A cefoperazone sodium and sulbactam sodium composition and a preparation method thereof

Abstract

This invention discloses a cefoperazone sodium and sulbactam sodium composition and its preparation method, comprising the following steps: preparing a chitosan-β-glycerophosphate sodium colloidal solution; mixing dry ice and sorbitol evenly, then adding the mixture to the colloidal solution, freezing, heating, and drying under reduced pressure to obtain chitosan-β-glycerophosphate sodium nanospheres; slowly adding cefoperazone sodium, sulbactam sodium, and chitosan-β-glycerophosphate sodium nanospheres to water for injection, stirring to dissolve; adjusting the pH to 7.1-7.5, adding an adsorbent for adsorption and filtration, adding dry ice; freeze-drying to obtain a cefoperazone sodium and sulbactam sodium mixed powder. The nanospheres of this invention, with a certain size gradient, are beneficial for the uniformity of the mixed powder of cefoperazone sodium and sulbactam sodium, resulting in a longer-lasting efficacy, better stability, lower hygroscopicity, and also playing an antibacterial role.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a cefoperazone sodium / sulbactam sodium composition and its preparation method. Background Technology

[0002] Cefoperazone sodium is a representative of third-generation cephalosporins. It exerts its antibacterial effect by inhibiting bacterial cell wall synthesis. It belongs to the lactam class of antibiotics and can counteract the degradation effects of various β-lactamases. It has a broad antibacterial spectrum and is effective against Gram-positive bacteria, such as Staphylococcus aureus (including penicillin-producing and non-penicillin-producing strains), Streptococcus pneumoniae, most β-hemolytic streptococcal strains, Escherichia coli, Klebsiella spp., Citric acid bacillus spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Salmonella spp. and Shigella spp., Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Neisseria meningitidis. Compared with other third-generation cephalosporins, it has advantages such as a broad antibacterial spectrum, strong antibacterial activity, low toxicity, good efficacy, and fewer allergic reactions. Therefore, it has been widely used in clinical practice since its launch.

[0003] Because cefoperazone is unstable against various β-lactamases, its antibacterial activity against certain producing bacterial strains is reduced. Current technology involves preparing a compound formulation by mixing cefoperazone sodium and sulbactam sodium in a specific ratio. Sulbactam sodium is a penicillin sulfone β-lactamase inhibitor with low antibacterial activity but strong enzyme inhibition. Sulbactam sodium inhibits β-lactamases, improving the stability of cefoperazone and allowing it to not only fully exert its antibacterial activity but also broaden its antibacterial spectrum against bacteria and Acinetobacter.

[0004] However, both cefoperazone sodium and sulbactam sodium contain a β-lactam ring. The unstable β-lactam ring is prone to hydrolysis and reduced efficacy, resulting in poor stability. They frequently undergo degradation and polymerization reactions, leading to a decrease in the content of the active pharmaceutical ingredient and an increase in impurities. Sulbactam sodium also has poor storage stability; related substances increase significantly in light and humid environments, resulting in high impurity levels during long-term storage. Currently, commercially available cefoperazone sodium and sulbactam sodium combination preparations have poor stability and a short shelf life.

[0005] Therefore, this patent application is filed. Summary of the Invention

[0006] To address the above issues, the purpose of this patent application is to provide a cefoperazone sodium / sulbactam sodium composition and its preparation method, resulting in a product with good quality stability, long shelf life, and low hygroscopicity.

[0007] This invention is achieved through the following technical solution:

[0008] The first objective of this invention is to provide a method for preparing a cefoperazone sodium / sulbactam sodium composition, comprising the following steps:

[0009] (1) Preparation of chitosan-β-glycerophosphate sodium colloidal solution;

[0010] (2) Dry ice and sorbitol were mixed evenly, and then added to the colloidal solution. The mixture was frozen, heated, and dried under reduced pressure to obtain chitosan-β-glycerophosphate sodium nanospheres.

[0011] (3) Slowly add cefoperazone sodium, sulbactam sodium, and chitosan-β-glycerophosphate sodium nanospheres to water for injection and stir to dissolve;

[0012] (4) Adjust the pH to 7.1-7.5, add adsorbent for adsorption and filtration, and add dry ice;

[0013] (5) Freeze-dry to obtain cefoperazone sodium and sulbactam sodium mixed powder.

