Compound preparation containing faropenem sodium as well as preparation method and application of compound preparation

Abstract

The invention belongs to the technical field of medicine manufacturing, and particularly relates to a compound preparation containing faropenem sodium as well as a preparation method and application of the compound preparation. According to the invention, the production prescription is optimized, the stability of the medicine can be effectively improved, the unpleasant smell of the medicine is covered, and the medication compliance of children is obviously improved. The epigallocatechin-aluminum complex can serve as a free radical scavenger in a preparation system, oxygen free radicals are effectively captured and neutralized, and the influence of oxidative stress on the medicine is reduced; moreover, the existence of aluminum ions not only enhances the stability of EGCG, but also reduces the drug degradation reaction under the catalysis of the ions through chelation with trace metal ions (such as iron, copper and the like) in the preparation. In addition, aluminum ions can also directly form a stable complex with faropenem sodium, so that the chemical stability of the faropenem sodium is further improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing technology, specifically relating to a compound preparation containing faropenem sodium, its preparation method, and its application. Background Technology

[0002] Faropenem is an atypical β-lactam antibiotic, belonging to the penicillin derivative class. Its mechanism of action is to block bacterial cell wall synthesis. It has a strong binding affinity to penicillin-binding protein (PBP), thereby exerting its bactericidal effect. It has a broad antibacterial spectrum, is stable against β-lactamases, and is also stable against renin-peptidase-I (DHP-I). Except for its inability to inhibit *Pseudomonas aeruginosa*, it is particularly effective against anaerobic bacteria, inhibiting *Staphylococcus*, *Streptococcus*, and many Gram-negative bacteria, including *Haemophilus influenzae*, *Neisseria gonorrhoeae*, and *Morchella catarrhalis*, outperforming carbapenem antibiotics. This product inhibits *Staphylococcus*, *Streptococcus*, and many Gram-negative bacteria, including *Haemophilus influenzae*, *Neisseria gonorrhoeae*, and *Morchella catarrhalis*, exhibiting strong biological activity, 5-10 times stronger than third-generation cephalosporins. Clinically, this product is particularly effective in pediatric bacterial infections, such as lower respiratory tract infections, with a 95-100% efficacy rate and high clinical evaluation.

[0003] However, faropenem sodium exhibits hygroscopicity and chemical instability, particularly in aqueous environments where it is prone to hydrolysis, leading to reduced efficacy or even complete loss of efficacy. Furthermore, the drug itself has an unpleasant odor, affecting patient adherence, especially in children. Therefore, developing a stable, palatable, and convenient pediatric faropenem sodium granule formulation is of significant clinical and social value. Summary of the Invention

[0004] The purpose of this invention is to provide a granule containing faropenem sodium, which effectively improves formulation stability, masks unpleasant drug odor, improves taste, and significantly enhances children's medication compliance.

[0005] This invention provides a compound formulation containing faropenem sodium, wherein, based on 100g of faropenem sodium, the compound formulation comprises 10-30g of sucrose, 400-550g of D-mannitol, 5-30g of aspartame, 5-20g of epigallocatechin-aluminum complex, 300-420g of hydroxypropyl cellulose, and 0.5-3g of flavoring; The preparation method of the epigallocatechin-aluminum complex includes the following steps: dissolving epigallocatechin gallate (EGCG) in water to obtain an EGCG aqueous solution; adding an aluminum salt aqueous solution dropwise to the EGCG aqueous solution to obtain an EGCG-Al complexation reaction system; adjusting the pH value of the EGCG-Al complexation reaction system to 5.0~5.5, and allowing it to stand to allow EGCG and Al to react. 3+The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation, washing, and recrystallization to obtain epigallocatechin-aluminum complex powder; the epigallocatechin gallate ester in the EGCG aqueous solution and the Al in the aluminum salt aqueous solution... 3+ The molar ratio is 1:0.8~1.5.

[0006] Preferably, the epigallocatechin-aluminum complex powder has an epigallocatechin gallate content ≥85% w / w, an aluminum content of 1~5% w / w, and a moisture content ≤3%.

[0007] Preferably, the aluminum salt aqueous solution is any one of aluminum chloride aqueous solution, aluminum sulfate aqueous solution, aluminum nitrate aqueous solution, or aluminum acetate aqueous solution.

[0008] Preferably, the standing time is: standing at 15~30℃ for 10~30 minutes.

[0009] Preferably, the recrystallization step includes: redissolving the obtained precipitate with a 40-60% v / v ethanol-water solution, adding 0.05-0.2% w / v ascorbic acid as an antioxidant, then allowing it to stand at 0-5°C for crystallization, filtering and drying.

