Liquid compositions of pemetrexed disodium, methods of making and using same

Abstract

The application discloses a liquid composition of disodium permethrexate, a preparation method and application thereof. The liquid composition of disodium permethrexate provided by the application comprises a pharmaceutical active ingredient and a stabilizer; the pharmaceutical active ingredient is one or more of disodium permethrexate, a pharmaceutically acceptable complex, a salt, a solvate and a hydrate of disodium permethrexate; and the stabilizer is one or more of an organic solvent, a pH regulator and an antioxidant. The liquid composition of disodium permethrexate has the advantages of simple preparation process, good physical and chemical stability, convenient clinical use without reconstitution, low risk of microbial contamination in the preparation process and suitability for industrial production.

Description

[0001] This application claims priority to an earlier application filed on June 9, 2022, with the China National Intellectual Property Administration, patent application number 202210645147.0, entitled "Pemetrexed Disodium Liquid Composition, Preparation Method Thereof, and Application". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention relates to a liquid composition of pemetrexed disodium, its preparation method and application. Background Technology

[0003] Pemetrexed is a multi-target antimetabolite antitumor drug, a folic acid antagonist that inhibits folic acid-dependent enzymes such as thymidylate synthase, dihydrofolate reductase, and glycine ribonucleoyltransferase. These enzymes participate in the biosynthesis of thymidine and purine nucleosides, thereby achieving its antitumor effect. Pemetrexed disodium was originally developed by Eli Lilly and Company, approved by the FDA in 2004, and received import permission in my country in August 2005, beginning its clinical use in my country. It is used in combination with cisplatin as first-line treatment for unresectable malignant pleural mesothelioma and as monotherapy as second-line treatment for non-squamous non-small cell lung cancer.

[0004] Currently marketed in multiple countries and regions worldwide, this drug is a lyophilized powder for injection. Before use, it needs to be reconstituted with 0.9% sodium chloride solution to a concentration of 25 mg / ml, according to the drug specifications, and then diluted twice before administration. This reconstitution process may lead to dosage errors, raising safety concerns and the risk of microbial contamination.

[0005] Therefore, finding a pemetrexed formulation that is easy to use, has good physical and chemical stability, is simple to prepare, and is suitable for industrial production is an urgent technical problem to be solved. Summary of the Invention

[0006] This invention provides a pemetrexed disodium liquid composition comprising: a pharmaceutically active ingredient and a stabilizer, wherein the pharmaceutically active ingredient is selected from one or more of pemetrexed disodium, pharmaceutically acceptable complexes, salts, solvates, and hydrates of pemetrexed disodium; and the stabilizer is selected from one or more of organic solvents, pH adjusters, and antioxidants.

[0007] According to an embodiment of the present invention, the content of the active pharmaceutical 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, 40 mg / mL, whereby the content refers to the ratio of the mass of the active pharmaceutical ingredient to the total volume of the pemetrexed disodium liquid composition.

[0008] According to an embodiment of the present invention, the organic solvent is selected from one or more of ethanol, propylene glycol, and polyethylene glycol. For example, the polyethylene glycol is selected from polyethylene glycol 400 (PEG400) and / or polyethylene glycol 300 (PEG300).

[0009] 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, exemplarily 90 mg / mL, 180 mg / mL, 260 mg / mL or 280 mg / mL; the content refers to the ratio of the mass of the organic solvent to the total volume of the pemetrexed disodium pharmaceutical composition.

[0010] According to embodiments of the present invention, the pH adjuster can be an acidic pH adjuster and / or an alkaline pH adjuster. For example, the acidic pH adjuster is preferably hydrochloric acid and / or citric acid, more preferably citric acid. For example, the alkaline pH adjuster can be one or more of sodium hydroxide, lysine, arginine, meglumine, and tromethamine, preferably tromethamine. For example, the lysine can be L-lysine and / or D-lysine. For example, the arginine can be L-arginine and / or D-arginine.

[0011] According to an embodiment of the present invention, the antioxidant is selected from one or more of anhydrous sodium sulfite, cysteine ​​hydrochloride, acetylcysteine, and methionine, with cysteine ​​hydrochloride being more preferred. The content of the antioxidant is preferably 0-15 mg / mL, more preferably 0.1 mg / mL-10 mg / mL, for example 0.3 mg / mL, 1 mg / mL, 1.63 mg / mL, or 3 mg / mL, where the content refers to the ratio of the mass of the antioxidant to the total volume of the pemetrexed disodium pharmaceutical composition.

