A pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection and its preparation method

Abstract

The present invention discloses an ampicillin sodium and sulbactam sodium pharmaceutical composition for injection and a preparation method thereof. The preparation method includes Step 1: uniformly mixing ampicillin sodium and sulbactam sodium; Step 2: uniformly mixing water-soluble chitosan microspheres with the mixture obtained in Step 1; Step 3: uniformly mixing sodium carboxymethyl cellulose with the mixture obtained in Step 2. In the present invention, by mixing water-soluble chitosan microspheres with ampicillin sodium and sulbactam sodium, the water-soluble chitosan microspheres can be uniformly dispersed in ampicillin sodium and sulbactam sodium. Then, the added sodium carboxymethyl cellulose forms a hydrogen bond with the water-soluble chitosan microspheres, so that a film is formed on the outside of the water-soluble chitosan microspheres by sodium carboxymethyl cellulose, and ampicillin sodium and sulbactam sodium can be dispersed in the dispersion system formed by sodium carboxymethyl cellulose and water-soluble chitosan microspheres, thereby providing long-term and stable protection for ampicillin sodium and sulbactam sodium.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection. Background Art

[0002] Ampicillin sodium is a β-lactam antibiotic, belonging to the broad-spectrum semi-synthetic penicillins. It can inhibit the synthesis of bacterial cell walls, has a broad-spectrum antibacterial effect, and is applicable to sepsis, upper urinary tract and complicated urinary tract infections, respiratory tract infections, biliary tract infections, abdominal infections, pelvic infections, and skin and soft tissue infections caused by sensitive Enterobacteriaceae bacteria, Pseudomonas aeruginosa, and Acinetobacter spp. It has a wide clinical application.

[0003] It has been found clinically that the β-lactamase produced by bacteria can rupture the β-lactam ring of ampicillin sodium, making ampicillin sodium unstable during use, prone to hydrolysis and inactivation, and unable to fully exert its antibacterial effect, thus affecting the drug efficacy. To solve this problem, the current method is to combine sulbactam sodium with ampicillin sodium. Sulbactam sodium is an irreversible competitive β-lactamase inhibitor, which can irreversibly bind to the β-lactamase produced by Staphylococcus aureus and most Gram-negative bacteria, thereby preventing the β-lactamase from hydrolyzing β-lactam antibiotics and effectively protecting the antibacterial activity of β-lactam antibiotics.

[0004] However, due to the strong hygroscopicity of ampicillin sodium, during both long-term storage and use, the β-lactam ring will be ruptured due to moisture, resulting in quality problems such as a significant decrease in the content of ampicillin sodium and sulbactam sodium and an increase in impurities. At the same time, the β-lactam ring of sulbactam sodium will also be hydrolyzed by water absorption, reducing its protective effect on ampicillin sodium and unable to effectively guarantee the product quality. Summary of the Invention

[0005] To solve the above problems, the purpose of this patent application is to provide a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection and its preparation method, which can provide long-term and stable protection for ampicillin sodium and sulbactam sodium.

[0006] The present invention is achieved through the following technical solutions:

[0007] The first object of the present invention is to provide a preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection, comprising:

[0008] Step 1, uniformly mixing ampicillin sodium and sulbactam sodium;

[0009] Step 2, uniformly mixing water-soluble chitosan microspheres with the mixture obtained in Step 1;

[0010] Step 3: Evenly mix the sodium carboxymethyl cellulose and the mixture obtained in step 2.

[0011] Based on the effect of water on the stability of ampicillin sodium and sulbactam sodium, this patent application utilizes a mixture of water-soluble chitosan microspheres and ampicillin sodium and sulbactam sodium to uniformly disperse the water-soluble chitosan microspheres throughout the ampicillin sodium and sulbactam sodium. The water-soluble chitosan microspheres themselves are hygroscopic, and the subsequently added sodium hydroxymethylcellulose, due to its numerous hydroxyl, ether, and aldehyde groups, can form hydrogen bonds with the water-soluble chitosan microspheres, thereby forming a film around the exterior of the water-soluble chitosan microspheres. Ampicillin sodium and sulbactam sodium can be dispersed within the dispersion formed by sodium hydroxymethylcellulose and the water-soluble chitosan microspheres. Furthermore, sodium hydroxymethylcellulose is also hygroscopic. Consequently, the combined action of the water-soluble chitosan microspheres and sodium hydroxymethylcellulose significantly reduces the destructive effects of moisture on ampicillin sodium and sulbactam sodium, thereby providing long-term, stable protection for ampicillin sodium and sulbactam sodium, ensuring product quality. Since both water-soluble chitosan microspheres and hydroxymethylcellulose sodium are water-soluble, they can be well dissolved in glucose injection during use and can still provide good protection for ampicillin sodium and sulbactam sodium.

