WO2008028347A1 - Combined antibiotics preparation - Google Patents

Abstract

A combined antibiotics preparation comprising piperacillin, sulbactam or clavulanic acid, ion chelants and/or buffers, which can be used to prepare a stable solution preparation, and can be used to prepare a stable solution preparation together with aminoglycoside antibiotics in one container.

Description

 Antibiotic combination preparation containing piperacillin

 The present invention relates to an antibiotic combination consisting of piperacillin, sulbactam or clavulanic acid, an ion chelating agent and/or a buffer component, which is characterized by a stable solution formulation and an aminoglycoside antibiotic A stable solution formulation is formulated in the same container for use as a medicament for controlling microbial infection. technical background:

 Piperacillin inhibits bacterial cell wall synthesis by inhibiting the activity of the D-alanylalanine transpeptidase in bacteria. Because mucopeptides are some sugar-containing polypeptides with a network structure, which are composed of N-acetylglucosamine (Glc-NAc) and N-acetyl-wally (Mur-NAc), which are linearly composed of linear glycan chain short peptides. The polymer needs to undergo trans-peptide cross-linking reaction under the catalysis of mucopeptide transpeptidase to convert the linear polymer into a cross-linked structure, thereby completing the synthesis of the cell wall. Piperacillin irreversibly inhibited the mucopeptide transpeptidase and prevented the bacteria from synthesizing the cell wall. Without cell walls, cells cannot be shaped and withstand high osmotic pressure within the cells, causing lysis and bacterial death.

 The bacteria then evolved to produce a beta-lactamase that hydrolyzes the amide bond of the beta lactam ring in piperacillin and converts piperacillin to a metabolite without antibacterial activity. In 1976, humans discovered that clavulanic acid isolated from the fermentation broth of Streptomyces faecalis has a unique activity of inhibiting β-lactamase, followed by other β-lactamase inhibitors, especially sulbactam and its Lipid prodrugs, sulindac and tazobactam are widely used clinically.

 The combination of piperacillin and sulbactam is one of the most widely used antibiotic injection preparations (petrozine preparations). It is widely used to treat hospital-type pneumonia caused by Staphylococcus aureus (Nosocomial Pneumonia), intra-abdominal infections, especially appendicitis and peritonitis caused by Escherichia coli, skin infections including cellulitis and skin abscess, ischemia / Diabetic foot infections and gynecological infections represented by postpartum endometritis and pelvic inflammatory disease.

 Another class of clinically widely used antibiotics are Aminoglycoside Antibiotics. An aminoglycoside antibiotic is a glycoside formed from an amino sugar (monosaccharide or disaccharide) and an amino cyclic alcohol. The compound is basic due to its amino group and other basic groups. Since the first aminoglycoside antibiotic, streptomycin, has been found in Streptomyces since 1940, since these antibiotics have a broad spectrum of antibacterial activity and strong antibacterial activity, they have been used clinically, and more than 20 varieties have been on the market.

 The antibacterial mechanism of aminoglycoside antibiotics is completely different from piperacillin. After the aminoglycoside antibiotic enters the bacterium, it binds to the protein of the 30S subunit, causing the tRNA to make a mistake in synthesizing the mRNA code to synthesize a non-functional protein, thereby inhibiting cell growth.

 Therefore, it is generally believed that the combination of piperacillin and aminoglycoside antibiotics has a good antibacterial synergistic effect. However, since piperacillin is an acidic compound and aminoglycoside antibiotics are alkaline substances, when these two kinds of antibiotics are used in the same container, they will form a precipitate due to salt formation, or an amino group in an aminoglycoside antibiotic. The beta-lactam reaction in piperacillin produces an inactive material which greatly reduces the potency of both. Therefore, it is generally clinically prohibited to use piperacillin in combination with aminoglycoside antibiotics in the same container.

One problem with the piperazine formulation is that the solution is less stable at room temperature, while unstable solutions tend to produce particles, especially When the cryopreserved pylori solution is remelted or the piperazine preparation prepared as a lyophilized powder is reconstituted into a solution, the longer it is left, the more particles are formed. The particles in the solution for intravenous injection are harmful to the patient. Studies have shown that infusion phlebitis is closely related to the amount of granules in the infusion (Remmington's Pharmaceutical Science, 18 Edition, Mark Publishing, 1990, page 1567).

 Further studies have found that the combination of piperazine and aminoglycoside antibiotics is more likely to produce particles, which is another problem to be solved in clinically combining piperacillin with aminoglycoside antibiotics in the same container.

