stir for at least 15 minutes until completely dissolved, and add tartaric acid to adjust the pH of the solution to 2.7-3.1.

[0039] (2) Filtration and filling: The drug solution is filtered through 0.45μm and 0.22μm polyethersulfone filter cartridges in sequence, and then filled into borosilicate glass vials at 2ml / vial to make 1000 vials of injection preparation.

[0040] (3) Freeze-drying: Pre-freeze at -48℃ for 2 to 3 hours, and then dry at -10 to 50℃ for 20 to 28 hours to obtain freeze-dried products.

[0041] Examples 2-5: Lyophilized Naphthol Mesylate Composition for Injection of this Application

[0042] Based on Example 1, the amount of cyclodextrin was adjusted so that the mass ratio of naphthostat mesylate to cyclodextrin was 1:0.5, 1:1, 1:3 and 1:4. The morphology, reconstitution time and pH value of the freeze-dried product were investigated and compared with those of Example 1.

[0043] Table 2. Formulation of Naphthol Mesylate Lyophilized Compositions in Examples 2-5

[0044]

[0045] The results showed that when the ratio of naphthostat mesylate to cyclodextrin was between 1:1 and 1:4, the freeze-dried products were all within the acceptable range, but the freeze-dried products prepared by the ratio in Example 1 had the best freeze-dried morphology and reconstitution properties.

[0046] Comparative Example 1

[0047] A lyophilized formulation of naphamostat mesylate for injection, referring to the product instructions of the Japanese marketed product, selects mannitol as the excipient and succinic acid as the pH adjuster, and prepares the lyophilized drug solution according to the ratio of naphamostat mesylate: mannitol: succinic acid = 1:2:0.1. The specific preparation process is the same as in Example 1.

[0048] Comparative Example 2

[0049] ZL 201510775602.9 discloses a naphthostat mesylate composition and its preparation method, wherein a lyophilized formulation of naphthostat mesylate for injection is prepared according to the formulation in Example 7 of the specification.

[0050] Table 3. Formulation of the Naphthol Mesylate Lyophilized Composition of Comparative Example 2

[0051]

[0052]

[0053] Preparation method:

[0054] (1) Weighing: Weigh the prescribed amounts of naphastol mesylate, mannitol, succinic acid, and amino acids;

[0055] (2) Preparation of excipient solution: Dissolve the weighed mannitol, succinic acid and glycine in water for injection at 25-30℃;

[0056] (3) pH adjustment: pH range is 2.8 to 3.5;

[0057] (4) Preparation of drug solution: Dissolve nafamostat mesylate in the above excipient solution to obtain drug solution;

[0058] (4) Sterilization filtration: The medicine solution is filtered through a PVDF filter cartridge;

[0059] (5) Filling: Fill the filtered drug solution into 10ml borosilicate tubular injection vials, with a filling volume of 2ml / vial, to make 1000 vials of injection preparation.

[0060] (6) Freeze-drying: Pre-freeze at -48℃ for 2 to 3 hours, and then dry at -10 to 50℃ for 20 to 28 hours to obtain freeze-dried products.

[0061] Test Example 1: Stability Test

[0062] The active ingredient in this product, nafamostatin mesylate, is an ester conjugate of 6-amino-2-naphthol (AN) and p-guanidinobenzoic acid (p-GBA). It is unstable in water (especially hot water), and under strong acid and alkaline conditions, readily hydrolyzing to form AN and p-GBA. This application introduces cyclodextrin as a lyophilization protectant. Its unique structure—hydrophilic on the outside and hydrophobic on the inside—can trap the active ingredient within its cavity to form an inclusion complex, thereby inhibiting hydrolysis of the active ingredient, reducing degradation by light, heat, and oxygen, and improving drug stability. Taking Example 1 of this application as an example, the lyophilized preparations obtained in Example 1, Comparative Examples 1 and 2 were placed under high temperature, light, and high humidity conditions for 30 days, respectively. Samples were taken and analyzed by HPLC to examine the growth of related substances. The results are shown in Table 4 below.

