Irinotecan hydrochloride injection and preparation method thereof

Abstract

The invention discloses an irinotecan hydrochloride injection. Every 50 L of the irinotecan hydrochloride injection is prepared from the following raw materials in parts by weight: 900-1100 g of irinotecan hydrochloride, 1800-2200 g of a conditioning agent, 120-180 g of a buffering agent and 5-10 g of sodium hydroxide, and the conditioning agent is a mixture of modified sorbitol and mannitol. The irinotecan hydrochloride injection is used for solving the technical problem that the irinotecan hydrochloride injection is poor in stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an irinotecan hydrochloride injection and a preparation method thereof. Background Art

[0002] Due to changes in living environments and lifestyles, as well as objective factors such as an aging population and increasing pressures of survival, the incidence of malignant tumors in my country continues to rise. Colorectal cancer is one of the most common malignant tumors. Among digestive tract tumors, its incidence is second only to gastric cancer and esophageal cancer.

[0003] Irinotecan hydrochloride is one of the new drugs in the camptothecin class that has been launched on the market. It is used as the first-line treatment for metastatic colorectal cancer after the failure of standard chemotherapy. It belongs to the camptothecin class of cytotoxic anticancer drugs. Research began in the 1980s and the mechanism of action was gradually elucidated. It has a unique molecular structure and mechanism of action, which can prolong the patient's survival without affecting the quality of life. In addition to being effective in the treatment of colorectal cancer, it is also used in gastric cancer, lung cancer, gynecological tumors and other cancers.

[0004] Since irinotecan hydrochloride injection is unstable in water and has poor antioxidant properties, it has poor stability, which will affect the efficacy of the injection. Summary of the Invention

[0005] The invention provides an irinotecan hydrochloride injection and a preparation method thereof, which are used to solve the technical problem of poor stability of the existing irinotecan hydrochloride injection.

[0006] In view of this, the present invention provides an irinotecan hydrochloride injection, wherein each 50L of the injection comprises the following raw materials in parts by weight: 900-1100g of irinotecan hydrochloride, 1800-2200g of a regulator, 120-180g of a buffer, and 5-10g of sodium hydroxide, wherein the regulator is a mixture of modified sorbitol and mannitol.

[0007] Optionally, the weight ratio of the modified sorbitol to mannitol is 1:(0.6-1).

[0008] Optionally, the modified sorbitol is prepared by the following method: placing gallic acid in an ethanol solution, adding sorbitol and a catalyst, mixing uniformly, heating and reacting, after the reaction is completed, rotary evaporation, adding water, mixing uniformly, cooling and crystallizing, and then purifying the crystals to obtain modified sorbitol.

[0009] Furthermore, the modified sorbitol is prepared by the following method: placing gallic acid in a 30% by mass ethanol solution, adding sorbitol and a catalyst, mixing uniformly, heating to 55-80° C., reacting for 3-5 hours, after the reaction is completed, rotary evaporation, adding water, mixing uniformly, cooling to 0-4° C. for crystallization, then adding the crystals into water, dissolving, cooling at 0-4° C., crystallizing again, filtering under reduced pressure to obtain a solid, and drying to obtain the modified sorbitol;

[0010] The amount of ethanol solution added to 1g of gallic acid is 10-20mL, the amount of catalyst added to 1g of sorbitol is 0.01-0.03g, the catalyst is zeolite molecular sieve, the amount of water added to 1g of the object after rotary evaporation is 10-15mL, and the amount of water added to 1g of the crystal is 8-12mL.

[0011] Optionally, the weight ratio of sorbitol to gallic acid is 1:(0.2-0.3).

[0012] Optionally, the irinotecan hydrochloride is further subjected to the following purification treatment:

[0013] A1: Dissolve irinotecan hydrochloride in an acetone-water mixture, cool, and allow to stand for crystallization. Filter by suction, collect the filter cake, and dry to obtain a preliminarily purified product.

[0014] A2: Dissolve the preliminarily purified product in ethanol solution, add methyl formate, mix well, let stand again for crystallization, filter, collect the solid, and dry to obtain purified irinotecan hydrochloride.

[0015] Furthermore, the irinotecan hydrochloride is further purified by the following treatments:

[0016] A1: Dissolve irinotecan hydrochloride in an acetone-water mixture, cool to -5-0°C, allow to stand for 45-50 hours for crystallization, then filter, collect the filter cake, and dry to obtain a preliminarily purified product;

[0017] A2: Dissolve the preliminarily purified product in 30% by mass ethanol solution, add methyl formate, mix thoroughly, and allow to crystallize again at 5-10°C for 20-28 hours. Filter, collect the solid, and dry to obtain purified irinotecan hydrochloride.