[0014] In this embodiment of the invention, chitosan and sodium β-glycerophosphate are cross-linked through electrostatic interactions between anions and cations to form nanoparticles. Then, dry ice and sorbitol are added, followed by low-temperature freezing. The nanoparticles are mixed with dry ice and sorbitol to form a mixed system in three states: solid, liquid, and colloidal. After freezing, mixed ice crystals are formed. Since the particle sizes in the solid, liquid, and colloidal systems are different, the mixed ice crystals are a composite of ice crystals of three particle sizes. Then, the system is heated and dried. The dry ice in the ice crystals sublimates rapidly, and water vapor evaporates. The presence of liquid sorbitol increases the evaporation rate of water vapor and reduces the difference between the evaporation rate of water vapor and the sublimation rate of solid dry ice. During the sublimation drying process, the evaporation of dry ice and water vapor causes the ice crystals to form pores in situ. After depressurization drying, nanospheres with a certain size gradient are finally formed, and pores with a size gradient are also formed on the surface of the microspheres. The gradient-sized nanospheres and their pores enhance the uniformity of cefoperazone sodium and sulbactam sodium powder mixing when loaded, resulting in a longer-lasting therapeutic effect in the patient. Furthermore, the interaction between the nanospheres and cefoperazone sodium and sulbactam sodium improves the stability of the active pharmaceutical ingredients and also exerts an antibacterial effect.

[0015] In this embodiment of the invention, the addition of dry ice and sorbitol to the nanoparticles can also facilitate the volatilization of water vapor in the system, increase the volatilization rate, reduce the moisture content in the chitosan-β-glycerophosphate sodium nanospheres, reduce the temperature and speed in the subsequent vacuum drying process, improve the drying effect, ensure the stability of the cefoperazone sodium-sulbactam sodium mixture, and increase the storage time.

[0016] In this embodiment of the invention, chitosan-β-glycerophosphate sodium is selected because it has better tissue compatibility. At the same time, it can reduce the temperature sensitivity of the cefoperazone sodium-sulbactam sodium mixture loaded on it, reduce the impact of temperature on the stability of the cefoperazone sodium-sulbactam sodium mixture, extend the storage time, and improve the quality of the drug.

[0017] In an optional embodiment, the chitosan-β-glycerophosphate sodium colloidal solution is prepared as follows:

[0018] (1) Take chitosan powder and sieve it. Dissolve it in acetic acid solution while stirring. Stir to obtain an acidic chitosan solution.

[0019] (2) Dissolve sodium β-glycerophosphate in deionized water to obtain a sodium β-glycerophosphate solution;

[0020] (3) Mix the acidic chitosan solution with the sodium β-glycerophosphate solution and adjust the pH to 7.87 with sodium dihydrogen phosphate to obtain the chitosan-β-glycerophosphate colloidal solution.

[0021] In this embodiment of the invention, sodium dihydrogen phosphate is used to adjust the pH instead of sodium hydroxide because dry ice is subsequently added to the colloidal solution, avoiding the counteracting effect of hydroxide ions on the dry ice caused by sodium hydroxide. Simultaneously, sodium dihydrogen phosphate and β-glycerophosphate form a phosphate buffer solution, which has strong buffering capacity, allowing for more precise pH adjustment and less susceptibility to temperature changes. In this embodiment of the invention, β-glycerophosphate serves both as a raw material for the formation of nanospheres and as a pH adjuster.

[0022] In an optional embodiment, the chitosan powder is passed through a 100-mesh sieve, and the acetic acid solution has a concentration of 0.01M to 0.1M.

[0023] The weight ratio of sodium β-glycerophosphate to chitosan is (2%–10%):2%.

[0024] In this embodiment of the invention, the weight ratio of β-glycerophosphate sodium solution to chitosan acidic solution is rationally designed to adjust the temperature sensitivity of the formed nanoparticles, thereby optimizing the stability of the cefoperazone sodium / sulbactam sodium mixture and significantly extending its shelf life. Simultaneously, the particle size of the formed nanospheres is adjusted to achieve the best overall effect in terms of loading efficiency, stability, and shelf life.

[0025] In an optional embodiment, after adding dry ice in step (2), the mixture is frozen to a temperature of -30°C to -20°C and kept at that temperature for 30 to 50 minutes. Then, the temperature is raised to -15°C to -12°C and kept there for 1 to 2 hours.

