Pemetrexed disodium liquid composition, method for producing the same, and applications

Abstract

The present invention discloses a pemetrexed disodium liquid composition, its preparation method and application. The pemetrexed disodium liquid composition provided by the present invention comprises a pharmaceutical active ingredient and a stabilizer, the pharmaceutical active ingredient being one or more of pemetrexed disodium, pharma- ceutically acceptable complexes, salts, solvates and hydrates of pemetrexed disodium, and the stabilizer being one or more of an organic solvent, a pH adjuster and an antioxidant. The pemetrexed disodium liquid composition of the present invention has the advantages of a simple preparation process, good physical and chemical stability, clinical ease of use without the need for reconstitution, low risk of microbial contamination during the preparation process, and suitability for industrial production.

Description

Technical Field

[0001] This application claims the priority of a prior application filed with the China National Intellectual Property Administration on June 9, 2022, with a patent application number of 202210645147.0 and an invention title of "Pemetrexed Disodium Liquid Composition, Its Manufacturing Method and Application". The above prior application is incorporated into this application by reference in its entirety. The present invention relates to a pemetrexed disodium liquid composition, its manufacturing method and application.

Background Art

[0002] Pemetrexed is a multi-targeted antimetabolic anti-tumor drug and a folic acid antagonist that can inhibit folic acid-dependent enzymes such as thymidylate synthase, dihydrofolate reductase, and glycine ribonucleoside formyltransferase. These enzymes are involved in the biosynthesis of thymidine and purine nucleosides, thereby achieving an anti-tumor effect. Pemetrexed disodium was first developed by Eli Lilly and Company, received sales approval from the FDA in 2004, obtained an import drug license in China in August 2005, and began to be clinically used in China. This drug is used in combination with cisplatin as a first-choice drug to treat inoperable malignant pleural mesothelioma and as a second-choice drug for non-squamous non-small cell lung cancer when used alone.

[0003] Currently, it is commercially available in multiple countries and regions around the world. This drug is a freeze-dried powder injection. Before use, it needs to be redissolved into a concentrated solution with a concentration of 25 mg / mL using a 0.9% sodium chloride solution based on the pharmaceutical standard, and then secondarily diluted for administration. The redissolution process may cause errors in the dosage administered to patients and may pose concerns about safety and the risk of microbial contamination.

[0004] Therefore, finding a pemetrexed dosage form that is easy to use, has good physical and chemical stability, a simple manufacturing process, and is suitable for industrial production is a technical problem that needs to be urgently solved at present.

Summary of the Invention

[0005] The pemetrexed disodium liquid composition provided by the present invention comprises a drug-active ingredient and a stabilizer, wherein the drug-active ingredient is one or more selected from pemetrexed disodium and pharmaceutically acceptable complexes, salts, solvates, and hydrates of pemetrexed disodium, and the stabilizer is one or more selected from organic solvents, pH adjusters, and antioxidants.

[0006] According to embodiments of the present invention, the content of the drug-active ingredient is 1 mg / mL to 50 mg / mL, preferably 15 mg / mL to 30 mg / mL, for example, 20 mg / mL, 25.00 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL, and the above content refers to the ratio of the mass of the drug-active ingredient to the total volume of the pemetrexed disodium liquid composition.

[0007] According to embodiments of the present invention, the organic solvent is one or more selected from ethanol, propylene glycol, and polyethylene glycol. For example, the polyethylene glycol is selected from polyethylene glycol 400 (PEG400) and / or polyethylene glycol 300 (PEG300).

[0008] According to some embodiments of the present invention, the content of the organic solvent is 70 mg / mL to 300 mg / mL, for example, 90 mg / mL to 260 mg / mL, and exemplary is 90 mg / mL, 180 mg / mL, 260 mg / mL, or 280 mg / mL, where the content refers to the ratio of the mass of the organic solvent to the total volume of the pemetrexed disodium pharmaceutical composition.

[0009] According to embodiments of the present invention, the pH adjusting agent may be an acidic pH adjusting agent and / or a basic pH adjusting agent. For example, the acidic pH adjusting agent is preferably hydrochloric acid and / or citric acid, and more preferably citric acid. For example, the basic pH adjusting agent may be one or more of sodium hydroxide, lysine, arginine, meglumine, and tromethamine, and is preferably tromethamine. For example, the lysine may be L-lysine and / or D-lysine. For example, the arginine may be L-arginine and / or D-arginine.

[0010] According to embodiments of the present invention, the antioxidant is one or more selected from anhydrous sodium sulfite, cysteine ​​hydrochloride, acetylcysteine, and methionine, and more preferably cysteine ​​hydrochloride. The content of the antioxidant is preferably 0 to 15 mg / mL, more preferably 0.1 mg / mL to 10 mg / mL, for example 0.3 mg / mL, 1 mg / mL, 1.63 mg / mL, or 3 mg / mL, and the above content refers to the ratio of the mass of the antioxidant to the total volume of the pemetrexed disodium pharmaceutical composition.

