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CN-122005469-A - Piperacillin sodium and tazobactam sodium preparation and preparation method thereof

CN122005469ACN 122005469 ACN122005469 ACN 122005469ACN-122005469-A

Abstract

The invention discloses a piperacillin sodium and tazobactam sodium preparation and a preparation method thereof, wherein the preparation method comprises the steps of mixing piperacillin sodium with chitosan and a surfactant 1, mixing tazobactam sodium with a surfactant 2, and respectively performing low-temperature mechanical ball milling activation; the activated piperacillin sodium and tazobactam sodium are respectively added into low-temperature water for injection to be dissolved, so as to obtain a piperacillin sodium solution and a tazobactam sodium solution, the piperacillin sodium solution and the tazobactam sodium solution are subjected to liquid co-dissolution and mixing under the protection of nitrogen, and the impurities are removed by multi-stage filtration and freeze-drying after uniform mixing, so that the piperacillin sodium tazobactam sodium preparation is obtained. According to the invention, before piperacillin sodium and tazobactam sodium are dissolved, chitosan and a surfactant are respectively adopted for low-temperature ball milling activation, so that the mixing uniformity of raw materials can be improved, and simultaneously, impurities embedded in raw material crystals can be adsorbed, trapped and flocculated to form a compound, so that the internal impurities can be removed efficiently.

Inventors

  • JIANG HAOWEI
  • HU YANXIA
  • LIAO CHUNMEI

Assignees

  • 成都晶富医药科技有限公司
  • 四川制药制剂有限公司

Dates

Publication Date
20260512
Application Date
20260409

Claims (10)

  1. 1. A method for preparing a piperacillin sodium and tazobactam sodium preparation, which is characterized by comprising the following steps: S1, mixing piperacillin sodium with chitosan and an injection-grade surfactant 1, mixing tazobactam sodium with an injection-grade surfactant 2, and performing low-temperature mechanical ball milling activation respectively; s2, respectively adding the activated piperacillin sodium and tazobactam sodium into low-temperature water for injection to dissolve, so as to obtain a piperacillin sodium solution and a tazobactam sodium solution; S3, under the protection of nitrogen, carrying out liquid co-dissolution and mixing on the piperacillin sodium solution and the tazobactam sodium solution; s4, uniformly mixing, removing impurities by multi-stage filtration, and freeze-drying to obtain the piperacillin sodium tazobactam sodium preparation.
  2. 2. The preparation method of the piperacillin sodium and tazobactam sodium preparation according to claim 1, wherein in the step S1, the chitosan is one of water-soluble chitosan, low molecular weight chitosan and carboxymethyl chitosan, and the addition amount is 0.01% -0.1% of the total mass of the raw materials.
  3. 3. The preparation method of the piperacillin sodium and tazobactam sodium preparation according to claim 1, wherein in the step S1, the surfactant 1 is selected from sodium deoxycholate or sodium lauroyl glutamate, and the surfactant 2 is selected from one or more of sodium cocoyl malate, lecithin, poloxamer and polysorbate.
  4. 4. The preparation method of the piperacillin sodium and tazobactam sodium preparation according to claim 3, wherein the addition amount of the surfactant 1 is 0.01% -0.1% of the total mass of the raw materials, and the addition amount of the surfactant 2 is 0.05% -0.2% of the total mass of the raw materials.
  5. 5. The method for preparing the piperacillin sodium and tazobactam sodium preparation according to claim 1, wherein in the step S2, after ball milling: The particle size D50 of the piperacillin sodium is 20-40 mu m; The particle size D50 of the tazobactam sodium is 15-35 mu m; the difference value of the particle sizes D50 of piperacillin sodium and tazobactam sodium is less than or equal to 15 mu m.
  6. 6. The preparation method of the piperacillin sodium and tazobactam sodium preparation according to claim 1, wherein in the step S2, the low-temperature mechanical ball milling condition is that the temperature is 0-15 ℃, the ball-to-material ratio is 5:1-20:1, the rotating speed is 200-500 rpm, and the time is 10-60 min.
  7. 7. The preparation method of the piperacillin sodium and tazobactam sodium preparation according to claim 2, wherein in the step S3, a double mixing mode of stirring and bottom nitrogen bubbling is adopted, and the materials are circularly and uniformly mixed for 15-30 min.
  8. 8. The method for preparing a piperacillin sodium and tazobactam sodium preparation according to claim 1, wherein in the step S3, a sodium hydroxide solution and a citric acid solution are adopted to adjust the pH of the solution to 6.3-6.6.
  9. 9. The piperacillin sodium and tazobactam sodium preparation and its preparation process as claimed in claim 1, wherein in step S4, the multistage filtration is performed sequentially through 0.45 μm filter core prefilter and 0.22 μm filter core degerming filter.
  10. 10. A piperacillin sodium tazobactam sodium formulation, prepared by the method of any one of claims 1-9.

