A pharmaceutical composition containing fosfomycin trometamol and a process for its preparation

Abstract

The application provides a fosfomycin trometamol-containing pharmaceutical composition and a preparation method thereof, wherein sucrose, glycine or mannitol is replaced by a phosphate, the particle size of the phosphate is controlled, and menthol is used as a flavoring agent; in the mixing process, the compatibility of the components is good, the mixing uniformity and stability can be improved, the types of excipients are less, the compatibility of the raw and auxiliary materials is good, the stability of the product is higher, the product is not suitable for people who are not tolerant to some excipients such as sucrose, mannitol and glycine, the taste is cool, the safety is high, and the application range is wider. The whole preparation method is simple, the cost is low, and the industrial large-scale production is suitable.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition containing fosfomycin tromethamine and its preparation method. Background Technology

[0002] Fosfomycin, the active fraction of fosfomycin tromethamine, is highly soluble in water. Its molecular formula is C3H7O4P. Initially isolated from fungi, it directly inhibits pyruvate transferase, essential for bacterial cell wall synthesis, thus hindering the first step in the bacterial cell wall synthesis process and exerting a bactericidal effect. It is effective against both Gram-positive and Gram-negative bacteria and is primarily used for infections of the urinary tract, skin and soft tissues, and intestines caused by susceptible Gram-negative bacteria. Its antibacterial spectrum includes Escherichia coli, Shigella, Proteus, Serratia, Staphylococcus aureus, and Pseudomonas aeruginosa. Currently, fosfomycin tromethamine preparations are mostly in powder or granule form, with relatively simple preparation processes, readily available raw materials and excipients, good taste, good stability, and low transportation costs. Fosfomycin tromethamine exhibits poor stability in high-humidity environments; therefore, humidity should be controlled during preparation, and the product should be stored in a dry place.

[0003] Chinese patent CN103282038A discloses a fosfomycin composition that requires the addition of a small amount of glycine. However, glycine should be used with caution or contraindicated in patients with liver damage, kidney damage, or impaired liver function. Introducing glycine without sucrose would make it unsuitable for these populations. Chinese patent CN116672309A discloses a dry suspension drug composition that requires the addition of mannitol as an excipient. This composition should be used with caution or contraindicated in patients with kidney disease, hyperkalemia or hypokalemia, those intolerant to mannitol, pregnant or lactating women, those with cardiopulmonary impairment, those with hypovolemia, children, and the elderly. Its applicability is even narrower. Furthermore, this invention uses too many types of excipients without investigating their compatibility, potentially leading to incompatibility issues between raw materials and excipients, resulting in poor product quality and the generation of impurities that could harm the human body.

[0004] Therefore, it is particularly important to explore a pharmaceutical composition containing fosfomycin tromethamine and its preparation method that has fewer types of excipients, better compatibility and taste, higher safety and stability, lower cost and wider applicability. Summary of the Invention

[0005] The purpose of this invention is to provide a pharmaceutical composition containing fosfomycin tromethamine, based on the existing technology, which has the advantages of fewer types of excipients, good compatibility and taste, high safety and stability, and wider applicability.

[0006] Another object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical composition containing fosfomycin tromethamine.

[0007] The technical solution of the present invention is as follows:

[0008] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight: 60g of fosfomycin tromethamine, 17.5-27.5g of phosphate, 0.5-2.5g of sodium saccharin, 0.2-1.8g of menthol, and 0.5-3.5g of flavoring.

[0009] For the purposes of this invention, the active pharmaceutical ingredient is fosfomycin tromethamine, and the excipients include fillers and flavoring agents. The filler is a phosphate, which can be anhydrous calcium phosphate or anhydrous calcium hydrogen phosphate; preferably, the filler is anhydrous calcium phosphate. The flavoring agents are sodium saccharin, menthol, and flavorings, such as orange flavoring powder and sour orange flavoring powder.

[0010] The original formulation used sucrose as a filler and flavoring agent, but this excipient is unsuitable for certain populations, such as diabetic patients, patients with fructose intolerance, glucose-galactose malabsorption, or sucrase deficiency (or other rare diseases), and obese individuals. To address these issues, existing technologies use glycine or mannitol to replace sucrose, but this also results in a narrower range of applications. For example, adding glycine to the formulation requires caution or prohibition for patients with liver damage, kidney damage, or liver dysfunction; introducing glycine without sucrose would make it unsuitable for these populations. Adding mannitol to the formulation requires caution or prohibition for patients with kidney disease, hyperkalemia or hypokalemia, mannitol intolerance, pregnant or lactating women, patients with cardiopulmonary impairment, hypovolemia, children, and the elderly, further narrowing its applicability.