[0012] In some embodiments, the content of the stabilizer (e.g., an alkaline 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., an alkaline pH adjuster) to the total volume of the pemetrexed disodium liquid composition.

[0013] According to some embodiments of the present invention, the stabilizer contains at least one or more of citric acid, tromethamine, cysteine ​​hydrochloride, meglumine, and arginine; in other embodiments, the stabilizer may also contain propylene glycol.

[0014] According to an embodiment of the present invention, the pH of the pemetrexed disodium liquid composition is preferably 7.5 to 9.5, more preferably 8.0 to 9.0.

[0015] According to an embodiment of the present invention, the pemetrexed disodium liquid composition may further comprise an osmotic pressure regulator. The osmotic pressure regulator is preferably selected from one or more of sodium chloride, mannitol, glycerol, and propylene glycol. The content of the osmotic pressure regulator is preferably 1 mg / mL to 300 mg / mL, for example 1 mg / mL to 100 mg / mL, 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 regulator to the total volume of the pemetrexed disodium liquid composition. When the pemetrexed disodium liquid composition contains propylene glycol, the propylene glycol can both regulate osmotic pressure and improve the stability of the pemetrexed disodium liquid composition.

[0016] According to an embodiment of the present invention, the pemetrexed disodium liquid composition further includes water, such as water for injection, for volume adjustment. Exemplarily, water is added to a final volume of 1 mL.

[0017] According to an embodiment of the present invention, the pemetrexed disodium liquid composition is selected from any of the following compositions:

[0018] Composition 1: comprising a pharmaceutically active ingredient, a stabilizer, and water, wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate, and the stabilizer is selected from tromethorphan and citric acid;

[0019] Preferably, in the first composition, the content of the active pharmaceutical ingredient is 25 mg / mL, and the content of the tromethamine is 2.4 mg / mL;

[0020] Composition 2: comprising a pharmaceutically active ingredient, a stabilizer, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises tromethorphan and citric acid, and further comprises anhydrous sodium sulfite, acetylcysteine, sodium thiosulfate, and / or cysteine ​​hydrochloride;

[0021] Preferably, in the second composition, the content of the active pharmaceutical ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of tromethamine is 2.4 mg / mL, the content of anhydrous sodium sulfite is 1 mg / mL, the content of acetylcysteine ​​is 1.63 mg / mL, the content of cysteine ​​hydrochloride is 0.3 mg / mL, and the content of sodium thiosulfate is 1 mg / mL.

[0022] Composition 3: comprising a pharmaceutically active ingredient, a stabilizer, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises citric acid and cysteine ​​hydrochloride, and further comprises meglumine and / or arginine;

[0023] Preferably, in the third composition, the content of the active pharmaceutical ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of cysteine ​​hydrochloride is 0.3 mg / mL, the content of meglumine is 2.4 mg / mL, and the content of arginine is 2.4 mg / mL.

[0024] Composition 4: comprising a pharmaceutically active ingredient, a stabilizer, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises tromethorphan and citric acid, and further comprises propylene glycol and / or polyethylene glycol (e.g., polyethylene glycol 300 or polyethylene glycol 400);

[0025] Preferably, in the fourth composition, the content of the active pharmaceutical ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of tromethamine is 2.4 mg / mL, the content of propylene glycol is 70-300 mg / mL (e.g. 90, 180, 260 mg / mL), and the content of polyethylene glycol is 70-300 mg / mL (e.g. 90, 180, 280 mg / mL).

[0026] Composition 5: comprises a pharmaceutically active ingredient, a stabilizer, an osmotic pressure regulator, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises tromethorphan and citric acid; and wherein the osmotic pressure regulator is selected from sodium chloride, mannitol, glycerol, and / or propylene glycol.

[0027] Preferably, in the fifth composition, the content of the active pharmaceutical ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of tromethamine is 2.4 mg / mL, the content of sodium chloride is 5.8 mg / mL, the content of mannitol is 23 mg / mL, the content of glycerol is 15 mg / mL, and the content of propylene glycol is 11 mg / mL;

[0028] The pH of any of the above compositions is 8.0 to 9.0.