[0011] In some embodiments, the content of the stabilizer (e.g., basic pH adjuster) in the pemetrexed disodium liquid composition is preferably 0.5 mg / mL to 50 mg / mL, more preferably 1 mg / mL to 10 mg / mL, for example, 2.4 mg / mL, where the content refers to the ratio of the mass of the stabilizer (e.g., basic pH adjuster) to the total volume of the pemetrexed disodium liquid composition.

[0012] According to some embodiments of the present invention, the stabilizer comprises at least one or more of citric acid, tromethamine, cysteine ​​hydrochloride, meglumine, and arginine, and in some other embodiments, the stabilizer may further comprise propylene glycol.

[0013] According to embodiments of the present invention, the pH of the above pemetrexed disodium liquid composition is preferably 7.5 to 9.5, and more preferably 8.0 to 9.0. According to embodiments of the present invention, the pemetrexed disodium liquid composition may further contain an osmotic pressure modifier. The osmotic pressure modifier is preferably one or more selected from sodium chloride, mannitol, glycerin, and propylene glycol. The content of the osmotic pressure modifier is preferably 1 mg / mL to 300 mg / mL, for example 1 mg / mL to 100 mg / mL, and more preferably 2 mg / mL to 30 mg / mL, for example 5.8 mg / mL, 11 mg / mL, 15 mg / mL, or 23 mg / mL, where the content refers to the ratio of the mass of the osmotic pressure modifier to the total volume of the pemetrexed disodium liquid composition. If the pemetrexed disodium liquid composition contains propylene glycol, propylene glycol can not only adjust the osmotic pressure but also improve the stability of the pemetrexed disodium liquid composition.

[0014] According to embodiments of the present invention, the pemetrexed disodium liquid composition further comprises water, such as sterile water for injection, to a fixed volume. For example, water is added to bring the total volume to 1 mL.

[0015] According to embodiments of the present invention, the above-mentioned pemetrexed disodium liquid composition is selected from any one of the following compositions.

[0016] Composition 1 comprises a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate, and the stabilizer is selected from tromethamine and citric acid. Preferably, in the above composition 1, the content of the pharmacoactive ingredient is 25 mg / mL, and the content of the tromethamine is 2.4 mg / mL. Composition II comprises a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, its pharmaceutically acceptable complex, salt, or hydrate, and the stabilizer comprises tromethamine and citric acid, and further comprises anhydrous sodium sulfite, acetylcysteine, sodium thiosulfate, and / or cysteine ​​hydrochloride. Preferably, in the above composition 2, the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL, the content of the tromethamine is 2.4 mg / mL, the content of the anhydrous sodium sulfite is 1 mg / mL, the content of the acetylcysteine ​​is 1.63 mg / mL, the content of the cysteine ​​hydrochloride is 0.3 mg / mL, and the content of the sodium thiosulfate is 1 mg / mL. Composition 3 comprises a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, its pharmaceutically acceptable complex, salt, or hydrate, and the stabilizer comprises citric acid and cysteine ​​hydrochloride, and further comprises meglumine and / or arginine. Preferably, in composition three, the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL, the content of the cysteine ​​hydrochloride is 0.3 mg / mL, the content of the meglumine is 2.4 mg / mL, and the content of the arginine is 2.4 mg / mL. Composition IV comprises a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, its pharmaceutically acceptable complex, salt, or hydrate, and the stabilizer comprises tromethamine and citric acid, and further comprises propylene glycol and / or polyethylene glycol (e.g., polyethylene glycol 300 or polyethylene glycol 400), Preferably, in the above composition four, the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL, the content of the tromethamine is 2.4 mg / mL, the content of the propylene glycol is 70 to 300 mg / mL (e.g., 90, 180, 260 mg / mL), and the content of the polyethylene glycol is 70 to 300 mg / mL (e.g., 90, 180, 280 mg / mL). Composition 5 comprises a pharmacoactive ingredient, a stabilizer, an osmotic pressure regulator, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, its pharmaceutically acceptable complex, salt, or hydrate; the stabilizer comprises tromethamine and citric acid; and the osmotic pressure regulator is selected from sodium chloride, mannitol, glycerin, and / or propylene glycol. Preferably, in composition five, the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL, the content of the tromethamine is 2.4 mg / mL, the content of the sodium chloride is 5.8 mg / mL, the content of the mannitol is 23 mg / mL, the content of the glycerin is 15 mg / mL, and the content of the propylene glycol is 11 mg / mL. The pH of any one of the above compositions is 8.0 to 9.0.