[0011] This invention addresses the aforementioned problems by replacing sucrose, glycine, or mannitol with phosphates and controlling the particle size of the phosphates. During mixing, the components exhibit better compatibility, improving mixing uniformity and stability. Fewer excipients are required, resulting in better compatibility of raw materials and excipients, higher product stability, and the absence of excipients such as sucrose, mannitol, and glycine that are intolerant or unsuitable for some individuals. The product also boasts a better taste, higher safety, and wider applicability. For this invention, the anhydrous phosphate particle size is 50-100 mesh, preferably 65-80 mesh. Particle sizes that are too high or too low result in poor compatibility of components during mixing, leading to reduced mixing uniformity and stability, and a poorer taste.

[0012] In this invention, it is also necessary to control the amount of anhydrous phosphate. If the amount is too high or too low, the compatibility of the components will be poor during the mixing process, which will also lead to a decrease in the uniformity and stability of the mixture and a poor taste.

[0013] Because of the sour taste of the raw material fosfomycin tromethamine, which leads to low acceptance among some people, this invention adds menthol to the formulation and uses it in combination with the filler phosphate, resulting in a drug composition with a cooler taste that is generally well-accepted by patients.

[0014] In a preferred embodiment, the pharmaceutical composition containing fosfomycin tromethamine provided by the present invention is made from the following components by weight: 60g fosfomycin tromethamine, 20-25g anhydrous calcium phosphate, 1-2g sodium saccharin, 0.5-1.5g menthol, 0.5-1.5g orange flavor powder, and 0.5-1.5g sour orange flavor powder.

[0015] In a more preferred embodiment, the pharmaceutical composition containing fosfomycin tromethamine provided by the present invention is made from the following components by weight: 60g fosfomycin tromethamine, 20g anhydrous calcium phosphate, 1g sodium saccharin, 0.5g menthol, 0.5g orange flavor powder, and 0.5g sour orange flavor powder. The fosfomycin tromethamine has a particle size of 65-100 mesh, and the anhydrous calcium phosphate has a particle size of 65-80 mesh.

[0016] In a more preferred embodiment, the pharmaceutical composition containing fosfomycin tromethamine provided by the present invention is made from the following components by weight: 60g fosfomycin tromethamine, 23g anhydrous calcium phosphate, 1.5g sodium saccharin, 1g menthol, 1g orange flavor powder, and 1g sour orange flavor powder. The fosfomycin tromethamine has a particle size of 65-100 mesh, and the anhydrous calcium phosphate has a particle size of 65-80 mesh.

[0017] In a more preferred embodiment, the pharmaceutical composition containing fosfomycin tromethamine provided by the present invention is made from the following components by weight: 60g fosfomycin tromethamine, 23g anhydrous calcium phosphate, 1.5g sodium saccharin, 1g menthol, 1g orange flavor powder, and 1g sour orange flavor powder. The fosfomycin tromethamine has a particle size of 65-100 mesh, and the anhydrous calcium phosphate has a particle size of 65-80 mesh.

[0018] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition containing fosfomycin tromethamine, which includes the following steps:

[0019] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol and flavoring are sieved and set aside for later use;

[0020] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0021] In step (1), the sieve mesh size is 20-60 mesh, preferably 40 mesh.

[0022] In step (1), the phosphate is anhydrous calcium phosphate or anhydrous calcium hydrogen phosphate; preferably, the phosphate is anhydrous calcium phosphate. The particle size of the active pharmaceutical ingredient fosfomycin tromethamine is 50-120 mesh, preferably 65-100 mesh; the particle size of the phosphate is 50-100 mesh, preferably 65-80 mesh.

[0023] In step (2), the mixing speed is 5 to 20 rpm and the mixing time is 15 to 30 min; preferably, the mixing speed is 10 rpm and the mixing time is 25 min.