 Therefore, if a compound preparation capable of stabilizing an aminoglycoside antibiotic and piperacillin in the same solution while maintaining the efficacy of the second type antibiotic is not reduced and particles are not easily formed, it is not only convenient in clinical use, but also can be developed. Moreover, the synergistic bactericidal action of the combination of the aminoglycoside antibiotic and piperacillin can be better utilized, and thus it will have great social and economic value.

 The key to the development of a compound preparation that stabilizes the aminoglycoside antibiotic and piperacillin in the same solution while maintaining the efficacy of the second class antibiotic is to find a stable system that not only inhibits aminoglycoside antibiotics and piperacillin. A precipitate is formed in the same solution, and the amino group in the aminoglycoside antibiotic can be completely inhibited from the β-lactam in piperacillin. After systematic research, we found that when the ρΗ value is controlled between 4-8, the aminoglycoside antibiotic and piperacillin form a salt formation reaction in the same solution to form a precipitation phenomenon and an amino group in the aminoglycoside antibiotic and piperacillin. The β-lactam reaction can be inhibited to a certain extent; when the pH value is controlled between 5 and 7.5, the aminoglycoside antibiotic and piperacillin form a salt formation reaction in the same solution to form a precipitation phenomenon and aminoglycosides. The amino group in the antibiotic reacts with the β-lactam in piperacillin to obtain a considerable degree of inhibition; when the pH value is controlled between 6 and 7, the aminoglycoside antibiotic and piperacillin are salt-reacted in the same solution. The formation of a precipitation phenomenon and the reaction of an amino group in an aminoglycoside antibiotic with a β-lactam in piperacillin can be almost completely inhibited.

 Further studies have found that the ion chelating agent can complex a divalent or polyvalent cation represented by zinc ion brought about by an aminoglycoside antibiotic, thereby inhibiting a solution prepared by piperacillin and sulbactam, and The solution is formed into a granule with a solution of an aminoglycoside antibiotic represented by amikacin sulfate injection.

Summary of the invention:

 Accordingly, the present invention discloses an antibiotic combination consisting of piperacillin or a pharmaceutically acceptable salt or hydrate thereof, at least one of the following β-lactamase inhibitors: clavulanic acid or a pharmaceutically acceptable salt thereof or a hydrate, sulbactam or a pharmaceutically acceptable salt or hydrate thereof, and at least one ion chelating agent capable of inhibiting particle formation or at least one antibiotic compound comprising an ion chelating agent capable of inhibiting particle formation and a buffer component . The solution formulation prepared by the compound is clear and transparent, does not form turbidity or precipitate, and can maintain the potency of the piperacillin and β-lactamase inhibitor in the compound for at least 8 hours. Further studies have found that the compound is characterized by being compounded with at least one aminoglycoside antibiotic in the same container, and the resulting complex solution is clear and transparent, does not form turbidity or precipitate, and can maintain the compound in the compound for at least 8 hours. The titer of raccillin and the aminoglycoside antibiotics did not decrease.

Formulations of antibiotics consisting of piperacillin or a pharmaceutically acceptable salt or hydrate thereof, clavulanic acid or sulbactam or a pharmaceutically acceptable salt or hydrate thereof, and at least one buffer component are also found in the study. The resulting solution preparation is clear and transparent, does not form turbidity or precipitate, and can maintain the potency of piperacillin and β-lactamase inhibitor in the compound for at least 8 hours, and can be combined with at least one aminoglycoside antibiotic. When compounded in the same container, the resulting compound solution is clear and transparent, does not form turbidity or precipitate, and can maintain the compound in the compound and the aminoglycoside antibiotics in at least 8 hours. The price does not fall.

 During the research of the present invention, three currently used aminoglycoside antibiotics were selected: etimicin, gentamicin, and amikacin, and these three antibiotics represent three subtypes of aminoglycoside antibiotics, thus having Wide range of representation. Therefore, the aminoglycoside antibiotic in the antibiotic combination of the present invention may be any aminoglycoside antibiotic, including but not limited to Streptomycin, Dibekacin, Kanamycin, Tobramycin^Amikacin, Arbekacin, Gentamicin, Sagamicin, Isopamicin, Sisomi Star (Sisomicin), Netilmicin, Neomycin, Paromoycin, Etimicin, Astromicin, Ribostamycin, Micronomicin, Spectinomycin.

