Imipenem cilastatin sodium injection preparation and preparation method thereof

Abstract

The invention discloses an imipenem and cilastatin sodium injection preparation and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, and the preparation method comprises the following steps: dissolving imipenem and cilastatin sodium in a buffer solution, and adding serine and tea polyphenol to completely dissolve the imipenem and cilastatin sodium to obtain an imipenem and cilastatin sodium mixed solution; the preparation method comprises the following steps: mixing hydroxyethyl methyl cellulose, glutaric anhydride, 4-dimethylaminopyridine and an ethanol solution, and reacting to obtain a solution A; mixing phenylalanine, glycine, sorbitan fatty acid ester and nano calcium carbonate, and reacting to obtain a solution B; mixing the solution A and the solution B, adding the mixed solution into an imipenem and cilastatin sodium mixed solution, uniformly stirring and mixing, cooling and crystallizing, filtering to obtain imipenem and cilastatin sodium, and freezing and drying to obtain the imipenem and cilastatin sodium injection preparation. The imipenem and cilastatin sodium injection preparation prepared by the preparation method is high in stability, purity and bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to an imipenem cilastatin sodium injection preparation and a preparation method thereof. Background Art

[0002] Imipenem cilastatin sodium for injection is a very broad-spectrum antibiotic, applicable to mixed infections caused by a variety of pathogens and aerobic / anaerobic bacteria, comprehensively treating various moderate and severe infections; and early treatment before the pathogen is determined. Imipenem cilastatin sodium for injection is a compound preparation, and its components are imipenem and cilastatin sodium. Imipenem is a novel β-lactam antibiotic thienamycin; cilastatin sodium is a specific enzyme inhibitor, which can block the metabolism of imipenem in the kidney, thereby increasing the concentration of the original drug of imipenem in the urinary tract. Imipenem belongs to the thienamycin class of antibiotics, and its bactericidal spectrum is wider than that of any other studied antibiotics.

[0003] Imipenem: (+)-(5R,6S)-3[[2-(iminomethylamino)ethyl]thio]-6-[(R)-1-cyanoethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate. Imipenem is the first stable thienamycin derivative and is a new β-lactam antibiotic. It shows broad-spectrum and high-efficiency antibacterial activity by specifically inhibiting the synthesis of bacterial cell wall peptidoglycan, and has an effect on both Gram-positive and negative bacteria, including anaerobic bacteria. In particular, its antibacterial activity against Staphylococcus aureus, Streptococcus faecalis, Pseudomonas aeruginosa, and Bacteroides fragilis is better than that of third-generation cephalosporene drugs such as cefoperazone.

[0004] Cilastatin sodium: (+)-(Z)-7-[[(R)-2-amino-2-carboxyethyl]thio]-2-[(S)-2,2-dimethylcyclopropanecarboxamido]-2-heptenoic acid sodium salt. Imipenem is stable to β-lactamase, but when used alone, it can be metabolized and inactivated by renal dehydropeptidase I. When used in combination with the inhibitor of this enzyme, cilastatin, cilastatin blocks the action of dehydropeptidase I on the antibiotic, thereby blocking the metabolism of imipenem in the kidney, increasing the concentration of imipenem in the urinary tract, and at the same time reducing the nephrotoxicity of imipenem.

[0005] During the research and development process, the inventors found that the current imipenem cilastatin sodium injection preparation still has the problems of low drug stability during storage, resulting in easy degradation of the drug and a short shelf life. Summary of the Invention

[0006] Based on the problems that the currently prepared imipenem and cilastatin sodium injection preparations usually have low drug stability during storage, resulting in easy degradation of the drug and a short shelf life, the purpose of the present invention is to provide an imipenem and cilastatin sodium injection preparation and its preparation method. The imipenem and cilastatin sodium injection preparation prepared by the preparation method of the present invention has high stability, extends the shelf life of the drug, and improves the quality of the drug.

[0007] The present invention is achieved through the following technical solutions:

[0008] In the first aspect, the present application provides a preparation method for an imipenem and cilastatin sodium injection preparation, comprising the following steps:

[0009] Dissolve imipenem and cilastatin sodium in a buffer solution, and add serine and tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution;

[0010] Mix hydroxyethyl methylcellulose, glutaric anhydride, 4-dimethylaminopyridine, and an ethanol solution and react them to obtain solution A;

[0011] Mix phenylalanine, glycine, sorbitan fatty acid ester, and nano calcium carbonate and react them to obtain solution B;

[0012] After mixing solution A and solution B, add them to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, then cool down to crystallize, and then filter to obtain imipenem and cilastatin sodium, and then perform freezing and drying to obtain an imipenem and cilastatin sodium injection preparation.

[0013] When the present invention prepares the imipenem and cilastatin sodium mixed solution, on the one hand, both the added serine and tea polyphenols contain hydroxyl groups, which can replace the hydrogen bonds in the solution to provide a stabilizing effect. On the other hand, the hydroxyl groups in tea polyphenols and the carboxyl groups in serine will also undergo an acylation reaction to form cross-linking points, causing serine to form a network structure. The formation of this cross-linked network structure can generate a certain mechanical strength to protect the imipenem and cilastatin sodium during the freezing process, avoid the influence of low temperature on the drug properties of imipenem and cilastatin sodium, and improve the quality of the prepared imipenem and cilastatin sodium preparation.