[0017] The present invention further provides a method for manufacturing the above pemetrexed disodium liquid composition, which may include a nitrogen filling process. The nitrogen filling process can select liquid compounding type nitrogen filling and / or container filling type nitrogen filling, preferably liquid compounding type nitrogen filling and container filling type nitrogen filling. In some embodiments, nitrogen is filled so that the dissolved oxygen content in the above pemetrexed disodium liquid composition is less than 5 mg / L, preferably less than 3 mg / L. The dissolved oxygen content refers to the ratio of the mass of oxygen gas to the volume of the pemetrexed disodium liquid composition. In some embodiments, the residual oxygen amount in the headspace is less than 6%, preferably less than 4%. The residual oxygen amount in the headspace refers to the volume fraction of oxygen gas in the mixed gas above the packaging sealed container that the pemetrexed disodium liquid composition directly contacts.

[0018] According to an embodiment of the present invention, the above manufacturing method includes non-final sterilization.

[0019] The present invention further provides the application of the above pemetrexed disodium liquid composition in the manufacture of anti-tumor drugs. Preferably, the above anti-tumor drug may be a liquid drug preparation, such as an oral liquid or an injection solution. [[ID=IO]]

[0020] The present invention further provides an anti-tumor drug, which includes the above pemetrexed disodium liquid composition or is obtained by being manufactured from the above pemetrexed disodium liquid composition. For example, the above anti-tumor drug may be an oral liquid or an injection solution.

[0021] The present invention further provides a method for treating tumors, which provides a therapeutically effective amount of the above pemetrexed disodium liquid composition or the above anti-tumor drug to a patient who needs it. Without departing from the common knowledge in the art, each of the above preferred conditions can be arbitrarily combined to obtain relatively preferred examples of the present invention.

[0022] The reagents and raw materials used in the present invention are all commercially available.

[0023] Beneficial effects of the present invention The pemetrexed disodium liquid composition of the present invention has the advantages that the manufacturing process is simple, the physical and chemical stability is good, it is clinically easy to use and does not require redissolution, the risk of microbial contamination in the preparation process is low, and it is suitable for industrial production.

[0024] In the prior art, the pemetrexed freeze-dried powder injection needs to be redissolved before use and then secondarily diluted for administration, so the operation is complicated, and the redissolution process can effectively overcome the defects such as differences in the dosage administered to patients and the risk of microbial contamination.

Brief description of the drawings

[0025] [Figure 1] Average drug-time graph (N = 6) after intravenous injection of formulation 16 and the control drug Alimta (registered trademark) in Beagle dogs, among which,

Chemical formula

Chemical formula

[0026] The present invention will be further described below with reference to examples, but this does not limit the present invention to the scope of the examples described. In the following examples, experimental methods for which specific conditions are not specified are selected according to usual methods and conditions or according to the product's instructions.

[0027] The amount of pemetrexed disodium in the formulations of the examples and comparative examples is calculated using anhydrous pemetrexed disodium in all cases.

[0028] Comparative Example 1 [Table 1] The drug solution was prepared according to the amount of formulation 1, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into a washed and sterilized vial and sealed.

[0029] Example 1 [Table 2] The drug solution was prepared according to the proportions of formulation 2, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into a washed and sterilized vial. Subsequently, it was purged with nitrogen gas to reduce the headspace residual oxygen to <4%, and then sealed.

[0030] Example 2 The samples obtained with formulations 1 and 2 were placed under high temperature / light illumination conditions (high temperature 40℃±2℃ / 75%±5%RH, light illumination total illuminance 1.2×10⁻⁶). 5 lux·hr, near-ultraviolet energy 24 w·hr / m 2 The stability of the system was investigated, and the appearance, pH, and related substances of the sample solution were measured. The data was summarized as follows. [Table 3] As is clear from the results of the solution appearance test, in formulation 1, the pemetrexed solution was directly filled into the container, and the appearance of the solution changed under high temperature and light illumination conditions, while in formulation 2, the stabilizers tromethamine and citric acid were added to the formulation, and the appearance of the solution changed only under light illumination.

[0031] As is clear from the pH results, formulation 1 showed a decrease in pH under both high temperature and light illumination conditions, with a maximum decrease of 1.7, while formulation 2 maintained a stable pH under high temperature and light illumination conditions.

[0032] As is clear from the results for related substances, formulation 1 showed a clear increase in total impurities under high temperature and light illumination conditions, while formulation 2 also showed an increase in total impurities, but the increase was less pronounced than in formulation 1.

[0033] As described above, formulation 2, after adding a stabilizer and filling with nitrogen, clearly shows increased physical and chemical stability of the solution compared to formulation 1.