[0026] In an optional embodiment, step (2) involves vacuum drying at 25°C to 30°C to obtain chitosan-β-glycerophosphate sodium nanospheres with a moisture content of less than 2% and a particle size of 50 to 200 nm.

[0027] In an optional embodiment, in step (2), the mass ratio of sorbitol to chitosan is (3-8):(30-80).

[0028] In this embodiment of the invention, the addition of a small amount of sorbitol can increase the evaporation rate of water vapor. At the same time, sorbitol can also serve as a freeze-drying skeleton agent when forming nanoparticles, and synergistically form a stable microsphere structure and porous structure with chitosan and sodium β-glycerophosphate.

[0029] In an optional embodiment, the mass ratio of cefoperazone sodium to sulbactam sodium is 2:1 or 1:1;

[0030] The mass ratio of the sum of the masses of cefoperazone sodium and sulbactam sodium to the mass of chitosan-β-glycerophosphate sodium nanospheres is (2-8):(1.5-3.5).

[0031] In an optional embodiment, disodium hydrogen phosphate is used to adjust the pH in step (4), and the adsorbent in step (4) is a magnetic material of mesoporous silica coated with Fe3O4 particles.

[0032] In this embodiment of the invention, using mesoporous silica-coated Fe3O4 particles as an adsorbent can quickly achieve adsorption and separation, while shortening the process time before freeze-drying and reducing the impact on cefoperazone sodium and sulbactam sodium during the preparation process.

[0033] In an optional embodiment, in step (5), the freeze-drying process is as follows:

[0034] Freezing: The solution obtained in step (4) is continuously cooled to -17℃ to -15℃ and kept at a constant temperature for 2h to 5h, then cooled to -45℃ to -40℃ and kept at that temperature for 2h to 5h;

[0035] Sublimation drying: Drying in a vacuum at a pressure of 0.10 mbar to 0.30 mbar, raising the set temperature to -5℃ to 0℃ and maintaining it for 1.5h to 3h;

[0036] Set the temperature to 30-40℃ and maintain it for 5-10 hours.

[0037] Heat to 50-55℃ and maintain for 1-1.5 hours to complete the drying process.

[0038] In this embodiment of the invention, dry ice is added again after adsorption filtration, followed by freeze-drying. Gradient temperature freezing is used during freeze-drying to avoid poor ice crystal growth caused by direct, drastic cooling and freezing at low temperatures, thus improving the effect of subsequent sublimation drying. During sublimation drying, drying is first carried out at -5℃ to 0℃ to remove water in ice crystal form. Then, the temperature is raised to 30 to 40℃ to remove bound water adsorbed in the interstices of the solid crystal lattice. Finally, the temperature is raised to 50 to 55℃ to obtain a product with good quality stability.

[0039] A second objective of this invention is to provide a cefoperazone sodium / sulbactam sodium composition obtained by any of the preparation methods described above.

[0040] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0041] (1) The present invention provides a method for preparing a cefoperazone sodium and sulbactam sodium composition. Chitosan and sodium β-glycerophosphate are cross-linked via electrostatic interactions between anions and cations to form nanoparticles. Dry ice and sorbitol are then added, followed by low-temperature freezing and high-temperature drying to form nanospheres with a certain size gradient. A pore size gradient is also formed on the surface of the nanospheres. The nanospheres with gradient sizes and pores are more conducive to the uniformity of cefoperazone sodium powder and sulbactam sodium powder when loaded, and the drug efficacy is more prolonged in the patient's body during administration. Simultaneously, the interaction between the nanospheres and cefoperazone sodium and sulbactam sodium can improve the stability of the active pharmaceutical ingredients and also play an antibacterial role.

[0042] (2) The method for preparing a cefoperazone sodium and sulbactam sodium composition provided in the embodiments of the present invention involves adding dry ice and sorbitol to the nanoparticles, which is beneficial to the volatilization of water vapor in the system, increases the volatilization rate, reduces the moisture content in the chitosan-β-glycerophosphate sodium nanospheres, reduces the temperature and speed in the subsequent vacuum drying process, improves the drying effect, ensures the stability of the cefoperazone sodium and sulbactam sodium mixed powder, and increases the storage time.

