Stable fosfomycin tromethamine preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a fosfomycin tromethamine preparation and a preparation method thereof.The fosfomycin tromethamine preparation is a granule, and the granule is prepared from, by weight, 40-70 parts of fosfomycin tromethamine, 15-25 parts of a protective agent, 1-4 parts of a moisture absorption inhibitor, 2-5 parts of microcrystalline cellulose, 0.5-1.5 parts of aspartame and 0.1-0.5 part of sweet orange essence. The protective agent comprises calcium phosphate and erythritol, and the moisture absorption inhibitor comprises magnesium stearate and hydrophobic silicon dioxide. According to the fosfomycin tromethamine preparation, calcium phosphate and erythritol are adopted as protective agents of fosfomycin tromethamine, the stability of fosfomycin tromethamine can be improved, magnesium stearate and hydrophobic silicon dioxide are combined to serve as a hydrophobic layer, moisture in air is prevented from entering the fosfomycin tromethamine preparation, and it is avoided that medicine absorbs moisture and is degraded.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a stable fosfomycin trometamol preparation and a preparation method thereof. BACKGROUND

[0002] Fosfomycin trometamol is a trometamol salt form of broad-spectrum antibiotic fosfomycin, and its molecular formula is C4H 11 NO3.C3H7O4P, which is a broad-spectrum bactericide that can directly prevent the action of pyruvate transferase necessary for bacterial cell wall synthesis, has good antibacterial activity on various gram-positive bacteria and gram-negative bacteria, and is highly sensitive to common urinary tract infection pathogens such as Escherichia coli and Enterococcus faecalis, and is widely used for treating respiratory tract infections, lower urinary tract infections such as cystitis, urethritis, intestinal infections, and skin and soft tissue infections.

[0003] The molecular structure of fosfomycin trometamol contains an epoxy group, which is relatively active in chemical properties and unstable in structure, and can form corresponding impurities after long-term storage. Fosfomycin trometamol has hygroscopicity, and the drug is prone to hygroscopic degradation after long-term storage, producing related impurities, which affects the long-term stability and safety of the drug. Fosfomycin trometamol is a synthetic drug with a certain chemical odor, which is difficult to take. At present, most of them only consider the adjustment of the flavor and the applicability, for example, the solid fosfomycin pharmaceutical composition disclosed in the patent with the publication number CN103282038A contains fosfomycin trometamol, glycine, and optionally other excipients such as sucralose, silicon dioxide, polyvinylpyrrolidone, and flavoring agents; and it is substantially free of sugar and sugar alcohols such as sucrose, fructose, glucose, xylitol, mannitol, sorbitol, or a mixture thereof, and does not pose any risk to diabetic patients, but the patent does not consider the hygroscopicity of the drug. The glycine itself is hygroscopic, and the total content of fosfomycin trometamol and glycine in the composition is more than 90%, so the hygroscopicity of the composition is relatively high, and long-term storage can easily affect the drug efficacy. The patent with the publication number CN118078757A discloses a pharmaceutical composition containing fosfomycin trometamol, which is prepared from the following components by weight: raw material drug fosfomycin trometamol 60g, phosphate 17.5-27.5g, sodium saccharin 0.5-2.5g, menthol 0.2-1.8g, and essence 0.5-3.5g. The phosphate replaces sucrose, glycine, or mannitol, and the menthol is used as a flavoring agent, which has good taste and stability, but does not consider the hygroscopic degradation problem. SUMMARY

[0004] In view of the above problems, the present application provides a stable fosfomycin trometamol preparation and a preparation method thereof, which can reduce the hygroscopicity of the fosfomycin trometamol preparation, improve the stability of the fosfomycin trometamol preparation, and improve the taste of the fosfomycin trometamol preparation by using sugar-free modification, and the specific technical solutions are as follows: A stable fosfomycin trometamol preparation is granules, which comprises the following components in parts by weight: fosfomycin trometamol 40-70 parts, a protective agent 15-25 parts, a moisture absorption inhibitor 1-4 parts, microcrystalline cellulose 2-5 parts, aspartame 0.5-1.5 parts, and orange flavor 0.1-0.5 parts, wherein the protective agent comprises calcium phosphate and erythritol, and the moisture absorption inhibitor comprises magnesium stearate and hydrophobic silicon dioxide.

