Organic-solvent-free pemetrexed disodium ready-to-use injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses an organic-solvent-free pemetrexed disodium ready-to-use injection and a preparation method thereof.The preparation method comprises the following steps that raw materials are pretreated, pemetrexed disodium raw materials are smashed and sieved through a 200-mesh sieve in the environment with the humidity smaller than 30% RH, raw material powder with the particle size D90 smaller than 50 micrometers is obtained and dissolved, and the pemetrexed disodium ready-to-use injection is obtained in a liquid preparation tank under nitrogen charging protection; the preparation method comprises the following steps: firstly, adding 50-70% of the total dosage of water for injection, cooling to 10-15 DEG C, adding an isotonic agent, a stabilizer and an antioxidant, stirring for dissolving, then adding pemetrexed disodium raw material powder, setting an organic solvent-free formula system, adopting a synergistic combination of the specific stabilizer and the antioxidant in the preparation process of the pemetrexed disodium ready-to-use injection, and preparing the pemetrexed disodium ready-to-use injection. The alkaline environment range is strictly limited, and the addition of a traditional organic solvent can be avoided, so that the injection site pain, hemolysis and liver and kidney toxicity risks caused by the organic solvent are eliminated.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a ready-to-use pemetrexed disodium injection without organic solvents and its preparation method. Background Technology

[0002] Pemetrexed disodium is a multi-target folate antagonist antitumor drug, mainly used clinically to treat malignant tumors such as non-small cell lung cancer, malignant pleural mesothelioma, and metastatic thymoma. It inhibits the proliferation of cancer cells by blocking the synthesis of DNA and RNA in tumor cells by inhibiting the activity of key enzymes such as thymidylate synthase and dihydrofolate reductase. Currently, the marketed pemetrexed disodium preparations are mainly lyophilized powder injections, which need to be reconstituted and diluted with sodium chloride injection before intravenous infusion. However, lyophilized powder injections have obvious drawbacks: the reconstitution process is cumbersome and prone to introducing the risk of microbial contamination; the reconstituted solution needs to be used within a short period of time, otherwise it is prone to degradation and inactivation; and the lyophilization process is complex, time-consuming, and energy-intensive, increasing production costs.

[0003] Furthermore, the organic solvents contained in pemetrexed disodium injection have strong elution and corrosive capabilities, which can easily wash impurities from the packaging material in direct contact into the drug solution. This process may cause visible foreign matter and insoluble particles to exceed the standard limits, and may also cause an increase in impurities in the drug solution, affecting product quality and stability, and thus bringing uncontrollable safety risks. To address these issues, we propose an organic solvent-free pemetrexed disodium ready-to-use injection and its preparation method. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a ready-to-use pemetrexed disodium injection without organic solvents and its preparation method, thus solving the problems mentioned in the background art.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a ready-to-use pemetrexed disodium injection solution without organic solvents and its preparation method, comprising the following components by weight / volume percentage: pemetrexed disodium 25-500 mg / mL, pH adjuster 0.1-1.5% w / v, isotonic agent 0.5-5% w / v, stabilizer 0.01-0.5% w / v, antioxidant 0.01-0.2% w / v, with the balance being water for injection. The pH value of the injection solution is 8.0-10.0. The stabilizer is at least one of L-arginine, glycine, or histidine, and the antioxidant is selected from at least one of sodium bisulfite, sodium metabisulfite, or L-cysteine ​​hydrochloride.

[0006] Preferably, the concentration of pemetrexed disodium is 100-400 mg / mL, and the pH adjuster is a composite system of sodium hydroxide and disodium hydrogen phosphate, wherein sodium hydroxide accounts for 30-60% of the total mass of the pH adjuster, and disodium hydrogen phosphate accounts for 40-70%.

[0007] Preferably, the isotonic agent is sodium chloride or mannitol with a concentration of 0.8-1.2% w / v, the stabilizer is L-arginine with a concentration of 0.05-0.3% w / v, and the molar ratio of L-arginine to pemetrexed disodium is 1:5 to 1:20.

[0008] Preferably, the antioxidant is a compound of sodium metabisulfite and L-cysteine ​​hydrochloride, wherein the mass ratio of sodium metabisulfite to L-cysteine ​​hydrochloride is 1:0.2 to 1:0.8, and the total concentration is 0.05-0.15%w / v.

