Improved ceftriaxone sodium long-acting preparation and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to an improved ceftriaxone sodium long-acting preparation and a preparation method thereof. Through comprehensive application of chemical modification, a PLGA wrapping technology, a moisture-resistant protective layer and an excipient, the prepared ceftriaxone sodium improved long-acting preparation not only realizes long-acting slow release of ceftriaxone sodium, but also remarkably improves the drug stability, which not only conforms to the development trend of current clinical medication, but also has good clinical application prospects. The method is an important measure for meeting the treatment requirements of the majority of patients, and has relatively high clinical application value and economic benefit.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an improved long-acting preparation of ceftriaxone sodium and a preparation method thereof. Background Art

[0002] Ceftriaxone sodium, as an outstanding representative of the third-generation cephalosporins, has won wide recognition and application in the medical community since its launch for its excellent antibacterial activity and relatively long half-life. It can effectively fight a variety of Gram-positive and Gram-negative bacteria, and has become the first choice for treating a variety of bacterial infections such as respiratory tract, urinary tract, abdominal cavity and skin soft tissue. With the continuous advancement of medical technology and the increasing diversification of clinical needs, the application scenarios of ceftriaxone sodium are also constantly expanding, which puts higher requirements on the performance of the preparation.

[0003] However, although ceftriaxone sodium has shown significant advantages in clinical treatment, there are still some problems that need to be solved in commercial preparations. These problems not only limit the full play of the drug's efficacy, but may also increase the cost and risk of treatment for patients. First, the uneven drug release caused by the immediate-release administration method forces patients to face the trouble of frequent dosing, which not only affects the quality of life, but may also reduce the therapeutic effect due to fluctuations in drug concentration. Secondly, ceftriaxone sodium is highly sensitive to humidity and light, which makes the preparation extremely easy to degrade during storage and use, thereby affecting its stability and efficacy. Furthermore, the side effects such as nephrotoxicity and allergies that may be caused by excessive peak drug concentrations pose a potential threat to patient safety.

[0004] Therefore, the development of an improved long-acting preparation of ceftriaxone sodium aims to comprehensively improve the efficacy and safety of the drug by optimizing the drug release mechanism and improving the stability of the preparation. This is not only in line with the current development trend of clinical drug use, but also an important measure to meet the treatment needs of the majority of patients. Summary of the invention

[0005] In view of the existing technical problems, the present invention aims to provide an improved long-acting preparation of ceftriaxone sodium and a preparation method thereof. The improved long-acting preparation of ceftriaxone sodium prepared by the preparation method has good sustained-release properties and high stability.

[0006] The present invention discloses a method for preparing an improved long-acting preparation of ceftriaxone sodium, and the preparation method comprises the following steps:

[0007] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve it. When a uniform solution is formed, a long-chain fatty acid is added and stirred to mix well, and then a catalyst is added, and a heating reaction is carried out under reflux conditions. After the reaction is completed, the reaction solution is cooled, filtered, extracted, and purified by spin drying to obtain a ceftriaxone sodium ester derivative;

[0008] S2 Preparation of improved ceftriaxone sodium microspheres: dissolving the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1: (1-2) and mixing them evenly, then slowly adding them into a polyvinyl alcohol solution, and emulsifying them by ultrasonic emulsification to form an oil-in-water emulsion; then transferring the emulsion to a rotary evaporator for low-temperature evaporation, and obtaining microspheres after the evaporation is completed; then washing the microspheres with deionized water and centrifuging and freeze-drying them to obtain improved ceftriaxone sodium microspheres;

[0009] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0010] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol; then pre-cooling treatment is performed, and after the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and after freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0011] Preferably, in step S1 of preparing the ceftriaxone sodium ester derivative, the molar ratio of the ceftriaxone sodium to the long-chain fatty acid is 1:(1-2); the mass ratio of the ceftriaxone sodium to dichloromethane is 1:(5-8).

[0012] Preferably, in step S1 of preparing ceftriaxone sodium derivatives, the reflux temperature is 60-70° C. and the reaction time is 4-6 h.