[0005] In the technical solution, the calcium phosphate and erythritol are used as the protective agent of the fosfomycin trometamol. The calcium phosphate is commonly used as a diluent in medicines, and also can be used as a filler and a carrier, and has a drying effect, so that a dry physical environment is provided for the fosfomycin trometamol. The erythritol is used as a filling sweetener, has a pure sweet taste, a high sweet degree, and a cool taste, can effectively mask the chemical odor of the medicine, and can improve the taste of the preparation. The erythritol does not contain calories, does not increase blood sugar, and is suitable for patients with diabetes. The erythritol is different from most sugar alcohols (such as mannitol, sorbitol, and maltitol), and almost does not absorb moisture under high-temperature and high-humidity conditions, and does not react with the amino group (trometamol) in the medicine to produce colored impurities. The erythritol and the calcium phosphate can form a protective barrier for the fosfomycin trometamol, so that the stability of the fosfomycin trometamol preparation is improved. The magnesium stearate and the hydrophobic silicon dioxide are combined to form a hydrophobic structure, so that the moisture absorption is reduced, and the stability of the preparation is further improved.

[0006] Preferably, in the fosfomycin trometamol preparation, the weight ratio of the calcium phosphate to the erythritol in the protective agent is 1:0.25-1.

[0007] Preferably, in the fosfomycin trometamol preparation, the weight ratio of the calcium phosphate to the erythritol is 1:0.4-0.8, and further preferably 1:0.6.

[0008] Preferably, in the fosfomycin trometamol preparation, the weight ratio of the magnesium stearate to the hydrophobic silicon dioxide is 1:0.3-1.

[0009] Preferably, in the fosfomycin trometamol preparation, the weight ratio of the magnesium stearate to the hydrophobic silicon dioxide is 1:0.4-0.6, and further preferably 1:0.5.

[0010] Preferably, in the fosfomycin trometamol preparation, the preparation method of the hydrophobic silicon dioxide comprises the following steps: dispersing silicon dioxide into ethanol, then adding 2-5% hexadecyl trimethoxysilane based on the weight of the silicon dioxide, ultrasonic oscillation reaction is performed at 40-50°C for 1-3h, filtration, washing, and drying to obtain the hydrophobic silicon dioxide.

[0011] Preferably, in the fosfomycin trometamol preparation, the ultrasonic oscillation power is 800-1000 W, the ultrasonic oscillation time is 1-3 h, and the ultrasonic frequency is 30-50 KHz.

[0012] Preferably, in the fosfomycin trometamol preparation, the granules comprise the following components by weight: 55 parts of fosfomycin trometamol, 20 parts of a protective agent, 3 parts of a moisture inhibitor, 3 parts of microcrystalline cellulose, 1 part of aspartame, and 0.2 parts of sweet orange essence; the protective agent is composed of calcium phosphate and erythritol, and the mass ratio of calcium phosphate to erythritol is 1:0.6; the moisture inhibitor comprises magnesium stearate and hydrophobic silicon dioxide, and the mass ratio of magnesium stearate to hydrophobic silicon dioxide is 1:0.5.