[0043] (3) The present invention provides a method for preparing a cefoperazone sodium-sulbactam sodium composition. Chitosan-β-glycerophosphate sodium is selected because it has better tissue compatibility and can reduce the temperature sensitivity of the cefoperazone sodium-sulbactam sodium mixture loaded on it, reduce the effect of temperature on the stability of the cefoperazone sodium-sulbactam sodium mixture, prolong the storage time, and improve the quality of the drug. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0045] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that these specific details are not necessary to practice the invention. In other embodiments, well-known methods have not been specifically described in order to avoid obscuring the invention.

[0046] Example 1:

[0047] The cefoperazone sodium / sulbactam sodium composition was prepared by the following method:

[0048] (1) Preparation of chitosan-β-glycerophosphate sodium colloidal solution

[0049] Weigh 50g of dried chitosan powder to constant weight, pass it through a 100-mesh sieve, and dissolve it in a 0.01M acetic acid solution while stirring to obtain an acidic chitosan solution.

[0050] Dissolve 100g of sodium β-glycerophosphate in deionized water to obtain a sodium β-glycerophosphate solution;

[0051] Take an acidic chitosan solution and a sodium β-glycerophosphate solution and mix them. Add sodium dihydrogen phosphate and adjust the pH of the mixed solution to 7.87 to obtain a chitosan-β-glycerophosphate colloidal solution.

[0052] (2) Mix 7.55g of dry ice with 5g of sorbitol evenly, then add it to the colloidal solution, freeze to -30℃, keep for 30min, raise the temperature to -15℃, and keep for 1h.

[0053] Chitosan-β-glycerophosphate sodium nanospheres were obtained by vacuum drying at 25°C. The particle size of the obtained nanospheres was 80 nm.

[0054] (3) Slowly add 20g of cefoperazone sodium, 10g of sulbactam sodium, and 30g of chitosan-β-glycerophosphate sodium nanospheres to water for injection and stir to dissolve.

[0055] (4) Adjust the pH to 7.1 using disodium hydrogen phosphate, then quickly add magnetic material coated with mesoporous silica Fe3O4 particles to adsorb impurities, filter precisely, and then add dry ice;

[0056] (5) Freeze-drying: First, continuously cool the solution obtained in step (4) to -17℃ and keep it at a constant temperature for 2 hours, then cool it to -45℃ and keep it at that temperature for 2 hours;

[0057] Sublimation drying: Drying was carried out in a vacuum at a pressure of 0.10 mbar. The set temperature was raised to 0°C and maintained for 2 hours; then the set temperature was raised to 30°C and maintained for 5 hours; finally, the temperature was raised to 50°C and maintained for 1.5 hours to complete the drying process. A mixture of cefoperazone sodium and sulbactam sodium powder was obtained.

[0058] The cefoperazone sodium-sulbactam sodium mixture prepared in Example 1 was tested, and the results are shown in Table 1.

[0059] Table 1

[0060] time Properties Moisture (%) acidity Related substances (%) 0 White powder 1.53 5.1 0.29 3 White powder 1.65 5.1 0.29 6 White powder 1.68 5.1 0.30 9 White powder 1.69 5.2 0.31 12 White powder 1.71 5.2 0.33 18 White powder 1.73 5.1 0.33 24 White powder 1.78 5.1 0.34 36 White powder 1.81 5.0 0.34

[0061] Example 2:

[0062] The cefoperazone sodium / sulbactam sodium composition was prepared by the following method:

[0063] (1) Preparation of chitosan-β-glycerophosphate sodium colloidal solution

[0064] Weigh 50g of dried chitosan powder to constant weight, pass it through a 100-mesh sieve, and dissolve it in a 0.1M acetic acid solution while stirring to obtain an acidic chitosan solution.

[0065] Dissolve 250g of sodium β-glycerophosphate in deionized water to obtain a sodium β-glycerophosphate solution;

[0066] Take an acidic chitosan solution and a sodium β-glycerophosphate solution and mix them. Add sodium dihydrogen phosphate and adjust the pH of the mixed solution to 7.87 to obtain a chitosan-β-glycerophosphate colloidal solution.

[0067] (2) Mix 6.5g of dry ice with 3g of sorbitol evenly, then add it to the colloidal solution, freeze to -20℃, keep for 50min, raise the temperature to -14℃, and keep for 2h.

[0068] Chitosan-β-glycerophosphate sodium nanospheres were obtained by vacuum drying at 30℃. The particle size of the obtained nanospheres was 200 nm.