[0010] The present invention also provides a method for preparing the composite formulation described in the above technical solution. The preparation method includes the following steps: sieving each substance separately, vacuum drying to a moisture content ≤0.3%, mixing evenly to obtain a mixture; mixing the mixture with 20% v / v~30% v / v ethanol to prepare a soft material, granulating it through an 18-mesh sieve, and then drying it by forced air to obtain dry granules; and finally granulating the composite formulation into granules.

[0011] Preferably, the sieving is performed through a 60-80 mesh sieve.

[0012] Preferably, the mass-to-volume ratio of the mixture to 20% v / v to 30% v / v ethanol is 100 g: 10 to 15 mL.

[0013] Preferably, the vacuum drying conditions are: drying at 40℃~60℃ and 1~10kPa for 4~6 hours.

[0014] Preferably, the conditions for the forced-air drying are: forced-air drying at 50℃~60℃ for 2~3 hours.

[0015] The beneficial effects of this invention are: This invention optimizes the manufacturing process, masks unpleasant drug odors, and significantly improves pediatric medication compliance. The pediatric faropenem sodium is administered in granule form, making it convenient to take. Compared to injection and tablet administration, children readily accept it. The epigallocatechin-aluminum complex acts as a free radical scavenger in the formulation system, effectively capturing and neutralizing oxygen free radicals, reducing the impact of oxidative stress on the drug. Furthermore, the presence of aluminum ions not only enhances the stability of EGCG but also reduces drug degradation catalyzed by trace metal ions (such as iron and copper) in the formulation through chelation. In addition, aluminum ions themselves can directly form stable complexes with faropenem sodium, further improving its chemical stability.

[0016] This invention optimizes the production process, resulting in a high degree of mechanization and automation, high output, low cost and selling price, and easy compliance with hygiene standards. Using ethanol at a concentration of 20% v / v to 30% v / v during granulation effectively reduces the risk of residue, meets the requirements for pediatric formulations, helps optimize particle size distribution and surface smoothness, thereby improving the flowability of the final product. It also effectively reduces adhesion between particles or between particles and equipment, ensuring production continuity and efficiency. Furthermore, compared to high-concentration ethanol, low-concentration ethanol is more effective in preventing β-lactam ring-opening during spray drying.

[0017] The pediatric faropenem sodium granules provided by this invention have accurate dosage, uniform content, and small differences in drug content between doses; they also have a large specific surface area and good solubility; and are convenient to carry, transport, and administer. Each bag of the pediatric faropenem sodium granules provided by this invention contains 50mg of faropenem sodium, requiring only one dose per day. Compared to commercially available pediatric antibacterial granules that require three daily doses (such as amoxicillin granules), this reduces the daily dosage by two doses, significantly improving medication adherence and reducing the adverse effects of missed or incorrect doses, especially for pediatric patients. Detailed Implementation

[0018] To further illustrate the present invention, the solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0019] Example 1 Adding aluminum chloride solution dropwise to an EGCG aqueous solution eventually causes the EGCG in the EGCG aqueous solution to react with the Al in the aluminum chloride aqueous solution. 3+ The molar ratio of EGCG to Al was 1:1 to obtain the EGCG-Al complexation reaction system; the pH of the EGCG-Al complexation reaction system was adjusted to 5.0-5.5, and the mixture was allowed to stand at 25°C for 15 minutes to allow EGCG and Al to react. 3+The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation and washing, and then redissolved with 60% v / v ethanol-water solution. 0.1% w / v ascorbic acid was added as an antioxidant, and then the mixture was allowed to stand at 0~5℃ to crystallize. After filtration and drying, epigallocatechin-aluminum complex powder was obtained.

[0020] Weigh out 100g of faropenem sodium, 20g of sucrose, 480g of D-mannitol, 20g of aspartame, 20g of epigallocatechin-aluminum complex, 360g of hydroxypropyl cellulose, and 0.5g of flavoring for later use.

[0021] Faropenem sodium and hydroxypropyl cellulose were passed through an 80-mesh sieve, while the remaining raw materials were passed through a 60-mesh sieve. The mixture was then dried under vacuum at 50°C and 1 kPa until the moisture content was ≤0.3%. The mixture was thoroughly mixed, and 110 mL of 20% v / v ethanol was added to prepare a soft mass. The mass was then granulated by passing the mass through an 18-mesh sieve. The wet granules were then dried in a forced-air dryer at 60°C for 2 hours. The granules were then sized using an 18-mesh sieve and packaged to obtain granules.