[0034] Example 3 [Table 4] The drug solution was prepared according to the proportions of formulations 3 to 7, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into washed and sterilized vials, then purged with nitrogen gas to reduce headspace residual oxygen to <4%, and sealed.

[0035] Example 4 The samples obtained with formulations 3-5 were placed under high temperature / light illumination conditions (high temperature 40℃±2℃ / 75%±5%RH, light illumination total illuminance 1.2×10⁻⁶). 5 lux·hr, near-ultraviolet energy 24 w·hr / m 2 The stability of the system was investigated, and the appearance, pH, and related substances of the sample solution were measured. The data was then compared with formulation 2 and summarized as follows. [Table 5] As is clear from the results of the solution appearance test, formulation 2, which did not contain an antioxidant, showed a slight change in color after being left under light illumination conditions for a while. Formulations 3-5, which contained different types of antioxidants, showed no change in appearance after being left at high temperature and under light illumination for 5 and 10 days, respectively.

[0036] As is evident from the pH results, the pH value of the system remains relatively stable after the addition of different types of antioxidants.

[0037] As is clear from the results for related substances, under high-temperature conditions, the total impurities in formulation 2 (without antioxidant) remained essentially unchanged. In formulations 3-5, the increase in impurities in formulation 3 (antioxidant: anhydrous sodium sulfite) and formulation 4 (antioxidant: acetylcysteine) was relatively rapid, but formulation 5 (antioxidant: cysteine ​​hydrochloride) showed even better stability, with a single impurity of 0.06% or less and total impurities of only 0.32% or less.

[0038] As mentioned above, when cysteine ​​hydrochloride is added to the pemetrexed solution as an antioxidant, the solution's stability is relatively good. At the same time, when the formulation does not include an antioxidant, excellent stability can be ensured even under high-temperature conditions, and the detection amount of single impurities is also relatively low.

[0039] Example 5 [Table 6] The drug solution was prepared according to the proportions of formulations 8-9, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into washed and sterilized vials, then purged with nitrogen gas to reduce headspace residual oxygen to <4%, and sealed.

[0040] Example 6 The samples obtained with formulations 8-9 were placed under high temperature / light illumination conditions (high temperature 40℃±2℃ / 75%±5%RH, light illumination total illuminance 1.2×10⁻⁶).5 lux·hr, near-ultraviolet energy 24 w·hr / m 2 The stability of the system was investigated, and the appearance, pH, and related substances of the sample solution were measured. The data was then compared with formulation 5 (pH adjuster: tromethamine) and summarized as follows. [Table 7] As can be seen from the above results, when the pH adjusters meglumine, arginine, and tromethamine were added to the formulation, the appearance of the system did not change after being left at 40°C high temperature / light illumination conditions for 5 and 10 days, the single impurity was less than 0.08%, and the total impurities were less than 0.33%. Therefore, it is shown that meglumine, arginine, and tromethamine have an excellent stabilizing effect on pemetrexed solution and function as stabilizers.

[0041] Example 7 [Table 8] The drug solution was prepared according to the proportions of 10 to 12, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into a washed and sterilized vial. Subsequently, it was purged with nitrogen gas to reduce the headspace residual oxygen to <4%, and then sealed.

[0042] The stability of the system was investigated by placing the samples obtained with formulations 10 to 12 under high-temperature conditions (high temperature 40℃±2℃ / 75%±5%RH), and the relevant substances in the sample solutions were measured. The data was then compared with formulation 5 (pH adjuster: tromethamine) and summarized as follows. [Table 9] As can be seen from the results above, when 180 mg / mL or more of the organic solvent propylene glycol is added to the formulation, the stability is equivalent to the increase in formulation 5 with the antioxidant added. This explains that adding propylene glycol to the formulation has a stabilizing effect on the product.

[0043] Example 8 [Table 10] The drug solution was prepared according to the proportions of formulation 13-15, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into a washed and sterilized vial. Subsequently, it was purged with nitrogen gas to reduce the headspace residual oxygen to <4%, and then sealed.

[0044] Example 9 [Table 11] The drug solution was prepared according to the proportions of formulations 16-19, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into washed and sterilized vials, then purged with nitrogen gas to reduce headspace residual oxygen to <4%, and sealed.

[0045] Example 10 The stability of the system was investigated by placing the samples obtained with formulations 16-19 under high-temperature conditions (high temperature 40°C ± 2°C / 75% ± 5% RH), and the relevant substance data was summarized as follows. [Table 12] The table above shows that the effect of different types of osmotic regulators on product stability is not clear.

[0046] Furthermore, sample solutions were prepared at the dilution ratios used in clinical practice, and their osmotic pressures were measured. The results are shown in the table below. [Table 13] As a result, the estimated clinical use method has shown that all samples prepared in this embodiment can satisfy the isotonic requirement.