[0014] In solution A of the present invention, the molecular weight of hydroxyethyl methylcellulose contains hydroxyl groups. When glutaric anhydride reacts with the hydroxyl groups on hydroxyethyl methylcellulose, the carbon-oxygen double bond will break, the acid anhydride ring will open, and the hydrogen atom on the hydroxyl group will combine with an oxygen atom formed after the acid anhydride breaks to generate water. At the same time, the group where the hydroxyl group is located is connected to the carbonyl carbon atom of the acid anhydride, thereby realizing the acylation reaction. Under the catalysis of 4-dimethylaminopyridine, the hydroxyl groups on hydroxyethyl methylcellulose further undergo a nucleophilic substitution reaction with the formed acyl group to form new ester bonds, so that the hydroxyethyl methylcellulose after the reaction has ester bonds. The hydroxyethyl methylcellulose with ester bonds can not only improve the biological activity of imipenem cilastatin sodium, but also improve the solubility of the imipenem cilastatin sodium preparation, avoid precipitation during use, and is also conducive to the absorption and distribution of imipenem cilastatin sodium in the body.

[0015] In addition, the amino group in phenylalanine in solution B can undergo a condensation reaction with the carboxyl group in glycine to form an amide bond. Under the emulsifying action of sorbitan fatty acid ester, the viscosity of the system is enhanced to obtain a colloid rich in pores, and nano-calcium carbonate is adsorbed through this colloid. After the hydroxyethyl methylcellulose with ester bonds formed in solution A is mixed with the colloid solution containing nano-calcium carbonate formed in solution B, a protective film with encapsulation ability can be formed. This protective film can tightly wrap imipenem cilastatin sodium to form a stable outer shell structure, effectively isolating the damage to drug molecules during ice crystal formation, improving the stability and bioavailability of the drug, and prolonging the shelf life of the imipenem cilastatin sodium injection preparation.

[0016] In a specific embodiment, the mass ratio of the hydroxyethyl methylcellulose, glutaric anhydride, and 4-dimethylaminopyridine is (3-5):(4-5):(1-1.2).

[0017] In a specific embodiment, the mass ratio of the phenylalanine, glycine, sorbitan fatty acid ester, and nano-calcium carbonate is (1.2-1.4):(1.4-1.6):(0.5-0.7):(0.2-0.3).

[0018] In a specific embodiment, the buffer solution includes a phosphoric acid-potassium hydrogen phosphate buffer solution.

[0019] In a specific embodiment, the mass ratio of the imipenem to the cilastatin sodium is 1:1.

[0020] In a specific embodiment, the dosage ratio of the serine to the tea polyphenols is (8-10):(3-5).

[0021] In a specific embodiment, filtration is sequentially carried out using 0.45 μm and 0.22 μm microporous membranes.

[0022] In a specific embodiment, the freezing process includes the following steps:

[0023] 1) First, cool down to -30°C to -25°C and freeze for 50 min to 60 min;

[0024] 2) Cool down to -45°C to -50°C and freeze for 25 min to 30 min;

[0025] 3) Heat up to -35°C to -30°C for annealing treatment for 40 min to 45 min;

[0026] 4) Then cool down to -55°C to -50°C and freeze for 25 min to 30 min.

[0027] In a specific embodiment, the drying process includes the following steps:

[0028] 1) The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First, heat up to 0 to 10°C and hold for 45 to 60 min, and then heat up to 45 to 50°C and hold for 4 to 5 h to complete the first drying;

[0029] 2) Adjust the vacuum degree of the freeze-drying equipment to 35 to 40%, heat up the temperature to 60 to 65°C and hold for 45 to 60 min to complete the second drying;

[0030] 3) Adjust the vacuum degree of the freeze-drying equipment to 25 to 30%, adjust the temperature to 40 to 45°C and hold for 1 to 1.5 h to complete the drying.

[0031] In the second aspect, the present application provides an imipenem and cilastatin sodium injection preparation, which is prepared by the above preparation method.

[0032] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0033] (1) When preparing the imipenem and cilastatin sodium mixed solution, on the one hand, both serine and tea polyphenols added contain hydroxyl groups, which can replace the hydrogen bonds in the solution to provide a stabilizing effect. On the other hand, the hydroxyl group in tea polyphenols and the carboxyl group in serine will also undergo an acylation reaction to generate cross-linking points, causing serine to form a network structure. The formation of this cross-linked network structure can generate a certain mechanical strength to protect the imipenem and cilastatin sodium during the freezing process, avoid the influence of low temperature on the drug properties of imipenem and cilastatin sodium, and improve the quality of the prepared imipenem and cilastatin sodium preparation.