[0013] Preferably, in step S1 of preparing ceftriaxone sodium derivatives, dichloromethane is used as the organic phase for extraction.

[0014] Preferably, in step S2 of preparing the improved ceftriaxone sodium microspheres, the ultrasonic frequency in the ultrasonic emulsification method is 800 to 1000 Hz; and the ultrasonic emulsification time is 20 to 30 min.

[0015] Preferably, in step S2 of preparing improved ceftriaxone sodium microspheres, the concentration of the polyethylene solution is 2 to 5 mol / L.

[0016] Preferably, in the step S2 of preparing the improved ceftriaxone sodium microspheres, the temperature of the low-temperature evaporation is 30-40°C.

[0017] Preferably, in the freeze-drying and packaging step S4, the pre-cooling treatment temperature is -20 to -40°C; and the pre-cooling treatment duration is 2 to 3 hours.

[0018] Preferably, in the freeze-drying packaging step S4, the freeze-drying temperature during the freeze-drying process is -70 to -80°C; and the freeze-drying time is 22 to 24 hours.

[0019] A modified long-acting preparation of ceftriaxone sodium is prepared by any of the above-mentioned methods for preparing the modified long-acting preparation of ceftriaxone sodium.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention provides a modified long-acting preparation of ceftriaxone sodium and a preparation method thereof. Before preparing ceftriaxone sodium into microspheres, the functional groups such as the carboxyl group, amino group or thioester group of the ceftriaxone sodium molecule are chemically modified, and the ceftriaxone sodium molecule is esterified by long-chain fatty acids (such as lauric acid and stearic acid) to form ester derivatives. This modification can significantly reduce the hydrolysis rate of ceftriaxone sodium in the body, thereby delaying the release of the drug. After the S3 protective layer coating step, hyaluronic acid (1-5% by mass) and polyethylene glycol 4000 (2-8% by mass) are further added as excipients to shape the modified ceftriaxone sodium microspheres.

[0022] The present invention not only realizes the long-acting sustained release of ceftriaxone sodium but also significantly improves the drug stability through the comprehensive application of chemical modification, PLGA encapsulation technology, moisture-resistant protective layer and excipients. DETAILED DESCRIPTION

[0023] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0024] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be purchased commercially.

[0025] Example 1: A method for preparing a modified long-acting preparation of ceftriaxone sodium, comprising the following steps:

[0026] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve it, wherein the mass ratio of ceftriaxone sodium to dichloromethane is 1:5. When a uniform solution is formed, long-chain fatty acids are added and stirred to mix well, and then a catalyst boron trifluoride is added, wherein the molar ratio of ceftriaxone sodium to long-chain fatty acids is 1:1, and the molar ratio of ceftriaxone sodium to boron trifluoride is 1:0.01; the reflux temperature is set to 60°C, and the heating reaction is carried out under reflux conditions for 4 hours; after the reaction is completed, the reaction solution is cooled, filtered and extracted, and the organic phase used for extraction is dichloromethane. The organic phases are collected and combined, and spin-dried and purified to obtain ceftriaxone sodium ester derivatives.

[0027] S2 Preparation of improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1:1, mix well, and then slowly add it to a polyvinyl alcohol solution, wherein the concentration of the pure polyethylene solution is 2 mol / L; emulsify by ultrasonic emulsification, wherein the frequency of ultrasound is 800 Hz, to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, the temperature of the low-temperature evaporation is 40°C, and microspheres are obtained after the evaporation is completed; then wash the microspheres with deionized water and then centrifuge and freeze-dry to obtain improved ceftriaxone sodium microspheres;

[0028] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0029] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol, wherein the mass fraction of hyaluronic acid is 2%, and the mass fraction of polyethylene glycol is 5%; then pre-cooling treatment is performed, the pre-cooling temperature is set to -20°C, and the pre-cooling treatment is performed for 2 hours. After the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and the freeze drying temperature of the freeze dryer is set to -70°C. The freeze drying is divided into two stages of freeze drying, the first stage of freeze drying is 7 hours, and the second stage of freeze drying is 15 hours. After freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0030] Example 2: A method for preparing a modified long-acting preparation of ceftriaxone sodium, comprising the following steps:

[0031] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve, wherein the mass ratio of ceftriaxone sodium to dichloromethane is 1:6. When a uniform solution is formed, long-chain fatty acids are added and stirred to mix, and then the catalyst boron trifluoride is added, wherein the molar ratio of ceftriaxone sodium to long-chain fatty acids is 1:1.3, and the molar ratio of ceftriaxone sodium to boron trifluoride is 1:0.02; the reflux temperature is set to 63°C, and the heating reaction is carried out under reflux conditions for 4.5 hours; after the reaction is completed, the reaction solution is cooled, filtered and extracted, and the organic phase used for extraction is dichloromethane. The organic phases are collected and combined, and spin-dried and purified to obtain ceftriaxone sodium ester derivatives.

[0032] S2 Preparation of improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1:1, mix well, and then slowly add it to a polyvinyl alcohol solution, wherein the concentration of the pure polyethylene solution is 2 mol / L; emulsify by ultrasonic emulsification, wherein the frequency of ultrasound is 800 Hz, to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, the temperature of the low-temperature evaporation is 40°C, and microspheres are obtained after the evaporation is completed; then wash the microspheres with deionized water and then centrifuge and freeze-dry to obtain improved ceftriaxone sodium microspheres;

[0033] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0034] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol, wherein the mass fraction of hyaluronic acid is 2%, and the mass fraction of polyethylene glycol is 5%; then pre-cooling treatment is performed, the pre-cooling temperature is set to -20°C, and the pre-cooling treatment is performed for 2 hours. After the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and the freeze drying temperature of the freeze dryer is set to -70°C. The freeze drying is divided into two stages of freeze drying, the first stage of freeze drying is 7 hours, and the second stage of freeze drying is 15 hours. After freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0035] Example 3: A method for preparing a modified long-acting preparation of ceftriaxone sodium, comprising the following steps:

[0036] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve, wherein the mass ratio of ceftriaxone sodium to dichloromethane is 1:7. When a uniform solution is formed, long-chain fatty acids are added and stirred to mix, and then a catalyst boron trifluoride is added, wherein the molar ratio of ceftriaxone sodium to long-chain fatty acids is 1:1.7, and the molar ratio of ceftriaxone sodium to boron trifluoride is 1:0.03; the reflux temperature is set to 66°C, and the heating reaction is carried out under reflux conditions for 5 hours; after the reaction is completed, the reaction solution is cooled, filtered and extracted, and the organic phase used for extraction is dichloromethane. The organic phases are collected and combined, and spin-dried and purified to obtain ceftriaxone sodium ester derivatives.

[0037] S2 Preparation of improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1:1, mix well, and then slowly add it to a polyvinyl alcohol solution, wherein the concentration of the pure polyethylene solution is 2 mol / L; emulsify by ultrasonic emulsification, wherein the frequency of ultrasound is 800 Hz, to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, the temperature of the low-temperature evaporation is 40°C, and microspheres are obtained after the evaporation is completed; then wash the microspheres with deionized water and then centrifuge and freeze-dry to obtain improved ceftriaxone sodium microspheres;

[0038] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0039] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol, wherein the mass fraction of hyaluronic acid is 2%, and the mass fraction of polyethylene glycol is 5%; then pre-cooling treatment is performed, the pre-cooling temperature is set to -20°C, and the pre-cooling treatment is performed for 2 hours. After the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and the freeze drying temperature of the freeze dryer is set to -70°C. The freeze drying is divided into two stages of freeze drying, the first stage of freeze drying is 7 hours, and the second stage of freeze drying is 15 hours. After freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0040] Example 4: A method for preparing a modified long-acting preparation of ceftriaxone sodium, comprising the following steps:

[0041] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve it, wherein the mass ratio of ceftriaxone sodium to dichloromethane is 1:7. When a uniform solution is formed, long-chain fatty acids are added and stirred to mix well, and then a catalyst boron trifluoride is added, wherein the molar ratio of ceftriaxone sodium to long-chain fatty acids is 1:2, and the molar ratio of ceftriaxone sodium to boron trifluoride is 1:0.04; the reflux temperature is set to 70°C, and the heating reaction is carried out under reflux conditions for 6 hours; after the reaction is completed, the reaction solution is cooled, filtered and extracted, and the organic phase used for extraction is dichloromethane. The organic phases are collected and combined, and spin-dried and purified to obtain ceftriaxone sodium ester derivatives.