[0063] Table 4. Results of the stability test

[0064]

[0065] As can be seen from the table above regarding the increase in related substances, after 30 days of storage under high temperature and light conditions, the increase in related substances in Example 1 was significantly lower than that in Comparative Example 1 and Comparative Example 2. After 30 days of storage under high humidity conditions, there was no significant increase in related substances in either the Comparative Example or the Example. This demonstrates that the inclusion complexation with cyclodextrin can significantly improve the stability of the lyophilized naphthostat mesylate composition.

[0066] Test Example 2: Special Safety Test

[0067] Comparative Examples 1 and 2 used succinic acid as a pH adjuster, with a ratio of 0.1:1 to nafamostat mesylate. Based on the dosage instructions (when used for in vitro anticoagulation, nafamostat mesylate is dissolved in 5% glucose injection and continuously injected at a rate of 20-50 mg per hour through the anticoagulant infusion tube), the maximum daily dose of this product is 50 mg × 24 h = 1200 mg (based on nafamostat mesylate), corresponding to 120 mg of succinic acid. This far exceeds the maximum daily dose of succinic acid (38 mg) published in the FDA inactive database. As a human immune metabolite, abnormal changes in the concentration of succinic acid may trigger an inflammatory response in the body.

[0068] Example 1 of this application uses tartaric acid instead of succinic acid as a pH adjuster. Compared with succinic acid, tartaric acid is a stronger acid, has better water solubility, and is safer. A comparison of safety data between succinic acid and tartaric acid is shown in Table 5 below:

[0069] Table 5 Comparison of safety data for succinic acid and tartaric acid

[0070]

[0071] Special safety tests, including allergy, local irritation, and hemolysis, were conducted on Example 1 and Comparative Example 1. The tests were conducted in accordance with the GLP regulations (Good Laboratory Practice for Non-Clinical Studies of Drugs, Order No. 34, September 2017) issued by the former China Food and Drug Administration (CFDA), the Regulations on the Administration of Laboratory Animals (revised in 2017) issued by the State Council of the People's Republic of China, and the 8th edition of the Guide for the Care and Use of Laboratory Animals (2011) issued by the National Research Council of the National Academies. The studies included vascular irritation tests in rabbits, systemic active anaphylaxis tests in guinea pigs, and in vitro hemolysis tests in rabbits. The irritant reactions and reversibility of the formulation to veins and surrounding tissues, its effect on erythrocyte status, and allergic reactions were observed, providing a reference for evaluating the safety of clinical use.

[0072] Experimental Example 2-1: Guinea Pig Systemic Active Hypersensitivity Test

[0073] Experimental objective: To observe the performance of guinea pigs sensitized by Example 1 and Comparative Example 1 after intravenous injection of the test product, in order to evaluate whether they have systemic allergic reactions and the intensity of the allergic reactions.

[0074] Experimental method: Forty Hartley guinea pigs that passed quarantine were selected for this experiment. Half were male and half were female. They were randomly divided into 5 groups according to weight and sex, with 8 rats in each group. The groups were negative control group, positive control group, comparative example 1 group, low-dose group of example 1, and high-dose group of example 1.

[0075] Sensitization: Each group of animals was sensitized three times every other day by intraperitoneal injection. The sensitization volume was 0.5 mL each time. The negative control group was given 5% glucose injection, the positive control was given egg white albumin (concentration of 3 mg / mL, dose of 1.5 mg / animal), the low-dose group of Example 1 was given a drug concentration of 0.00415 mg / mL, the high-dose group of Example 1 was given a drug concentration of 0.0083 mg / mL, and the comparative example 1 group was given a drug concentration of 0.0083 mg / mL.

[0076] Challenge: On days 14 and 21 after the last sensitization, challenge drugs were administered once. The drugs were administered via plantar vein injection. Each group was given the same concentration of drug as during sensitization, and the volume of drug administered was twice the volume of the sensitization, i.e., 1.0 mL / animal.

[0077] Observation: Observe and record the allergic reactions of the animals in detail, continuing observation for at least 30 minutes, and generally for 3 hours. Results are shown in Table 6:

[0078] Table 6 Record of Guinea Pig Systemic Active Allergy Experiment

[0079]

[0080] Conclusion: Under the conditions of this experiment, neither Comparative Example 1 nor Example 1 induced an active systemic allergic reaction at different concentrations.