[0047] Example 11 The drug solution was prepared according to the proportions of formulation 16, filled into a colorless, neutral borosilicate glass injection bottle, and nitrogen gas was added to the solution to reduce the dissolved oxygen content. The oxygen content in the solution was measured, and the results are shown in the table below. [Table 14] After ampoule fusion sealing, the obtained samples were subjected to high-temperature conditions (high temperature 40°C ± 2°C / 75% ± 5% RH) to investigate the stability of the system, and the data on appearance and related substances were summarized as follows. [Table 15] As can be seen from the above results, when the amount of dissolved oxygen in the solution is reduced, the amplification of total impurities in the pemetrexed disodium solution is further reduced, suggesting that the amount of dissolved oxygen in the solution has a certain effect on the stability of pemetrexed disodium. Therefore, in order to reduce the effect of dissolved oxygen in water, in the liquid formulation process, the effect of dissolved oxygen on the pemetrexed disodium solution can be reduced by first filling the water for injection with high-purity nitrogen gas and replacing the dissolved oxygen in the water.

[0048] Example 12 [Table 16] The drug solution was prepared according to the proportions shown in the table above, filled into colorless neutral borosilicate glass injectable vials, and examined whether nitrogen filling under headspace conditions affected stability.

[0049] The prepared samples were subjected to high-temperature conditions (40°C ± 2°C / 75% ± 5% RH) to investigate the stability of the system. The appearance of the sample solution and related substances were also examined, and the results are shown in the table below. [Table 17] As is evident from the results of the solution appearance test, when the unfilled sample was left at high temperature for 10 days, the appearance of the solution began to change, transforming from a colorless, transparent liquid to a slightly yellowish, transparent liquid. However, after the headspace nitrogen filling process was added, the solution systems with different residual oxygen levels did not show any significant change in appearance after being left at high temperature for different periods, remaining as colorless, transparent solutions.

[0050] As is evident from the results for related substances, the headspace nitrogen-filled sample had an impurity level of 0.31% after 10 days at 40°C, which is 0.26% less than the sample without headspace nitrogen filling. Therefore, headspace nitrogen filling must be performed on the product.

[0051] For formulation 5, headspace nitrogen filling was investigated to determine the limit of residual oxygen in the headspace. [Table 18] The drug solution was prepared according to the proportions shown in the table above, pre-filtered using a 0.22 μm filtration core, and the resulting solution was filled into washed and sterilized vials. The effect of different nitrogen filling processes on stability was then investigated.

[0052] Samples with different residual oxygen levels were prepared and placed under high-temperature conditions (40°C ± 2°C / 75% ± 5% RH) to investigate the stability of the system. The appearance of the sample solutions and related substances were also examined, and the results are shown in the table below. [Table 19] The samples with headspace residual oxygen levels of 3.9% and 1.8% showed relatively small amplification of total impurities, both close to the results for day 0, and there was no significant difference between the two groups.

[0053] As mentioned above, the nitrogen filling process has a relatively large impact on system stability, and the system stability is relatively good when the headspace residual oxygen is controlled to 4% or less.

[0054] Example 13 Using formulation 16 and the corresponding process, i.e., replacing oxygen gas by filling sterile water for injection with nitrogen before liquid formulation, and then controlling the headspace residual oxygen to within 4% by vacuuming and filling with nitrogen using a freeze-dryer. Three lots of the product, code 1, 2, and 3 respectively, were commercially produced. The samples from the three obtained lots were subjected to accelerated conditions (25°C / 60%RH) and long-term conditions (5±3°C), respectively. The results of the measurements of the obtained related substances are shown in Tables A-B and Figures 2-7 below. [Table 20] As can be seen from Table A and Figures 2-4, under acceleration conditions, the 6-month stability data is well within the limits and meets the standards. [Table 21] As can be seen from Table B and Figures 5-7, the data from 6 months under long-term conditions (5±3℃) shows that the relevant substances remain well within limits, indicating good stability.

[0055] From the above data, it can be seen that the pemetrexed disodium liquid composition of the present invention has good stability, a stable manufacturing process, and is suitable for commercial production.

[0056] Considering the general principle that the formulation of the injectable solution should be as simple as possible, formulation 16 was selected and subsequent nonclinical experiments were considered.

[0057] Example 14 This experiment involved a total of 12 Beagle dogs, half male and half female. Following a two-cycle crossover design, each dog was intravenously administered either Formula 16 or the control drug Alimta®. The dose was 25 mg / kg in both cases. Sampling times were before administration, immediately after administration (0-1 minute), 5 min, 20 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, and 36 h. Table 1 shows the mean pharmacokinetic parameters of pemetrexed in the plasma of each group of Beagle dogs, and Figure 1 shows the mean drug concentration-time graph. [Table 22] As is clear from the results above, formulation 16 was able to achieve an exposure level close to that of the control drug, and its important pharmacokinetic parameters were essentially identical.