[0013] In another aspect, the present application also provides a preparation method of the above-mentioned fosfomycin trometamol preparation, comprising the following steps: (1) Pre-mixing: the fosfomycin trometamol and the protective agent are first put into a mixer and mixed for 10-15 min, and then the moisture inhibitor, the microcrystalline cellulose, 1 / 2 of the silicon dioxide, the aspartame, and the sweet orange essence are added and mixed to obtain a pre-mixing material; (2) Granulation: the pre-mixing material obtained in step (1) is added into a dry granulator to obtain dry granules; (3) Total mixing: the dry granules, the remaining silicon dioxide, and the magnesium stearate are put into a mixer and mixed for 5-10 min to obtain the fosfomycin trometamol preparation.

[0014] Preferably, in the preparation method of the above-mentioned fosfomycin trometamol preparation, the particle size of the fosfomycin trometamol preparation is 30-80 mesh.

[0015] In the preparation method, the fosfomycin trometamol and the protective agent are first mixed, which is beneficial to the formation of a micro-protective structure of the protective agent on the surface of the fosfomycin trometamol, and then the microcrystalline cellulose, the aspartame, and the sweet orange essence are added and mixed until the materials are uniformly mixed; then, the dry granulation is adopted, and no liquid (water or ethanol) is added in the whole process, which fundamentally avoids the degradation of the main drug caused by the introduction of moisture in the granulation process; and then the dry granules, the remaining hydrophobic silicon dioxide, and the magnesium stearate are mixed, so that the hydrophobic silicon dioxide and the magnesium stearate are uniformly distributed on the surface of the granules to form a hydrophobic layer. The moisture absorption and degradation of the fosfomycin trometamol are greatly inhibited, the impurity growth is slow, and the effective period is significantly prolonged.

[0016] Compared with the prior art, the present application has the following beneficial effects: 1. The fosfomycin trometamol preparation of the present application uses calcium phosphate and erythritol as the protective agent of fosfomycin trometamol, which can improve the stability of fosfomycin trometamol, and in combination with magnesium stearate and hydrophobic silicon dioxide as the hydrophobic layer, reduces the hygroscopicity of the drug, avoids the entry of moisture in the air, and avoids the degradation of the drug due to moisture absorption; in addition, erythritol also serves as a sugar-free sweetener, combined with aspartame non-sugar sweetener and sweet orange essence to improve the taste of the drug preparation, solving the medication contraindication of diabetic patients and other sugar-restricted populations, and expanding the applicable population.

[0017] 2. The preparation method of the fosfomycin trometamol preparation of the present application uses dry granulation, and no liquid (water or ethanol) is added throughout the process, which fundamentally avoids the degradation of the main drug caused by the introduction of moisture during the granulation process; then the prepared dry granules are mixed with the remaining hydrophobic silicon dioxide and magnesium stearate, so that the hydrophobic silicon dioxide and magnesium stearate are evenly distributed on the surface of the granules to form a hydrophobic layer, which greatly inhibits the moisture absorption and degradation of fosfomycin trometamol, slows down the increase of impurities, and significantly prolongs the shelf life.

[0018] 3. The preparation method of the fosfomycin trometamol preparation of the present application is simple, and the equipment used is conventional solid preparation equipment, which is easy to realize large-scale production. DETAILED DESCRIPTION

[0019] The specific embodiments of the present application are described in detail below, but it should be understood that the protection scope of the present application is not limited by the specific embodiments. Unless otherwise defined, all professional terms used below have the same meaning as generally understood by those skilled in the art. The professional terms used in this paper are only for the purpose of describing the specific embodiments and are not intended to limit the protection scope of the present application. Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or prepared by existing methods.

[0020] Example 1 A stable fosfomycin trometamol granule is composed of the following components by weight: fosfomycin trometamol 55 parts, protective agent 20 parts, hygroscopicity inhibitor 3 parts, microcrystalline cellulose 3 parts, aspartame 1 part, sweet orange essence 0.2 part, the protective agent is composed of calcium phosphate and erythritol, the mass ratio of calcium phosphate and erythritol is 1:0.6, the hygroscopicity inhibitor is composed of magnesium stearate and hydrophobic silicon dioxide, the mass ratio of magnesium stearate and hydrophobic silicon dioxide is 1:0.5.