[0081] Experimental Example 2-2: Vascular Irritation Test in Experimental Rabbits

[0082] Experimental objective: To conduct vascular irritation tests on New Zealand rabbits in Example 1 and Comparative Example 1, and to observe the irritant reaction and severity of the test product on the blood vessels at the administration site after intravenous administration, so as to evaluate the local vascular toxicity of injectable nafamostatin mesylate and provide a basis for safe clinical use.

[0083] Experimental Methods: Twelve New Zealand rabbits, half male and half female, were selected for this experiment and randomly divided into two groups of six rabbits each, based on weight and sex. These groups were designated as Example 1 and Comparative Example 1, respectively. The experiment employed a self-controlled left-right approach, using a micro-infusion pump at a constant rate of 2 mL / min. The test substance or reference formulation was administered via the right marginal ear vein of each group of rabbits. The concentration for both Example 1 and Comparative Example 1 was 0.0083 mg / mL, and the administration volume was 5 mL / kg. An equal volume of 5% glucose injection was administered via the left marginal ear vein as a negative control. Administration was once daily for seven consecutive days. During the experiment, general clinical and local observations were conducted, and the rabbits' weight was measured periodically. At 72 hours after the last administration and after the 14-day recovery period, half of the rabbits in each group were euthanized, and the administration sites were collected for gross anatomical observation and histopathological examination. The vascular irritation of the test substance was determined based on a comprehensive assessment of the local vascular observations and histopathological examinations after administration.

[0084] Experimental results:

[0085] 1. General clinical observation results: During the experiment, no obvious abnormalities were observed in the general clinical observation of each experimental rabbit.

[0086] 2. Results of local observation at the administration site: During the experiment, no obvious abnormalities were observed at the administration site in any of the experimental rabbits in Example 1 group / Comparative Example 1 group.

[0087] 3. Gross pathological examination results: No abnormalities were found in the local gross examination of the rabbits in Example 1 group and Comparative Example 1 group 72 hours after the last administration (D10) and at the end of the recovery period (D24).

[0088] 4. Histopathological examination results: 72 hours after the last administration (D10), no abnormalities were found in the administration sites of the rabbits in Example 1 and Comparative Example 1 under a microscope. At the end of the recovery period (D24), no abnormalities were found in the administration sites of the rabbits in Example 1 under a microscope; mild focal inflammatory cell infiltration around blood vessels was observed in the A segment of the left ear of the rabbits in Comparative Example 1.

[0089] Experimental conclusion: When rabbits were intravenously injected with the drugs in Example 1 and Comparative Example 1 (concentration 0.0083 mg / mL) once a day for 7 consecutive days, Example 1 showed no significant irritation to the marginal ear veins of the rabbits, while Comparative Example 1 may have caused an inflammatory response in the rabbits.

[0090] Experimental Example 2-3: Hemolytic activity of rabbit erythrocytes in vitro

[0091] Experimental objective: To observe the effects of direct contact between the clinical concentrations of Example 1 / Comparative Example 1 and rabbit erythrocytes under in vitro conditions, in order to evaluate whether they induce hemolysis and erythrocyte aggregation.

[0092] Experimental method: In this experiment, defibrinated rabbit blood was routinely prepared and then diluted with 0.9% sodium chloride injection to form a 2% red blood cell suspension for later use. Take 12 test tubes, numbered 01 to 12. Add 2.5 mL of 2% red blood cell suspension to each test tube. Add 2.0 to 2.4 mL of sodium chloride injection to test tubes 01 to 05 and 08 to 12 respectively. Add 0.5 mL, 0.4 mL, 0.3 mL, 0.2 mL and 0.1 mL of Example 1 solution with a concentration of 0.0083 mg / mL to test tubes 01 to 05 respectively. Add 0.5 mL, 0.4 mL, 0.3 mL, 0.2 mL and 0.1 mL of Comparative Example 1 solution with a concentration of 0.0083 mg / mL to test tubes 08 to 12 respectively. Add 2.5 mL of 0.9% sodium chloride injection to test tube 06 (negative control) and 2.5 mL of purified water to test tube 07 (positive control). Mix well and incubate in a carbon dioxide incubator at a temperature range of 37℃ ± 0.5℃. The presence of hemolysis and agglutination was observed at 15 min ± 2 min, 30 min ± 5 min, 45 min ± 5 min, 60 min ± 10 min, 120 min ± 10 min, and 180 min ± 10 min.