[0058] Example 15 Using equilibrium dialysis, the binding rates of formulation 16 at different concentrations (based on pharmacokinetic results after intravenous injection of formulation 16 in Beagle dogs, and in conjunction with preclinical data of the reference formulation, this study set the low, medium, and high concentrations in the experimental groups to 10, 100, and 1000 μg / mL, respectively) to human plasma proteins were investigated and compared with the binding rates of the control drug Alimta®. At concentrations of 10, 100, and 1000 μg / mL, formulation 16 had binding rates of 86.50%, 90.19%, and 74.72% to human plasma proteins, respectively, while the control drug (Alimta®) had binding rates of 86.14%, 89.94%, and 80.96% at the corresponding concentrations. Detailed data on plasma protein binding rates are shown in Table 2 below. [Table 23] As a result, under the conditions of this study, the 10 μg / mL, 100 μg / mL, and 1000 μg / mL formulations 16 and the control drug Alimta® all showed moderate binding levels (50% to 90%) of pemetrexed disodium to human plasma proteins.

[0059] Example 16 Pemetrexed disodium is a multi-target antimetabolite antitumor drug. Clinically, it was diluted with 0.9% sodium chloride injection and administered intravenously, and an in vitro hemolysis test was performed on the 16-component formulation.

[0060] The study included a negative control group (0.9% sodium chloride injection, tube 1), a positive control group (sterile water for injection, tube 2), a control drug Alimta® group (pemetrexed disodium for injection, administration concentration 10 mg / mL, 0.1, 0.2, 0.3, 0.4, 0.5 mL / tube, tubes 3-7), and a combination 16 group (administration concentration 10 mg / mL, 0.1, 0.2, 0.3, 0.4, 0.5 mL / tube, tubes 8-12), with each group consisting of three parallel tubes. After uniformly mixing 2% red blood cell suspension, 0.9% sodium chloride injection solution, sterile water for injection, and the control drug Alimta® (registered trademark) in the specified proportions for each of the 16 formulations, the mixtures were placed in an incubator and allowed to stand within a temperature range of 37±0.5℃. Each mixture was observed once at 0, 15, 30, 45, 60, 120, and 180 minutes (±10%), and the specific results are shown in detail in Table 3. [Table 24] The results showed that after standing at 37±0.5℃ for 180 minutes, all red blood cells in the negative control tubes settled, the upper layer was colorless and transparent, and after appropriate shaking, the settled red blood cells redispersed, with no hemolysis or agglutination observed. In contrast, the positive control tubes showed a clear red solution, no red blood cells remaining at the bottom of the tubes, indicating total hemolysis. These results suggest that this test system is normal and reliable.

[0061] In the Alimta (registered trademark) group tube, all red blood cells settled, the upper layer was colorless and transparent, and no hemolysis was observed. However, agglutinated red blood cells were also observed among the settled red blood cells, and they did not disperse even when shaken. Microscopic examination also showed that the agglutinated red blood cells did not disperse, and it was determined that agglutination was occurring, although hemolysis was not present.

[0062] In the tube containing mixture group 16, all red blood cells settled, and the upper layer of liquid was colorless and transparent. After appropriate shaking, the settled red blood cells redispersed, and no abnormalities were observed in the red blood cells under a microscope, nor was hemolysis or agglutination detected.

[0063] As mentioned above, the 16 formulations with a concentration of 10 mg / mL showed no hemolytic or agglutinative activity against rabbit red blood cells, and the in vitro hemolysis test was negative.

[0064] Example 17 For clinical use, this product must be diluted with 0.9% sodium chloride injection solution and administered intravenously. A guinea pig active systemic anaphylaxis test was performed on formulation 16, and the presence or absence of anaphylaxis after administering the test product to guinea pigs was observed to serve as a reference for evaluating the safety of clinical use.