[0009] Preferably, it includes the following steps: Step 1: Raw material pretreatment: Pemetrexed disodium raw material is pulverized through a 200-mesh sieve in an environment with a humidity of less than 30%RH to obtain raw material powder with a particle size D90 of less than 50μm. Step 2, Dissolution: In a nitrogen-protected mixing tank, first add 50-70% of the total volume of water for injection, cool to 10-15℃, add isotonic agent, stabilizer and antioxidant, stir to dissolve, and then add pemetrexed disodium raw material powder. Step 3, pH adjustment: At 15-25℃, add pH adjusting agent solution dropwise at a rate of 0.5-1.0L / min to control the pH value within the range of 8.5-9.5; Step 4, replenishing and adjusting the volume: Add the remaining water for injection to the total volume, maintain the temperature at 20±2℃, and stir at 300-500r / min for 15-30min; Step 5, Sterilization Filtration: Pass through a 1.0μm pre-filter and a 0.22μm polyethersulfone sterilization filter cartridge in sequence; Step 6, Filling and Sealing: Fill neutral borosilicate glass vials in an ISO 5 clean environment, with a filling accuracy error of less than ±1%, and immediately seal with nitrogen. Step 7, Terminal sterilization: Use a moist heat sterilization program, maintaining an F0 value greater than 8 minutes at 121°C.

[0010] Preferably, the dissolution process in step two is divided into two stages: the first stage is to stir at 100-200 r / min for 10-20 min at 10-15℃, and the second stage is to raise the temperature to 20-25℃ and stir at 500-800 r / min for 30-45 min, and the nitrogen purging protection maintains the dissolved oxygen content at less than 0.5 ppm.

[0011] Preferably, the pH adjusting agent solution in step three is a composite system of 5-10% w / v sodium hydroxide solution and 2-5% w / v disodium hydrogen phosphate solution, with a volume ratio of 1:0.5 to 1:2. The dropping rate is dynamically adjusted according to online pH monitoring, and the pH fluctuation range is less than ±0.2.

[0012] Preferably, the neutral borosilicate glass vials in step six are pretreated by rinsing with 0.1% w / v sodium pyrophosphate solution and then dry heat sterilizing at 250°C for 30 min. The nitrogen purity of the nitrogen-filled and sealed vials is greater than 99.999%, and the oxygen content in the headspace of the vials is less than 2%.

[0013] Preferably, the process also includes a freeze-drying process: after filling in step six, the product is immediately transferred to a freeze dryer. In the pre-freezing stage, the temperature is lowered to below -45°C at a rate of 1-2°C / min and maintained for 2-4 hours. In the main drying stage, the product is sublimated at -20°C and 10Pa for 12-18 hours. In the desorption drying stage, the temperature is raised to 25-30°C and maintained for 4-8 hours. The final product has a moisture content of less than 1.0% and a reconstitution time of less than 30 seconds.

[0014] Preferably, a cooling control stage is added after terminal sterilization in step seven: A gradient cooling program was used to reduce the temperature from 121℃ to 80℃ at a rate of 1.5-2.5℃ / min, and then to 25℃ at a rate of 0.5-1.0℃ / min. Maintain a positive pressure of 0.1-0.3 MPa in the sterilization chamber during the cooling process; The entire cooling process is carried out under Class A air protection, with the concentration of viable microorganisms in the environment being less than 0.1 CFU / m³; The final product was verified by accelerated testing, and the total amount of related substances increased by less than 0.5% and the pH value changed by less than ±0.3 within 6 months.

[0015] Preferably, the product contains no organic solvents and maintains stability at 25°C for 24 months after terminal sterilization.

[0016] Compared with the prior art, the present invention provides a ready-to-use pemetrexed disodium injection without organic solvents and its preparation method, which has the following beneficial effects: 1. In this invention, by setting up an organic solvent-free formulation system, a synergistic combination of specific stabilizers and antioxidants is used in the preparation of ready-to-use pemetrexed disodium injection, and the alkaline environment range is strictly limited. This avoids the addition of traditional organic solvents, thereby eliminating the risks of injection site pain, hemolysis, and hepatotoxicity caused by organic solvents. At the same time, by inhibiting the oxidative degradation of pemetrexed disodium in solution, the chemical stability of the formulation is improved, ensuring that it can be stored at room temperature for a long time after terminal sterilization. This solves the problem that existing liquid formulations need to be refrigerated and frequently reconstituted due to insufficient stability.