[0034] (2) In the solution A of the present invention, the molecular weight of hydroxyethyl methylcellulose contains hydroxyl groups. When glutaric anhydride reacts with the hydroxyl groups on hydroxyethyl methylcellulose, the carbon-oxygen double bond will break, the acid anhydride ring opens, and the hydrogen atom on the hydroxyl group combines with an oxygen atom formed after the acid anhydride breaks to generate water. At the same time, the group where the hydroxyl group is located is connected to the carbonyl carbon atom of the acid anhydride, thereby realizing the acylation reaction. Under the catalytic action of 4-dimethylaminopyridine, the hydroxyl groups on hydroxyethyl methylcellulose further undergo a nucleophilic substitution reaction with the formed acyl group to form new ester bonds, so that the hydroxyethyl methylcellulose after the reaction has ester bonds. The hydroxyethyl methylcellulose with ester bonds can not only improve the biological activity of imipenem cilastatin sodium, but also improve the solubility of the imipenem cilastatin sodium preparation, avoid precipitation during use, and is also conducive to the absorption and distribution of imipenem cilastatin sodium in the body.

[0035] (3) After the hydroxyethyl methylcellulose with ester bonds formed in the solution A of the present invention is mixed with the colloidal solution containing nano-calcium carbonate formed in the solution B, a protective film with encapsulation ability can be formed. This protective film can tightly wrap imipenem cilastatin sodium to form a stable outer shell structure, effectively isolating the damage to drug molecules during ice crystal formation, improving the stability and bioavailability of the drug, and extending the shelf life of the imipenem cilastatin sodium injection preparation. Detailed implementation mode

[0036] To make the purpose, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in combination with embodiments. The illustrative embodiments of the present invention and their descriptions are only used to explain the present invention and are not used as a limitation to the present invention.

[0037] 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: these specific details do not have to be adopted to implement the present invention. In other embodiments, well-known materials or methods are not specifically described in order to avoid confusing the present invention.

[0038] Throughout the specification, references to "an embodiment", "embodiments", "an example" or "examples" 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 "an embodiment", "embodiments", "an example" or "examples" that appear throughout the specification do not necessarily all refer to the same embodiment or example. Additionally, the particular features, structures, or characteristics may be combined in any suitable combination and / or sub-combination in one or more embodiments or examples. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. Further, without contradiction, those skilled in the art are able to combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0039] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundary of a particular range. The ranges defined in this way can include the end values or not include the end values, and can be combined arbitrarily, that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60 to 120 and 80 to 110 are listed for a particular parameter, ranges of 60 to 110 and 80 to 120 are also contemplated. Additionally, if the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, then the following ranges are all contemplated: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, and 2 to 5. In this application, unless otherwise specified, the numerical range "a to b" represents an abbreviated representation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0 to 5" means that all real numbers between "0 to 5" have been fully listed herein, and "0 to 5" is only an abbreviated representation of these numerical combinations. Additionally, when stating that a certain parameter is an integer ≥2, it is equivalent to disclosing that the parameter is, for example, the integers 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0040] If there is no special instruction, all steps of this application can be carried out in sequence or randomly, and preferably in sequence. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) carried out in sequence, or may also include steps (b) and (a) carried out in sequence. For example, it is mentioned that the method may further include step (c), which means that step (c) can be added to the method in any order. For example, the method may include steps (a), (b), and (c), or may also include steps (a), (c), and (b), or may also include steps (c), (a), and (b), etc.

[0041] Embodiment 1

[0042] This embodiment provides a preparation method of imipenem and cilastatin sodium injection preparation, which is carried out according to the following steps:

[0043] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate - dipotassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0044] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4 - dimethylaminopyridine, and 50 ml of 50% ethanol solution and react them to obtain solution A.

[0045] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano - calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain solution B.

[0046] S4. After mixing solution A and solution B, add them to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, and then crystallize at a temperature of - 20°C.

[0047] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0048] S6. Fill the imipenem and cilastatin sodium prepared in step S5 at a temperature of 3°C.

[0049] S7. Carry out freezing treatment on the filled imipenem and cilastatin sodium:

[0050] S7 - 1. First cool down to - 30°C and freeze for 60 min;

[0051] S7 - 2. Cool down to - 50°C and freeze for 25 min;

[0052] S7 - 3. Heat up to - 35°C and carry out annealing treatment for 40 min;

[0053] S7 - 4. Then cool down to - 55°C and freeze for 25 min.

[0054] S8. Carry out drying treatment on the imipenem and cilastatin sodium after freezing treatment:

[0055] S8 - 1. The freeze - drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5°C and maintain for 50 min, and then heat up to 45°C and maintain for 4 h to complete the first drying;

[0056] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, raise the temperature to 60 °C and hold for 45 min to complete secondary drying;

[0057] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40 °C and hold for 1 h to complete drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0058] Example 2

[0059] This example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, the dosage ratio of serine to tea polyphenols in this example is 8:3, and other processes are the same as those in Example 1. The steps are as follows:

[0060] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphoric acid-dipotassium hydrogen phosphate buffer solution, and add 8 mg of serine and 3 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0061] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain Solution A.

[0062] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0063] S4. After mixing Solution A and Solution B, add them to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, and crystallize at a temperature of -20 °C.