[0024] The advantages of using the technical solution of this invention are as follows:

[0025] The pharmaceutical composition containing fosfomycin tromethamine provided by this invention uses phosphate to replace sucrose, glycine, or mannitol, controls the particle size of the phosphate, and uses menthol as a flavoring agent. During mixing, the components exhibit good compatibility, improving mixing uniformity and stability. It requires fewer excipients, has good compatibility with raw materials and excipients, and offers higher product stability. It is free of excipients such as sucrose, mannitol, and glycine, which may cause intolerance in some individuals. It has a refreshing taste, high safety, and a wider range of applications. The entire preparation method is simple, low-cost, and suitable for large-scale industrial production. Detailed Implementation

[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] Example 1

[0028] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0029]

[0030] Its preparation method includes the following steps:

[0031] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0032] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0033] (3) Packaging: Weight difference ±3%, 8g / bag;

[0034] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0035] Example 2

[0036] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0037]

[0038] Its preparation method includes the following steps:

[0039] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0040] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0041] (3) Packaging: Weight difference ±3%, 8g / bag;

[0042] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0043] Example 3

[0044] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0045]

[0046] Its preparation method includes the following steps:

[0047] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0048] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0049] (3) Packaging: Weight difference ±3%, 8g / bag;

[0050] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0051] Comparative Example 1

[0052] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0053]

[0054] Its preparation method includes the following steps:

[0055] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0056] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0057] (3) Packaging: Weight difference ±3%, 8g / bag;

[0058] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0059] Comparative Example 2

[0060] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0061]

[0062] Its preparation method includes the following steps:

[0063] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0064] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0065] (3) Packaging: Weight difference ±3%, 8g / bag;

[0066] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0067] Comparative Example 3

[0068] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0069]

[0070]

[0071] Its preparation method includes the following steps:

[0072] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0073] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0074] (3) Packaging: Weight difference ±3%, 8g / bag;

[0075] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0076] Comparative Example 4

[0077] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0078]

[0079] Its preparation method includes the following steps:

[0080] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, mannitol, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0081] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0082] (3) Packaging: Weight difference ±3%, 8g / bag;

[0083] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0084] Comparative Example 5

[0085] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0086]

[0087]

[0088] Its preparation method includes the following steps:

[0089] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0090] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0091] (3) Packaging: Weight difference ±3%, 8g / bag;

[0092] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0093] Comparative Example 6

[0094] A pharmaceutical composition containing fosfomycin tromethamine, comprising the following components by weight:

[0095]

[0096] Its preparation method includes the following steps:

[0097] (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 40-mesh sieve and then set aside for use.

[0098] (2) Mixing: Mix the components after sieving in step (1) evenly to obtain a drug composition containing fosfomycin tromethamine.

[0099] (3) Packaging: Weight difference ±3%, 8g / bag;

[0100] (4) Packaging: 1 bag / box, packed in a cardboard box.

[0101] 1. The content uniformity results of the samples in Examples 1-3 and Comparative Examples 1-2 were compared (each test item can be referred to the 2020 edition of the Chinese Pharmacopoeia, Part IV). The specific experimental results are as follows.

[0102] Table 1 Results of content uniformity test

[0103]

[0104] As shown in Table 1, the uniformity of the content of the active pharmaceutical ingredient (API) fosfomycin tromethamine in the samples of Examples 1-3 was better than that in Comparative Examples 1-2, indicating that controlling the particle size of API fosfomycin tromethamine and anhydrous calcium phosphate can yield a product with better content uniformity. In Comparative Example 3, no excipient menthol was added, resulting in a higher uniformity of API fosfomycin tromethamine content. In Comparative Example 4-, mannitol or glycine was used instead of anhydrous calcium phosphate, also resulting in a higher uniformity of API fosfomycin tromethamine content, and mannitol or glycine has a narrower applicable population. In Comparative Example 6, the amount of anhydrous calcium phosphate was too high, leading to a higher uniformity of API fosfomycin tromethamine content, indicating that controlling the amount of anhydrous calcium phosphate can yield a product with better content uniformity.

[0105] 2. The taste and flavor of the products in the examples and comparative examples were compared. Ten volunteers were recruited to taste the products, and the conclusions were drawn. The specific results are shown in Table 2 below.

[0106] Table 2 Taste Comparison

[0107] Example 1 All 10 people agreed that it had a refreshing taste, was quite sweet, and was easy to accept in terms of both taste and texture, with almost no sour or astringent taste. Example 2 All 10 people agreed that it had a refreshing taste, was quite sweet, and was easy to accept in terms of both taste and texture, with almost no sour or astringent taste. Example 3 All 10 people agreed that it had a refreshing taste, was quite sweet, and was easy to accept in terms of both taste and texture, with almost no sour or astringent taste. Comparative Example 1 All 10 people agreed that the taste was rather astringent, sweet but lacked a cooling sensation, and the texture was poor. Comparative Example 2 All 10 people agreed that the taste was rather astringent, sweet but lacked a cooling sensation, and the texture was poor. Comparative Example 3 All 10 people agreed that the taste was rather astringent, sweet but lacked a cooling sensation, and the texture was poor. Comparative Example 4 All 10 people agreed that the taste was refreshing, with both sweetness and a cooling sensation, but the texture was just average. Comparative Example 5 All 10 people agreed that the taste was somewhat astringent, with a sweet and refreshing sensation, and the overall texture was just average. Comparative Example 6 All 10 people agreed that the taste was somewhat astringent, with a sweet and refreshing sensation, and the overall texture was just average.