[0017] 2. In this invention, by setting up a gradient cooling terminal sterilization process, after the injection solution is filled and sealed, a staged programmed cooling control is adopted, and positive pressure and high-cleanliness air protection are maintained in the sterilization chamber. This can effectively inhibit the aggregation and degradation of drug molecules caused by thermal stress after high-temperature sterilization, and at the same time prevent the container from cracking due to internal stress and sealing failure caused by sudden temperature changes. Combined with online particle monitoring, it ensures that the product maintains a stable solution state, no visible particles and a sterile state after moist heat sterilization, thus breaking through the industry bottleneck of surge in related substances and excessive visible foreign matter after terminal sterilization in the prior art.

[0018] 3. In this invention, by setting up a ready-to-use clinical adaptation mechanism, the defect of pemetrexed disodium lyophilized powder injection requiring reconstitution is addressed. Through a combination of raw material pre-pulverization, staged temperature-controlled dissolution, and nitrogen protection in the preparation method, the rapid dissolution and physical stability of high-concentration drug solution are achieved, allowing the injection solution to be directly administered intravenously. This avoids the risk of microbial contamination and operation time delays introduced by clinical reconstitution, providing a safe and immediate medication plan for the treatment of non-small cell lung cancer and malignant pleural mesothelioma, and improving patient compliance and drug delivery efficiency in emergency scenarios. Detailed Implementation

[0019] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0020] Example 1: Pemetrexed disodium ready-to-use injection without organic solvents and its preparation method, comprising the following components by weight / volume percentage: 25 mg / mL pemetrexed disodium, 0.1% w / v pH adjuster, 0.5% w / v isotonic agent, 0.01% w / v stabilizer, 0.01% w / v antioxidant, with the remainder being water for injection. The pH of the injection is 8.0, without the addition of any organic solvents, and after terminal sterilization, it can maintain stability at 25°C for 24 months. The stabilizer is at least one of L-arginine, glycine, or histidine, and the antioxidant is selected from at least one of sodium bisulfite, sodium metabisulfite, or L-cysteine ​​hydrochloride. The concentration of pemetrexed disodium is 100 mg / mL. The pH adjuster is a composite system of sodium hydroxide and disodium hydrogen phosphate, in which sodium hydroxide accounts for 30% of the total mass of the pH adjuster and disodium hydrogen phosphate accounts for 40%. The isotonic agent is sodium chloride or mannitol at a concentration of 0.8% w / v, and the stabilizer is L-arginine at a concentration of 0.05% w / v, with a molar ratio of L-arginine to pemetrexed disodium of 1:5. The antioxidant is a compound of sodium metabisulfite and L-cysteine ​​hydrochloride, with a mass ratio of sodium metabisulfite to L-cysteine ​​hydrochloride of 1:0.2 and a total concentration of 0.05% w / v. Includes the following steps: Step 1: Raw material pretreatment: Pemetrexed disodium raw material is pulverized through a 200-mesh sieve in an environment with a humidity of less than 30%RH to obtain raw material powder with a particle size D90 of less than 50μm. Step 2, Dissolution: In a nitrogen-protected mixing tank, first add 50% of the total volume of water for injection, cool to 10°C, add isotonic agent, stabilizer and antioxidant, stir to dissolve, and then add pemetrexed disodium raw material powder. Step 3, pH adjustment: At 15℃, add pH adjusting agent solution dropwise at a rate of 0.5L / min to control the pH value within the range of 8.5; Step 4: Add the remaining water for injection to the total volume, maintain the temperature at 20±2℃, and stir at 300r / min for 15min; Step 5, Sterilization Filtration: Pass through a 1.0μm pre-filter and a 0.22μm polyethersulfone sterilization filter cartridge in sequence; Step 6, Filling and Sealing: Fill neutral borosilicate glass vials in an ISO 5 clean environment, with a filling accuracy error of less than ±1%, and immediately seal with nitrogen. Step 7, Terminal sterilization: Use a moist heat sterilization program, maintain an F0 value greater than 8 min at 121℃; The dissolution process in step two is divided into two stages: the first stage is to stir at 100 r / min for 10 min at 10℃, and the second stage is to raise the temperature to 20℃ and stir at 500 r / min for 30 min, with nitrogen protection to maintain the dissolved oxygen content at less than 0.5 ppm; In step three, the pH adjusting agent solution is a composite system of 5% w / v sodium hydroxide solution and 2% w / v disodium hydrogen phosphate solution, with a volume ratio of 1:0.5. The dropping rate is dynamically adjusted according to online pH monitoring, and the pH fluctuation range is less than ±0.2. Step 6: Pretreatment of neutral borosilicate glass vials: First, rinse with 0.1% w / v sodium pyrophosphate solution, then dry heat sterilize at 250℃ for 30 min, nitrogen gas purity of nitrogen gas for nitrogen filling and sealing is greater than 99.999%, and headspace oxygen content of vials is less than 2%; It also includes freeze-drying process: after filling in step six, the product is immediately transferred to a freeze dryer. In the pre-freezing stage, the temperature is reduced to below -45℃ at a rate of 1℃ / min and held for 2 hours. In the main drying stage, the product is sublimated at -20℃ and 10Pa for 12 hours. In the desorption drying stage, the temperature is raised to 25℃ and held for 4 hours. The final product has a moisture content of less than 1.0% and a reconstitution time of less than 30 seconds. A cooling control stage is added after terminal sterilization in step seven: A gradient cooling program was used to reduce the temperature from 121℃ to 80℃ at a rate of 1.5℃ / min, and then to 25℃ at a rate of 0.5℃ / min. Maintain a positive pressure of 0.1 MPa in the sterilization chamber during the cooling process; The entire cooling process is carried out under Class A air protection, with the concentration of viable microorganisms in the environment being less than 0.1 CFU / m³; The final product, after accelerated testing, showed that the total amount of related substances increased by less than 0.5% and the pH value changed by less than ±0.3 within 6 months. The product contains no organic solvents and maintains stability for 24 months at 25°C after terminal sterilization.