[0064] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0065] S6. Fill the imipenem and cilastatin sodium prepared in step S5 at a temperature of 3 °C.

[0066] S7. Perform freezing treatment on the filled imipenem and cilastatin sodium:

[0067] S7-1. First cool down to -30 °C and freeze for 60 min;

[0068] S7-2. Cool down to -50 °C and freeze for 25 min;

[0069] S7-3. Raise the temperature to -35 °C for annealing treatment for 40 min;

[0070] S7-4. Cool the temperature to -55°C and freeze for 25 min.

[0071] S8. Dry the imipenem cilastatin sodium after the freezing treatment:

[0072] S8-1. Evacuate the freeze-drying equipment until the vacuum degree reaches more than 50%. First, raise the temperature to 5°C and hold for 50 min, then raise the temperature to 45°C and hold for 4 h to complete one drying.

[0073] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, raise the temperature to 60°C and hold for 45 min to complete the secondary drying.

[0074] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and hold for 1 h to complete the drying, and obtain the imipenem cilastatin sodium injection preparation.

[0075] Example 3

[0076] This example provides a preparation method of an imipenem cilastatin sodium injection preparation. Different from Example 1, in this example, the dosage ratio of serine to tea polyphenols is 2:1, and other processes are the same as those in Example 1. It is carried out according to the following steps:

[0077] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphoric acid-dipotassium hydrogen phosphate buffer solution, and add 10 mg of serine and 5 mg of tea polyphenols to completely dissolve them to obtain an imipenem cilastatin sodium mixed solution.

[0078] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain Solution A.

[0079] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano-calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0080] S4. After mixing Solution A and Solution B, add them to the imipenem cilastatin sodium mixed solution, stir and mix evenly, and crystallize at a temperature of -20°C.

[0081] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem cilastatin sodium.

[0082] S6. Fill the imipenem cilastatin sodium prepared in step S5 at a temperature of 3°C.

[0083] S7. Freeze the imipenem and cilastatin sodium after filling:

[0084] S7-1. First cool down to -30°C and freeze for 60 min;

[0085] S7-2. Cool down to -50°C and freeze for 25 min;

[0086] S7-3. Heat up to -35°C and perform annealing treatment for 40 min;

[0087] S7-4. Then cool down to -55°C and freeze for 25 min.

[0088] S8. Dry the imipenem and cilastatin sodium after freezing treatment:

[0089] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5°C and hold for 50 min, then heat up to 45°C and hold for 4 h to complete the first drying;

[0090] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and hold for 45 min to complete the second drying;

[0091] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and hold for 1 h to complete the drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0092] Example 4

[0093] This example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, in this example, the mass ratio of hydroxyethyl methylcellulose, glutaric anhydride, and 4-dimethylaminopyridine is 3:4:1, and it is carried out according to the following steps:

[0094] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate-potassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0095] S2. Mix 3 mg of hydroxyethyl methylcellulose, 4 mg of glutaric anhydride, 1 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain Solution A.

[0096] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano-calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0097] S4. Mix solution A and solution B and then add them to the imipenem and cilastatin sodium mixed solution. After stirring and mixing evenly, crystallize at a temperature of -20°C.

[0098] S5. Filter successively with 0.45μm and 0.22μm microporous membranes to obtain imipenem and cilastatin sodium.

[0099] S6. Fill the imipenem and cilastatin sodium prepared in step S5 at a temperature of 3°C.

[0100] S7. Perform freezing treatment on the filled imipenem and cilastatin sodium:

[0101] S7-1. First cool down to -30°C and freeze for 60 min;

[0102] S7-2. Cool down to -50°C and freeze for 25 min;

[0103] S7-3. Heat up to -35°C and perform annealing treatment for 40 min;

[0104] S7-4. Then cool down to -55°C and freeze for 25 min.

[0105] S8. Perform drying treatment on the imipenem and cilastatin sodium after freezing treatment:

[0106] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5°C and keep for 50 min, then heat up to 45°C and keep for 4 h to complete one drying;

[0107] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and keep for 45 min to complete the secondary drying;

[0108] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and keep for 1 h to complete the drying and obtain the imipenem and cilastatin sodium injection preparation.

[0109] Example 5

[0110] This example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, in this example, the mass ratio of hydroxyethyl methyl cellulose, glutaric anhydride, and 4-dimethylaminopyridine is 5:5:1.2, and it is carried out according to the following steps:

[0111] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate-potassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0112] S2. Mix 5 mg of hydroxyethyl methylcellulose, 5 mg of glutaric anhydride, 1.2 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react them to obtain Solution A.

[0113] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano-calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0114] S4. After mixing Solution A and Solution B, add them to the imipenem cilastatin sodium mixed solution, stir and mix evenly, and then crystallize at a temperature of -20°C.

[0115] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem cilastatin sodium.

[0116] S6. Fill the imipenem cilastatin sodium prepared in Step S5 at a temperature of 3°C.