[0108] A taste comparison was made between Examples 1-3 and Comparative Example 3. Out of 10 participants, all 10 considered Examples 1-3 to have a better taste than Comparative Example 3, with a more refreshing and less astringent flavor. This indicates that adding an appropriate amount of menthol to the product can reduce its astringent taste, making it more refreshing and palatable to most patients. Comparative Examples 4-5, containing mannitol and glycine as excipients, had a better taste than Comparative Examples 1-2, but worse than Examples 1-3. Comparative Example 6, with its increased use of anhydrous calcium phosphate, had a poorer taste.

[0109] 3. The stability of Examples 1-3 and Comparative Examples 4-6 was compared, and the results are shown in the table below.

[0110] Table 3. Results of stability study

[0111]

[0112]

[0113] Note: The above placement conditions are for packaging, specifically paper / aluminum composite film bags.

[0114] As shown in Table 3, the related substance content in Examples 1-3 was low, and after 30 days of accelerated and light irradiation, the related substance content did not increase significantly, indicating good stability. However, the related substance content in Comparative Examples 4-5 increased significantly under accelerated and light irradiation conditions, indicating that the addition of mannitol or glycine as excipients to the formulation resulted in poor stability. The related substance content in Comparative Example 6 also increased significantly under accelerated and light irradiation conditions, indicating that the amount of anhydrous calcium phosphate was inadequate, leading to poor stability.

[0115] 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 pharmaceutical composition containing fosfomycin tromethamine, characterized in that, It is composed of the following components by weight: 60g of fosfomycin tromethamine, 20-25g of anhydrous calcium phosphate, 1-2g of sodium saccharin, 0.5-1.5g of menthol, 0.5-1.5g of orange flavoring powder, and 0.5-1.5g of sour orange flavoring powder; the particle size of the fosfomycin tromethamine is 65-100 mesh; the particle size of the anhydrous calcium phosphate is 65-80 mesh; wherein, the preparation method of this pharmaceutical composition includes the following steps: (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, anhydrous calcium phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 20-60 mesh sieve and then set aside for use; (2) Mixing: Mix the components after sieving in step (1) evenly. The mixing speed is 5~20 rpm and the mixing time is 15~30 min. This is the drug composition containing fosfomycin tromethamine.

2. The pharmaceutical composition containing fosfomycin tromethamine according to claim 1, characterized in that, It is made from the following components by weight: 60g fosfomycin tromethamine, 20g anhydrous calcium phosphate, 1g sodium saccharin, 0.5g menthol, 0.5g orange flavor powder, and 0.5g sour orange flavor powder.

3. The pharmaceutical composition containing fosfomycin tromethamine according to claim 1, characterized in that, It is made from the following components by weight: 60g fosfomycin tromethamine, 23g anhydrous calcium phosphate, 1.5g sodium saccharin, 1g menthol, 1g orange flavor powder, and 1g sour orange flavor powder.

4. The pharmaceutical composition containing fosfomycin tromethamine according to claim 1, characterized in that, It is made from the following components by weight: 60g fosfomycin tromethamine, 25g anhydrous calcium phosphate, 2g sodium saccharin, 1.5g menthol, 1.5g orange flavor powder, and 1.5g sour orange flavor powder.

5. The method for preparing the pharmaceutical composition containing fosfomycin tromethamine according to claim 1, characterized in that, Includes the following steps: (1) Pretreatment of raw materials and excipients: The raw materials fosfomycin tromethamine, anhydrous calcium phosphate, sodium saccharin, menthol, orange flavor powder and sour orange flavor powder are passed through a 20-60 mesh sieve and then set aside for use; (2) Mixing: Mix the components after sieving in step (1) evenly. The mixing speed is 5~20 rpm and the mixing time is 15~30 min. This is the drug composition containing fosfomycin tromethamine.

6. The method for preparing the pharmaceutical composition containing fosfomycin tromethamine according to claim 5, characterized in that, In step (1), the sieve mesh size is 40 mesh.

7. The method for preparing the pharmaceutical composition containing fosfomycin tromethamine according to claim 5, characterized in that, In step (2), the mixing speed is 10 rpm and the mixing time is 25 min.

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