A high-stability fosfomycin sodium injection and a preparation method thereof

Abstract

The application provides a high-stability fosfomycin sodium injection and a preparation method thereof. The fosfomycin sodium injection is prepared by using multivariate buffer (succinic acid+glutamic acid+anhydrous sodium dihydrogen phosphate), metal ion chelating agent (disodium edetate or calcium disodium edetate) and arginine anti-acid and alkali catalysis synergy, combining temperature and humidity control (humidity < 45%, temperature is 18-26 DEG C) and powder direct mixing method. The fosfomycin sodium injection can simultaneously inhibit the four ring-opening paths of the active ingredient fosfomycin sodium, i.e. alkali / neutral nucleophilic, acid catalysis, thermal catalysis and metal ion catalysis, reduces the generation of impurities, has extremely high stability, and the accelerated test shows that the diol is less than or equal to 0.05% and the maximum single impurity is less than or equal to 0.15% at 6 months. The whole preparation method is simple and suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a highly stable sodium fosfomycin injection and its preparation method. Background Technology

[0002] Fosfomycin sodium's chemical name is (-)-cis-1,2-epoxypropylphosphonic acid disodium salt. Its epoxy ring has a high-strain structure, and it is easily hydrolyzed and ring-opened when exposed to heat, alkali, or during long-term storage to generate the impurity 1,2-dihydroxypropylphosphonic acid (hereinafter referred to as "diol"). Its chemical structural formula is as follows:

[0003] The ring-opening chemical mechanism of epoxy rings is as follows: (1) Base / neutral nucleophilic ring opening: In the presence of aqueous solution or adsorbed water, trace amounts of OH⁻ or H₂O themselves act as nucleophiles to attack carbons with less steric hindrance / less substitution in the epoxy ring.

[0004] (2) Acid-catalyzed ring opening: Under acidic conditions, the epoxy ring will first protonate (COH). + When subjected to H2O, the rate of attack first increases and then decreases as pH decreases (protonation saturation occurs at pH < 4, but nucleophilic water also competes for H2O). + decline).

[0005] (3) Thermocatalytic ring opening: The ring opening of epoxy rings follows first-order kinetics, that is, the increase in temperature will lead to an increase in water activity and faster molecular motion, which will cause the exponential increase of trace acid / base catalytic constant.

[0006] (4) Metal ion catalytic ring opening: Fe 3+ / Cu 2+ / Ca 2+ Metal ions coordinate with the oxygen in the epoxy ring, polarizing the CO bond, and coordinate with water molecules, enhancing the nucleophilicity of water oxygen, leading to the opening of the epoxy ring.

[0007] Addressing the core contradiction of ring-opening of the epoxy bond in sodium fosfomycin, CN118319850A discloses a sodium fosfomycin injection and its preparation method, employing moist heat sterilization at 121℃ for 15 minutes. However, this method introduces H2O nucleophiles into the water for injection, and the high temperature causes the acid / base catalytic constant to increase exponentially with temperature, failing to avoid the three ring-opening pathways of "aqueous phase-acid-base-heat". CN122320890A discloses a lyophilized sodium fosfomycin injection formulation and its preparation method, using a quaternary excipient system composed of sodium fosfomycin, L-histidine, trehalose, glycine, and disodium edetate. The process involves solution preparation, pH adjustment, fine filtration, pre-freezing annealing, primary / secondary drying, and nitrogen sealing to produce a lyophilized powder injection. However, the solution preparation stage still uses water for injection, and the trace amounts of ring-opening generated before lyophilization are irreversibly carried into the finished product. Therefore, this lyophilization scheme also fails to resolve the fundamental contradiction of ring-opening under the synergistic effect of aqueous phase / metal ion / acid-base fluctuations and thermal catalysis.