[0012] In an optional embodiment, the water-soluble chitosan microspheres are water-soluble carboxylated chitosan microspheres;

[0013] The preparation process of the water-soluble carboxylated chitosan microspheres comprises:

[0014] A certain amount of emulsifier and ionic liquid are mixed and stirred evenly, and then a water-soluble carboxylated chitosan acetic acid aqueous solution is added, stirred, and ultrasonicated to obtain a microemulsion system;

[0015] Add glutaraldehyde to the microemulsion system and stir. After the reaction is completed, chitosan microspheres are obtained.

[0016] Wash with ethanol and dry.

[0017] The present invention uses water-soluble carboxylated chitosan microspheres to increase the hydrogen bonding sites between the chitosan microspheres and sodium hydroxymethyl cellulose, forming a stable structure with the chitosan microspheres inside and the sodium hydroxymethyl cellulose outside, thereby providing long-term and stable protection for ampicillin sodium and sulbactam sodium.

[0018] In an optional embodiment, the emulsifier is a composite emulsifier formed by TX-100 and n-butanol, and the mass ratio of TX-100 to n-butanol is (5-7):1;

[0019] The ionic liquid is 1-butyl-3-methylimidazolium hexafluorophosphate.

[0020] In an alternative embodiment, during the ethanol washing process, an ethanol solution with a mass fraction of 98% is used, and dry ice is added to the ethanol solution.

[0021] In the present invention, an ethanol solution with a mass fraction of 98% is used, and dry ice is dissolved in the solution. The dry ice and a small amount of water in the ethanol solution act together. Since carboxylated chitosan is soluble in water, during the washing process, the volatilization of dry ice will carry away the water dissolved with a small amount of carboxylated chitosan, thereby forming a small amount of microstructures on the surface of the chitosan microspheres. Thus, the surface of the microspheres and these microstructures provide more dispersion sites for the dispersion of sodium ampicillin sulbactam, and the absorption of water is also significantly increased at the absorption positions.

[0022] In an alternative embodiment, the drying process is as follows:

[0023] (1) Add frozen dry ice to the chitosan microspheres washed with ethanol;

[0024] (2) Evacuate the freeze-drying equipment, and the degree of vacuum reaches more than 55%;

[0025] Raise the temperature to 0 °C and maintain for 45 - 60 min;

[0026] Continue to raise the temperature to 40 - 45 °C and maintain for 90 - 120 min;

[0027] Continue to raise the temperature to 65 - 70 °C and maintain for 20 - 30 min;

[0028] (3) Adjust the degree of vacuum of the freeze-drying equipment to 25 - 35%, and adjust the temperature to 55 - 60 °C and maintain for 45 min to complete drying.

[0029] In the present invention, frozen dry ice is added during the drying process of the chitosan microspheres. The drying process is stage drying. By adjusting the degree of vacuum of the freeze-drying equipment and the temperature of stage freeze-drying, the free carbon dioxide carries away the water in the chitosan microspheres to achieve sufficient drying, avoiding the influence of water on sodium ampicillin sulbactam after mixing; at the same time, microstructures are also formed on the surface of the microspheres to fully absorb water during long-term storage and use.

[0030] In an alternative embodiment, the angle of repose of the water-soluble chitosan microspheres is (38.5 ± 0.4) °. The chitosan microspheres have good fluidity and are evenly distributed, and have a better dispersion and flow effect in the sodium ampicillin sulbactam mixture.