[0022] Example 2 Adding aluminum chloride solution dropwise to an EGCG aqueous solution eventually causes the EGCG in the EGCG aqueous solution to react with the Al in the aluminum chloride aqueous solution. 3+ The molar ratio of EGCG to Al was 1:0.8, resulting in an EGCG-Al complexation reaction system. The pH of the EGCG-Al complexation reaction system was adjusted to 5.0–5.5, and the system was allowed to stand at 25°C for 20 minutes to allow EGCG and Al to react. 3+ The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation and washing, and then redissolved with 40% v / v ethanol-water solution. 0.05% w / v ascorbic acid was added as an antioxidant, and then the mixture was allowed to stand at 0~5℃ to crystallize. After filtration and drying, epigallocatechin-aluminum complex powder was obtained.

[0023] Weigh out 100g of faropenem sodium, 10g of sucrose, 550g of D-mannitol, 30g of aspartame, 5g of epigallocatechin-aluminum complex, 300g of hydroxypropyl cellulose, and 3g of flavoring for later use.

[0024] Faropenem sodium and hydroxypropyl cellulose were passed through an 80-mesh sieve, while the remaining raw materials were passed through a 60-mesh sieve. The mixture was then vacuum dried at 50°C and 10 kPa until the moisture content was ≤0.3%. The mixture was thoroughly mixed, and 150 mL of 20% v / v ethanol was added to prepare a soft mass. The mass was then granulated by passing it through an 18-mesh sieve. The wet granules were then dried in a forced-air dryer at 60°C for 2 hours. The granules were then sized using an 18-mesh sieve and packaged to obtain granules.

[0025] Example 3 Adding aluminum chloride solution dropwise to an EGCG aqueous solution eventually causes the EGCG in the EGCG aqueous solution to react with the Al in the aluminum chloride aqueous solution. 3+The molar ratio of EGCG to Al was 1:0.8 to obtain the EGCG-Al complexation reaction system; the pH of the EGCG-Al complexation reaction system was adjusted to 5.0-5.5, and the system was allowed to stand at 15℃ for 30 minutes to allow EGCG and Al to react. 3+ The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation and washing, and then redissolved with 60% v / v ethanol-water solution. 0.15% w / v ascorbic acid was added as an antioxidant, and then the mixture was allowed to stand at 0~5℃ to crystallize. After filtration and drying, epigallocatechin-aluminum complex powder was obtained.

[0026] Weigh out 100g of faropenem sodium, 30g of sucrose, 400g of D-mannitol, 5g of aspartame, 10g of epigallocatechin-aluminum complex, 420g of hydroxypropyl cellulose, and 1g of flavoring for later use.

[0027] Faropenem sodium and hydroxypropyl cellulose were passed through an 80-mesh sieve, while the remaining raw materials were passed through a 60-mesh sieve. The mixture was then dried under vacuum at 50°C and 5 kPa until the moisture content was ≤0.3%. The mixture was thoroughly mixed, and 100 mL of 30% v / v ethanol was added to prepare a soft mass. The mass was then granulated by passing the soft mass through an 18-mesh sieve. The wet granules were then dried under forced air at 60°C for 2 hours. The granules were then sized using an 18-mesh sieve and packaged to obtain granules.

[0028] Comparative Example 1 The difference from Example 1 is that the epigallocatechin-aluminum complex is replaced with EGCG.

[0029] Weigh out 100g of faropenem sodium, 20g of sucrose, 480g of D-mannitol, 20g of aspartame, 20g of EGCG, 360g of hydroxypropyl cellulose, and 0.5g of flavoring for later use.

[0030] Faropenem sodium and hydroxypropyl cellulose were passed through an 80-mesh sieve, while the remaining raw materials were passed through a 60-mesh sieve. The mixture was then dried under vacuum at 50°C and 1 kPa until the moisture content was ≤0.3%. The mixture was thoroughly mixed, and 110 mL of 20% v / v ethanol was added to prepare a soft mass. The mass was then granulated by passing the mass through an 18-mesh sieve. The wet granules were then dried in a forced-air dryer at 60°C for 2 hours. The granules were then sized using an 18-mesh sieve and packaged to obtain granules.

[0031] Comparative Example 2 The difference from Example 1 is that a medium-concentration ethanol solution is used for granulation.

[0032] Adding aluminum chloride solution dropwise to an EGCG aqueous solution eventually causes the EGCG in the EGCG aqueous solution to react with the Al in the aluminum chloride aqueous solution. 3+ The molar ratio of EGCG to Al was 1:1 to obtain the EGCG-Al complexation reaction system; the pH of the EGCG-Al complexation reaction system was adjusted to 5.0-5.5, and the mixture was allowed to stand at 25°C for 15 minutes to allow EGCG and Al to react. 3+The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation and washing, and then redissolved with 60% v / v ethanol-water solution. 0.1% w / v ascorbic acid was added as an antioxidant, and then the mixture was allowed to stand at 0~5℃ to crystallize. After filtration and drying, epigallocatechin-aluminum complex powder was obtained.