[0018] In step A1, the volume ratio of acetone to water in the acetone-water mixed solution is (2-4):1, the amount of acetone-water mixed solution added to 1 g of irinotecan hydrochloride is 8-12 mL, the amount of ethanol solution added to 1 g of the preliminary purified product in step A2 is 10-15 mL, and the weight ratio of the preliminary purified product to methyl formate is 1:(0.2-0.4).

[0019] Optionally, the buffer is any one of lactic acid, phosphoric acid, acetic acid, tartaric acid, and fumaric acid.

[0020] Optionally, the buffer is lactic acid.

[0021] A method for preparing irinotecan hydrochloride injection comprises the following steps:

[0022] S1: External cleaning: Preparation of ultrafiltration membrane package and silicone tube before production;

[0023] S2: Liquid preparation: Weigh the prescribed amount of each material component: irinotecan hydrochloride, regulator, buffer, and sodium hydroxide, set aside, add water for injection into the liquid preparation tank A, turn on the temperature control system of the liquid preparation tank A to control the water temperature, then add the regulator, buffer, and irinotecan hydrochloride, stir to dissolve, and cool;

[0024] S3: Pre-filtration: Connect the peristaltic pump inlet pipe to the bottom valve of the liquid distribution tank A, and the liquid outlet pipe to the filter. Start the peristaltic pump to filter the liquid through the filter element to the liquid distribution tank B to complete the pre-filtration.

[0025] S4: Ultrafiltration: Ultrafiltration using flat membrane;

[0026] S5: Intermediate inspection: The central control personnel take the intermediates for inspection;

[0027] S6: Filtration: The liquid medicine is filtered once and twice before being put on the filling machine. The filling is started and the vials are fully stoppered. Then they are capped, sterilized and inspected by light. After passing the inspection, they are packaged.

[0028] Furthermore, a method for preparing irinotecan hydrochloride injection comprises the following steps:

[0029] S1: External cleaning: Preparation of ultrafiltration membrane package and silicone tube before production:

[0030] S1.1: Ultrafiltration membrane cassette: The ultrafiltration membrane cassette is cleaned according to the following process: first, circulate and clean with 0.1% sodium hydroxide solution for 30-50 minutes, drain the cleaning agent, then circulate and flush with injection water for 10-20 minutes, and finally rinse with injection water for 20-40 minutes;

[0031] The ultrafiltration membrane package is tested for integrity before and after production, and after production, the membrane package is cleaned and then tested for water flux;

[0032] Integrity test qualification standard: The air flow rate (ml / min) standard of the fully wetted intact ultrafiltration membrane is ≤34ml / min;

[0033] Water flux test qualification standard: After the membrane package is used once, the measured membrane water flux (NWP) should not be less than 80% of the initial standard. After repeated use, the attenuation of NWP each time should not exceed 15%. When the membrane package water flux decays to 60% of the initial water flux, the membrane package has reached its service life and the membrane package should be replaced.

[0034] The ultrafiltration membrane package can be used 100 times.

[0035] S1.2: Silicone tubing: Silicone tubing should be cleaned according to the following process: soak in water for injection for 30-50 minutes, rinse with purified water, soak in 1% sodium hydroxide solution for ≥4 hours, and then rinse with water for injection until neutral. After cleaning the silicone tubing for filling, sterilize it with moist heat at 120-125℃ for 10-20 minutes.

[0036] After cleaning the silicone tube, use compressed air to dry it until there is no water droplets on the surface and then use it. If the silicone tube is found to be sticky, cracked, or aged, it should be replaced in time;

[0037] The silicone tube can be used 20 times.

[0038] S2: Liquid preparation:

[0039] S2.1: Turn on the yellow light source, prepare 80% of the total amount of water for injection, and place it in a 300L enameled liquid preparation tank. Start the liquid preparation tank temperature control system to control the water temperature at 60-70°C. Simultaneously start the online temperature recorder to record the temperature of the solution in the liquid preparation tank.

[0040] S2.2: Weigh the prescribed amount of buffer, place it in a 300 L enamel preparation tank, and stir to dissolve;

[0041] S2.3: Weigh the prescribed amount of irinotecan hydrochloride into a beaker. Open the bottom valve of a 300-L enamel dispensing tank and start the peristaltic pump to slowly flush the irinotecan hydrochloride into the 300-L enamel tank. Maintain the solution temperature within the range of 60-70°C. Dissolve the solution in a circulating agitator at 15-20 Hz for 15-20 minutes.