[0031] In the prior art, chitosan is used in the pharmaceutical field. For example, in Patent CN 103536561 A, chitosan nanoparticles are used to prepare sulbactam sodium, and chitosan nanoparticles are used as the matrix agent of sulbactam sodium. However, due to the strong adsorption of chitosan nanoparticles, if added to the finished product of ampicillin sodium and sulbactam sodium, it will strongly adsorb ampicillin sodium and sulbactam sodium, resulting in problems with the release of ampicillin sodium and sulbactam sodium during injection. In the present invention, chitosan microspheres are used, and chitosan microspheres with a repose angle of (38.5±0.4)° are selected to better mix chitosan microspheres with ampicillin sodium and sulbactam sodium, so that ampicillin sodium and sulbactam sodium are dispersed in a dispersion system formed by fluid and uniformly distributed chitosan microspheres and sodium carboxymethyl cellulose added later, rather than serving as the matrix of ampicillin sodium and sulbactam sodium.

[0032] In an optional embodiment, the mass ratio of the water-soluble chitosan microspheres to sodium carboxymethyl cellulose is 2:1;

[0033] The mass ratio of ampicillin sodium to sulbactam sodium is 2:1.

[0034] In an optional embodiment, the ampicillin sodium is prepared by the solvent crystallization method. The ampicillin sodium obtained by the solvent crystallization method is crystalline, and its performance is superior to that of amorphous ampicillin sodium.

[0035] In an optional embodiment, it further includes mixing sodium dihydrogen phosphate with the mixture obtained in step three and adjusting the pH to 7.0 - 7.3. Sodium dihydrogen phosphate further acts as a hygroscopic agent to strengthen the protection of ampicillin sodium and sulbactam sodium. Adjusting the pH to 7.0 - 7.3 also ensures the stable existence of water-soluble chitosan microspheres and sodium carboxymethyl cellulose, and can also prevent the degradation of water-soluble chitosan microspheres and sodium carboxymethyl cellulose during long-term storage.

[0036] Another object of the present invention is to provide an ampicillin sodium and sulbactam sodium pharmaceutical composition for injection, which is prepared by using the preparation method described in any one of the above;

[0037] The ampicillin sodium and sulbactam sodium pharmaceutical composition is used by mixing it in zedoary turmeric oil glucose injection.

[0038] Injecting the ampicillin sodium and sulbactam sodium pharmaceutical composition into zedoary turmeric oil glucose injection has better stability.

[0039] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0040] A pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection provided by an embodiment of the present invention is prepared by mixing a mixture of water-soluble chitosan microspheres and ampicillin sodium and sulbactam sodium, which can evenly disperse ampicillin sodium and sulbactam sodium on the water-soluble chitosan microspheres. Then, due to the presence of a large number of hydroxyl groups, ether oxygen groups, and aldehyde groups in the structure of sodium carboxymethyl cellulose added later, hydrogen bonding can be formed with the water-soluble chitosan microspheres, so that sodium carboxymethyl cellulose forms a protective film on the outside of the water-soluble chitosan microspheres. Thus, under the combined action of the water-soluble chitosan microspheres and sodium carboxymethyl cellulose, the destructive effect of water on ampicillin sodium and sulbactam sodium is greatly reduced, thereby forming long-term and stable protection for ampicillin sodium and sulbactam sodium and ensuring the product quality. Since both the water-soluble chitosan microspheres and sodium carboxymethyl cellulose are water-soluble, they can also be well dissolved in glucose injection during use and still provide good protection for ampicillin sodium and sulbactam sodium. Detailed implementation mode

[0041] To make the objectives, technical solutions, and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.

[0042] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is obvious to those of ordinary skill in the art that the present invention does not have to be implemented with these specific details. In other embodiments, well-known methods are not specifically described in order to avoid obscuring the present invention.

[0043] Throughout the specification, references to "one embodiment", "embodiment", "one example", or "example" mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present invention. Thus, the phrases "one embodiment", "embodiment", "one example", or "example" that appear throughout the specification do not necessarily all refer to the same embodiment or example. In addition, specific features, structures, or characteristics may be combined in any suitable combination and / or sub-combination in one or more embodiments or examples.

[0044] In the description of the present invention, the orientation or positional relationship indicated by terms such as "front", "rear", "left", "right", "upper", "lower", "vertical", "horizontal", "high", "low", "inner", "outer", etc. is only for the convenience of describing the present invention and simplifying the description, and does not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be construed as limiting the protection scope of the present invention.

[0045] Example 1:

[0046] The preparation of an ampicillin sodium and sulbactam sodium for injection pharmaceutical composition is obtained by the following process.

[0047] Step 1: Mix 100 g of ampicillin sodium and 50 g of sulbactam sodium evenly to obtain a first mixture.