[0069] (3) Slowly add 20g of cefoperazone sodium, 10g of sulbactam sodium, and 35g of chitosan-β-glycerophosphate sodium nanospheres to water for injection and stir to dissolve.

[0070] (4) Adjust the pH to 7.1 using disodium hydrogen phosphate, then quickly add magnetic material coated with mesoporous silica Fe3O4 particles to adsorb impurities, filter precisely, and then add dry ice;

[0071] (5) Freeze-drying: First, continuously cool the solution obtained in step (4) to -16℃ and keep it at a constant temperature for 3 hours, then cool it to -42℃ and keep it at that temperature for 3.5 hours;

[0072] Sublimation drying: Drying was carried out in a vacuum at a pressure of 0.30 mbar. The set temperature was raised to -5°C and maintained for 3 hours; then the set temperature was raised to 40°C and maintained for 8 hours; finally, the temperature was raised to 52°C and maintained for 1 hour to complete the drying. A mixture of cefoperazone sodium and sulbactam sodium powder was obtained.

[0073] The cefoperazone sodium-sulbactam sodium mixture prepared in Example 2 was tested, and the results are shown in Table 2.

[0074] Table 2

[0075] time Properties Moisture (%) acidity Related substances (%) 0 White powder 1.45 5.1 0.25 3 White powder 1.45 5.1 0.25 6 White powder 1.48 5.1 0.28 9 White powder 1.49 5.0 0.29 12 White powder 1.53 5.0 0.32 18 White powder 1.56 4.9 0.35 24 White powder 1.61 4.9 0.35 36 White powder 1.67 4.9 0.35

[0076] Example 3:

[0077] The cefoperazone sodium / sulbactam sodium composition was prepared by the following method:

[0078] (1) Preparation of chitosan-β-glycerophosphate sodium colloidal solution

[0079] Weigh 50g of dried chitosan powder to constant weight, pass it through a 100-mesh sieve, and dissolve it in a 0.1M acetic acid solution while stirring to obtain an acidic chitosan solution.

[0080] Dissolve 150g of sodium β-glycerophosphate in deionized water to obtain a sodium β-glycerophosphate solution;

[0081] Take an acidic chitosan solution and a sodium β-glycerophosphate solution and mix them. Add sodium dihydrogen phosphate and adjust the pH of the mixed solution to 7.87 to obtain a chitosan-β-glycerophosphate colloidal solution.

[0082] (2) Mix 7g dry ice with 8g sorbitol evenly, then add it to the colloidal solution, freeze to -25℃, keep for 40min, raise the temperature to -13℃, and keep for 1.5h.

[0083] Chitosan-β-glycerophosphate sodium nanospheres were obtained by vacuum drying at 27°C. The particle size of the obtained nanospheres was 120 nm.

[0084] (3) Slowly add 10g of cefoperazone sodium, 10g of sulbactam sodium, and 15g of chitosan-β-glycerophosphate sodium nanospheres to water for injection and stir to dissolve.

[0085] (4) Adjust the pH to 7.4 using disodium hydrogen phosphate, then quickly add magnetic material coated with mesoporous silica Fe3O4 particles to adsorb impurities, filter precisely, and then add dry ice;

[0086] (5) Freeze-drying: First, continuously cool the solution obtained in step (4) to -16℃ and keep it at a constant temperature for 2 hours, then cool it to -40℃ and keep it at that temperature for 4 hours;

[0087] Sublimation drying: Drying was carried out in a vacuum at a pressure of 0.30 mbar. The set temperature was raised to 0°C and maintained for 2 hours; then the set temperature was raised to 35°C and maintained for 6 hours; finally, the temperature was raised to 55°C and maintained for 1 hour to complete the drying. A mixture of cefoperazone sodium and sulbactam sodium powder was obtained.

[0088] The cefoperazone sodium-sulbactam sodium mixture prepared in Example 3 was tested, and the results are shown in Table 3.

[0089] Table 3

[0090] time Properties Moisture (%) acidity Related substances (%) 0 White powder 1.51 5.2 0.21 3 White powder 1.54 5.1 0.23 6 White powder 1.55 5.1 0.23 9 White powder 1.62 5.0 0.29 12 White powder 1.67 5.0 0.31 18 White powder 1.70 5.0 0.31 24 White powder 1.72 4.9 0.31 36 White powder 1.76 4.9 0.33

[0091] Comparative Example 1:

[0092] The cefoperazone sodium / sulbactam sodium composition was prepared by the following method:

[0093] (1) Preparation of chitosan-β-glycerophosphate sodium colloidal solution

[0094] Weigh 50g of dried chitosan powder to constant weight, pass it through a 100-mesh sieve, and dissolve it in a 0.01M acetic acid solution while stirring to obtain an acidic chitosan solution.