[0008] Therefore, developing a highly stable fosfomycin sodium injection that can solve the ring-opening problem of epoxide bonds in fosfomycin sodium and its preparation method has important practical application value. Summary of the Invention

[0009] The purpose of this invention is to provide a highly stable sodium fosfomycin injection based on existing technology. This is achieved through the synergistic effect of a multi-element buffer (succinic acid + glutamic acid + anhydrous sodium dihydrogen phosphate), a metal ion chelating agent (disodium edetate or calcium sodium edetate), and arginine for acid-base catalysis, combined with temperature and humidity control (humidity <45%, temperature 18-26℃) and direct powder mixing. This injection can simultaneously inhibit four epoxide ring-opening pathways of the active ingredient sodium fosfomycin: "base / neutral nucleophilic, acid catalysis, thermal catalysis, and metal ion catalysis," reducing the generation of impurities and exhibiting extremely high stability. Accelerated testing shows that after 6 months, the diol content is ≤0.05%, and the maximum single impurity is ≤0.15%.

[0010] The second objective of this invention is to provide a method for preparing the above-mentioned fosfomycin sodium injection, which is simple and suitable for large-scale industrial production.

[0011] The technical solution of the present invention is as follows: A highly stable sodium fosfomycin injection is prepared from anhydrous sodium fosfomycin, a pH adjuster, and a metal ion chelating agent. The pH adjuster is succinic acid, glutamic acid, arginine, and anhydrous sodium dihydrogen phosphate; the metal ion chelating agent is disodium edetate or calcium sodium edetate; and the pH is controlled to 7.0-7.8 during its preparation.

[0012] In a preferred embodiment, the metal ion chelating agent is disodium edetate.

[0013] This invention utilizes a multi-mechanism synergistic inhibition of the ring-opening of the active ingredient, fosfomycin sodium, through a combination of buffers (succinic acid + glutamic acid + anhydrous sodium dihydrogen phosphate), metal ion chelators (disodium edetate or calcium sodium edetate), and arginine to counteract acid-base catalysis. Specifically, ① the metal ion chelator (e.g., disodium edetate): complexes Fe... 3+ / Cu 2+ / Ca 2+ This reduces the polarization of the epoxy ring (avoiding metal ion-catalyzed ring-opening). ② A multi-component buffer (succinic acid + glutamic acid + anhydrous sodium dihydrogen phosphate): stabilizes the pH at 7.0-7.8, preventing OH⁻ / H⁺ saturation under strong acid / base conditions. + Attacking the epoxy ring. ③ Arginine: Neutralizes trace amounts of OH⁻ / H⁺ produced during the stabilization process. + ④ Temperature-controlled direct mixing: humidity <45%, temperature 18-26℃, to avoid heat / water phase induced ring opening.

[0014] In a preferred embodiment, the highly stable fosfomycin sodium injection provided by the present invention comprises the following components in parts by weight: 2.0-6.0 parts anhydrous fosfomycin sodium, 1.0-8.0 parts succinic acid, 1.0-8.0 parts glutamic acid, 1.0-8.0 parts arginine, 0.1-1.0 parts anhydrous sodium dihydrogen phosphate, and 0.001-0.01 parts disodium edetate.

[0015] In a more preferred embodiment, the highly stable fosfomycin sodium injection provided by the present invention comprises the following components in parts by weight: 3.0-5.0 parts anhydrous fosfomycin sodium, 2.0-5.5 parts succinic acid, 2.0-5.5 parts glutamic acid, 2.0-5.5 parts arginine, 0.4-0.8 parts anhydrous sodium dihydrogen phosphate, and 0.002-0.008 parts disodium edetate.

[0016] In a particularly preferred embodiment, the highly stable fosfomycin sodium injection provided by the present invention comprises the following components in parts by weight: 3.5-4.5 parts anhydrous fosfomycin sodium, 2.8-5.0 parts succinic acid, 2.8-5.0 parts glutamic acid, 2.5-5.0 parts arginine, 0.5-0.7 parts anhydrous sodium dihydrogen phosphate, and 0.004-0.006 parts disodium edetate.

[0017] For example, the highly stable fosfomycin sodium injection provided by the present invention comprises the following components in parts by weight: 4.0 parts anhydrous fosfomycin sodium, 2.8 parts succinic acid, 2.8 parts glutamic acid, 2.5 parts arginine, 0.6 parts anhydrous sodium dihydrogen phosphate, and 0.005 parts disodium edetate.

[0018] For example, the highly stable sodium fosfomycin injection provided by the present invention comprises the following components in parts by weight: 4.0 parts anhydrous sodium fosfomycin, 2.8 parts succinic acid, 2.8 parts glutamic acid, 5.0 parts arginine, 0.6 parts anhydrous sodium dihydrogen phosphate, and 0.005 parts disodium edetate.