[0048] Step 2: Mix 20 g of water-soluble chitosan microspheres with the first mixture evenly to obtain a second mixture.

[0049] Step 3: Mix 10 g of sodium carboxymethylcellulose with the second mixture evenly to obtain a third mixture.

[0050] Step 4: Mix 2.5 g of sodium dihydrogen phosphate with the third mixture evenly, and the pH is 7.0.

[0051] The preparation process of the water-soluble chitosan microspheres is as follows:

[0052] Mix 50 g of TX-100, 10 g of n-butanol, and 12 g of 1-butyl-3-methylimidazolium hexafluorophosphate evenly, then dissolve them in an aqueous acetic acid solution of water-soluble carboxymethyl chitosan with a mass fraction of 0.6%. Stir for 10 min under the condition of a constant temperature water bath at 40 °C, and then perform ultrasonic treatment to obtain a microemulsion system; then add glutaraldehyde to the microemulsion system and stir and react fully for 2 h under the condition of a constant temperature water bath at 45 °C. After the cross-linking is completed, chitosan microspheres are obtained.

[0053] Add 5 g of dry ice to 300 ml of an ethanol solution with a mass fraction of 98%. After dissolution, wash the chitosan microspheres multiple times to obtain crude chitosan microspheres.

[0054] Then add frozen dry ice to the crude chitosan microspheres, and then dry the crude chitosan microspheres. Specifically:

[0055] (1) Vacuumize the freeze-drying equipment, and the vacuum degree reaches 60%; heat up to 0 °C and keep it for 45 min; continue to heat up to 42 °C and keep it for 90 min; continue to heat up to 65 °C and keep it for 25 min;

[0056] (3) Adjust the vacuum degree of the freeze-drying equipment to 25% and the temperature to 55 °C and keep it for 45 min to complete the drying.

[0057] The angle of repose of the obtained water-soluble carboxymethyl chitosan microspheres is 38.9°.

[0058] Ampicillin sodium is prepared by the solvent crystallization method. The specific preparation process can adopt the existing technology and will not be elaborated here.

[0059] Example 2:

[0060] The preparation of an ampicillin sodium and sulbactam sodium for injection pharmaceutical composition is obtained by the following process.

[0061] Step 1: Mix 100 g of ampicillin sodium and 50 g of sulbactam sodium evenly to obtain a first mixture.

[0062] Step 2: Mix 25 g of water-soluble chitosan microspheres with the first mixture evenly to obtain a second mixture.

[0063] Step 3: Mix 12.5 g of sodium carboxymethylcellulose with the second mixture evenly to obtain a third mixture.

[0064] Step 4: Mix 4 g of sodium dihydrogen phosphate with the third mixture evenly, and the pH is 7.3.

[0065] The preparation process of the water-soluble chitosan microspheres is as follows:

[0066] Mix 60 g of TX-100, 10 g of n-butanol, and 10 g of 1-butyl-3-methylimidazolium hexafluorophosphate evenly, then dissolve them in an aqueous acetic acid solution of water-soluble carboxymethyl chitosan with a mass fraction of 0.6%. Stir for 20 min under the condition of a constant temperature water bath at 45 °C, and then perform ultrasonic treatment to obtain a microemulsion system; then add glutaraldehyde to the microemulsion system and stir and react fully for 2 h under the condition of a constant temperature water bath at 40 °C. After the cross-linking is completed, chitosan microspheres are obtained.

[0067] Add 8 g of dry ice to 350 ml of an ethanol solution with a mass fraction of 98%. After dissolution, wash the chitosan microspheres multiple times to obtain crude chitosan microspheres.

[0068] Then add frozen dry ice to the crude chitosan microspheres, and then dry the crude chitosan microspheres. Specifically:

[0069] (1) Vacuumize the freeze-drying equipment, and the vacuum degree reaches 55%; heat up to 0 °C and keep it for 60 min; continue to heat up to 45 °C and keep it for 120 min; continue to heat up to 70 °C and keep it for 20 min;

[0070] (3) Adjust the vacuum degree of the freeze-drying equipment to 35% and the temperature to 60 °C and keep it for 45 min to complete the drying.

[0071] The angle of repose of the obtained water-soluble carboxymethyl chitosan microspheres is 38.5°.