[0029] This invention also provides a method for preparing the above-mentioned pemetrexed disodium liquid composition, which may include a nitrogen purging step; the nitrogen purging step may be either solution preparation nitrogen purging and / or filling nitrogen purging, preferably solution preparation nitrogen purging and filling nitrogen purging. In some embodiments, nitrogen is purged until the dissolved oxygen content in the 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 to the volume of the pemetrexed disodium liquid composition. In some embodiments, the headspace residual oxygen content is less than 6%, preferably less than 4%, the headspace residual oxygen content refers to the volume fraction of oxygen in the mixed gas at the top of the sealed packaging container directly contacted by the pemetrexed disodium liquid composition.

[0030] According to an embodiment of the present invention, the preparation method includes non-terminal sterilization.

[0031] The present invention also provides the use of the described pemetrexed disodium liquid composition in the preparation of antitumor drugs. Preferably, the antitumor drug can be a liquid pharmaceutical preparation, such as an oral solution or injection.

[0032] The present invention also provides an antitumor drug comprising or prepared from the above-mentioned pemetrexed disodium liquid composition. For example, the antitumor drug may be an oral solution or an injection.

[0033] The present invention also provides a method for treating tumors, which involves providing a patient in need with a therapeutically effective amount of the pemetrexed disodium liquid composition or the antitumor drug.

[0034] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0035] The reagents and raw materials used in this invention are all commercially available.

[0036] The beneficial effects of this invention are:

[0037] The pemetrexed disodium liquid composition of the present invention has the advantages of simple preparation process, good physical and chemical stability, convenient clinical use without the need for reconstitution, low risk of microbial contamination during preparation process, and suitability for industrial production.

[0038] It effectively overcomes the shortcomings of existing technologies such as pemetrexed lyophilized powder injection, which requires reconstitution before use and then secondary dilution for administration, is cumbersome, and may lead to differences in patient dosage and risks of microbial contamination during the reconstitution process. Attached Figure Description

[0039] Figure 1 Prescription 16 and control drug were administered intravenously to Beagle dogs. The average drug-time curve after the drug was administered (N=6); among which,

[0040] This represents the average drug-time curve for prescription 16. Indicates the control drug The average drug duration curve after that.

[0041] Figure 2 The trend of impurity PMQS-IM-B in the accelerated test of Formulation 16;

[0042] Figure 3 The trend of impurity PMQS-IM-C changes in the accelerated test of Formulation 16;

[0043] Figure 4 The trend of impurity PMQS-IM-F in the accelerated test of Formulation 16;

[0044] Figure 5 The trend of impurity PMQS-IM-B in the long-term experiment of formulation 16;

[0045] Figure 6 The changing trend of impurity PMQS-IM-C in the long-term experiment of formulation 16;

[0046] Figure 7 The changing trend of impurity PMQS-IM-F in the long-term experiment of formulation 16. Detailed Implementation

[0047] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0048] The amounts of pemetrexed disodium involved in the formulations of the examples and comparative examples are all based on anhydrous pemetrexed disodium.

[0049] Comparative Example 1

[0050]

[0051] Prepare the medicine solution according to the prescription. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is then filled into a clean and sterilized vial and sealed.

[0052] Example 1

[0053]

[0054] Prepare the medicine solution according to the prescription 2. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is filled into a clean and sterilized vial, then purged with nitrogen gas until the headspace residual oxygen is <4%, and then sealed.

[0055] Example 2

[0056] Samples obtained from formulations 1 and 2 were tested under high temperature / light conditions (high temperature: 40℃±2℃ / 75%±5%RH, light: total illuminance 1.2×10⁻⁶). 5 lux·hr, near-ultraviolet energy 24w·hr / m 2 The system stability was assessed, and the appearance, pH, and related substances of the sample solution were measured. The data are summarized below:

[0057]

[0058] The results of the solution appearance test showed that in Formula 1, the appearance of the pemetrexed solution changed when directly filled under high temperature and light conditions; in Formula 2, the appearance of the solution changed only under light conditions after the addition of stabilizers tromethorphan and citric acid.

[0059] pH results showed that the pH of formulation 1 decreased under high temperature and light conditions, with a maximum decrease of 1.7; the pH of formulation 2 remained stable under high temperature and light conditions.