[0042] S2.4: Weigh the prescribed amount of regulator into a beaker. Open the bottom valve of a 300L enamel dispensing tank and start the peristaltic pump to slowly flush the regulator into the 300L enamel tank. Stir and dissolve the regulator in a circulating pump at 15-20 Hz for 5-10 minutes. The solution should be a light yellow, clear liquid.

[0043] S2.5: Turn on the temperature control system of the 300L enamel liquid preparation tank and lower the temperature to 20-30°C. Reduce the temperature of the solution in the liquid preparation tank to 20-30°C.

[0044] S3: Pre-filtration: Connect the peristaltic pump inlet pipe to the bottom valve of the 300L enamel tank, and the outlet pipe to the 0.22μm filter. Start the peristaltic pump and filter the drug through the 0.22μm filter element into the 30L glass liquid preparation tank to complete the pre-filtration operation and reduce the microbial load.

[0045] S4: Ultrafiltration: Ultrafiltration was performed using a 10 kd flat membrane to remove bacterial endotoxins. The permeate was collected in a 50 L enamel preparation tank. During the ultrafiltration process, the transmembrane pressure (TMP) was less than 14.0 psi. After the ultrafiltration was completed, the ultrafiltration system was flushed with 12 kg of cooled water for injection (3 kg each time) in four portions. The permeate was combined and placed in a 50 L enamel preparation tank.

[0046] Adjust the pH to 3.2-3.5, add water for injection, and make the volume to 50L, i.e. 50.58kg (solution density is 1.017g / cm 3 ), take samples to test the quality of intermediates (properties, pH, content, bacterial endotoxins, microbial limits).

[0047] The preparation of the drug solution and the first sterilization should be completed within 6 hours. The above sterilization and drying are completed in the Class A area, and the rest of the operations are completed in the Class C area.

[0048] S5: Intermediate inspection: The central control personnel take the intermediates for inspection. The inspection items are shown in Table 1.

[0049] Table 1 Test items and qualification standards

[0050] Test items Eligibility criteria Traits Light yellow clear liquid pH 3.2-3.5 content <![CDATA[本品含盐酸伊立替康(C 33 H 38 N4O6·HCl·3H2O) should be 19.0-21.8 mg / mL]]> bacterial endotoxins ≤3.0EU / mg Microbial limits <100 CFU / 100 mL

[0051] S6: Filtration: Measure 500mL of liquid medicine and use compressed air at a pressure of ≤0.15MPa to filter it from the liquid distribution pressure tank in the Class C area through the primary filter element to the filling filter press tank in the Class B area. The liquid medicine in the filling filter press tank is then filtered through the secondary filter element to the liquid medicine recovery dish in the Class A area. Rinse and filter 4 times, a total of 1500mL, to achieve the purpose of flushing the filter element. Note that the liquid medicine should be discarded after each flushing of the filter element;

[0052] The drug solution is filtered once (0.22μm filter element) in the liquid preparation room and transferred to the 10L filter press tank in the Class B area. The drug solution is filtered twice (0.22 filter element) in the filling room and transferred to the 10L liquid storage bottle on the filling machine. It is filtered in batches through the 10L filter press tank and then the filling is started.

[0053] The liquid filtration system should be cleaned and disinfected according to the cleaning procedures of the liquid filtration system before use. The filter elements used for filtration are all disposable. The filter element integrity test should be carried out before and after sterilization. The filter element should be cleaned and sterilized according to the filter element cleaning and disinfection procedures. The filter requirements are shown in Table 2.

[0054] Table 2 Filter requirements

[0055] filter Aperture Filter membrane material Function Bubble Point Sterile filter 0.22μm PES (polyethersulfone) Sterile filtration ≥3600mbar

[0056] Full filling: After the tunnel oven dry heat sterilization, the vials are transferred to the bottle inverting device under the protection of A-level laminar flow, and then are sent to the filling machine after being straightened. The sterilized rubber stopper is added in the stopper shaker hopper, the sterilized ceramic pump is installed, and the filling needle is connected. The machine is started according to the standard operation procedure of ZGS04 aseptic liquid filling machine. After the filling amount is adjusted to meet the requirements, the filling machine is operated at a frequency of 10-25 Hz. The center filling amount of 2.25 ml is controlled within ±4% (2.09-2.31 ml) for the 2 ml:40 mg product. During the filling process, the filling amount difference is checked every 30 minutes, and visible foreign matter in the liquid is checked before, during and after filling. All of them should meet the quality standards of internal control. The filled and stoppered products are collected in a stainless steel transfer tray, and are transferred to the bottle track under the protection of A-level laminar flow. The time from the first sterilization of the liquid to the completion of filling should be controlled within 10 hours;