[0042] S2 Preparation of improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1:1, mix well, and then slowly add it to a polyvinyl alcohol solution, wherein the concentration of the pure polyethylene solution is 2 mol / L; emulsify by ultrasonic emulsification, wherein the frequency of ultrasound is 800 Hz, to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, the temperature of the low-temperature evaporation is 40°C, and microspheres are obtained after the evaporation is completed; then wash the microspheres with deionized water and then centrifuge and freeze-dry to obtain improved ceftriaxone sodium microspheres;

[0043] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0044] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol, wherein the mass fraction of hyaluronic acid is 2%, and the mass fraction of polyethylene glycol is 5%; then pre-cooling treatment is performed, the pre-cooling temperature is set to -20°C, and the pre-cooling treatment is performed for 2 hours. After the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and the freeze drying temperature of the freeze dryer is set to -70°C. The freeze drying is divided into two stages of freeze drying, the first stage of freeze drying is 7 hours, and the second stage of freeze drying is 15 hours. After freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0045] Example 5: A method for preparing a modified long-acting preparation of ceftriaxone sodium, comprising the following steps:

[0046] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve, wherein the mass ratio of ceftriaxone sodium to dichloromethane is 1:7. When a uniform solution is formed, long-chain fatty acids are added and stirred to mix, and then a catalyst boron trifluoride is added, wherein the molar ratio of ceftriaxone sodium to long-chain fatty acids is 1:1.7, and the molar ratio of ceftriaxone sodium to boron trifluoride is 1:0.03; the reflux temperature is set to 66°C, and the heating reaction is carried out under reflux conditions for 5 hours; after the reaction is completed, the reaction solution is cooled, filtered and extracted, and the organic phase used for extraction is dichloromethane. The organic phases are collected and combined, and spin-dried and purified to obtain ceftriaxone sodium ester derivatives.

[0047] Preparation of S2 improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1:1.5, mix well, and then slowly add it to a polyvinyl alcohol solution, wherein the concentration of the pure polyethylene solution is 3.5 mol / L; emulsify by ultrasonic emulsification, wherein the frequency of ultrasound is 900 Hz, to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, the temperature of the low-temperature evaporation is 35°C, and microspheres are obtained after the evaporation is completed; then wash the microspheres with deionized water and then centrifuge and freeze-dry to obtain improved ceftriaxone sodium microspheres;

[0048] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0049] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol, wherein the mass fraction of hyaluronic acid is 2%, and the mass fraction of polyethylene glycol is 5%; then pre-cooling treatment is performed, the pre-cooling temperature is set to -30°C, and the pre-cooling treatment is performed for 2.5 hours. After the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and the freeze drying temperature of the freeze dryer is set to -75°C. The freeze drying is divided into two stages, the first stage is freeze-dried for 8 hours, and the second stage is freeze-dried for 15 hours. After freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0050] Example 6: A method for preparing a modified long-acting preparation of ceftriaxone sodium, comprising the following steps:

[0051] S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve, wherein the mass ratio of ceftriaxone sodium to dichloromethane is 1:7. When a uniform solution is formed, long-chain fatty acids are added and stirred to mix, and then a catalyst boron trifluoride is added, wherein the molar ratio of ceftriaxone sodium to long-chain fatty acids is 1:1.7, and the molar ratio of ceftriaxone sodium to boron trifluoride is 1:0.03; the reflux temperature is set to 66°C, and the heating reaction is carried out under reflux conditions for 5 hours; after the reaction is completed, the reaction solution is cooled, filtered and extracted, and the organic phase used for extraction is dichloromethane. The organic phases are collected and combined, and spin-dried and purified to obtain ceftriaxone sodium ester derivatives.