[0060] The results of the relevant substances showed that the total impurities of Formula 1 increased significantly under high temperature and light conditions; although the total impurities of Formula 2 increased, the growth trend was lower than that of Formula 1.

[0061] In summary, compared with Formula 1, Formula 2, with the addition of a stabilizer and nitrogen purging, significantly increases the physical and chemical stability of the solution.

[0062] Example 3

[0063]

[0064] Prepare the medicine solution according to prescription 3-7. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is filled into a clean and sterilized vial, then purged with nitrogen gas until the headspace residual oxygen is <4%, and then sealed.

[0065] Example 4

[0066] Samples obtained from formulations 3-5 were tested under high temperature / light conditions (high temperature: 40℃±2℃ / 75%±5%RH, light: total illuminance 1.2×10⁻⁶). 5 lux·hr, near-ultraviolet energy 24w·hr / m 2 The stability of the system was assessed, including the appearance, pH, and related substances of the sample solution. The results were compared with those of Formulation 2, and the data are summarized below:

[0067]

[0068]

[0069] The results of the solution appearance showed that no antioxidant was added in formulation 2, and the color of the system changed after being placed under light for a period of time; different types of antioxidants were added in formulations 3 to 5, and their appearance did not change after being placed under high temperature and light for 5 days and 10 days, respectively.

[0070] pH results showed that the pH value of the system remained relatively stable after the addition of different types of antioxidants.

[0071] Related substances results showed that under high temperature conditions, the total impurities of formulation 2 (without antioxidant) remained basically unchanged; among formulations 3-5, the impurities of formulation 3 (antioxidant is anhydrous sodium sulfite) and formulation 4 (antioxidant is acetylcysteine) increased more rapidly; while the individual impurities of formulation 5 (antioxidant is cysteine ​​hydrochloride) were 0.06% or less, and the total impurities were only 0.32% or less, showing better stability.

[0072] In summary, when cysteine ​​hydrochloride is added to pemetrexed solution as an antioxidant in the formulation, the solution stability is good; while the formulation without antioxidant can also maintain good stability under high temperature conditions and the detection amount of single impurities is also low.

[0073] Example 5

[0074]

[0075] Prepare the medicine solution according to prescription 8-9. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is filled into a clean and sterilized vial, then purged with nitrogen gas until the headspace residual oxygen is <4%, and then sealed.

[0076] Example 6

[0077] Samples obtained from formulations 8 and 9 were tested under high temperature / light conditions (high temperature: 40℃±2℃ / 75%±5%RH, light: total illuminance 1.2×10⁻⁶). 5 lux·hr, near-ultraviolet energy 24w·hr / m 2 The stability of the system was assessed, including the appearance, pH, and related substances of the sample solution. The results were compared with those of Formulation 5 (pH adjuster: tromethamine). The data are summarized below:

[0078]

[0079] The results above show that when the pH adjuster meglumine, arginine, and tromethorphan are added to the formulation, and the samples are placed at 40℃ under high temperature / light conditions for 5 and 10 days, the appearance of the system does not change, the individual impurities are 0.08% or less, and the total impurities are only 0.33% or less. This indicates that meglumine, arginine, and tromethorphan have a good stabilizing effect on pemetrexed solution and act as stabilizers.

[0080] Example 7

[0081]

[0082] Prepare the medicine solution according to 10-12 times the prescription. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is filled into a clean and sterilized vial, then purged with nitrogen gas until the headspace residual oxygen is <4%, and then sealed.

[0083] The stability of the samples obtained from formulations 10-12 was investigated under high-temperature conditions (40℃±2℃ / 75%±5%RH). Related substances in the sample solutions were measured and compared with those from formulation 5 (pH adjuster: tromethamine). The data are summarized below:

[0084]

[0085]

[0086] The results above show that when the organic solvent propylene glycol is added to the formulation at concentrations of 180 mg / ml or higher, the stability increase is comparable to that of formulation 5, which includes an antioxidant. This indicates that the addition of propylene glycol to the formulation also has a stabilizing effect on the product.

[0087] Example 8

[0088]

[0089] Prepare the medicine solution according to the dosage of prescription 13-15. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is filled into a clean and sterilized vial, then purged with nitrogen gas until the headspace residual oxygen is <4%, and then sealed.

[0090] Example 9

[0091]

[0092] Prepare the medicine solution according to the dosage of prescription 16-19. The medicine solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is filled into a clean and sterilized vial, then purged with nitrogen gas until the headspace residual oxygen is <4%, and then sealed.