[0021] Example 2: Pemetrexed disodium ready-to-use injection without organic solvents and its preparation method, comprising the following components by weight / volume percentage: 300 mg / mL pemetrexed disodium, 1.0% w / v pH adjuster, 3% w / v isotonic agent, 0.2% w / v stabilizer, 0.1% w / v antioxidant, with the remainder being water for injection. The pH of the injection is 9.0, without the addition of any organic solvents, and after terminal sterilization, it can maintain stability at 25°C for 24 months. The stabilizer is at least one of L-arginine, glycine, or histidine, and the antioxidant is selected from at least one of sodium bisulfite, sodium metabisulfite, or L-cysteine ​​hydrochloride. The concentration of pemetrexed disodium is 200 mg / mL. The pH adjuster is a composite system of sodium hydroxide and disodium hydrogen phosphate, in which sodium hydroxide accounts for 50% of the total mass of the pH adjuster and disodium hydrogen phosphate accounts for 60%. The isotonic agent is sodium chloride or mannitol at a concentration of 1.0% w / v, and the stabilizer is L-arginine at a concentration of 0.2% w / v, with a molar ratio of L-arginine to pemetrexed disodium of 1:12. The antioxidant is a compound of sodium metabisulfite and L-cysteine ​​hydrochloride, with a mass ratio of sodium metabisulfite to L-cysteine ​​hydrochloride of 1:0.5 and a total concentration of 0.10% w / v. Includes the following steps: Step 1: Raw material pretreatment: Pemetrexed disodium raw material is pulverized through a 200-mesh sieve in an environment with a humidity of less than 30%RH to obtain raw material powder with a particle size D90 of less than 50μm. Step 2, Dissolution: In a nitrogen-protected mixing tank, first add 60% of the total volume of water for injection, cool to 12°C, add isotonic agent, stabilizer and antioxidant, stir to dissolve, and then add pemetrexed disodium raw material powder. Step 3, pH adjustment: At 20℃, add pH adjusting agent solution dropwise at a rate of 0.8L / min to control the pH value within the range of 9.0; Step 4, replenishing and adjusting the volume: Add the remaining water for injection to the total volume, maintain the temperature at 20±2℃, and stir at 400r / min for 25min; Step 5, Sterilization Filtration: Pass through a 1.0μm pre-filter and a 0.22μm polyethersulfone sterilization filter cartridge in sequence; Step 6, Filling and Sealing: Fill neutral borosilicate glass vials in an ISO 5 clean environment, with a filling accuracy error of less than ±1%, and immediately seal with nitrogen. Step 7, Terminal sterilization: Use a moist heat sterilization program, maintain an F0 value greater than 8 min at 121℃; The dissolution process in step two is divided into two stages: the first stage is to stir at 150 r / min for 15 min at 12℃, and the second stage is to raise the temperature to 23℃ and stir at 700 r / min for 40 min, with nitrogen protection to maintain the dissolved oxygen content at less than 0.5 ppm; In step three, the pH adjusting agent solution is a composite system of 8% w / v sodium hydroxide solution and 4% w / v disodium hydrogen phosphate solution, with a volume ratio of 1:0.8. The dropping rate is dynamically adjusted according to online pH monitoring, and the pH fluctuation range is less than ±0.2. Step 6: Pretreatment of neutral borosilicate glass vials: First, rinse with 0.1% w / v sodium pyrophosphate solution, then dry heat sterilize at 250℃ for 30 min, nitrogen gas purity of nitrogen gas for nitrogen filling and sealing is greater than 99.999%, and headspace oxygen content of vials is less than 2%; It also includes freeze-drying process: after filling in step six, the product is immediately transferred to a freeze dryer. In the pre-freezing stage, the temperature is reduced to below -45℃ at a rate of 1.5℃ / min and held for 3 hours. In the main drying stage, the product is sublimated at -20℃ and 10Pa for 15 hours. In the desorption drying stage, the temperature is raised to 28℃ and held for 5 hours. The final product has a moisture content of less than 1.0% and a reconstitution time of less than 30 seconds. A cooling control stage is added after terminal sterilization in step seven: A gradient cooling program was used to reduce the temperature from 121℃ to 80℃ at a rate of 2.0℃ / min, and then to 25℃ at a rate of 0.7℃ / min. Maintain a positive pressure of 0.2 MPa in the sterilization chamber during the cooling process; The entire cooling process is carried out under Class A air protection, with the concentration of viable microorganisms in the environment being less than 0.1 CFU / m³; The final product, after accelerated testing, showed that the total amount of related substances increased by less than 0.5% and the pH value changed by less than ±0.3 within 6 months. The product contains no organic solvents and maintains stability for 24 months at 25°C after terminal sterilization.