[0117] S7. Freeze the filled imipenem cilastatin sodium:

[0118] S7-1. First cool down to -30°C and freeze for 60 min;

[0119] S7-2. Cool down to -50°C and freeze for 25 min;

[0120] S7-3. Heat up to -35°C and perform annealing treatment for 40 min;

[0121] S7-4. Then cool down to -55°C and freeze for 25 min.

[0122] S8. Dry the imipenem cilastatin sodium after freezing treatment:

[0123] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5°C and hold for 50 min, then heat up to 45°C and hold for 4 h to complete the first drying;

[0124] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and hold for 45 min to complete the second drying;

[0125] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and hold for 1 h to complete the drying and obtain the imipenem cilastatin sodium injection preparation.

[0126] Example 6

[0127] This example provides a method for preparing an imipenem and cilastatin sodium injection preparation. Different from Example 1, in this example, the mass ratio of phenylalanine, glycine, sorbitan fatty acid ester, and nano-calcium carbonate is 1.2:1.4:0.5:0.2, and the following steps are carried out:

[0128] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of a phosphoric acid-potassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0129] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of a 50% ethanol solution and react them to obtain Solution A.

[0130] S3. Add 1.2 mg of phenylalanine, 1.4 mg of glycine, 0.5 mg of sorbitan fatty acid ester, and 0.2 mg of nano-calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0131] S4. After mixing Solution A and Solution B, add them to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, and then crystallize at a temperature of -20 °C.

[0132] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0133] S6. Fill the imipenem and cilastatin sodium prepared in step S5 at a temperature of 3 °C.

[0134] S7. Perform a freezing treatment on the filled imipenem and cilastatin sodium:

[0135] S7-1. First cool down to -30 °C and freeze for 60 min;

[0136] S7-2. Cool down to -50 °C and freeze for 25 min;

[0137] S7-3. Heat up to -35 °C and perform an annealing treatment for 40 min;

[0138] S7-4. Then cool down to -55 °C and freeze for 25 min.

[0139] S8. Perform a drying treatment on the imipenem and cilastatin sodium after the freezing treatment:

[0140] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5 °C and maintain for 50 min, and then heat up to 45 °C and maintain for 4 h to complete the first drying;

[0141] S8 - 2. Adjust the vacuum degree of the freeze - drying equipment to 35%, raise the temperature to 60 °C and maintain for 45 min to complete the secondary drying.

[0142] S8 - 3. Adjust the vacuum degree of the freeze - drying equipment to 25%, adjust the temperature to 40 °C and maintain for 1 h to complete the drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0143] Example 7

[0144] This example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, in this example, the mass ratio of phenylalanine, glycine, sorbitan fatty acid ester, and nano - calcium carbonate is 1.4:1.6:0.7:0.3, and the steps are as follows:

[0145] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate - dipotassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0146] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4 - dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain Solution A.

[0147] S3. Add 1.4 mg of phenylalanine, 1.6 mg of glycine, 0.7 mg of sorbitan fatty acid ester, and 0.3 mg of nano - calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0148] S4. After mixing Solution A and Solution B, add them to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, and crystallize at a temperature of - 20 °C.

[0149] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0150] S6. Fill the imipenem and cilastatin sodium prepared in step S5 at a temperature of 3 °C.

[0151] S7. Conduct a freezing treatment on the filled imipenem and cilastatin sodium:

[0152] S7 - 1. First cool down to - 30 °C and freeze for 60 min;

[0153] S7 - 2. Cool down to - 50 °C and freeze for 25 min;

[0154] S7 - 3. Raise the temperature to - 35 °C for annealing treatment for 40 min;

[0155] S7-4. Cool down the temperature to -55°C and freeze for 25 min.

[0156] S8. Dry the imipenem cilastatin sodium after freezing treatment:

[0157] S8-1. Evacuate the freeze-drying equipment until the vacuum degree reaches more than 50%. First, heat up to 5°C and hold for 50 min, then heat up to 45°C and hold for 4 h to complete one drying.

[0158] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and hold for 45 min to complete the secondary drying.

[0159] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and hold for 1 h to complete the drying, and obtain the imipenem cilastatin sodium injection preparation.

[0160] Comparative Example 1

[0161] This comparative example provides a preparation method of an imipenem cilastatin sodium injection preparation. Different from Example 1, in step S1 of this comparative example, serine and tea polyphenols are not added, and other processes are the same as those in Example 1. It is carried out according to the following steps:

[0162] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate-potassium hydrogen phosphate buffer solution to make it completely dissolve, and obtain an imipenem cilastatin sodium mixed solution.

[0163] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain solution A.

[0164] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano-calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain solution B.

[0165] S4. After mixing solution A and solution B, add them to the imipenem cilastatin sodium mixed solution, stir and mix evenly, and crystallize at a temperature of -20°C.

[0166] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem cilastatin sodium.

[0167] S6. Fill the imipenem cilastatin sodium prepared in step S5 at a temperature of 3°C.

[0168] S7. Freeze the imipenem and cilastatin sodium after filling:

[0169] S7-1. First cool down to -30°C and freeze for 60 min;

[0170] S7-2. Cool down to -50°C and freeze for 25 min;

[0171] S7-3. Heat up to -35°C and perform annealing treatment for 40 min;

[0172] S7-4. Then cool down to -55°C and freeze for 25 min.