[0093] Example 10

[0094] The stability of the samples obtained from formulations 16–19 was investigated under high-temperature conditions (40℃±2℃ / 75%±5%RH). The relevant data are summarized in the table below:

[0095]

[0096]

[0097] As shown in the table above, different types of osmotic pressure regulators have no significant impact on the stability of the product.

[0098] In addition, sample solutions were prepared according to the dilution ratios used in clinical applications, and their osmotic pressures were measured. The results are shown in the table below:

[0099]

[0100] The results show that, under the intended clinical use, the samples prepared in this embodiment all meet the isotonic requirements.

[0101] Example 11

[0102] Prepare the medication solution according to the prescription dosage in Prescription 16, and fill it into colorless borosilicate glass injection vials. Nitrogen gas is then introduced into the solution to reduce dissolved oxygen levels. The oxygen content of the solution is measured, and the results are shown in the table below:

[0103]

[0104] The stability of the system, appearance, and related material data of the samples obtained after ampoule sealing were investigated under high temperature conditions (40℃±2℃ / 75%±5%RH). The data are summarized in the table below:

[0105]

[0106] The results above show that reducing the dissolved oxygen content in the solution resulted in a smaller increase in total impurities in the pemetrexed disodium solution, indicating that the dissolved oxygen content has a certain impact on the stability of pemetrexed disodium. Therefore, to reduce the influence of dissolved oxygen in the water, the water for injection can be purged with high-purity nitrogen during solution preparation to replace the dissolved oxygen and reduce its impact on the pemetrexed disodium solution.

[0107] Example 12

[0108]

[0109] Prepare the drug solution according to the prescription in the table above, fill the solution into colorless borosilicate glass injection bottles, and investigate the effect of nitrogen purging on stability under headspace conditions.

[0110] The stability of the prepared sample system was investigated under high temperature conditions (40℃±2℃ / 75%±5%RH). The appearance and related substances of the sample solution were also tested. The results are shown in the table below:

[0111]

[0112] The results of the solution appearance showed that the unnitrogenated sample began to change in appearance after being placed under high temperature for 10 days, changing from a colorless clear liquid to a yellow clear liquid; while after adding the headspace nitrogen filling process, the solution systems with different residual oxygen contents did not show obvious changes in appearance when placed under high temperature for different times, and remained colorless clear solutions.

[0113] Related matter analysis results showed that the headspace nitrogen-purged sample had an impurity level of 0.31% after 10 days at 40°C, which was 0.26% less than the impurity increase in the unpurged sample. Therefore, headspace nitrogen purging is necessary for the product.

[0114] Headspace nitrogen filling was investigated for prescription 5 to determine the limit of residual oxygen in the headspace.

[0115]

[0116]

[0117] Prepare the drug solution according to the prescription in the table above. The solution is pre-filtered using a 0.22μm filter cartridge. The resulting solution is then filled into cleaned and sterilized vials to investigate the effect of different nitrogen filling processes on stability.

[0118] The stability of the prepared samples with different residual oxygen contents was investigated under high temperature conditions (40℃±2℃ / 75%±5%RH). The appearance and related substances of the sample solutions were also tested. The results are shown in the table below:

[0119]

[0120] The samples with headspace residual oxygen of 3.9% and 1.8% showed relatively small increases in total impurities, which were similar to the results at day 0, and the difference between the two groups was not significant.

[0121] In summary, the nitrogen purging process has a significant impact on the stability of the system, and the system stability is better when the residual oxygen in the headspace is controlled below 4%.

[0122] Example 13

[0123] Formula 16 and corresponding process: before solution preparation, oxygen was replaced by nitrogen in the water for injection; the lyophilizer was vacuum-sealed and nitrogen-filled, with headspace residual oxygen controlled below 4%. Three batches of products were commercially produced, designated as 1, 2, and 3. The three batches of samples were placed under accelerated conditions (25℃ / 60%RH) and long-term conditions (5±3℃), respectively. The results of related substance testing are shown in Tables A and B below. Figure 2-7 .

[0124] Table A

[0125]

[0126] From Table A and Figure 2-4 It can be seen that under accelerated conditions, the stability data for 6 months is well within the limits and meets the standards.