[0022] Example 3: Pemetrexed disodium ready-to-use injection without organic solvents and its preparation method, comprising the following components by weight / volume percentage: 500 mg / mL pemetrexed disodium, 1.5% w / v pH adjuster, 5% w / v isotonic agent, 0.5% w / v stabilizer, 0.2% w / v antioxidant, with the balance being water for injection. The pH of the injection is 10.0, without the addition of any organic solvents, and after terminal sterilization, it can maintain stability at 25°C for 24 months. The stabilizer is at least one of L-arginine, glycine, or histidine, and the antioxidant is selected from at least one of sodium bisulfite, sodium metabisulfite, or L-cysteine ​​hydrochloride. The concentration of pemetrexed disodium is 400 mg / mL. The pH adjuster is a composite system of sodium hydroxide and disodium hydrogen phosphate, in which sodium hydroxide accounts for 60% of the total mass of the pH adjuster and disodium hydrogen phosphate accounts for 70%. The isotonic agent is sodium chloride or mannitol at a concentration of 1.2% w / v, and the stabilizer is L-arginine at a concentration of 0.3% w / v, with a molar ratio of L-arginine to pemetrexed disodium of 1:20. The antioxidant is a compound of sodium metabisulfite and L-cysteine ​​hydrochloride, with a mass ratio of sodium metabisulfite to L-cysteine ​​hydrochloride of 1:0.8 and a total concentration of 0.15% w / v. Includes the following steps: Step 1: Raw material pretreatment: Pemetrexed disodium raw material is pulverized through a 200-mesh sieve in an environment with a humidity of less than 30%RH to obtain raw material powder with a particle size D90 of less than 50μm. Step 2, Dissolution: In a nitrogen-protected mixing tank, first add 70% of the total volume of water for injection, cool to 15°C, add isotonic agent, stabilizer and antioxidant, stir to dissolve, and then add pemetrexed disodium raw material powder. Step 3, pH adjustment: At 25℃, add pH adjusting agent solution dropwise at a rate of 1.0 L / min to control the pH value within the range of 9.5; Step 4, replenishing and adjusting the volume: Add the remaining water for injection to the total volume, maintain the temperature at 20±2℃, and stir at 500r / min for 30min; Step 5, Sterilization Filtration: Pass through a 1.0μm pre-filter and a 0.22μm polyethersulfone sterilization filter cartridge in sequence; Step 6, Filling and Sealing: Fill neutral borosilicate glass vials in an ISO 5 clean environment, with a filling accuracy error of less than ±1%, and immediately seal with nitrogen. Step 7, Terminal sterilization: Use a moist heat sterilization program, maintain an F0 value greater than 8 min at 121℃; The dissolution process in step two is divided into two stages: the first stage is to stir at 200 r / min for 20 min at 15℃, and the second stage is to raise the temperature to 25℃ and stir at 800 r / min for 45 min, with nitrogen protection to maintain the dissolved oxygen content at less than 0.5 ppm; In step three, the pH adjusting agent solution is a composite system of 10% w / v sodium hydroxide solution and 5% w / v disodium hydrogen phosphate solution, with a volume ratio of 1:2. The dropping rate is dynamically adjusted according to online pH monitoring, and the pH fluctuation range is less than ±0.2. Step 6: Pretreatment of neutral borosilicate glass vials: First, rinse with 0.1% w / v sodium pyrophosphate solution, then dry heat sterilize at 250℃ for 30 min, nitrogen gas purity of nitrogen gas for nitrogen filling and sealing is greater than 99.999%, and headspace oxygen content of vials is less than 2%; It also includes freeze-drying process: after filling in step six, the product is immediately transferred to a freeze dryer. In the pre-freezing stage, the temperature is reduced to below -45℃ at a rate of 2℃ / min and held for 4 hours. In the main drying stage, the product is sublimated at -20℃ and 10Pa for 18 hours. In the desorption drying stage, the temperature is raised to 30℃ and held for 8 hours. The final product has a moisture content of less than 1.0% and a reconstitution time of less than 30 seconds. A cooling control stage is added after terminal sterilization in step seven: A gradient cooling program was used to reduce the temperature from 121℃ to 80℃ at a rate of 2.5℃ / min, and then to 25℃ at a rate of 1.0℃ / min. Maintain a positive pressure of 0.3 MPa in the sterilization chamber during the cooling process; The entire cooling process is carried out under Class A air protection, with the concentration of viable microorganisms in the environment being less than 0.1 CFU / m³; The final product, after accelerated testing, showed that the total amount of related substances increased by less than 0.5% and the pH value changed by less than ±0.3 within 6 months. The product contains no organic solvents and maintains stability for 24 months at 25°C after terminal sterilization.