[0095] Dissolve 100g of sodium β-glycerophosphate in deionized water to obtain a sodium β-glycerophosphate solution;

[0096] Take an acidic chitosan solution and a sodium β-glycerophosphate solution and mix them. Add sodium dihydrogen phosphate and adjust the pH of the mixed solution to 7.87 to obtain a chitosan-β-glycerophosphate colloidal solution.

[0097] (2) Freeze the colloidal solution to -30°C and hold for 30 min, then raise the temperature to -15°C and hold for 1 h.

[0098] Chitosan-β-glycerophosphate sodium nanospheres were obtained by vacuum drying at 25°C. The particle size of the obtained nanospheres was 80 nm.

[0099] (3) Slowly add 20g of cefoperazone sodium, 10g of sulbactam sodium, and 30g of chitosan-β-glycerophosphate sodium nanospheres to water for injection and stir to dissolve.

[0100] (4) Adjust the pH to 7.1 using disodium hydrogen phosphate, then quickly add magnetic material coated with mesoporous silica Fe3O4 particles to adsorb impurities, filter precisely, and then add dry ice;

[0101] (5) Freeze-drying: First, continuously cool the solution obtained in step (4) to -17℃ and keep it at a constant temperature for 2 hours, then cool it to -45℃ and keep it at that temperature for 2 hours;

[0102] Sublimation drying: Drying was carried out in a vacuum at a pressure of 0.10 mbar. The set temperature was raised to 0°C and maintained for 2 hours; then the set temperature was raised to 30°C and maintained for 5 hours; finally, the temperature was raised to 50°C and maintained for 1.5 hours to complete the drying process. A mixture of cefoperazone sodium and sulbactam sodium powder was obtained.

[0103] The cefoperazone sodium and sulbactam sodium mixture prepared in Comparative Example 1 was tested, and the results are shown in Table 4.

[0104] Table 4

[0105] time Properties Moisture (%) acidity Related substances (%) 0 White powder 2.21 5.1 0.48 3 White powder 2.28 5.0 0.49 6 White powder 2.21 4.9 0.52 9 White powder 2.32 4.9 0.54 12 White powder 2.34 4.8 0.61 18 White powder 2.39 4.6 0.65 24 White powder 2.45 4.6 0.72 36 White powder 2.50 4.5 0.98

[0106] Comparative Example 2:

[0107] The cefoperazone sodium / sulbactam sodium composition was prepared by the following method:

[0108] (1) Preparation of chitosan-sodium tripolyphosphate colloidal solution

[0109] Weigh 50g of dried chitosan powder to constant weight, pass it through a 100-mesh sieve, and dissolve it in a 0.01M acetic acid solution while stirring to obtain an acidic chitosan solution.

[0110] Dissolve 100g of sodium tripolyphosphate in deionized water to obtain a sodium tripolyphosphate solution;

[0111] Take an acidic chitosan solution and a sodium tripolyphosphate solution and mix them. Add sodium dihydrogen phosphate and adjust the pH of the mixed solution to 7.87 to obtain a chitosan-sodium tripolyphosphate colloidal solution.

[0112] (2) Mix 7.55g of dry ice with 5g of sorbitol evenly, then add it to the colloidal solution, freeze to -30℃, keep for 30min, raise the temperature to -15℃, and keep for 1h.

[0113] Chitosan-sodium tripolyphosphate nanospheres were obtained by vacuum drying at 25°C. The particle size of the obtained nanospheres was 80 nm.

[0114] (3) Slowly add 20g of cefoperazone sodium, 10g of sulbactam sodium, and 30g of chitosan-sodium tripolyphosphate nanospheres to water for injection and stir to dissolve.