[0127] Table B

[0128]

[0129]

[0130] From Table B and Figure 5-7 It can be seen that under long-term conditions (5±3℃), the data after 6 months show that the relevant substances are well within the limits and have good stability.

[0131] The data above show that the pemetrexed disodium liquid composition of the present invention has good stability, a stable preparation process, and is suitable for commercial production.

[0132] Considering the general principle of keeping injection prescriptions as simple as possible, prescription 16 was selected for further non-clinical trial evaluation.

[0133] Example 14

[0134] This experiment used 12 Beagle dogs (half male and half female) and administered prescription drug 16 intravenously in a two-period crossover design, with the control drug being administered intravenously separately. The dosage was 25 mg / kg. Sampling time points were: before administration and 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. The mean pharmacokinetic parameters of pemetrexed in the plasma of Beagle dogs in each group are shown in Table 1, and the mean drug concentration-time curves are shown in [Table 1]. Figure 1 .

[0135] Table 1: Prescription 16 and Control Drug for Intravenous Injection in Beagle Dogs Mean pharmacokinetic parameters after (Mean±SD, N=12)

[0136]

[0137] The above results indicate that formulation 16 can achieve an exposure level similar to that of the control drug, and the key pharmacokinetic parameters are basically consistent.

[0138] Example 15

[0139] The binding rate of different concentrations of Formulation 16 (based on the pharmacokinetic results of intravenous injection of Formulation 16 in Beagle dogs, combined with preclinical data of the reference formulation, the experimental groups were set at low, medium, and high concentrations of 10, 100, and 1000 μg / mL, respectively) to human plasma proteins was investigated using the balanced dialysis method, and compared with the control drug. The binding rates of formulation 16 to human plasma proteins were compared. At concentrations of 10, 100, and 1000 μg / mL, the binding rates of formulation 16 to human plasma proteins were 86.50%, 90.19%, and 74.72%, respectively; the control drug... The binding rates to human plasma proteins at the corresponding concentrations were 86.14%, 89.94%, and 80.96%, respectively. Detailed data on plasma protein binding rates are shown in Table 2 below.

[0140] Table 2: Plasma protein binding rates of prescription 16 and control drug at different concentrations in humans

[0141]

[0142] The results showed that, under the conditions of this experiment, formulation 16 at concentrations of 10 μg / mL, 100 μg / mL, and 1000 μg / mL, and the control drug... The binding rates of pemetrexed disodium to human plasma proteins were at a moderate level (50%–90%).

[0143] Example 16

[0144] Pemetrexed disodium is a multi-target antimetabolite antitumor drug. Clinically, it is diluted with 0.9% sodium chloride injection and administered intravenously. An in vitro hemolysis test was performed on prescription 16.

[0145] The experiment included a negative control group (0.9% sodium chloride injection, tube 1), a positive control group (sterile water for injection, tube 2), and a control drug. Group 1 (pemetrexed disodium for injection, concentration 10 mg / mL, 0.1, 0.2, 0.3, 0.4, 0.5 mL / tube, tubes 3-7), 16 prescription groups (concentration 10 mg / mL, 0.1, 0.2, 0.3, 0.4, 0.5 mL / tube, tubes 8-12), 3 parallel tubes per group. 2% red blood cell suspension, 0.9% sodium chloride injection, sterile water for injection, and control drug were prepared. After the 16 prescription groups were mixed according to the set ratio, they were placed in a constant temperature incubator and allowed to stand within the temperature range of 37±0.5℃. The results were observed once at 0, 15, 30, 45, 60, 120 and 180 minutes (±10%). The specific results are detailed in Table 3.

[0146] Table 3: Results of in vitro hemolysis tests for different formulations

[0147]

[0148]

[0149] Remark:

[0150] 1) "-" means "no hemolysis or agglutination", "+" means "partial hemolysis", "++" means "complete hemolysis", and "*" means "agglutination".

[0151] 2) Tube 1 is the negative control group, tube 2 is the positive control group, and tubes 3-7 are... Group 16, tubes 8-12 are prescription groups. The same applies below.

[0152] The results showed that after standing at 37±0.5℃ for 180 minutes, all red blood cells in the negative control group tube sank, and the supernatant was colorless and clear. After appropriate shaking, the sank red blood cells dispersed again, and no hemolysis or aggregation was observed. The solution in the positive control group tube was clear red, with no red blood cells remaining at the bottom, indicating complete hemolysis. These results suggest that the experimental system is normal and reliable.