[0021] The preparation method of the fosfomycin trometamol preparation granule of the present embodiment includes the following steps: (1) Premix: the fosfomycin trometamol and the protective agent are first put into a mixer and mixed for 15 min, then microcrystalline cellulose, aspartame and sweet orange flavor are added and mixed for 20 min to obtain a premix; (2) Granulation: the premix obtained in step (1) is added into a dry granulator to obtain dry granules; (3) Total mixing: the dry granules, silicon dioxide and magnesium stearate are put into a mixer and mixed for 10 min to obtain the fosfomycin trometamol preparation.

[0022] The method for preparing the hydrophobic silicon dioxide comprises: dispersing silicon dioxide in ethanol, then adding 3% hexadecyl trimethoxysilane by weight of the silicon dioxide, ultrasonic oscillation reaction at 45°C for 2 h, filtration, washing and drying to obtain the hydrophobic silicon dioxide.

[0023] Example 2 A stable fosfomycin trometamol granule is composed of the following components by weight: fosfomycin trometamol 55 parts, protective agent 18 parts, hygroscopicity inhibitor 4 parts, microcrystalline cellulose 4 parts, aspartame 1.2 parts, and sweet orange flavor 0.1 part. The protective agent is composed of calcium phosphate and erythritol, and the mass ratio of calcium phosphate to erythritol is 1:0.3. The hygroscopicity inhibitor is composed of magnesium stearate and hydrophobic silicon dioxide, and the mass ratio of magnesium stearate to hydrophobic silicon dioxide is 1:0.6.

[0024] The method for preparing the fosfomycin trometamol preparation granule of the present example comprises the following steps: (1) Premix: the fosfomycin trometamol and the protective agent are first put into a mixer and mixed for 15 min, then microcrystalline cellulose, aspartame and sweet orange flavor are added and mixed for 20 min to obtain a premix; (2) Granulation: the premix obtained in step (1) is added into a dry granulator to obtain dry granules; (3) Total mixing: the dry granules, silicon dioxide and magnesium stearate are put into a mixer and mixed for 10 min to obtain the fosfomycin trometamol preparation.

[0025] The hydrophobic silicon dioxide is the same as in Example 1.

[0026] Example 3 A stable fosfomycin trometamol granule is composed of the following components by weight: fosfomycin trometamol 55 parts, protective agent 18 parts, hygroscopicity inhibitor 4 parts, microcrystalline cellulose 4 parts, aspartame 1.2 parts, and sweet orange flavor 0.1 part. The protective agent is composed of calcium phosphate and erythritol, and the mass ratio of calcium phosphate to erythritol is 1:0.3. The hygroscopicity inhibitor is composed of magnesium stearate and hydrophobic silicon dioxide, and the mass ratio of magnesium stearate to hydrophobic silicon dioxide is 1:0.6.

[0027] The preparation method of the fosfomycin trometamol granules of the present embodiment comprises the following steps: (1) Premixing: Fosfomycin trometamol and a protective agent are first put into a mixer and mixed for 15 min, and then microcrystalline cellulose, aspartame and sweet orange flavor are added and mixed for 20 min to obtain a premixing material; (2) Granulation: The premixing material obtained in step (1) is added into a dry granulator for granulation to obtain dry granules; (3) Total mixing: The prepared dry granules, silicon dioxide and magnesium stearate are put into a mixer and mixed for 10 min to obtain fosfomycin trometamol granules.

[0028] The hydrophobic silicon dioxide is the same as that in Example 1.