[0173] S8. Dry the imipenem and cilastatin sodium after freezing treatment:

[0174] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First, heat up to 5°C and maintain for 50 min, then heat up to 45°C and maintain for 4 h to complete the first drying;

[0175] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and maintain for 45 min to complete the second drying;

[0176] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and maintain for 1 h to complete the drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0177] Comparative Example 2

[0178] This comparative example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, this comparative example does not include step S3, and other processes are the same as those in Example 1. It is carried out according to the following steps:

[0179] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate-potassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0180] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain solution A.

[0181] S3. Add solution A to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, and crystallize at -20°C.

[0182] S4. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0183] S5. Fill the imipenem and cilastatin sodium prepared in step S4 at a temperature of 3°C.

[0184] S6. Freeze the filled imipenem and cilastatin sodium:

[0185] S6-1. First, cool down to -30°C and freeze for 60 min;

[0186] S6-2. Cool down to -50°C and freeze for 25 min;

[0187] S6-3. Heat up to -35°C and perform annealing treatment for 40 min;

[0188] S6-4. Then cool down to -55°C and freeze for 25 min.

[0189] S7. Dry the imipenem and cilastatin sodium after freezing treatment:

[0190] S7-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First, heat up to 5°C and hold for 50 min, then heat up to 45°C and hold for 4 h to complete the first drying;

[0191] S7-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and hold for 45 min to complete the second drying;

[0192] S7-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and hold for 1 h to complete the drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0193] Comparative Example 3

[0194] This comparative example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, this comparative example does not include step S2. The steps are as follows:

[0195] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate-potassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0196] S2. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain solution B.

[0197] S3. Add solution B to the imipenem and cilastatin sodium mixed solution, stir and mix evenly, and then crystallize at a temperature of -20°C.

[0198] S4. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0199] S5. Fill the imipenem and cilastatin sodium prepared in step S4 at a temperature of 3°C.

[0200] S6. Freeze the filled imipenem and cilastatin sodium:

[0201] S6-1. First cool down to -30°C and freeze for 60 min;

[0202] S6-2. Cool down to -50°C and freeze for 25 min;

[0203] S6-3. Heat up to -35°C for annealing treatment for 40 min;

[0204] S6-4. Then cool down to -55°C and freeze for 25 min.

[0205] S7. Dry the imipenem and cilastatin sodium after freezing treatment:

[0206] S7-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5°C and hold for 50 min, then heat up to 45°C and hold for 4 h to complete the first drying;

[0207] S7-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60°C and hold for 45 min to complete the second drying;

[0208] S7-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40°C and hold for 1 h to complete the drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0209] Comparative Example 4

[0210] This comparative example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, in step S1 of this comparative example, it does not contain tea polyphenols, and other processes are the same as those in Example 1, and it is carried out according to the following steps:

[0211] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate-potassium hydrogen phosphate buffer solution, and add 9 mg of serine to completely dissolve it to obtain an imipenem and cilastatin sodium mixed solution.

[0212] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of 50% ethanol solution and react to obtain solution A.

[0213] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano calcium carbonate into 50 ml of pure water, stir and mix evenly, and then react to obtain Solution B.

[0214] S4. After mixing Solution A and Solution B, add them into the imipenem cilastatin sodium mixed solution, stir and mix evenly, and then crystallize at a temperature of -20 °C.

[0215] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem cilastatin sodium.

[0216] S6. Fill the imipenem cilastatin sodium prepared in Step S5 at a temperature of 3 °C.

[0217] S7. Perform freezing treatment on the filled imipenem cilastatin sodium:

[0218] S7-1. First, cool down to -30 °C and freeze for 60 min;

[0219] S7-2. Cool down to -50 °C and freeze for 25 min;

[0220] S7-3. Heat up to -35 °C and perform annealing treatment for 40 min;

[0221] S7-4. Then cool down to -55 °C and freeze for 25 min.

[0222] S8. Perform drying treatment on the imipenem cilastatin sodium after freezing treatment:

[0223] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First, heat up to 5 °C and maintain for 50 min, and then heat up to 45 °C and maintain for 4 h to complete the first drying;

[0224] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, heat up the temperature to 60 °C and maintain for 45 min to complete the second drying;

[0225] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40 °C and maintain for 1 h to complete the drying, and obtain the imipenem cilastatin sodium injection preparation.

[0226] Comparative Example 5

[0227] This example provides a preparation method of an imipenem cilastatin sodium injection preparation. Different from Example 1, this comparative example directly uses a hydroxyethyl methyl cellulose solution as Solution A and Solution B for mixing, and proceeds according to the following steps:

[0228] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of phosphate - dipotassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to it to make it completely dissolve, obtaining an imipenem - cilastatin sodium mixed solution.

[0229] S2. Dissolve 4 mg of hydroxyethyl methylcellulose in 50 ml of 50% ethanol solution to obtain solution A.