[0019] For example, the highly stable fosfomycin sodium injection provided by the present invention comprises the following components in parts by weight: 4.0 parts anhydrous fosfomycin sodium, 2.8 parts succinic acid, 5.0 parts glutamic acid, 2.5 parts arginine, 0.6 parts anhydrous sodium dihydrogen phosphate, and 0.005 parts disodium edetate.

[0020] For example, the highly stable fosfomycin sodium injection provided by the present invention comprises the following components in parts by weight: 4.0 parts anhydrous fosfomycin sodium, 5.0 parts succinic acid, 2.8 parts glutamic acid, 2.5 parts arginine, 0.6 parts anhydrous sodium dihydrogen phosphate, and 0.005 parts disodium edetate.

[0021] The present invention also provides a method for preparing the above-mentioned highly stable fosfomycin sodium injection, comprising the following steps: (1) Environmental control: Control the ambient humidity to <45% and the temperature to 15~30℃; (2) Direct mixing of powders: anhydrous sodium fosfomycin, pH adjuster and metal ion chelating agent are sieved and then mixed evenly to control the pH to 7.0-7.8; (3) Dispensing: The obtained mixture is dispensed into vials, capped, and then injected.

[0022] In this invention, in step (1), the ambient humidity is controlled to be <45% and the temperature is controlled to be 15~30℃, preferably, the ambient humidity is controlled to be <45% and the temperature is controlled to be 18~26℃.

[0023] In this invention, in step (1), anhydrous fosfomycin sodium, pH adjuster and metal ion chelating agent are passed through a 20-60 mesh sieve, preferably 40 mesh.

[0024] In this invention, in step (2), the mixing time is 100-150 minutes, preferably 120 minutes.

[0025] The advantages of using the technical solution of this invention are as follows: This invention utilizes a multi-element buffer (succinic acid + glutamic acid + anhydrous sodium dihydrogen phosphate), a metal ion chelating agent (disodium edetate or calcium sodium edetate), and arginine for acid-base catalytic synergy. Combined with temperature and humidity control (humidity <45%, temperature 18-26℃) and direct powder mixing, a sodium fosfomycin injection is prepared. This injection can simultaneously inhibit four epoxide ring-opening pathways of the active ingredient sodium fosfomycin: "base / neutral nucleophilic, acid catalysis, thermal catalysis, and metal ion catalysis," reducing impurity generation and exhibiting extremely high stability. Accelerated testing shows that after 6 months, the diol content is ≤0.05%, and the maximum single impurity is ≤0.15%. The entire preparation method is simple and suitable for large-scale industrial production.

[0026] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0027] Examples 1-4 A highly stable sodium fosfomycin injection is mainly composed of the following components by weight, and the specific components and weights of Examples 1-4 are shown in Table 1.

[0028]

[0029] The preparation method of the injection in Example 1 includes the following steps: (1) Environmental control: control the ambient humidity to <45% and the temperature to 18~30℃.

[0030] (2) Direct mixing of powders: Anhydrous sodium fosfomycin, succinic acid, glutamic acid, arginine, anhydrous sodium dihydrogen phosphate and disodium edetate are passed through a 40-mesh sieve and then mixed for 120 minutes to make them uniform and control their pH to 7.0-7.8.

[0031] (3) Dispensing: The obtained mixture is dispensed into vials, capped, and then injected.

[0032] The preparation methods of Examples 2-4 are the same as those of Example 1.

[0033] Example 5 uses the same components and preparation method as Example 1, but adds 0.01% FeCl3 metal ions to artificially simulate metal ion contamination, in order to investigate the effect of adding disodium edetate, a metal ion chelating agent, to the formulation.

[0034] Comparative Examples 1-5 A highly stable sodium fosfomycin injection is mainly composed of the following components by weight, and the specific components and weights of Comparative Examples 1-5 are shown in Table 2.