[0072] Ampicillin sodium is prepared by the solvent crystallization method. The specific preparation process can adopt the existing technology and will not be elaborated here.

[0073] Example 3:

[0074] The preparation of an ampicillin sodium and sulbactam sodium for injection pharmaceutical composition is obtained by the following process.

[0075] Step 1: Mix 100 g of ampicillin sodium and 50 g of sulbactam sodium evenly to obtain a first mixture.

[0076] Step 2: Mix 22 g of water-soluble chitosan microspheres with the first mixture evenly to obtain a second mixture.

[0077] Step 3: Mix 11 g of sodium carboxymethylcellulose with the second mixture evenly to obtain a third mixture.

[0078] Step 4: Mix 2.8 g of sodium dihydrogen phosphate with the third mixture evenly, and the pH is 7.1.

[0079] The preparation process of the water-soluble chitosan microspheres is as follows:

[0080] Mix 70 g of TX-100, 10 g of n-butanol, and 10 g of 1-butyl-3-methylimidazolium hexafluorophosphate evenly, then dissolve them in an aqueous solution of water-soluble carboxymethyl chitosan acetate with a mass fraction of 0.6%. Stir for 15 min under the condition of a constant temperature water bath at 40 °C, and then perform ultrasonic treatment to obtain a microemulsion system; then add glutaraldehyde to the microemulsion system and stir and react fully for 2 h under the condition of a constant temperature water bath at 43 °C. After the cross-linking is completed, chitosan microspheres are obtained.

[0081] Add 8 g of dry ice to 400 ml of an ethanol solution with a mass fraction of 98%. After dissolution, wash the chitosan microspheres multiple times to obtain crude chitosan microspheres.

[0082] Then add frozen dry ice to the crude chitosan microspheres, and then dry the crude chitosan microspheres. Specifically:

[0083] (1) Vacuumize the freeze-drying equipment until the vacuum degree reaches 65%; heat up to 0 °C and maintain for 45 min; continue to heat up to 45 °C and maintain for 100 min; continue to heat up to 65 °C and maintain for 20 min;

[0084] (3) Adjust the vacuum degree of the freeze-drying equipment to 30% and the temperature to 55 °C and maintain for 45 min to complete the drying.

[0085] The angle of repose of the obtained water-soluble carboxymethyl chitosan microspheres is 38.3°.

[0086] Ampicillin sodium is prepared by the solvent crystallization method. The specific preparation process can adopt the existing technology and will not be elaborated here.

[0087] Comparative Example 1:

[0088] It is different from Example 1 in that sodium carboxymethyl cellulose is not added, and the rest are the same.

[0089] Comparative Example 2:

[0090] It is different from Example 1 in that water-soluble chitosan microspheres are not added, and the rest are the same.

[0091] Comparative Example 3:

[0092] It is different from Example 1 in that when preparing water-soluble carboxylated chitosan microspheres, absolute ethanol is used for ethanol washing and dry ice is not added.

[0093] Comparative Example 4:

[0094] It is different from Example 1 in that when preparing water-soluble carboxylated chitosan microspheres, the final drying treatment is a conventional vacuum drying treatment.

[0095] Comparative Example 5:

[0096] It is different from Example 1 in that when preparing water-soluble carboxylated chitosan microspheres, the final drying treatment adopts the following process:

[0097] (1) Add frozen dry ice to the chitosan microspheres washed with ethanol;

[0098] (2) Vacuumize the freeze-drying equipment until the vacuum degree reaches more than 60%; heat up to 42 °C and maintain for 90 min.

[0099] The ampicillin sodium sulbactam drug compositions obtained in each example and comparative example were detected, and the results are shown in Table 1 below:

[0100] Table 1

[0101]

[0102]

[0103] As can be seen from Table 1 above, the ampicillin sodium sulbactam prepared by the method of the present invention has good drug stability. After storage for 12 months, the content of ampicillin sodium is still at a relatively high level, above 99.0%, the content of sulbactam sodium is also above 99.0%, the water content is always at a low level, the content of ampicillin dimer is also very low, and the content of related impurities is also at a low level, below 1.5%.