[0065] This study established six groups: a negative control group, a positive control group, an Alimta® low-dose and high-dose group, and a Combination 16 low-dose and high-dose group. Each group consisted of six guinea pigs, with an equal number of males and females. During the sensitization phase, the negative control group received intravenous injection of 0.9% sodium chloride solution at a volume of 4 mL / kg, the positive control group received intraperitoneal injection of 8 mg / mL chicken ovoalbumin solution at a volume of 0.5 mL / pig, and the Alimta® and Combination 16 low-dose and high-dose groups received intravenous injection of 10 mg / mL of Alimta® or Combination 16 at volumes of 2 mL / kg and 4 mL / kg, respectively, with doses of 20 mL / kg and 40 mg / kg, which are approximately 1.5 and 3 times the maximum dose intended for clinical use. The day of the first administration was defined as day 1 of the study. Sensitization occurred once every other day, for three consecutive sensitizations (i.e., sensitization on days 1, 3, and 5 of the study). On days 14 and 21 after the final sensitization (i.e., days 19 and 26 of the experiment), the guinea pigs were induced by intravenous injection of twice the sensitizing dose, and their systemic reactions and mortality rates were observed after induction. [Table 25] [Table 26] The results showed that during the sensitization period, the guinea pigs in each group were generally in good condition, exhibiting normal spontaneous movement, clean skin and coat, no abnormal secretions, normal weight gain, and no other abnormal symptoms.

[0066] Within 30 minutes of the initial induction, no anaphylaxis was observed in any of the guinea pigs in the negative control group, the Alimta® low and high-dose groups, or the Combination 16 low and high-dose groups. However, all guinea pigs in the positive control group exhibited anaphylactic symptoms and died within 7 minutes of administration, indicating a strong positive for anaphylaxis.

[0067] Within 30 minutes after the final stimulation, no anaphylaxis was observed in any of the guinea pigs in the negative control group, the Alimta® low and high-dose groups, or the Combination 16 low and high-dose groups.

[0068] As described above, under the conditions of this study, British breed guinea pigs were intravenously injected with formulation 16 at a concentration of 10 mg / mL in volumes of 2 and 4 mL / kg, respectively, i.e., the administered doses were 20 and 40 mg / kg, and the results of the active systemic anaphylaxis test were negative.

[0069] Example 18 A single intravenous injection stimulation test was performed on formulation 16 in rabbits. The irritant response and reversibility of the rabbit ear margin veins and surrounding tissues were observed and used as a reference for evaluating the safety of clinical use.

[0070] This study established two groups: the Alimta® group and the Combination 16 group, each consisting of eight rabbits, with an equal number of males and females. Each rabbit group received an intravenous injection of 10 mg / mL of either Alimta® or Combination 16 in a volume of 4 mL / kg via the right ear margin, resulting in a total dose of 40 mg / kg, approximately three times the maximum dose intended for clinical use. Simultaneously, an autologous control was administered an equal volume of 0.9% sodium chloride injection intravenously via the left ear margin. A single dose was administered, and the rabbits were observed continuously for 21 days afterward. The day of administration was defined as day 1 of the study.

[0071] During the study period, the general condition of the rabbits and the injection site were observed daily. On days 3 and 21 after administration (i.e., days 4 and 22 of the study), four rabbits (half male and half female) were taken from each group, euthanized, and then dissected. The local irritation response after injection was visually observed, and the collected tissue was pathologically examined.

[0072] During the observation period after administration, no redness, swelling, congestion, or necrosis was observed at either injection site in any of the rabbit groups. The rabbits were in good general condition, exhibited normal spontaneous movement, and no other abnormal symptoms were observed.

[0073] Three and twenty-one days after administration, no visible abnormal changes were observed at either injection site in any of the rabbit groups.

[0074] Three days after administration, mild vasculitis related to mechanical irritation from the injection puncture appeared at one of the control injection sites (1 / 8 of the participants). Otherwise, no abnormalities were observed at any other injection sites in any of the groups on days 3 and 21 after administration.

[0075] As is clear from the results above, under the conditions of this study, when a 10 mg / mL dose of Formula 16 was intravenously administered to Japanese white rabbits via the right ear margin in a volume of 4 mL / kg, i.e., a total dose of 40 mg / kg, no irritation was observed in the blood vessels and surrounding tissues at the injection site.

[0076] As described above, the pemetrexed disodium liquid composition provided in the present invention can achieve exposure levels close to those of commercially available control products, while also being less irritating to the body, having even lower adverse reactions, being safer, and being easier to use, thereby improving patient medication compliance and the convenience of clinical administration, and thus has promising prospects for commercialization.

[0077] Although several embodiments of the present invention have been described in detail, those skilled in the art can make various improvements and modifications to the specific embodiments described without substantially departing from the teachings and advantages of the gist of the invention. Such improvements and modifications are included in the spirit and scope of the invention as contained in the appended claims.