[0057] Cap rolling: The filled and stoppered products are transferred to the cap rolling track under the protection of A-level laminar flow, and are sent to the cap rolling room by the conveying belt. The sterilized and dried aluminum cap is loaded into the cap rolling machine hopper, and the cap rolling is started according to the standard operation procedure of KGL-1120 rolling cap machine. The cap rolling machine is operated at a frequency of 25-40 Hz. During the cap rolling process, 10 bottles are taken out every 30 minutes for checking the cap rolling quality, including the appearance and tightness of the cap. The tightness is determined by the cap rolling torque test, and the torque should be ≥2.1 kgf.cm. The cap rolling yield should be ≥95%;

[0058] The following operations are carried out in the general production area:

[0059] Sterilization: The capped products are placed in the sterilizer according to about 5000 bottles / batch, and are sterilized according to the standard operation procedure of XG1.0DE-0.6 ampoule sterilizer. The sterilization conditions are 121℃ for 10 min. The products are sterilized in batches according to the sub-batch, and are managed according to the "SMP-PM-3004 three workshop production process management procedure". The storage time of the drug from the end of filling to sterilization is not more than 6 hours;

[0060] Light inspection: The sterilized products are subjected to light inspection one by one according to the standard operation procedure of the three workshop light inspection post. The unqualified products include broken bottles, cap rolling quality, visible foreign matter, filling amount, etc. The qualified products are sampled by QA, and are handled for packaging and storage in the corresponding product (to be packaged) temporary storage warehouse. The light inspection illuminance is 2500-3000 lx; the appearance should be free of broken bottles, bad caps and filling amount difference; and there should be no obvious visible foreign matter;

[0061] Packaging: After labeling, each bottle of product is manually packed into a carton. 40 boxes of 2ml:40mg specification products are packed into a carton. After passing the test, they are put into storage.

[0062] Optionally, the liquid preparation tank A is an enamel liquid preparation tank, and the liquid preparation tank B is a glass liquid preparation tank.

[0063] It can be seen from the above technical solutions that the embodiments of the present invention have the following advantages:

[0064] 1. The present invention uses modified sorbitol and mannitol as regulators. First, modified sorbitol can improve thermal stability and light stability. In addition, the two can adjust the osmotic pressure of the injection solution to make it close to the human physiological environment, reduce stimulation to blood vessels and tissues, and maintain the chemical stability and biological activity of the drug. Moreover, the two have antioxidant properties, which can reduce the degradation of the drug due to oxidation during storage and use, and also help maintain the chemical stability and biological activity of the drug, maintain the drug in a suitable acid-base environment, prevent drug decomposition due to pH fluctuations, and ensure uniform distribution of the drug, thereby improving stability.

[0065] 2. In the present invention, gallic acid is used to modify sorbitol. Gallic acid, as a natural polyphenol compound, has significant antioxidant activity. By modifying sorbitol, sorbitol can obtain stronger antioxidant capacity, reduce the degradation of irinotecan hydrochloride injection due to oxidation during storage and use, and improve the chemical stability; gallic acid can also improve the thermal stability of sorbitol, and can also form a more stable light protection system by combining with sorbitol, reducing the possibility of photodegradation and improving photostability, thereby helping to improve the stability of irinotecan hydrochloride injection.

[0066] 3. The present invention purifies irinotecan hydrochloride to reduce impurities in irinotecan hydrochloride and reduce the influence of other substances on its action, so that it can play a better role in the injection, thereby helping to improve the efficacy of the injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0068] Figure 1 It is a schematic diagram of the overall process of the present invention. DETAILED DESCRIPTION

[0069] In order to make those skilled in the art better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or can be prepared by existing methods.

[0070] Preparation Example

[0071] Preparation Example 1

[0072] A modified sorbitol is prepared by the following method:

[0073] 0.4 kg of gallic acid was added to a 30% ethanol solution by mass, 2 kg of sorbitol and 0.04 kg of catalyst were added, mixed evenly, heated to 70° C., reacted for 4 h, and after the reaction was completed, rotary evaporated, water was added, mixed evenly, cooled to 2° C. for crystallization, and then the crystals were added to water, dissolved, cooled at 2° C., crystallized again, filtered under reduced pressure to obtain a solid, and dried to obtain modified sorbitol;

[0074] The amount of ethanol solution added to each 1g of gallic acid was 15mL, the amount of water added to each 1g of the rotary evaporated object was 12mL, and the amount of water added to each 1g of the crystalline material was 10mL.