[0052] S2 Preparation of improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1:2, mix well, and then slowly add it to a polyvinyl alcohol solution, wherein the concentration of the pure polyethylene solution is 5 mol / L; emulsify by ultrasonic emulsification, wherein the frequency of ultrasound is 1000 Hz, to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, the temperature of the low-temperature evaporation is 40°C, and microspheres are obtained after the evaporation is completed; then wash the microspheres with deionized water and then centrifuge and freeze-dry to obtain improved ceftriaxone sodium microspheres;

[0053] S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film;

[0054] S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol, wherein the mass fraction of hyaluronic acid is 2%, and the mass fraction of polyethylene glycol is 5%; then pre-cooling treatment is performed, the pre-cooling temperature is set to -40°C, and the pre-cooling treatment is performed for 3 hours. After the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and the freeze drying temperature of the freeze dryer is set to -80°C. The freeze drying is divided into two stages, the first stage is freeze-dried for 14 hours, and the second stage is freeze-dried for 10 hours. After freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

[0055] The modified long-acting preparation of ceftriaxone sodium prepared in Examples 1 to 6 was tested for sustained release properties. The experimental setting is as follows: a phosphate buffer solution with a pH of 7.4 was set to simulate the gastrointestinal environment of the human body, the temperature was 37°C ± 0.5°C, the rotation speed was 100 rpm, the modified long-acting preparation of ceftriaxone sodium was added to the solution, and samples were taken at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h to detect the amount of ceftriaxone sodium released in the sample. The experimental results are shown in Table 1:

[0056] Table 1

[0057]

[0058] From the above table data, it can be seen that the improved long-acting preparations of ceftriaxone sodium prepared in Examples 1 to 6 showed obvious slow release characteristics in the in vitro dissolution experiment, and the release amount gradually increased with the passage of time, and there was no phenomenon of excessive initial release. The improved long-acting preparations of ceftriaxone sodium prepared in Examples 1 to 6 can release the drug more slowly, avoiding the rapid release characteristics of the control group drug, which helps to prolong the drug's action time, reduce the frequency of administration, and thus improve patient compliance.

[0059] The improved long-acting preparations of ceftriaxone sodium prepared in Examples 1 to 6 were subjected to a humidity stability test. The experimental setting is as follows: the samples of the improved long-acting preparations of ceftriaxone sodium were exposed to humidity environments of 1%, 30%, 60%, and 90%, respectively. After 2 weeks, samples were taken for testing. The test results are shown in Table 2:

[0060] Table 2

[0061] Example 1% group (mg / g) 30% group (mg / g) 60% group (mg / g) 90% group (mg / g) 1 100 90 88 83 2 100 92 90 86 3 100 95 93 90 4 100 93 91 88 5 100 92 90 86 6 100 96 95 92

[0062] It can be seen from the data in Table 2 that the improved long-acting preparations of ceftriaxone sodium prepared in Examples 1 to 6 have good stability in various humidity environments, among which Examples 3 and 6 have the best properties.

[0063] The improved long-acting preparations of ceftriaxone sodium prepared in Examples 1 to 6 were subjected to a light stability test. The experimental setting is as follows: the samples of the improved long-acting preparations of ceftriaxone sodium were exposed to light intensity environments of 0 Lux, 20 Lux, 500 Lux, and 1000 Lux, respectively. After 2 weeks, samples were taken for testing. The test results are shown in Table 3:

[0064] Table 3

[0065] Example 0Lux(mg / g) 20Lux(mg / g) 500Lux(mg / g) 1000Lux(mg / g) 1 100 90 85 73 2 100 92 88 79 3 100 95 92 90 4 100 93 89 85 5 100 92 88 80 6 100 96 95 93

[0066] It can be seen from the data in Table 3 that the improved long-acting preparations of ceftriaxone sodium prepared in Examples 1 to 6 have good stability in various humidity environments, among which Examples 3 and 6 have the best properties.