[0230] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, 0.6 mg of sorbitan fatty acid ester, and 0.25 mg of nano - calcium carbonate to 50 ml of pure water, stir and mix evenly, and then react to obtain solution B.

[0231] S4. After mixing solution A and solution B, add them to the imipenem - cilastatin sodium mixed solution, stir and mix evenly, and then crystallize at a temperature of - 20 °C.

[0232] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem - cilastatin sodium.

[0233] S6. Fill the imipenem - cilastatin sodium prepared in step S5 at a temperature of 3 °C.

[0234] S7. Conduct a freezing treatment on the filled imipenem - cilastatin sodium:

[0235] S7 - 1. First, cool down to - 30 °C and freeze for 60 min;

[0236] S7 - 2. Cool down to - 50 °C and freeze for 25 min;

[0237] S7 - 3. Heat up to - 35 °C for annealing treatment for 40 min;

[0238] S7 - 4. Then cool down to - 55 °C and freeze for 25 min.

[0239] S8. Conduct a drying treatment on the imipenem - cilastatin sodium after the freezing treatment:

[0240] S8 - 1. The freeze - drying equipment is evacuated until the vacuum degree reaches more than 50%. First, heat up to 5 °C and hold for 50 min, and then heat up to 45 °C and hold for 4 h to complete the first drying;

[0241] S8 - 2. Adjust the vacuum degree of the freeze - drying equipment to 35%, heat up the temperature to 60 °C and hold for 45 min to complete the second drying;

[0242] S8 - 3. Adjust the vacuum degree of the freeze - drying equipment to 25%, adjust the temperature to 40 °C and hold for 1 h to complete the drying, obtaining an imipenem - cilastatin sodium injection preparation.

[0243] Comparative Example 6

[0244] This comparative example provides a preparation method of an imipenem and cilastatin sodium injection preparation. Different from Example 1, in step S3 of this comparative example, nano-calcium carbonate is not included, and other processes are the same as those in Example 1. The steps are as follows:

[0245] S1. Dissolve 500 mg of imipenem and 500 mg of cilastatin sodium in 400 ml of a phosphoric acid-dipotassium hydrogen phosphate buffer solution, and add 9 mg of serine and 4 mg of tea polyphenols to completely dissolve them to obtain an imipenem and cilastatin sodium mixed solution.

[0246] S2. Mix 4 mg of hydroxyethyl methylcellulose, 4.5 mg of glutaric anhydride, 1.1 mg of 4-dimethylaminopyridine, and 50 ml of a 50% ethanol solution and react them to obtain solution A.

[0247] S3. Add 1.3 mg of phenylalanine, 1.5 mg of glycine, and 0.6 mg of sorbitan fatty acid ester to 50 ml of pure water, stir and mix well, and then react to obtain solution B.

[0248] S4. After mixing solution A and solution B, add them to the imipenem and cilastatin sodium mixed solution, stir and mix well, and then crystallize at a temperature of -20°C.

[0249] S5. Filter successively with 0.45 μm and 0.22 μm microporous membranes to obtain imipenem and cilastatin sodium.

[0250] S6. Fill the imipenem and cilastatin sodium prepared in step S5 at a temperature of 3°C.

[0251] S7. Perform freezing treatment on the filled imipenem and cilastatin sodium:

[0252] S7-1. First cool down to -30°C and freeze for 60 min;

[0253] S7-2. Cool down to -50°C and freeze for 25 min;

[0254] S7-3. Heat up to -35°C and perform annealing treatment for 40 min;

[0255] S7-4. Then cool down to -55°C and freeze for 25 min.

[0256] S8. Perform drying treatment on the imipenem and cilastatin sodium after freezing treatment:

[0257] S8-1. The freeze-drying equipment is evacuated until the vacuum degree reaches more than 50%. First heat up to 5°C and maintain for 50 min, and then heat up to 45°C and maintain for 4 h to complete the first drying;

[0258] S8-2. Adjust the vacuum degree of the freeze-drying equipment to 35%, raise the temperature to 60 °C and keep it for 45 min to complete the secondary drying.

[0259] S8-3. Adjust the vacuum degree of the freeze-drying equipment to 25%, adjust the temperature to 40 °C and keep it for 1 h to complete the drying, and obtain the imipenem and cilastatin sodium injection preparation.

[0260] The purity of the imipenem and cilastatin sodium injection preparations prepared in Examples 1-7 and Comparative Examples 1-6 was detected, and the detection results are shown in Table 1.

[0261] Table 1

[0262] Sample Purity Example 1 99.5％ Example 2 99.3％ Example 3 99.3％ Example 4 99.5％ Example 5 99.5％ Example 6 99.6％ Example 7 99.4％ Comparative Example 1 89.3％ Comparative Example 2 99.2％ Comparative Example 3 99.0％ Comparative Example 4 90.1％ Comparative Example 5 99.3％ Comparative Example 6 99.4％

[0263] It can be seen from the above experimental data that although some substances were added in the preparation process of the present invention, the purity of the final product still reached 99.6%, and the purity of each example was not lower than that of the comparative example, which proved that the substances added by using the preparation method of the present application would not affect the purity of the imipenem and cilastatin sodium injection preparation.