[0104] For Comparative Examples 1 and 2, since sodium carboxymethyl cellulose and water-soluble chitosan microspheres were not added, the contents of sodium ampicillin and sulbactam sodium were relatively lower than those in the Examples. Especially after storage for 12 months, the reduction in content was relatively large, the moisture and impurities increased significantly, and the clarity was significantly inferior to that of each Example, indicating poor stability. It can be seen that sodium carboxymethyl cellulose and water-soluble chitosan microspheres play a crucial role in the product stability and are both indispensable.

[0105] For Examples 3, 4, and 5, since sodium carboxymethyl cellulose and water-soluble chitosan microspheres were added, after storage for 12 months, the reduction in content was less than that in Comparative Examples 1 and 2, and the contents of moisture and impurities were also less than those in Comparative Examples 1 and 2. However, the overall product stability of Comparative Examples 3, 4, and 5 was not as good as that of each Example.

[0106] When the sodium ampicillin and sulbactam sodium pharmaceutical composition obtained in the Examples of the present invention is used, it is preferably mixed with zedoary turmeric oil glucose injection, which is more beneficial to the stability of the product.

[0107] The above specific embodiments further elaborate on the purpose, technical solutions, and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A preparation method of ampicillin sodium and sulbactam sodium for injection, characterized in that, Comprising: Step 1: Mix ampicillin sodium and sulbactam sodium evenly. Step 2: Mix the water-soluble chitosan microspheres with the mixture obtained in Step 1 evenly. Step 3: Mix sodium carboxymethyl cellulose with the mixture obtained in Step 2 evenly.

2. The preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection according to claim 1, characterized in that, The water-soluble chitosan microspheres are water-soluble carboxylated chitosan microspheres. The preparation process of the water-soluble carboxylated chitosan microspheres includes: Mix a certain amount of emulsifier and ionic liquid evenly by stirring, then add an aqueous solution of water-soluble carboxylated chitosan acetate, stir and ultrasonicate to obtain a microemulsion system. Add glutaraldehyde to the microemulsion system, stir, and chitosan microspheres are obtained after the reaction ends. Wash with ethanol and perform drying treatment.

3. The preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection according to claim 2, characterized in that, The emulsifier is a composite emulsifier formed by TX-100 and n-butanol, and the mass ratio of TX-100 to n-butanol is (5-7):

1. The ionic liquid is 1-butyl-3-methylimidazolium hexafluorophosphate. The mass ratio of the emulsifier to the ionic liquid is (5-8):

1.

4. The preparation method of an ampicillin sodium and sulbactam sodium pharmaceutical composition for injection according to claim 2, characterized in that, During the ethanol washing process, an ethanol solution with a mass fraction of 98% is used, and dry ice is added to the ethanol solution.

5. The preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection according to claim 2, characterized in that, The drying treatment process is as follows: (1) Add frozen dry ice to the chitosan microspheres washed with ethanol. (2) Vacuumize the freeze-drying equipment, and the vacuum degree reaches more than 55%. Raise the temperature to 0 °C and maintain for 45-60 min. Continue to raise the temperature to 40-45 °C and maintain for 90-120 min. Continue to raise the temperature to 65-70 °C and maintain for 20-30 min. (3) Adjust the vacuum degree of the freeze-drying equipment to 25-35%, and adjust the temperature to 55-60 °C and maintain for 45 min to complete drying.

6. The preparation method of an ampicillin sodium and sulbactam sodium pharmaceutical composition for injection according to claim 5, wherein, The angle of repose of the water-soluble chitosan microspheres is (38.5±0.4)°.

7. The preparation method of an ampicillin sodium and sulbactam sodium pharmaceutical composition for injection according to claim 2, characterized in that, The mass ratio of the water-soluble chitosan microspheres to sodium carboxymethyl cellulose is 2:

1. The mass ratio of ampicillin sodium to sulbactam sodium is 2:

1.

8. The preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection according to claim 1, characterized in that, The ampicillin sodium is prepared by the solvent crystallization method.

9. The preparation method of a pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection according to claim 1, characterized in that, It also includes mixing sodium dihydrogen phosphate with the mixture obtained in Step 3 and adjusting the pH to 7.0-7.

3.

10. A pharmaceutical composition of ampicillin sodium and sulbactam sodium for injection, characterized in that, Prepared by the preparation method according to any one of claims 1-9. The ampicillin sodium and sulbactam sodium pharmaceutical composition is used by mixing it in zedoary turmeric oil glucose injection.

Images