[0033] Weigh out 100g of faropenem sodium, 20g of sucrose, 480g of D-mannitol, 20g of aspartame, 20g of epigallocatechin-aluminum complex, 360g of hydroxypropyl cellulose, and 0.5g of flavoring for later use.

[0034] Faropenem sodium and hydroxypropyl cellulose were passed through an 80-mesh sieve, while the remaining raw materials were passed through a 60-mesh sieve. The mixture was then dried under vacuum at 50°C and 1 kPa until the moisture content was ≤0.3%. The mixture was thoroughly mixed, and 110 mL of 60% v / v ethanol was added to prepare a soft mass. The mass was then granulated by passing it through an 18-mesh sieve. The wet granules were then dried in a forced-air dryer at 60°C for 2 hours. The granules were then sized using an 18-mesh sieve and packaged to obtain granules.

[0035] Comparative Example 3 The difference from Example 1 is that a high concentration of ethanol solution is used for granulation.

[0036] Adding aluminum chloride solution dropwise to an EGCG aqueous solution eventually causes the EGCG in the EGCG aqueous solution to react with the Al in the aluminum chloride aqueous solution. 3+ The molar ratio of EGCG to Al was 1:1 to obtain the EGCG-Al complexation reaction system; the pH of the EGCG-Al complexation reaction system was adjusted to 5.0-5.5, and the mixture was allowed to stand at 25°C for 15 minutes to allow EGCG and Al to react. 3+ The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation and washing, and then redissolved with 60% v / v ethanol-water solution. 0.1% w / v ascorbic acid was added as an antioxidant, and then the mixture was allowed to stand at 0~5℃ to crystallize. After filtration and drying, epigallocatechin-aluminum complex powder was obtained.

[0037] Weigh out 100g of faropenem sodium, 20g of sucrose, 480g of D-mannitol, 20g of aspartame, 20g of epigallocatechin-aluminum complex, 360g of hydroxypropyl cellulose, and 0.5g of flavoring for later use.

[0038] Faropenem sodium and hydroxypropyl cellulose were passed through an 80-mesh sieve, while the remaining raw materials were passed through a 60-mesh sieve. The mixture was then dried under vacuum at 50°C and 1 kPa until the moisture content was ≤0.3%. The mixture was thoroughly mixed, and 110 mL of 95% v / v ethanol was added to prepare a soft mass. The mass was then granulated by passing it through an 18-mesh sieve. The wet granules were then dried in a forced-air dryer at 60°C for 2 hours. The granules were then sized using an 18-mesh sieve and packaged to obtain granules.

[0039] Test Example 1 Stability test The granules prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were used as samples, and commercially available feropenem sodium granules were used as controls for the experiment.

[0040] The experimental design followed ICH Q1A guidelines, setting up four types of experiments: long-term, accelerated, intense light exposure, and high-temperature damage. The specific conditions were as follows: Long-term test: Samples were taken for testing after being stored at 25℃ and 60% RH for 12 months; Accelerated testing: Store at 40℃ and 75% RH for 6 months, and take samples for testing at 0 days, 1 month, 2 months, 3 months and 6 months of storage; Strong light exposure: Samples were stored under 4500 lx light for 10 days and then tested. High temperature damage: Samples were taken for testing after being stored at 60℃ for 10 days.

[0041] The core testing indicators are content, related substances, dissolution, appearance, moisture, and pH. Content and related substances are tested using a validated HPLC method, dissolution is tested using the paddle or basket method, moisture is determined by Karl Fischer titration, and appearance is determined visually.

[0042] The stability standards are as follows: content variation not exceeding ±5%, total new impurities ≤1%, dissolution rate maintained within ±10% of the initial value, and no obvious abnormalities such as clumping or discoloration in appearance.

[0043] The results are shown in Table 1.

[0044] Table 1 Results of Long-Term Tests

[0045] Table 2 Accelerated Test Results

[0046] Table 3 Results of the high-intensity light test

[0047] Table 4 High Temperature Test Results

[0048] As shown in Tables 1 to 4, the faropenem sodium particles prepared in the embodiments of the present invention have higher stability compared with the comparative examples. This indicates that the use of epigallocatechin-aluminum complex as a stabilizer and the use of low concentration ethanol for granulation are more conducive to improving the stability of faropenem sodium particles.