[0115] (4) Adjust the pH to 7.1 using disodium hydrogen phosphate, then quickly add magnetic material coated with mesoporous silica Fe3O4 particles to adsorb impurities, filter precisely, and then add dry ice;

[0116] (5) Freeze-drying: First, continuously cool the solution obtained in step (4) to -17℃ and keep it at a constant temperature for 2 hours, then cool it to -45℃ and keep it at that temperature for 2 hours;

[0117] Sublimation drying: Drying was carried out in a vacuum at a pressure of 0.10 mbar. The set temperature was raised to 0°C and maintained for 2 hours; then the set temperature was raised to 30°C and maintained for 5 hours; finally, the temperature was raised to 50°C and maintained for 1.5 hours to complete the drying process. A mixture of cefoperazone sodium and sulbactam sodium powder was obtained.

[0118] The cefoperazone sodium and sulbactam sodium mixture prepared in Comparative Example 2 was tested, and the results are shown in Table 5.

[0119] Table 5

[0120]

[0121]

[0122] The above specific embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the preparation of cefoperazone sodium sulbactam sodium composition characterized in that, Includes the following steps: (1) Preparation of chitosan-β-glycerophosphate sodium colloidal solution; (2) Dry ice and sorbitol were mixed evenly, and then added to the colloidal solution. The mixture was frozen, heated, and dried under reduced pressure to obtain chitosan-β-glycerophosphate sodium nanospheres. (3) Slowly add cefoperazone sodium, sulbactam sodium, and chitosan-β-glycerophosphate sodium nanospheres to water for injection and stir to dissolve; (4) Adjust the pH to 7.1-7.5, add adsorbent for adsorption and filtration, and add dry ice; (5) Freeze-dry to obtain cefoperazone sodium and sulbactam sodium mixed powder.

2. A process for the preparation of a cefoperazone sodium sulbactam sodium composition as claimed in claim 1, wherein, The preparation method of the chitosan-β-glycerophosphate sodium colloidal solution is as follows: (1) Take chitosan powder and sieve it. Dissolve it in acetic acid solution while stirring. Stir to obtain an acidic chitosan solution. (2) Dissolve sodium β-glycerophosphate in deionized water to obtain a sodium β-glycerophosphate solution; (3) Mix the acidic chitosan solution with the sodium β-glycerophosphate solution and adjust the pH to 7.87 with sodium dihydrogen phosphate to obtain the chitosan-β-glycerophosphate colloidal solution.

3. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 2, characterized in that, The chitosan powder is passed through a 100-mesh sieve, and the acetic acid solution has a concentration of 0.01M to 0.1M. The weight ratio of sodium β-glycerophosphate to chitosan is (2%–10%):2%.

4. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 1, characterized in that, After adding dry ice in step (2), freeze to a temperature of -30℃ to -20℃ and keep it constant for 30 min to 50 min, then raise the temperature to -15℃ to -12℃ and keep it for 1 to 2 hours.

5. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 1, characterized in that, In step (2), the chitosan-β-glycerophosphate sodium nanospheres were dried under reduced pressure at 25℃~30℃, with a moisture content of less than 2% and a particle size of 50~200nm.

6. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 1, characterized in that, In step (2), the mass ratio of sorbitol to chitosan is (3-8):(30-80).

7. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 1, characterized in that, The mass ratio of cefoperazone sodium to sulbactam sodium is 2:1 or 1:1; The mass ratio of the sum of the masses of cefoperazone sodium and sulbactam sodium to the mass of chitosan-β-glycerophosphate sodium nanospheres is (2-8):(1.5-3.5).

8. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 1, characterized in that, In step (4), disodium hydrogen phosphate is used to adjust the pH. The adsorbent in step (4) is a magnetic material of mesoporous silica coated with Fe3O4 particles.

9. The method for preparing a cefoperazone sodium / sulbactam sodium composition according to claim 1, characterized in that, In step (5), the freeze-drying process is as follows: Freezing: The solution obtained in step (4) is continuously cooled to -17℃ to -15℃ and kept at a constant temperature for 2h to 5h, then cooled to -45℃ to -40℃ and kept at that temperature for 2h to 5h; Sublimation drying: Drying in a vacuum at a pressure of 0.10 mbar to 0.30 mbar, raising the set temperature to -5℃ to 0℃ and maintaining it for 1.5h to 3h; Set the temperature to 30-40℃ and maintain it for 5-10 hours. Heat to 50-55℃ and maintain for 1-1.5 hours to complete the drying process.

10. A cefoperazone sodium / sulbactam sodium composition, obtained by the preparation method according to any one of claims 1 to 9.

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