[0075] Preparation Example 2

[0076] A modified sorbitol is different from Preparation Example 1 in that the amount of gallic acid added in Preparation Example 2 is different, and the amount of gallic acid added in Preparation Example 2 is 0.5 kg.

[0077] Preparation Example 3

[0078] A modified sorbitol is different from Preparation Example 1 in that the amount of gallic acid added in Preparation Example 3 is different, and the amount of gallic acid added in Preparation Example 3 is 0.6 kg.

[0079] Example

[0080] Example 1

[0081] An irinotecan hydrochloride injection, the raw material ratios of which are shown in Table 3.

[0082] Reference Figure 1 A method for preparing irinotecan hydrochloride injection comprises the following steps: wherein the modified sorbitol in the buffer is prepared by the method of Preparation Example 1,

[0083] S1: External cleaning: Preparation of ultrafiltration membrane package and silicone tube before production:

[0084] S1.1: Ultrafiltration membrane cassette: The ultrafiltration membrane cassette is cleaned according to the following process: first, circulate and rinse with 0.1% sodium hydroxide solution for 40 minutes, drain the cleaning agent, then circulate and rinse with injection water for 15 minutes, and finally rinse with injection water for 30 minutes;

[0085] The ultrafiltration membrane package is tested for integrity before and after production, and after production, the membrane package is cleaned and then tested for water flux;

[0086] Integrity test qualification standard: The air flow rate (ml / min) standard of the fully wetted intact ultrafiltration membrane is ≤34ml / min;

[0087] Water flux test qualification standard: After the membrane package is used once, the measured membrane water flux (NWP) should not be less than 80% of the initial standard. After repeated use, the attenuation of NWP each time should not exceed 15%. When the membrane package water flux decays to 60% of the initial water flux, the membrane package has reached its service life and the membrane package should be replaced.

[0088] The ultrafiltration membrane package can be used 100 times.

[0089] S1.2: Silicone tubing: Silicone tubing should be cleaned according to the following process: soak in water for injection for 40 minutes, rinse with purified water, soak in 1% sodium hydroxide solution for ≥4 hours, and then rinse with water for injection until neutral. After cleaning the silicone tubing for filling, sterilize it with moist heat at 122°C for 15 minutes.

[0090] After cleaning the silicone tube, use compressed air to dry it until there is no water droplets on the surface and then use it. If the silicone tube is found to be sticky, cracked, or aged, it should be replaced in time;

[0091] The silicone tube can be used 20 times.

[0092] S2: Liquid preparation:

[0093] S2.1: Turn on the yellow light source, prepare 80% of the total amount of water for injection, and place it in a 300L enameled liquid preparation tank. Start the liquid preparation tank temperature control system to control the water temperature at 65°C. Simultaneously start the online temperature recorder to record the temperature of the solution in the liquid preparation tank.

[0094] S2.2: Weigh the prescribed amount of buffer, place it in a 300 L enamel preparation tank, and stir to dissolve;

[0095] S2.3: Weigh the prescribed amount of irinotecan hydrochloride into a beaker, open the 300 L porcelain liquid preparation tank bottom valve, start the peristaltic pump, and slowly flush the solution in the tank with irinotecan hydrochloride into the 300 L porcelain tank. Note that the solution temperature should be controlled within 65°C, and the solution should be stirred at 18 Hz for 18 min to dissolve it.

[0096] S2.4: Weigh the prescribed amount of the adjusting agent into a beaker, open the 300 L porcelain liquid preparation tank bottom valve, start the peristaltic pump, and slowly flush the solution in the tank with the adjusting agent into the 300 L porcelain tank. Stir the solution at 18 Hz for 8 min to dissolve it, and the solution should be a light yellow clear liquid.

[0097] S2.5: Turn on the temperature control system of the 300 L porcelain liquid preparation tank and reduce the temperature to 25°C to reduce the temperature of the solution in the tank to 25°C.

[0098] S3: Pre-filtering: Connect the inlet tube of the peristaltic pump to the 300 L porcelain tank bottom valve, connect the outlet tube to a 0.22 μm filter, start the peristaltic pump, and filter the drug through the 0.22 μm filter into a 30 L glass liquid preparation tank to complete the initial filtering operation and reduce the microbial load.