Claims

1. A liquid composition of pemetrexed disodium comprising a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is one or more of pemetrexed disodium and pharmaceutically acceptable salts thereof, the content of the pharmacoactive ingredient is 1 mg / mL to 50 mg / mL, and the content refers to the ratio of the mass of the pharmacoactive ingredient to the total volume of the liquid composition of pemetrexed disodium; The stabilizer is a pH adjuster, an organic solvent and a pH adjuster, a pH adjuster and an antioxidant, or a pH adjuster, an organic solvent and an antioxidant; The pH adjusting agent is citric acid and tromethamine, the tromethamine content being 1 to 10 mg / mL, and the content refers to the ratio of the mass of tromethamine to the total volume of the pemetrexed disodium liquid composition; The organic solvent is one or more of ethanol, propylene glycol, and polyethylene glycol, and the content of the organic solvent is 70 mg / mL to 300 mg / mL, and the content refers to the ratio of the mass of the organic solvent to the total volume of the pemetrexed disodium liquid composition; The antioxidant is cysteine ​​hydrochloride, and the content of the antioxidant is 0 to 15 mg / mL, where the content refers to the ratio of the mass of the antioxidant to the total volume of the pemetrexed disodium liquid composition; The pH of the pemetrexed disodium liquid composition is 8.0 to 9.

0. A liquid composition of pemetrexed disodium characterized by the following features.

2. The polyethylene glycol is polyethylene glycol 300 and / or polyethylene glycol 400. The pemetrexed disodium liquid composition according to claim 1.

3. The content of tromethamine is 1 mg / mL to 2.4 mg / mL, and / or, The content of the antioxidant is 0.1 mg / mL to 10 mg / mL. and / or, The content of the aforementioned organic solvent is 90 mg / mL to 260 mg / mL. The pemetrexed disodium liquid composition according to claim 1.

4. The pemetrexed disodium liquid composition further comprises an osmotic pressure regulator. The pemetrexed disodium liquid composition according to claim 1.

5. The osmotic pressure adjusting agent is one or more of sodium chloride, mannitol, glycerin, and propylene glycol. and / or, The content of the osmotic pressure adjusting agent is 1 mg / mL to 300 mg / mL, and the content refers to the ratio of the mass of the osmotic pressure adjusting agent to the total volume of the pemetrexed disodium liquid composition. The pemetrexed disodium liquid composition according to feature 4.

6. The content of the osmotic pressure adjusting agent is 1 mg / mL to 100 mg / mL. The pemetrexed disodium liquid composition according to feature 4.

7. The content of the osmotic pressure adjusting agent is 2 mg / mL to 30 mg / mL. The pemetrexed disodium liquid composition according to feature 4.

8. The pemetrexed disodium liquid composition is selected from any of the following compositions: The pemetrexed disodium liquid composition according to claim 1: Composition 1: comprising a drug-active ingredient, a stabilizer, and water, wherein the drug-active ingredient is pemetrexed disodium, and its content is 25 mg / mL; the stabilizer is tromethamine and citric acid, and its tromethamine content is 2.4 mg / mL; Composition II: comprising a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, and the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL; the stabilizer is tromethamine, citric acid, and cysteine ​​hydrochloride, with a tromethamine content of 2.4 mg / mL and a cysteine ​​hydrochloride content of 0.3 mg / mL; Composition IV: comprising a pharmacoactive ingredient, a stabilizer, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, and the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL; the stabilizer is tromethamine and citric acid, or further comprising propylene glycol and / or polyethylene glycol, wherein the content of tromethamine is 2.4 mg / mL, the content of propylene glycol is 70 to 300 mg / mL, and the content of polyethylene glycol is 70 to 300 mg / mL; Composition 5: comprises a pharmacoactive ingredient, a stabilizer, an osmotic pressure regulator, and water, wherein the pharmacoactive ingredient is pemetrexed disodium, and the content of the pharmacoactive ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL, or 40 mg / mL; the stabilizer is tromethamine and citric acid; and the osmotic pressure regulator is selected from sodium chloride, mannitol, glycerin, and / or propylene glycol, with a tromethamine content of 2.4 mg / mL, a sodium chloride content of 5.8 mg / mL, a mannitol content of 23 mg / mL, a glycerin content of 15 mg / mL, and a propylene glycol content of 11 mg / mL.

9. A method for producing a liquid pemetrexed disodium composition according to any one of claims 1 to 8, comprising a nitrogen filling process, The nitrogen filling process is a liquid-compound type nitrogen filling and / or a container-compound type nitrogen filling. The nitrogen filling process involves filling the liquid pemetrexed disodium composition with nitrogen such that the dissolved oxygen content is less than 5 mg / L and / or the headspace residual oxygen content is less than 6%. A manufacturing method characterized by the following features.

10. The nitrogen filling process is to fill the liquid composition with nitrogen such that the dissolved oxygen content in the pemetrexed disodium liquid composition is less than 3 mg / L and / or the headspace residual oxygen content is less than 4%. The manufacturing method according to claim 9.

11. An application of the pemetrexed disodium liquid composition according to any one of claims 1 to 8 in the manufacture of an antitumor drug, wherein the antitumor drug is an oral solution or an injectable solution.

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