[0153] All red blood cells in the tube sank to the bottom, and the supernatant was colorless and clear, with no hemolysis observed. However, aggregated red blood cells were still visible in the sank red blood cells. They did not disperse after shaking, and microscopic examination showed that the aggregated red blood cells were not dispersed, indicating that the red blood cells were not hemolyzed but aggregated.

[0154] All red blood cells in the 16 groups of prescriptions sank, and the supernatant was colorless and clear. After appropriate shaking, the sank red blood cells dispersed again, and no abnormalities were found in the red blood cells under microscopic examination, with no hemolysis or aggregation observed.

[0155] In summary, the 10 mg / mL formulation in group 16 showed no hemolytic or agglutinating effect on rabbit erythrocytes, and the in vitro hemolysis test results were negative.

[0156] Example 17

[0157] When this product is used clinically, it should be diluted with 0.9% sodium chloride injection and administered intravenously. An active systemic allergy test should be performed on guinea pigs for prescription 16 to observe whether allergic reactions occur after guinea pigs are given the test product, so as to provide a reference for evaluating the safety of clinical use.

[0158] This experiment consisted of 6 groups: a negative control group, a positive control group, and... Low-dose and high-dose groups, and prescription 16: 6 guinea pigs in each group, half male and half female. During the sensitization phase, the negative control group was intravenously injected with 0.9% sodium chloride injection at a volume of 4 mL / kg, and the positive control group was intraperitoneally injected with 8 mg / mL egg white albumin solution at a volume of 0.5 mL / guinea pig. In prescription 16, the low- and high-dose groups were administered 10 mg / mL intravenously at volumes of 2 mL / kg and 4 mL / kg, respectively. Alternatively, prescription 16 was administered at doses of 20 mg / kg and 40 mg / kg, approximately 1.5 and 3 times the highest clinically intended dose, respectively. Day 1 of the experiment was defined as the day of the first administration. Sensitization was performed every other day for a total of three times (i.e., sensitization on days 1, 3, and 5 of the experiment). Challenge was initiated on days 14 and 21 after the last sensitization (i.e., days 19 and 26 of the experiment) via intravenous injection at twice the sensitizing dose. Systemic reactions and mortality in the guinea pigs were observed after challenge.

[0159] Table 4. Observation results of the systemic anaphylaxis test after the first provocation.

[0160]

[0161] Note: *The number of animals with allergic reactions is based on the highest level of allergic reaction observed in that animal. See Appendix 5 for the same.

[0162] Table 5. Results of the systemic anaphylaxis test after the final provocation.

[0163]

[0164] The results showed that during the sensitization period, the guinea pigs in each group were in good general condition, had normal spontaneous activity, clean skin and fur, no abnormal secretions, and normal weight gain, with no other abnormal symptoms observed.

[0165] Within 30 minutes of the first stimulation, the negative control group, No allergic reactions were observed in any of the guinea pigs in the low-dose and high-dose groups, or in prescription 16. The guinea pigs in the positive control group showed allergic symptoms and all died within 7 minutes after administration, indicating a very strong positive allergic reaction.

[0166] Within 30 minutes after the last stimulation, the negative control group, No allergic reactions were observed in any of the guinea pigs in the low-dose and high-dose groups, as well as in prescription 16.

[0167] In summary, under the conditions of this experiment, British guinea pigs were intravenously injected with 10 mg / mL prescription 16 at volumes of 2 and 4 mL / kg, respectively (i.e., dosages of 20 and 40 mg / kg), and the active systemic anaphylaxis test results were negative.

[0168] Example 18

[0169] A single intravenous injection stimulation test was conducted on Prescription 16 in rabbits to observe the irritant response and reversibility of the test product to the rabbit marginal ear vein and surrounding tissues, providing a reference for evaluating the safety of clinical use.

[0170] This experiment was conducted in two groups, namely: Sixteen groups and prescriptions were administered, with eight rabbits in each group, half male and half female. Each group of rabbits received an injection of 10 mg / mL via the right marginal ear vein at a volume of 4 mL / kg. Alternatively, prescription 16 was administered at a dose of 40 mg / kg, approximately three times the highest clinically intended dose. A self-controlled trial was conducted, with an equal volume of 0.9% sodium chloride injection injected via the left marginal ear vein. A single dose was administered, followed by 21 days of continuous observation. The day of administration was defined as day 1 of the trial.