[0035]

[0036] The preparation methods of Comparative Examples 1-5 are similar to those of Example 1, except that Comparative Example 1 lacks component disodium edetate; Comparative Example 2 lacks component succinic acid; Comparative Example 3 lacks component glutamic acid; Comparative Example 4 lacks component anhydrous sodium dihydrogen phosphate; and Comparative Example 5 lacks component arginine.

[0037] Comparative Example 6 The injectable preparation of Example 5 in Patent CN118319850B.

[0038] Comparative Example 7 The freeze-dried powder injection prepared in Example 1 of Patent CN122320890A.

[0039] The samples from the examples and comparative examples were tested for pH (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0631), content (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 1201), and related substances (titration method, HPLC method). The results are shown in Table 3.

[0040]

[0041] Note: For related substances, the maximum single impurity and total impurity limits refer to the ICH Q3B(R2) guideline "Impurities in new drug substance preparations", and the limits for other test items refer to the 2025 edition of the Chinese Pharmacopoeia, Part II.

[0042] As shown in Table 3, the injections prepared by the multi-component buffer (succinic acid + glutamic acid + anhydrous sodium dihydrogen phosphate), metal ion chelating agent (disodium edetate or sodium calcium edetate) and arginine for acid-base catalysis in Examples 1-4 of the present invention showed that, after 6 months of accelerated reaction, the related substances did not increase significantly, and the diol content was ≤0.05% and the maximum single impurity was ≤0.15% at 6 months, demonstrating extremely high stability.

[0043] Example 5, compared to Examples 1-4, added an additional 0.01% FeCl3 metal ion to artificially simulate metal ion contamination, accelerating the process until all indicators remained unchanged in June. This demonstrates that adding the metal ion chelating agent disodium edetate to the formulation can reduce metal ion contamination and improve sample stability.

[0044] In Comparative Example 1, compared to Example 1, the sample without the metal ion chelating agent disodium edetate showed a significant upward trend in diols and related substances during the 6-month accelerated period, and failed the test after 6 months of accelerated testing.

[0045] As shown in Comparative Example 1, the presence of disodium edetate can weaken the effect of Fe. 3+ / Cu 2+ / Ca 2+ The ability of metal ions to polarize CO bonds and their nucleophilicity to water and oxygen prevents the opening of the epoxy ring.

[0046] Compared to Example 1, Comparative Examples 2-4 successively lacked the components succinic acid, glutamic acid, and anhydrous sodium dihydrogen phosphate, and lacked a ternary buffer. During the 6-month accelerated period, the levels of diols and related substances showed a significant upward trend, and the samples failed the test after 3 months of accelerated testing. Because the succinic acid, glutamic acid, and anhydrous sodium dihydrogen phosphate form a multi-component buffer, the pH can be controlled within the range of 7.0-7.8, preventing OH⁻ and H⁺ from attacking the epoxy ring under strong alkaline or acidic conditions, thus avoiding alkaline / acid-catalyzed ring-opening.

[0047] Comparative Example 5, compared to Example 1, contained no arginine. After 3 months of acceleration, the diol content was 0.12% (higher than 0.03% in Example 1). The presence of arginine demonstrates its resistance to acid and base catalysis because it can neutralize trace amounts of OH⁻ and H⁺ generated during the stability period, preventing base / acid-catalyzed ring-opening.

[0048] Compared to the sample in the examples, Comparative Example 6 did not meet the requirements for total impurities at day 0, and the related substances showed a significant upward trend during the acceleration period. Based on the analysis of this invention, it can be seen that the lack of a ternary buffer component to control the pH of the finished product, as well as the lack of arginine to neutralize trace amounts of OH⁻ and H⁺, failed to avoid the significant upward trend of impurities during the stability period caused by base / acid catalytic ring opening, thus proving the necessity of polybasic acid buffer.

[0049] Compared to the sample in the examples, the pH of Comparative Example 7 did not meet the requirements at day 0, and the diol content showed a significant upward trend during the acceleration period. Based on the analysis of this invention, it can be seen that when water for injection is used as a solvent to prepare the sample, in the presence of aqueous solution, trace amounts of OH⁻ or H₂O themselves act as nucleophiles to attack carbons with less steric hindrance / less substitution in the epoxy ring, resulting in a higher diol content at day 0.