[0067] In summary, the improved long-acting preparation of ceftriaxone sodium prepared by the preparation method of the improved long-acting preparation of ceftriaxone sodium provided by the present invention has good drug release properties, excellent drug stability, is not easily decomposed and ineffective, comprehensively improves the efficacy and safety of the drug, and has high clinical application value and economic benefits.

[0068] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing an improved long-acting preparation of ceftriaxone sodium, characterized in that: The following steps are involved: S1 Preparation of ceftriaxone sodium ester derivatives: Ceftriaxone sodium is added to a reactor, and then dichloromethane is added to dissolve it. When a uniform solution is formed, a long-chain fatty acid is added and stirred to mix well, and then a catalyst is added, and a heating reaction is carried out under reflux conditions. After the reaction is completed, the reaction solution is cooled, filtered, extracted, and purified by spin drying to obtain a ceftriaxone sodium ester derivative; Preparation of S2 improved ceftriaxone sodium microspheres: dissolve the ceftriaxone sodium ester derivative obtained in step S1 in a mixed solution of deionized water and ethanol in a volume ratio of 1: (1-2) and mix well, then slowly add it into a polyvinyl alcohol solution, and emulsify it by ultrasonic emulsification to form an oil-in-water emulsion; then transfer the emulsion to a rotary evaporator for low-temperature evaporation, and obtain microspheres after the evaporation is completed; The microspheres are then washed with deionized water and centrifuged and freeze-dried to obtain improved ceftriaxone sodium microspheres; S3 protective layer coating: polyethylene glycol and phospholipids are dissolved in deionized water and mixed to prepare a mixed aqueous solution with a mass fraction of 0.5%, and the microspheres prepared in step S2 are immersed in the solution, and adsorbed for 30 minutes each time, and the coating is repeated for 5 layers to form an anti-humidity protective film; S4 freeze-drying packaging: the improved ceftriaxone sodium microspheres coated with a protective film obtained in step S3 are mixed with hyaluronic acid and polyethylene glycol; then pre-cooling treatment is performed, and after the pre-cooling treatment, the coated microspheres are placed in a freeze dryer for freeze drying, and after freeze drying, the improved ceftriaxone powder is obtained, which is then packaged in a sterile environment and vacuum-sealed to obtain a modified long-acting preparation of ceftriaxone sodium.

2. The method for preparing a modified long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the step S1 of preparing the ceftriaxone sodium ester derivative, the molar ratio of the ceftriaxone sodium to the long-chain fatty acid is 1:(1-2); the mass ratio of the ceftriaxone sodium to dichloromethane is 1:(5-8).

3. The method for preparing a modified long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In step S1 of preparing ceftriaxone sodium derivatives, the reflux temperature is 60-70° C. and the reaction time is 4-6 hours.

4. The method for preparing a modified long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the step S1 of preparing ceftriaxone sodium derivatives, dichloromethane is used as the organic phase for extraction.

5. The method for preparing a modified long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the S2 improved ceftriaxone sodium microsphere preparation step, the ultrasonic frequency in the ultrasonic emulsification method is 800-1000 Hz; the ultrasonic emulsification time is 20-30 min.

6. The method for preparing an improved long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the step S2 of preparing the improved ceftriaxone sodium microspheres, the concentration of the polyvinyl alcohol solution is 2 to 5 mol / L.

7. The method for preparing a modified long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the step S2 of preparing the improved ceftriaxone sodium microspheres, the temperature of the low-temperature evaporation is 30-40°C.

8. The method for preparing a modified long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the freeze-drying and packaging step S4, the pre-cooling treatment temperature is -20 to -40°C; the pre-cooling treatment duration is 2 to 3 hours.

9. The method for preparing an improved long-acting preparation of ceftriaxone sodium according to claim 1, characterized in that: In the freeze-drying packaging step S4, the freeze-drying temperature during the freeze-drying process is -70 to -80°C; the freeze-drying time is 22 to 24 hours.

10. An improved long-acting preparation of ceftriaxone sodium prepared by the method for preparing an improved long-acting preparation of ceftriaxone sodium according to any one of claims 1 to 9.

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