[0099] S4: Ultrafiltration: Use a 10 kd flat membrane for ultrafiltration to remove bacterial endotoxins, and collect the permeate in a 50 L porcelain liquid preparation tank. During the ultrafiltration process, the transmembrane pressure TMP is < 14.0 psi. After the ultrafiltration is complete, use 12 kg of cooled water for injection to flush the ultrafiltration system four times, 3 kg each time, and combine the permeate in the 50 L porcelain liquid preparation tank.

[0100] Adjust the pH to 3.3, supplement with water for injection, and dilute to 50 L, i.e., 50.58 kg (the solution density is 1.017 g / cm3). Take samples to test the intermediate quality (properties, pH, content, bacterial endotoxins, and microbial limit).

[0101] The drug solution should be controlled to be completed within 6 hours from preparation to the first sterilization. The above sterilization and drying are completed in a Class A area, and the remaining operations are completed in a Class C area.

[0102] S5: Intermediate inspection: The intermediate is taken by the control personnel for inspection, and the detection items are shown in Table 1.

[0103] Table 1: Detection items and qualified standards

[0104] Test items Eligibility criteria Traits Light yellow clear liquid pH 3.2-3.5 content <![CDATA[本品含盐酸伊立替康(C 33 H 38 N4O6·HCl·3H2O) should be 19.0-21.8 mg / mL]]> bacterial endotoxins ≤3.0EU / mg Microbial limits <100 CFU / 100 mL

[0105] S6: Filtration: Measure 500mL of liquid medicine and use compressed air at a pressure of ≤0.15MPa to filter it from the liquid distribution pressure tank in the Class C area through the primary filter element to the filling filter press tank in the Class B area. The liquid medicine in the filling filter press tank is then filtered through the secondary filter element to the liquid medicine recovery dish in the Class A area. Rinse and filter 4 times, a total of 1500mL, to achieve the purpose of flushing the filter element. Note that the liquid medicine should be discarded after each flushing of the filter element;

[0106] The drug solution is filtered once (0.22μm filter element) in the liquid preparation room and transferred to the 10L filter press tank in the Class B area. The drug solution is filtered twice (0.22 filter element) in the filling room and transferred to the 10L liquid storage bottle on the filling machine. It is filtered in batches through the 10L filter press tank and then the filling is started.

[0107] The liquid filtration system should be cleaned and disinfected according to the cleaning procedures of the liquid filtration system before use. The filter elements used for filtration are all disposable. The filter element integrity test should be carried out before and after sterilization. The filter element should be cleaned and sterilized according to the filter element cleaning and disinfection procedures. The filter requirements are shown in Table 2.

[0108] Table 2 Filter requirements

[0109] filter Aperture Filter membrane material Function Bubble Point Sterile filter 0.22μm PES (polyethersulfone) Sterile filtration ≥3600mbar

[0110] Filling and Fully Stoppering: After dry heat sterilization in a tunnel oven, vials are conveyed to the inverting device via a feed carousel under Class A laminar airflow. After being flipped and placed upright, they are transferred to the filler. Sterilized stoppers are added to the stopper shaker hopper, a sterilized ceramic pump is installed, and the filling needle is connected. The machine is then started according to the standard operating procedures for the ZGS04 sterile liquid filling machine. After the fill volume is adjusted to meet the specified requirements, filling is carried out. The filling machine operates at an 18Hz frequency. The center fill volume for 2ml and 40mg products is 2.25ml, with a fill volume range of ±4%, i.e., 2.09-2.31ml. The filling needle is spot-checked every 30 minutes during the filling process for fill volume discrepancies. The liquid is also inspected for visible foreign matter before, during, and after filling, ensuring compliance with internal quality control standards. Filled, fully stoppered products are collected on a stainless steel transfer tray and transferred to the capping and bottle loading track via a non-powered track under Class A laminar airflow. The time from the first sterilization of the liquid medicine to the completion of filling should be controlled within 10 hours;

[0111] Capping: Under Class A laminar flow protection, filled, fully corked products are transferred to the capping carousel and transported via a conveyor to the capping room. Sterilized and dried aluminum caps are loaded into the capping machine's lower hopper. The KGL-1120 roller capping machine is started and capped according to the standard operating procedures. The caps are then conveyed to the visual inspection and labeling station and collected on a stainless steel sterilization tray. The capping machine operates at a frequency of 30 Hz. During the capping process, 10 bottles are inspected every 30 minutes for capping quality, including appearance and tightness. Tightness is determined by a capping torque test, which should be ≥ 2.1 kgf.cm. The capping yield should be ≥ 95%.