[0171] During the experiment, the general condition of the rabbits and the condition of the injection site were observed daily. On days 3 and 21 after administration (i.e., days 4 and 22 of the experiment), four rabbits (half male and half female) from each group were euthanized and dissected. The irritation response at the injection site was observed visually, and the tissues were examined pathologically.

[0172] During the observation period after drug administration, no redness, swelling, congestion, necrosis or other reactions were observed at the bilateral injection sites in rabbits of each group. The rabbits were in good general condition, had normal spontaneous activity, and no other abnormal symptoms were observed.

[0173] No visible abnormalities were observed at either injection site in rabbits of any group 3 and 21 days after administration.

[0174] Three days after administration, mild vascular inflammation related to mechanical stimulation of the injection puncture was observed at one injection site (1 / 8 of the control group). Apart from this, no abnormalities were observed at other injection sites in each group at 3 and 21 days after administration.

[0175] The above results indicate that, under the conditions of this experiment, the injection of 10 mg / mL Prescription 16 into the right marginal ear vein of Japanese white rabbits at a volume of 4 mL / kg (i.e., a dose of 40 mg / kg) did not cause any irritation to the blood vessels and surrounding tissues at the injection site.

[0176] In summary, the pemetrexed disodium liquid composition provided by this invention can achieve an exposure level similar to that of commercially available reference products, while exhibiting low irritation in vivo, fewer adverse reactions, greater safety, and greater convenience. It can improve patient compliance and the convenience of clinical medication, and has good market prospects.

[0177] Although some embodiments of the invention have been described in detail, those skilled in the art can make various modifications and variations to the specific embodiments shown without substantially departing from the spirit and advantages of the invention. Such modifications and variations are included within the spirit and scope of the invention as defined in the appended claims.

Claims

1. A liquid composition of pemetrexed disodium, characterized in that, The pemetrexed disodium liquid composition comprises the active pharmaceutical ingredient, stabilizer, osmotic pressure regulator, and water; The active pharmaceutical ingredient is pemetrexed disodium, and the content of the active pharmaceutical ingredient is 15~40 mg / mL. The content refers to the ratio of the mass of the active pharmaceutical ingredient to the total volume of the pemetrexed disodium liquid composition. The stabilizers are citric acid and tromethorphan, with the tromethorphan content being 1~2.4 mg / mL. The content refers to the ratio of the mass of tromethorphan to the total volume of the pemetrexed disodium liquid composition. The osmotic pressure regulator is sodium chloride, and the content of the osmotic pressure regulator is 2~11 mg / mL. The content refers to the ratio of the mass of the osmotic pressure regulator to the total volume of the pemetrexed disodium liquid composition. The pH of the pemetrexed disodium liquid composition is 8.0 to 9.

0.

2. The pemetrexed disodium liquid composition according to claim 1, characterized in that: The content of the active pharmaceutical ingredient is 20 mg / mL to 30 mg / mL, and the content refers to the ratio of the mass of the active pharmaceutical ingredient to the total volume of the pemetrexed disodium liquid composition.

3. The pemetrexed disodium liquid composition according to claim 1, characterized in that: The content of the osmotic pressure regulator is 2 mg / mL to 5.8 mg / mL.

4. The pemetrexed disodium liquid composition as described in claim 1, characterized in that: The pemetrexed disodium liquid composition comprises the following components: pemetrexed disodium 27.57 mg / mL, tromethorphan 2.4 mg / mL, sodium chloride 5.8 mg / mL, water for injection 1 mL, and citric acid.

5. The pemetrexed disodium liquid composition according to any one of claims 1-4, characterized in 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%.

6. The method for preparing the pemetrexed disodium liquid composition as described in claim 5, characterized in that: Includes nitrogen purging process; The nitrogen purging process involves purging nitrogen until 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%.

7. The preparation method according to claim 6, characterized in that: The nitrogen filling process is nitrogen filling with solution and / or nitrogen filling during filling.

8. The use of the pemetrexed disodium liquid composition according to any one of claims 1 to 5 in the preparation of antitumor drugs.

9. The application as described in claim 8, characterized in that, The antitumor drug is an oral solution or an injection.

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