[0264] The stability of the imipenem and cilastatin sodium injection preparations prepared by the methods of Examples 1-7 and Comparative Examples 1-6 was detected. After being placed at a temperature of 30 °C and a humidity of 65% RH for 1, 3, and 6 months, the detection results are shown in Table 2. The appearance standard is specified as: white or off-white; the related substances standard is specified as: ≤2.0; the insoluble particles standard is specified as: 10 μm ≤ 6000 particles.

[0265] Table 2

[0266]

[0267]

[0268]

[0269] It can be seen from the above experimental data that compared with the comparative example, the stability of the imipenem and cilastatin sodium injection preparation prepared by the method of the embodiment of the present invention was improved, which proved that there was a synergistic effect between the preparation process in the present invention and the added substances in improving the stability of the imipenem and cilastatin sodium injection preparation.

[0270] The bioavailability of imipenem and cilastatin sodium injection preparations prepared by the methods of Example 1 and Comparative Examples 1-6 was detected. 78 beagle dogs about 1 year old were randomly divided into 13 groups, and were respectively injected with imipenem and cilastatin sodium injections (0.25 g / 0.25 g) of Example 1-7 and Comparative Examples 1-6. After the administration, 1 ml of venous blood was collected at 0, 0.25, 0.5, 1, 1.5, 2.5, 3.5, 5.5 and 7.5 h, and HPLC-MS analysis was carried out. The pharmacokinetic data was processed with the WinNonline version 5.2 program. The test results are shown in Table 3 below.

[0271] Table 3

[0272]

[0273]

[0274] It can be seen from the above experimental data that compared with the comparative examples, the bioavailability of the imipenem and cilastatin sodium injection preparations prepared by the method of the embodiment of the present invention is greatly improved, which proves that there is a synergistic effect between the preparation process of the present invention and the added substances in promoting the bioavailability of the imipenem and cilastatin sodium injection preparations.

[0275] Combined with the detection results in Table 1, Table 2 and Table 3, it can be seen that the imipenem and cilastatin sodium injection preparations prepared by the preparation method of the present application not only have improved pure stability, but also have improved purity and bioavailability.

[0276] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: it is still possible to modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered by the scope of the claims and the description of the present invention.

Claims

1. A method for preparing an imipenem-cilastatin sodium injection preparation, characterized in that: The following steps are involved: Dissolving imipenem and cilastatin sodium in a buffer solution, and adding serine and tea polyphenols to completely dissolve them to obtain an imipenem-cilastatin sodium mixed solution; Hydroxyethyl methyl cellulose, glutaric anhydride, 4-dimethylaminopyridine and ethanol solution are mixed and reacted to obtain solution A; Phenylalanine, glycine, sorbitan fatty acid ester and nano-calcium carbonate are mixed and reacted to obtain solution B; Solution A and solution B are mixed and added into the mixed solution of imipenem-cilastatin sodium, stirred and mixed, cooled and crystallized, and then filtered to obtain imipenem-cilastatin sodium, which is then frozen and dried to obtain imipenem-cilastatin sodium injection preparation.

2. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The mass ratio of the hydroxyethyl methyl cellulose, glutaric anhydride and 4-dimethylaminopyridine is (3-5): (4-5): (1-1.2).

3. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The mass ratio of phenylalanine, glycine, sorbitan fatty acid ester and nano-calcium carbonate is (1.2-1.4): (1.4-1.6): (0.5-0.7): (0.2-0.3).

4. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The buffer solution includes a phosphoric acid-dipotassium hydrogen phosphate buffer solution.

5. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The mass ratio of the imipenem to the cilastatin sodium is 1:

1.

6. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The usage ratio of the serine to the tea polyphenols is (8-10):(3-5).

7. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: Filtration was performed using 0.45 μm and 0.22 μm microporous membranes in sequence.

8. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The freezing process includes the following steps: 1) First cool down to -30℃~-25℃ and freeze for 50min~60min; 2) Cool down to -45℃~-50℃ and freeze for 25min~30min; 3) Heating to -35℃~-30℃ and annealing for 40min~45min; 4) Cool down the temperature to -55℃~-50℃ and freeze for 25min~30min.

9. The method for preparing an imipenem-cilastatin sodium injection according to claim 1, characterized in that: The drying process includes the following steps: 1) The freeze-drying equipment is vacuumed until the vacuum degree reaches more than 50%, and the temperature is first raised to 0-10°C and maintained for 45-60 minutes, and then raised to 45-50°C and maintained for 4-5 hours to complete the primary drying; 2) Adjust the vacuum degree of the freeze-drying equipment to 35-40%, raise the temperature to 60-65°C and maintain for 45-60 minutes to complete secondary drying; 3) Adjust the vacuum degree of the freeze-drying equipment to 25-30% and the temperature to 40-45°C for 1-1.5 hours to complete the drying.

10. An imipenem-cilastatin sodium injection preparation, characterized in that: The preparation method is described in any one of claims 1 to 9.

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