[0093] Results: During the experiment, the solution in tube 07 (positive control group) turned clear red with a uniform color distribution within 15 minutes, and there was virtually no red blood cell precipitation at the bottom, indicating significant hemolysis. In tubes 06 (negative control group), 01-05 (Example 1 group), and 08-12 (Comparative Example 1 group), red blood cells sank, and the liquid in the tubes showed clear stratification, with a colorless and clear upper layer and red blood cell precipitation at the bottom. No red blood cell aggregation was observed during the experiment, indicating that no hemolysis occurred.

[0094] Experimental conclusion: Under the experimental conditions, neither Example 1 nor Comparative Example 1 induced hemolysis or erythrocyte aggregation in rabbit blood at a high concentration (0.0083 mg / ml), and the in vitro hemolysis results were negative.

[0095] Special safety tests showed that the active systemic anaphylaxis test, vascular irritation test, and in vitro hemolytic test of Example 1 indicated no allergic reaction in guinea pigs, no irritation to the marginal ear veins and surrounding tissues of rabbits, and no in vitro hemolytic reaction in rabbit erythrocytes. In contrast, the vascular irritation test of Comparative Example 1 showed mild focal inflammatory cell infiltration around the blood vessels in the left ear of the experimental rabbit. This demonstrates that Example 1 has better safety than Comparative Example 1 and a lower risk of inducing inflammatory reactions.

[0096] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A naphthostat mesylate composition, said composition being a lyophilized formulation, characterized in that, The composition contains naphthostat mesylate, cyclodextrin, tartaric acid, and water for injection, wherein the mass ratio of naphthostat mesylate to cyclodextrin is 1:0.5 to 1:4; tartaric acid is used as a pH adjuster in the composition, and the pH value of the composition is 2.7 to 3.

1.

2. The composition according to claim 1, characterized in that, The mass ratio of naphthostat mesylate to cyclodextrin is 1:0.5 to 1:

2.

3. The composition according to claim 2, characterized in that, The mass ratio of naphthostat mesylate to cyclodextrin is 1:

2.

4. The composition according to any one of claims 1-3, characterized in that, The formulation of the composition is as follows: 。 5. A method for preparing the composition according to any one of claims 1-4, characterized in that: The method includes the following steps: S1: Solution preparation: Dissolve the prescribed amount of cyclodextrin in water for injection, add the prescribed amount of nafamostat mesylate and stir until completely dissolved, then add tartaric acid to adjust the pH of the solution; S2: Filtration and filling: Filter the liquid obtained in S1 and dispense it into containers; S3: Freeze-drying: Place the sample obtained in S2 into a freeze dryer for freeze-drying. After the freeze-drying is completed, purge with nitrogen and perform full stoppering to obtain the freeze-dried formulation.

6. The method according to claim 5, characterized in that: The pH value of the medicinal solution in S1 is 2.7~3.

1.

7. The method according to claim 5, characterized in that: The filtration conditions in S2 are sequential filtration through 0.45μm and 0.22μm polyethersulfone filter cartridges.

8. The method according to claim 5, characterized in that: The freeze-drying conditions in S3 are as follows: pre-freezing at -48℃ for 2~3 hours, and then drying at -10~50℃ for 20~28 hours.

9. The method according to any one of claims 5-8, characterized in that: The method includes the following steps: S1: Solution preparation: Dissolve the prescribed amount of cyclodextrin in water for injection, add the prescribed amount of nafamostat mesylate and stir until completely dissolved, then add tartaric acid to adjust the pH of the solution to 2.7~3.1; S2: Filtration and filling: The medicine solution is filtered sequentially through 0.45μm and 0.22μm polyethersulfone filter cartridges and then filled into 4ml / vial. S3: Freeze-drying: Place the sample obtained in S2 into a freeze dryer and pre-freeze it at -48℃ for 2~3h, then dry it at -10~50℃ for 20~28h to obtain the freeze-dried preparation.

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