[0050] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A highly stable fosfomycin sodium injection, characterized in that, The injection is made of anhydrous fosfomycin sodium, a pH adjuster and a metal ion chelating agent, wherein the pH adjuster is succinic acid, glutamic acid, arginine and anhydrous sodium dihydrogen phosphate; the metal ion chelating agent is disodium edetate or calcium sodium edetate; and during its preparation, its pH is controlled to 7.0-7.

8.

2. The highly stable fosfomycin sodium injection according to claim 1, characterized in that, During the preparation of the injection, under the conditions of controlling the ambient humidity <45% and the temperature between 15 and 30°C, the anhydrous fosfomycin sodium, pH adjuster and metal ion chelating agent are first sieved, then mixed evenly, and the resulting mixture is dispensed into vials, capped and crimped to obtain the injection.

3. The highly stable fosfomycin sodium injection according to claim 2, characterized in that, The metal ion chelating agent is disodium edetate.

4. The highly stable fosfomycin sodium injection according to claim 3, characterized in that, The injection comprises the following components in parts by weight: 2.0-6.0 parts anhydrous fosfomycin sodium, 1.0-8.0 parts succinic acid, 1.0-8.0 parts glutamic acid, 1.0-8.0 parts arginine, 0.1-1.0 parts anhydrous sodium dihydrogen phosphate, and 0.001-0.01 parts disodium edetate.

5. The highly stable fosfomycin sodium injection according to claim 4, characterized in that, The injection comprises the following components in parts by weight: 3.0-5.0 parts anhydrous fosfomycin sodium, 2.0-5.5 parts succinic acid, 2.0-5.5 parts glutamic acid, 2.0-5.5 parts arginine, 0.4-0.8 parts anhydrous sodium dihydrogen phosphate, and 0.002-0.008 parts disodium edetate.

6. The highly stable fosfomycin sodium injection according to claim 5, characterized in that, The injection comprises the following components in parts by weight: 3.5-4.5 parts anhydrous fosfomycin sodium, 2.8-5.0 parts succinic acid, 2.8-5.0 parts glutamic acid, 2.5-5.0 parts arginine, 0.5-0.7 parts anhydrous sodium dihydrogen phosphate, and 0.004-0.006 parts disodium edetate.

7. The highly stable fosfomycin sodium injection according to claim 6, characterized in that, The injection comprises the following components in parts by weight: 4.0 parts anhydrous fosfomycin sodium, 2.8 parts succinic acid, 2.8 parts glutamic acid, 2.5 parts arginine, 0.6 parts anhydrous sodium dihydrogen phosphate, and 0.005 parts disodium edetate; Anhydrous fosfomycin sodium 4.0 parts, succinic acid 2.8 parts, glutamic acid 2.8 parts, arginine 5.0 parts, anhydrous sodium dihydrogen phosphate 0.6 parts, disodium edetate 0.005 parts; Anhydrous fosfomycin sodium 4.0 parts, succinic acid 2.8 parts, glutamic acid 5.0 parts, arginine 2.5 parts, anhydrous sodium dihydrogen phosphate 0.6 parts, disodium edetate 0.005 parts; 4.0 parts anhydrous fosfomycin sodium, 5.0 parts succinic acid, 2.8 parts glutamic acid, 2.5 parts arginine, 0.6 parts anhydrous sodium dihydrogen phosphate, and 0.005 parts disodium edetate.

8. The method for preparing the highly stable fosfomycin sodium injection according to claim 1, characterized in that, Includes the following steps: (1) Environmental control: Control the ambient humidity to <45% and the temperature to 15~30℃; (2) Direct mixing of powders: The anhydrous sodium fosfomycin, pH adjuster and metal ion chelating agent are sieved and then mixed evenly to control the pH to 7.0-7.8; (3) Dispensing: The obtained mixture is dispensed into vials, capped, and then injected.

9. The method for preparing the highly stable fosfomycin sodium injection according to claim 8, characterized in that, In step (1), the temperature is 18~26℃; the mixture is passed through a 20-60 mesh sieve, preferably 40 mesh; in step (2), the mixing time is 100-150 minutes, preferably 120 minutes.

10. The method for preparing the highly stable fosfomycin sodium injection according to claim 8, characterized in that, The metal ion chelating agent is disodium edetate.

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