[0029] Example 4 (different from Example 1 in that the mass ratio of calcium phosphate and erythritol is 1:0.25) A stable fosfomycin trometamol granule is composed of the following components by weight: 55 parts of fosfomycin trometamol, 20 parts of a protective agent, 3 parts of a hygroscopicity inhibitor, 3 parts of microcrystalline cellulose, 1 part of aspartame, and 0.2 parts of sweet orange flavor. The protective agent is composed of calcium phosphate and erythritol, and the mass ratio of calcium phosphate and erythritol is 1:0.25. The hygroscopicity inhibitor is composed of magnesium stearate and hydrophobic silicon dioxide, and the mass ratio of magnesium stearate and hydrophobic silicon dioxide is 1:0.5.

[0030] The preparation method of the fosfomycin trometamol granules of the present embodiment comprises the following steps: (1) Premixing: Fosfomycin trometamol and a protective agent are first put into a mixer and mixed for 15 min, and then microcrystalline cellulose, aspartame and sweet orange flavor are added and mixed for 20 min to obtain a premixing material; (2) Granulation: The premixing material obtained in step (1) is added into a dry granulator for granulation to obtain dry granules; (3) Total mixing: The prepared dry granules, silicon dioxide and magnesium stearate are put into a mixer and mixed for 10 min to obtain fosfomycin trometamol granules.

[0031] The hydrophobic silicon dioxide is the same as that in Example 1.

[0032] Example 5 (different from Example 1 in that the mass ratio of calcium phosphate and erythritol is 1:1) A stable fosfomycin trometamol granule is composed of the following components by weight: fosfomycin trometamol 55 parts, a protective agent 20 parts, a moisture absorption inhibitor 3 parts, microcrystalline cellulose 3 parts, aspartame 1 part, and sweet orange essence 0.2 part, wherein the protective agent is composed of calcium phosphate and erythritol, the mass ratio of calcium phosphate to erythritol is 1:1, the moisture absorption inhibitor is composed of magnesium stearate and hydrophobic silicon dioxide, and the mass ratio of magnesium stearate to hydrophobic silicon dioxide is 1:0.5.

[0033] The preparation method of the fosfomycin trometamol granule of the embodiment comprises the following steps: (1) Pre-mixing: first put the fosfomycin trometamol and the protective agent into a mixer and mix for 15 min, then add the microcrystalline cellulose, aspartame, and sweet orange essence and mix for 20 min to obtain a pre-mixing material; (2) Granulation: add the pre-mixing material obtained in step (1) into a dry granulator to obtain dry granules; (3) Total mixing: put the prepared dry granules, silicon dioxide, and magnesium stearate into a mixer and mix for 10 min to obtain the fosfomycin trometamol preparation.

[0034] The hydrophobic silicon dioxide is the same as that in Example 1.

[0035] Example 6 (different from Example 1 in that the mass ratio of magnesium stearate to hydrophobic silicon dioxide is 1:0.3) A stable fosfomycin trometamol granule is composed of the following components by weight: fosfomycin trometamol 55 parts, a protective agent 20 parts, a moisture absorption inhibitor 3 parts, microcrystalline cellulose 3 parts, aspartame 1 part, and sweet orange essence 0.2 part, wherein the protective agent is composed of calcium phosphate and erythritol, the mass ratio of calcium phosphate to erythritol is 1:0.6, the moisture absorption inhibitor is composed of magnesium stearate and hydrophobic silicon dioxide, and the mass ratio of magnesium stearate to hydrophobic silicon dioxide is 1:0.3.

[0036] The preparation method of the fosfomycin trometamol granule of the embodiment comprises the following steps: (1) Pre-mixing: first put the fosfomycin trometamol and the protective agent into a mixer and mix for 15 min, then add the microcrystalline cellulose, aspartame, and sweet orange essence and mix for 20 min to obtain a pre-mixing material; (2) Granulation: add the pre-mixing material obtained in step (1) into a dry granulator to obtain dry granules; (3) Total mixing: put the prepared dry granules, silicon dioxide, and magnesium stearate into a mixer and mix for 10 min to obtain the fosfomycin trometamol preparation.

[0037] The hydrophobic silicon dioxide is the same as that in Example 1.