Description

Piperacillin sodium and tazobactam sodium preparation and preparation method thereof Technical Field The invention relates to the technical field of pharmacy, in particular to a piperacillin sodium and tazobactam sodium preparation and a preparation method thereof. Background Piperacillin sodium is a semisynthetic penicillin antibiotic, has broad-spectrum antibacterial effect, plays a bactericidal role by inhibiting bacterial cell wall synthesis, and has good antibacterial effect on escherichia coli, bacillus proteus, serratia, klebsiella, enterobacter, citric acid bacteria, salmonella, shigella and other gram-negative bacteria such as pseudomonas aeruginosa, acinetobacter, haemophilus influenzae, neisseria and the like. Tazobactam sodium is a type II-V beta-lactamase inhibitor, has strong enzyme inhibition activity, and can effectively inhibit various plasmid-mediated beta-lactamase, including novel ultra-broad spectrum enzyme and chromosome-mediated class I beta-lactamase. Meanwhile, tazobactam sodium is also a suicide inhibitor of irreversible beta-lactamase, has irreversible inhibition effect on most important beta-lactamase generated by beta-lactam antibiotic resistant strains, and can prevent the damage of drug-resistant bacteria to penicillin antibiotics and cephalosporin antibiotics. When the tazobactam sodium is used for corresponding protection, the tazobactam sodium and piperacillin sodium are combined to generate obvious synergistic effect, and the tazobactam sodium is widely used for treating serious systemic and local infection, abdominal cavity infection, lower respiratory tract infection, soft tissue infection, septicemia and the like, has wider antibacterial spectrum and indication than other antibacterial complexing agents which are used, and has great advantages in overcoming drug resistance. The prior industrial production of piperacillin sodium and tazobactam sodium mainly adopts a solid powder direct mixing and then dissolving or raw material direct and separate dissolving and mixing process, and has the problems that the particle size, bulk density and flowability of the raw materials of piperacillin sodium and tazobactam sodium are large, uneven mixing is easy to cause, the content uniformity is poor, synthetic byproducts, degradation impurities and fat-soluble impurities are easy to embed in raw material crystals, the conventional dissolving process is difficult to fully release and remove the internal impurities, the related substances of a finished product are relatively high, the clarity is poor, the dissolving rate of the two raw materials is inconsistent, local over-concentration, particle wrapping and incomplete dissolving are easy to occur during mixing, and the content fluctuation and impurity rising are aggravated. In view of this, the present application has been made. Disclosure of Invention The invention aims to solve the technical problems that the raw materials are insufficiently mixed and dissolved, the clarity is poor, the internal impurities are difficult to release and remove when the piperacillin sodium and tazobactam sodium preparation is prepared by the prior art, aims to provide a piperacillin sodium and tazobactam sodium preparation and a preparation method thereof, which can improve the mixing uniformity, efficiently remove internal impurities and improve the quality of finished products. The invention is realized by the following technical scheme: in a first aspect, the present invention provides a method for preparing a piperacillin sodium tazobactam sodium formulation, comprising the steps of: S1, mixing piperacillin sodium with chitosan and an injection-grade surfactant 1, mixing tazobactam sodium with an injection-grade surfactant 2, and performing low-temperature mechanical ball milling activation respectively; s2, respectively adding the activated piperacillin sodium and tazobactam sodium into low-temperature water for injection to dissolve, so as to obtain a piperacillin sodium solution and a tazobactam sodium solution; S3, under the protection of nitrogen, carrying out liquid co-dissolution and mixing on the piperacillin sodium solution and the tazobactam sodium solution; s4, uniformly mixing, removing impurities by multi-stage filtration, and freeze-drying to obtain the piperacillin sodium tazobactam sodium preparation. In a specific embodiment, in step S1, the chitosan is one of water-soluble chitosan, low molecular weight chitosan and carboxymethyl chitosan, and the addition amount is 0.01% -0.1% of the total mass of the raw materials. In a specific embodiment, in step S1, the surfactant 1 is selected from sodium deoxycholate or sodium lauroyl glutamate, and the surfactant 2 is selected from one or more of sodium cocoyl malate, lecithin, poloxamer, and polysorbate. Before piperacillin sodium and tazobactam sodium are prepared and dissolved, the auxiliary agents are adopted for low-temperature ball milling activation, during ball milling, the auxil