[0112] The following operations are carried out in the general production area:

[0113] Sterilization: Place the capped product in batches of approximately 5,000 bottles in an autoclave and sterilize according to the standard operating procedures for the XG1.0DE-0.6 ampoule sterilizer at 121°C for 10 minutes. Sterilize the product in sub-batches, each managed in accordance with the "SMP-PM-3004 Production Process Management Procedure for Workshop 3." The drug should not be stored for more than six hours from the completion of filling until sterilization.

[0114] Light inspection: After sterilization, each product is inspected individually according to the standard operating procedures for visual inspection in Workshop 3. Unqualified products include broken bottles, capping quality, visible foreign matter, and filling quantity. Products that pass the light inspection are sampled by QA and sent to the warehouse for packaging. They are then placed in the corresponding temporary storage warehouse for products (to be packaged). The light inspection illumination is 2800lx. There should be no defective products such as broken bottles, damaged caps, or different filling quantities. There should be no obvious visible foreign matter.

[0115] Packaging: After labeling, each bottle of product is manually packed into a carton. 40 boxes of 2ml:40mg specification products are packed into a carton. After passing the test, they are put into storage.

[0116] Examples 2-8

[0117] An irinotecan hydrochloride injection is different from Example 1 in that the raw material ratio is different. The raw material ratio is shown in Table 3.

[0118] Table 3 Weight of each raw material of irinotecan hydrochloride injection (g)

[0119]

[0120] Example 9

[0121] An irinotecan hydrochloride injection is provided, which differs from Example 7 in that the source of the modified sorbitol is different. The modified sorbitol in Example 9 is prepared using Preparation Example 2.

[0122] Example 10

[0123] An irinotecan hydrochloride injection is provided, which differs from Example 7 in that the source of the modified sorbitol is different. The modified sorbitol in Example 10 is prepared using Preparation Example 3.

[0124] Example 11

[0125] An irinotecan hydrochloride injection, which differs from Example 9 in that the irinotecan hydrochloride is further purified by the following treatments:

[0126] A1: Dissolve irinotecan hydrochloride in an acetone-water mixed solution, cool to -2℃, and let stand for crystallization for 48 hours, then perform suction filtration, collect the filter cake, and dry to obtain a primary purified product;

[0127] A2: Dissolve the primary purified product in a 30% ethanol solution, add methyl formate, mix well, and let stand for crystallization at 8℃ for 24 hours, then perform suction filtration, collect the solid, and dry to obtain purified irinotecan hydrochloride;

[0128] In step A1, the volume ratio of acetone to water in the acetone-water mixed solution is 3:1, and the amount of the acetone-water mixed solution added per 1g of irinotecan hydrochloride is 10mL. In step A2, the amount of the ethanol solution added per 1g of the primary purified product is 12mL, and the weight ratio of the primary purified product to methyl formate is 1:0.3.

[0129] Comparative Example

[0130] Comparative Example 1

[0131] An irinotecan hydrochloride injection, which differs from Example 1 in that the modified sorbitol is replaced by unmodified sorbitol.

[0132] Comparative Example 2

[0133] An irinotecan hydrochloride injection, which differs from Example 1 in that mannitol is not added to the adjusting agent.

[0134] Comparative Example 3

[0135] An irinotecan hydrochloride injection, which differs from Example 1 in that no adjusting agent is added.

[0136] Performance Test Detection

[0137] The irinotecan hydrochloride injections in Examples 1-11 and Comparative Examples 1-3 were subjected to the following test detection:

[0138] Stability: HPLC detection was used to determine the stability of each irinotecan hydrochloride injection at 60℃ and under light irradiation of 4500Lx, and the detection results are shown in Table 4.

[0139] Table 4 Detection Results

[0140]

[0141] As can be seen from Table 4, the irinotecan hydrochloride injection and the preparation method thereof can improve the stability of the irinotecan hydrochloride injection through the combined action of the raw materials, and can better ensure the safety, effectiveness, and stability of the drug.

[0142] Combining Example 1 and Comparative Examples 1-3, it can be seen that the content and related substances of the injection in Example 1 are better than those of Comparative Examples 1-3, indicating that modified sorbitol and mannitol are more suitable as regulators. Modified sorbitol can improve thermal stability and photostability. In addition, both have antioxidant properties, which can reduce the degradation of the drug due to oxidation during storage and use, and also help maintain the chemical stability and biological activity of the drug, ensure the uniform distribution of the drug, and improve stability.