[0038] Example 7 (differing from Example 1 in that the mass ratio of magnesium stearate, hydrophobic silicon dioxide is 1:1) A stable fosfomycin trometamol granule is composed of the following components in parts by weight: fosfomycin trometamol 55 parts, a protective agent 20 parts, a hygroscopicity inhibitor 3 parts, microcrystalline cellulose 3 parts, aspartame 1 part, sweet orange flavor 0.2 part, the protective agent being composed of calcium phosphate and erythritol, the mass ratio of calcium phosphate and erythritol being 1:0.6, the hygroscopicity inhibitor being composed of magnesium stearate, hydrophobic silicon dioxide, the mass ratio of magnesium stearate, hydrophobic silicon dioxide being 1:1.

[0039] The preparation method of the fosfomycin trometamol preparation granule of the present example comprises the following steps: (1) Pre-mixing: first put fosfomycin trometamol and a protective agent into a mixer and mix for 15 min, then add microcrystalline cellulose, aspartame, and sweet orange flavor and mix for 20 min to obtain a pre-mixing material; (2) Granulation: add the pre-mixing material obtained in step (1) into a dry granulator to obtain dry granules; (3) Total mixing: put the dry granules, silicon dioxide, and magnesium stearate into a mixer and mix for 10 min to obtain a fosfomycin trometamol preparation.

[0040] The hydrophobic silicon dioxide is the same as in Example 1.

[0041] Comparative Example 1 The present comparative example is the same as Example 1, except that the protective agent is calcium phosphate.

[0042] Comparative Example 2 The present comparative example is the same as Example 1, except that the protective agent is erythritol.

[0043] Comparative Example 3 The present comparative example is the same as Example 1, except that the hygroscopicity inhibitor is hydrophobic silicon dioxide.

[0044] Comparative Example 4 The present comparative example is the same as Example 1, except that the hygroscopicity inhibitor is magnesium stearate.

[0045] Comparative Example 5 The present comparative example is the same as Example 1, except that the preparation method is as follows: add fosfomycin trometamol, a protective agent, microcrystalline cellulose, aspartame, sweet orange flavor, silicon dioxide, and magnesium stearate into a mixer and mix for 35 min to obtain a fosfomycin trometamol preparation.

[0046] Comparative Example 6 The comparative example 1 is the same as example 1, except that the preparation method comprises: (1) premixing: mixing phosphomyxin amiftrin, protective agent, microcrystalline cellulose, aspartame and sweet orange flavor in a mixer for 35 min to obtain a premix; (2) granulation: adding the premix obtained in step (1) into a dry granulator to obtain dry granules; (3) total mixing: adding the dry granules, silicon dioxide and magnesium stearate into a mixer and mixing for 10 min to obtain phosphomyxin amiftrin preparation.

[0047] Comparative example 7 The comparative example 1 is the same as example 1, except that maltitol is used to replace erythritol.

[0048] Comparative example 8 The comparative example 1 is the same as example 1, except that sorbitol is used to replace erythritol.

[0049] According to the accelerated test in Chinese Pharmacopoeia 2020 edition, the phosphomyxin amiftrin granules of examples 1-7 and comparative examples 1-8 are placed in a temperature of 40±2℃ and a relative humidity of 75±5% for 6 months, and then the related substances (impurity content) and moisture are measured. The specific test is carried out according to the relevant provisions of Chinese Pharmacopoeia 2020 edition (second part) under phosphomyxin amiftrin. At the same time, the appearance of the phosphomyxin amiftrin granules is measured, and the specific results are shown in table 1.