[0049] Test Example 2 Flavoring effect evaluation Faropenem sodium granules prepared in Examples 1-3 and Comparative Examples 1-3 were used as samples, and blank control group samples were prepared in the following manner: Weigh out 100g of faropenem sodium and 360g of hydroxypropyl cellulose for later use. Pass faropenem sodium and hydroxypropyl cellulose separately through an 80-mesh sieve, then dry them under vacuum at 50℃ and 1kPa until the moisture content is ≤0.3%. Mix them evenly, add 110mL of 20% v / v ethanol to prepare a soft mass, granulate it through an 18-mesh sieve, then dry the wet granules at 60℃ for 2 hours. Squeeze the granules through an 18-mesh sieve and package them to obtain granules.

[0050] To verify the effect of flavoring agents on improving the taste of faropenem sodium granules, an electronic tongue was used to evaluate the flavoring effect of the sample granules. The results are shown in Table 5.

[0051] Table 5. Experimental Results of Electronic Tongue

[0052] As shown in Table 5, the flavored blank granules exhibited a strong bitter and astringent taste, with a sharp overall flavor, making them difficult to take directly. Although flavoring agents were introduced in Comparative Examples 1-3, the bitterness value remained between 7.20 and 8.90, indicating low masking efficiency. In contrast, Examples 1-3, by adjusting the formulation, used epigallocatechin-aluminum complex as a stabilizer and adjusted the concentration of granulation ethanol, significantly reducing the bitterness and astringency values, effectively masking the unpleasant odor of the drug, and improving medication compliance.

[0053] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A compound preparation containing faropenem sodium, characterized in that, The compound preparation, based on 100g of faropenem sodium, includes 10-30g of sucrose, 400-550g of D-mannitol, 5-30g of aspartame, 5-20g of epigallocatechin-aluminum complex, 300-420g of hydroxypropyl cellulose, and 0.5-3g of flavoring. The preparation method of the epigallocatechin-aluminum complex includes the following steps: Epigallocatechin gallate was dissolved in water to obtain an EGCG aqueous solution; an aluminum salt aqueous solution was added dropwise to the EGCG aqueous solution to obtain an EGCG-Al complexation reaction system; the pH of the EGCG-Al complexation reaction system was adjusted to 5.0-5.5, and the mixture was allowed to stand to allow EGCG and Al to react. 3+ The precipitate was fully complexed and precipitated; the precipitate was subjected to solid-liquid separation, washing and recrystallization to obtain epigallocatechin-aluminum complex powder; Epigallocatechin gallate in EGCG aqueous solution and Al in aluminum salt aqueous solution 3+ The molar ratio is 1:0.8~1.

5.

2. The compound formulation according to claim 1, characterized in that, The epigallocatechin-aluminum complex powder has an epigallocatechin gallate content ≥85% w / w, an aluminum content of 1~5% w / w, and a moisture content ≤3%.

3. The compound formulation according to claim 1, characterized in that, The aluminum salt aqueous solution is any one of aluminum chloride aqueous solution, aluminum sulfate aqueous solution, aluminum nitrate aqueous solution, or aluminum acetate aqueous solution.

4. The compound formulation according to claim 1, characterized in that, The standing time is: standing at 15℃~30℃ for 10~30 minutes.

5. The compound formulation according to claim 1, characterized in that, The recrystallization step includes: redissolving the obtained precipitate with 40-60% v / v ethanol-water solution, adding 0.05-0.2% w / v ascorbic acid as an antioxidant, then allowing it to stand at 0-5°C for crystallization, filtering and drying.

6. The method for preparing the compound formulation according to claim 1, characterized in that, The preparation method includes the following steps: Each substance was sieved separately, vacuum dried until the moisture content was ≤0.3%, and then mixed evenly to obtain a mixture. A soft mass is prepared by mixing the mixture with 20% v / v to 30% v / v ethanol, granulating it by passing it through an 18-mesh sieve, and then drying it by blowing air to obtain dry granules. After granulation, the granules are packaged to obtain the granules of the composite preparation.

7. The method according to claim 6, characterized in that, The sieving process involves passing the material through a 60-80 mesh sieve.

8. The method according to claim 6, characterized in that, The mass-to-volume ratio of the mixture to 20% v / v to 30% v / v ethanol is 100 g: 10 to 15 mL.

9. The method according to claim 6, characterized in that, The vacuum drying conditions are: drying at 40℃~60℃ and 1~10kPa for 4~6 hours.

10. The method according to claim 6, characterized in that, The conditions for blower drying are: blower drying at 50℃~60℃ for 2~3 hours.

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