[0143] In combination with Examples 1-5, it can be seen that the content and related substances of the injection in Example 5 are better than those in other examples, indicating that the addition amount and weight ratio of the modified sorbitol and mannitol in Example 5 are more appropriate. If the addition amount is too small, it will not have a better effect; if the addition amount is too large, it may affect the distribution of the injection in the body, affect metabolism, and may cause harm to human health. Only when it is within a certain range can the modified sorbitol and mannitol play a better role and can it be more helpful to improve the stability of the injection.

[0144] In combination with Examples 7-10, it can be seen that the content and related substances of the injection in Example 9 are better than those of other examples, indicating that the modified sorbitol prepared by Preparation Example 2 is more suitable, and the amount of gallic acid added in Preparation Example 2 is more appropriate. If the amount is too little, the modification effect of sorbitol is not good; if the amount is too much, it will not only affect the chemical properties of sorbitol and the effect of sorbitol, but may also affect human health. Therefore, when the amount of gallic acid added is within a certain range, the modified sorbitol can play a better role and is more conducive to improving the stability of the injection.

[0145] Combining Example 9 and Example 11, it can be seen that the content and related substances of the injection in Example 11 are better than those in Example 9, indicating that it is more appropriate to purify irinotecan hydrochloride before use, thereby reducing impurities in irinotecan hydrochloride and reducing the effects of other substances on its effects, thereby facilitating its better effect in the injection, thereby helping to improve the efficacy and stability of the injection.

[0146] As described above, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments can still be modified, or some of the technical features thereof can be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An irinotecan hydrochloride injection, characterized in that: The injection solution comprises the following raw materials in parts by weight per 50 L: 900-1100 g of irinotecan hydrochloride, 1800-2200 g of a regulator, 120-180 g of a buffer, and 5-10 g of sodium hydroxide. The regulator is a mixture of modified sorbitol and mannitol.

2. The irinotecan hydrochloride injection according to claim 1, characterized in that: The weight ratio of the modified sorbitol to mannitol is 1:(0.6-1).

3. The irinotecan hydrochloride injection according to claim 1, characterized in that: The modified sorbitol is prepared by the following method: putting gallic acid into an ethanol solution, adding sorbitol and a catalyst, mixing evenly, heating and reacting, after the reaction is completed, rotary evaporation, adding water, mixing evenly, cooling and crystallizing, and then purifying the crystals to obtain the modified sorbitol.

4. The irinotecan hydrochloride injection according to claim 3, characterized in that: The weight ratio of the sorbitol to gallic acid is 1:(0.2-0.3).

5. The irinotecan hydrochloride injection according to claim 1, characterized in that: The irinotecan hydrochloride is further subjected to the following purification treatments: A1: Dissolve irinotecan hydrochloride in an acetone-water mixture, cool, and allow to stand for crystallization. Filter by suction, collect the filter cake, and dry to obtain a preliminarily purified product. A2: Dissolve the preliminarily purified product in ethanol solution, add methyl formate, mix well, let stand again for crystallization, filter, collect the solid, and dry to obtain purified irinotecan hydrochloride.

6. The irinotecan hydrochloride injection according to claim 1, characterized in that: The buffer is any one of lactic acid, phosphoric acid, acetic acid, tartaric acid and fumaric acid.

7. The irinotecan hydrochloride injection according to claim 6, characterized in that: The buffer is lactic acid.

8. A method for preparing the irinotecan hydrochloride injection according to any one of claims 1 to 7, characterized in that: The steps include: S1: External cleaning: Preparation of ultrafiltration membrane package and silicone tube before production; S2: Liquid preparation: Weigh the prescribed amount of each material component: irinotecan hydrochloride, regulator, buffer, and sodium hydroxide, set aside, add water for injection into the liquid preparation tank A, turn on the temperature control system of the liquid preparation tank A to control the water temperature, then add the regulator, buffer, and irinotecan hydrochloride, stir to dissolve, and cool; S3: Pre-filtration: Connect the peristaltic pump inlet pipe to the bottom valve of the liquid distribution tank A, and the liquid outlet pipe to the filter. Start the peristaltic pump to filter the liquid through the filter element to the liquid distribution tank B to complete the pre-filtration. S4: Ultrafiltration: Ultrafiltration using flat membrane; S5: Intermediate inspection: The central control personnel take the intermediates for inspection; S6: Filtration: The liquid medicine is filtered once and twice before being put on the filling machine. The filling is started and the vials are fully stoppered. Then they are capped, sterilized and inspected by light. After passing the inspection, they are packaged.

9. The method for preparing irinotecan hydrochloride injection according to claim 8, characterized in that: The liquid preparation tank A is an enamel liquid preparation tank, and the liquid preparation tank B is a glass liquid preparation tank.

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