[0023] Comparative Example 1: The difference between this comparative example and Example 1 is that 0.5% w / v propylene glycol is added to the formulation as an organic solvent to replace the arginine stabilizer system, while the remaining components and preparation process are the same as in Example 1.

[0024] Comparative Example 2 differs from Example 2 in that the stabilizer is omitted and only the antioxidant is retained, while the remaining components and preparation process are the same as in Example 2.

[0025] Comparative Example 3 differs from Example 3 in that the pH adjuster is replaced with a single sodium hydroxide solution, and a composite buffer system is not used. The remaining components and preparation process are the same as in Example 3.

[0026] Comparative Example 4 differs from Example 3 in that: after terminal sterilization, it is directly cooled to room temperature, while the rest of the preparation process is the same as in Example 3.

[0027] The performance of the organic solvent-free pemetrexed disodium ready-to-use injections prepared in Examples 1-3 and Comparative Examples 1-4 was tested. The test items and test methods are as follows: 1. Total amount of related substances Methods: Degradation impurities were detected by HPLC; Standard: ICH Q3B requires single impurities to be less than 0.1% and total impurities to be less than 0.5%.

[0028] 2. pH stability Method: pH shift was measured at 6 months of accelerated testing; Standard: An offset of less than ±0.3 is considered acceptable.

[0029] 3. Visible foreign objects Methods: The number of particles larger than 10 μm was counted using a light inspection method combined with a particle analyzer. Standard: The Chinese Pharmacopoeia requires less than 5 tablets per bottle.

[0030] 4. Reconstitution time Method: Redissolve the sample in 0.9% sodium chloride injection and record the time to complete dissolution; Standard: Less than 30 seconds is considered ready to use.

[0031] 5. Accelerated stability testing Method: After being stored at 40℃±2℃ and RH75%±5% for 6 months, the increase in related substances was detected; Standard: Total value increase is less than 0.5%.