[0050] As can be seen from table 1, after the accelerated test, the impurity A content of examples 1-7 of the present application is less than 0.1%, the impurity B content is basically less than 0.12%, and the total impurity content is less than 0.4%, which indicates that they can maintain good stability in a high humidity environment, especially the effect of example 1 is better. From the comparison of example 1 and comparative examples 1-2 and examples 4-5, it can be seen that the interaction of calcium phosphate and erythritol significantly improves the stability of the preparation, and the ratio of calcium phosphate and erythritol will affect the stability of the drug in a high humidity environment. When the ratio of the two is 1:0.6, the impurity content increases relatively less, and the preparation is more stable. From examples 1 and comparative examples 3-4, it can be seen that the combination of magnesium stearate and hydrophobic silicon dioxide can isolate water and improve the moisture-proof performance of the preparation.

[0051] Table 1 wet stability of different phosphomyxin amiftrin preparation granules The foregoing description of specific exemplary embodiments of the application has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the application to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. It is intended that the scope of the application be limited not with this detailed description, but rather by the claims appended hereto.

Claims

1. A stable fosfomycin tromethamine formulation, characterized in that, The fosfomycin tromethamine preparation is in granule form, and the granule comprises the following components in parts by weight: 40-70 parts of fosfomycin tromethamine, 15-25 parts of protective agent, 1-4 parts of moisture-absorbing inhibitor, 2-5 parts of microcrystalline cellulose, 0.5-1.5 parts of aspartame, and 0.1-0.5 parts of sweet orange flavor. The protective agent includes calcium phosphate and erythritol, and the moisture-absorbing inhibitor includes magnesium stearate and hydrophobic silica.

2. The fosfomycin tromethamine preparation according to claim 1, characterized in that, In the protective agent, the weight ratio of calcium phosphate to erythritol is 1:0.25~1.

3. The fosfomycin tromethamine preparation according to claim 2, characterized in that, The weight ratio of calcium phosphate to erythritol is 1:0.4~0.

8.

4. The fosfomycin tromethamine preparation according to claim 1, characterized in that, The weight ratio of magnesium stearate to hydrophobic silica is 1:0.3~1.

5. The fosfomycin tromethamine preparation according to claim 4, characterized in that, The weight ratio of magnesium stearate to hydrophobic silica is 1:0.4~0.

6.

6. The fosfomycin tromethamine preparation according to claim 1, characterized in that, The method for preparing the hydrophobic silica includes: dispersing silica in ethanol, then adding 2-5% hexadecyltrimethoxysilane by weight of silica, ultrasonically vibrating the reaction at 40-50°C for 1-3 hours, filtering, washing, and drying to obtain hydrophobic silica.

7. The fosfomycin tromethamine preparation according to claim 6, characterized in that, The ultrasonic oscillation power is 600~1000W, and the ultrasonic frequency is 30~50KHz.

8. The fosfomycin tromethamine preparation according to claim 1, characterized in that, The granules comprise the following components by weight: 55 parts fosfomycin tromethamine, 20 parts protective agent, 3 parts moisture-absorbing inhibitor, 3 parts microcrystalline cellulose, 1 part aspartame, and 0.2 parts sweet orange flavor. The protective agent is composed of calcium phosphate and erythritol in a mass ratio of 1:0.

6. The moisture-absorbing inhibitor comprises magnesium stearate and hydrophobic silica in a mass ratio of 1:0.

5.

9. A method for preparing a fosfomycin tromethamine formulation as described in any one of claims 1 to 8, characterized in that, Includes the following steps: (1) Premix: Fosfomycin tromethamine and the preservative are first put into a mixer and mixed for 10-15 minutes. Then microcrystalline cellulose, aspartame, and sweet orange flavoring are added and mixed to obtain the premix. (2) Granulation: The premix obtained in step (1) is added to a dry granulator for granulation to obtain dry granules; (3) Total mixing: The prepared dry granules, silica and magnesium stearate are put into a mixer and mixed for 5-10 minutes to obtain fosfomycin tromethamine preparation.

10. The method for preparing the fosfomycin tromethamine formulation according to claim 9, characterized in that, The particle size of the fosfomycin tromethamine preparation is 30-80 mesh.

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