[0032] The test data of the organic solvent-free pemetrexed disodium ready-to-use injections prepared in Examples 1-3 and Comparative Examples 1-4 are recorded in the table below:

[0033] Comparison and analysis of the data in the table show that the ready-to-use pemetrexed disodium injection without organic solvents in Examples 1-3 exhibits significantly superior performance compared to the ready-to-use pemetrexed disodium injection without organic solvents in Comparative Examples 1-4. This indicates that by setting up an organic solvent-free formulation system, employing a synergistic combination of specific stabilizers and antioxidants during the preparation of ready-to-use pemetrexed disodium injection, and strictly limiting the alkaline environment range, the addition of traditional organic solvents can be avoided. This eliminates the risks of injection site pain, hemolysis, and hepatotoxicity caused by organic solvents. Simultaneously, by inhibiting the oxidative degradation of pemetrexed disodium in solution, the chemical stability of the formulation is improved, ensuring long-term storage at room temperature after terminal sterilization. This solves the problem of existing liquid formulations requiring refrigeration and frequent reconstitution due to insufficient stability. By setting up a gradient cooling terminal sterilization process, after the injection solution is filled and sealed, a staged programmed cooling control is adopted to maintain sterilization. The positive pressure and high-cleanliness air protection of the sterilization chamber effectively inhibits the aggregation and degradation of drug molecules caused by thermal stress after high-temperature sterilization. It also prevents container rupture and sealing failure due to internal stress caused by sudden temperature changes. Combined with online particle monitoring, it ensures that the product maintains a stable solution state, free of visible particles, and aseptic condition after moist heat sterilization. This overcomes the industry bottleneck of increased related substances and excessive visible foreign matter after terminal sterilization in existing technologies. By setting up a ready-to-use clinical adaptation mechanism, it addresses the deficiency of pemetrexed disodium lyophilized powder injection requiring reconstitution. Through a combination of raw material pre-pulverization, staged temperature-controlled dissolution, and nitrogen protection in the preparation method, it achieves rapid dissolution and physical stability of high-concentration drug solutions, allowing direct intravenous infusion. This avoids the risk of microbial contamination and operation time delays introduced by clinical reconstitution, providing a safe and immediate medication plan for the treatment of non-small cell lung cancer and malignant pleural mesothelioma, improving patient compliance and drug delivery efficiency in emergency scenarios.

[0034] By comparing and analyzing the relevant data in the table, it can be seen that the ready-to-use pemetrexed disodium injection without organic solvents prepared by the molding process of the present invention has good stability, sterility and ready-to-use properties. This indicates that the ready-to-use pemetrexed disodium injection without organic solvents provided by the present invention meets the clinical need for direct intravenous infusion and has promotional value.

[0035] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0036] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A ready-to-use pemetrexed disodium injection solution without organic solvents and its preparation method, characterized in that, The solution is composed of the following components by weight / volume percentage: pemetrexed disodium 25-500 mg / mL, pH adjuster 0.1-1.5% w / v, isotonic agent 0.5-5% w / v, stabilizer 0.01-0.5% w / v, antioxidant 0.01-0.2% w / v, with the balance being water for injection. The pH of the injection solution is 8.0-10.

0. The stabilizer is at least one of L-arginine, glycine, or histidine, and the antioxidant is at least one of sodium bisulfite, sodium metabisulfite, or L-cysteine ​​hydrochloride.

2. The ready-to-use pemetrexed disodium injection without organic solvent according to claim 1 and its preparation method, characterized in that: The concentration of pemetrexed disodium is 100-400 mg / mL, and the pH adjuster is a composite system of sodium hydroxide and disodium hydrogen phosphate, wherein sodium hydroxide accounts for 30-60% of the total mass of the pH adjuster, and disodium hydrogen phosphate accounts for 40-70%.

3. The ready-to-use pemetrexed disodium injection without organic solvent according to claim 1 and its preparation method, characterized in that: The isotonic agent is sodium chloride or mannitol with a concentration of 0.8-1.2% w / v, the stabilizer is L-arginine with a concentration of 0.05-0.3% w / v, and the molar ratio of L-arginine to pemetrexed disodium is 1:5 to 1:

20.

4. The ready-to-use pemetrexed disodium injection without organic solvent according to claim 1 and its preparation method, characterized in that: The antioxidant is a compound of sodium metabisulfite and L-cysteine ​​hydrochloride, wherein the mass ratio of sodium metabisulfite to L-cysteine ​​hydrochloride is 1:0.2 to 1:0.8, and the total concentration is 0.05-0.15%w / v.

5. A method for preparing ready-to-use pemetrexed disodium injection without organic solvents, characterized in that, Includes the following steps: Step 1: Raw material pretreatment: Pemetrexed disodium raw material is pulverized through a 200-mesh sieve in an environment with a humidity of less than 30%RH to obtain raw material powder with a particle size D90 of less than 50μm. Step 2, Dissolution: In a nitrogen-protected mixing tank, first add 50-70% of the total volume of water for injection, cool to 10-15℃, add isotonic agent, stabilizer and antioxidant, stir to dissolve, and then add pemetrexed disodium raw material powder. Step 3, pH adjustment: At 15-25℃, add pH adjusting agent solution dropwise at a rate of 0.5-1.0L / min to control the pH value within the range of 8.5-9.5; Step 4, replenishing and adjusting the volume: Add the remaining water for injection to the total volume, maintain the temperature at 20±2℃, and stir at 300-500r / min for 15-30min; Step 5, Sterilization Filtration: Pass through a 1.0μm pre-filter and a 0.22μm polyethersulfone sterilization filter cartridge in sequence; Step 6, Filling and Sealing: Fill neutral borosilicate glass vials in an ISO 5 clean environment, with a filling accuracy error of less than ±1%, and immediately seal with nitrogen. Step 7, Terminal sterilization: Use a moist heat sterilization program, maintaining an F0 value greater than 8 minutes at 121°C.

6. The method for preparing the organic solvent-free pemetrexed disodium ready-to-use injection according to claim 5, characterized in that, The dissolution process in step two is divided into two stages: the first stage involves stirring at 100-200 r / min for 10-20 min at 10-15℃, and the second stage involves heating to 20-25℃ and stirring at 500-800 r / min for 30-45 min, with nitrogen purging maintaining a dissolved oxygen content of less than 0.5 ppm.

7. The method for preparing the organic solvent-free pemetrexed disodium ready-to-use injection according to claim 5, characterized in that, The pH adjusting agent solution mentioned in step three is a composite system of 5-10% w / v sodium hydroxide solution and 2-5% w / v disodium hydrogen phosphate solution, with a volume ratio of 1:0.5 to 1:

2. The dropping rate is dynamically adjusted according to online pH monitoring, and the pH fluctuation range is less than ±0.

2.

8. The method for preparing the organic solvent-free pemetrexed disodium ready-to-use injection according to claim 5, characterized in that, In step six, the neutral borosilicate glass vials are pretreated by rinsing with a 0.1% w / v sodium pyrophosphate solution and then dry heat sterilizing at 250°C for 30 minutes. The nitrogen purity of the nitrogen-filled and sealed vials is greater than 99.999%, and the oxygen content in the headspace of the vials is less than 2%.

9. The method for preparing the organic solvent-free pemetrexed disodium ready-to-use injection according to claim 5, characterized in that, It also includes a freeze-drying process: after filling in step six, the product is immediately transferred to a freeze dryer. In the pre-freezing stage, the temperature is lowered to below -45℃ at a rate of 1-2℃ / min and maintained for 2-4 hours. In the main drying stage, the product is sublimated at -20℃ and 10Pa for 12-18 hours. In the desorption drying stage, the temperature is raised to 25-30℃ and maintained for 4-8 hours. The final product has a moisture content of less than 1.0% and a reconstitution time of less than 30 seconds.

10. The method for preparing the organic solvent-free pemetrexed disodium ready-to-use injection according to claim 5, characterized in that, A cooling control stage is added after terminal sterilization in step seven: A gradient cooling program was used to reduce the temperature from 121℃ to 80℃ at a rate of 1.5-2.5℃ / min, and then to 25℃ at a rate of 0.5-1.0℃ / min. Maintain a positive pressure of 0.1-0.3 MPa in the sterilization chamber during the cooling process; The entire cooling process is carried out under Class A air protection, with the concentration of viable microorganisms in the environment being less than 0.1 CFU / m³; The final product, after accelerated testing, showed that the total amount of related substances increased by less than 0.5% and the pH value changed by less than ±0.3 within 6 months. The product contains no organic solvents and maintains stability for 24 months at 25°C after terminal sterilization.

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