 Two currently used β-lactamase inhibitors were selected in the study of the present invention: clavulanic acid (clavulanic acid) potassium salt and sulbactam sodium salt for the study of the composition.

 In the research process of the present invention, three currently the most commonly used buffer solution systems are selected: a citric acid/citrate system, a phosphoric acid/phosphate system, and an acetic acid/acetate system, and thus have a broad representativeness. Therefore, the buffer solution in the above antibiotic combination may be any buffer solution system, including but not limited to citric acid/citrate system and other polyacid systems, phosphoric acid/phosphate systems and other inorganic acid systems, acetic acid/acetate systems. And other organic acid systems, arginine systems and other amino acid systems, boric acid systems; suitable buffer solutions are citric acid / citrate system, phosphoric acid / phosphate system, acetic acid / acetate system, arginine, Carbonic acid/carbonate system, citric acid/citrate system, Tris-HCl system. Sodium citrate is used as a representative buffer component in the specific formulation of the examples of the present invention.

 The pH of the buffer solution in the antibiotic combination of the present invention ranges from 4 to 8. The pH of the suitable buffer solution ranges from 5.5 to 7.5, and the pH of the most suitable buffer solution ranges from 6 to 6.75.

 The buffer solution in the antibiotic combination of the present invention has a suitable concentration ranging from 1 to 500 mM, a suitable buffer solution having a concentration ranging from 5 to 100 mM, and the most suitable buffer solution having a concentration ranging from 10 to 60 mM.

 The ion chelating agent capable of inhibiting particle formation according to the present invention may be ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylethylenediaminetriacetic acid (HEDTA), or nitrilotriacetic acid ( NTA), or their pharmaceutically acceptable salts or hydrates; suitable ion chelators are EDTA and HEDTA and their sodium salts; the most suitable ion chelating agent is EDTA and its salts or hydrates.

 The antibiotic combination of the present invention includes, but is not limited to, four specific application modes in clinical application: the first method consists of piperacillin sodium, clavulanic acid (clavulanic acid) potassium salt or sulbactam sodium salt, at least one kind The aminoglycoside antibiotic and the buffer solution plus the ion chelating agent constitute an antibiotic compound and can be formulated into a solution preparation for cryopreservation or preparation into a powder needle, a lyophilized powder needle for storage, and used as a solution before use. The solution prepared by the compound is clear and transparent, does not form turbidity or precipitates, and can maintain the potency of the piperacillin and aminoglycoside antibiotics in the compound. The representative formula of the compound (unit dosage) is from 0.1 to 5 grams of piperacillin sodium, 0.1 to 5 grams of sulbactam sodium, 0.1 to 100 milligrams of EDTA, 0.01 to 5 grams of sodium citrate, and 0.01 to 5 grams. Aminoglycoside antibiotic composition.

The second method consists of an antibiotic compound consisting of a compound of lacillin sodium, clavulanic acid (clavulanic acid) potassium salt or sulbactam sodium salt, at least one aminoglycoside antibiotic and an ion chelating agent, and can be formulated into a solution preparation for cryopreservation or preparation. The powdered needle and the lyophilized powder are stored and used as a solution before use. When the compound is formulated into a solution, the buffer component (the most suitable buffer component is citric acid/citrate) is used to adjust the pH to 6-7, and the obtained preparation is clear and transparent, does not form turbidity or precipitate, and can maintain the compound. Piper The potency of ralcillin and aminoglycoside antibiotics did not decrease. The compound representative formula (unit dosage) is composed of 0.1-5 g of piperacillin sodium, 0.1-5 g of sulbactam sodium, 0.1-100 mg of EDTA, and 0.01-5 g of aminoglycoside antibiotic.

 The third method consists of antibiotics consisting of piperacillin sodium, clavulanic acid (clavulanic acid) potassium salt or sulbactam sodium salt plus ion chelating agent, and can be formulated into a solution preparation for cryopreservation or preparation into a powder needle, lyophilized The powder needle is stored and used as a solution before use. If the compound is formulated into a solution and mixed with at least one aminoguanidine antibiotic solution preparation in the same container, the buffer component (the most suitable buffer component is citric acid/citrate) is used to adjust the pH. Up to 6-7, a clear solution formulation, no turbidity or precipitation, can be obtained, and the potency of piperacillin and aminoglycoside antibiotics can be maintained. A representative formulation of the compound (unit dosage) consists of 0.1-5 grams of piperacillin sodium, 0.1-5 grams of sulbactam sodium, 0.1-100 milligrams of EDTA.

 The fourth method consists of piperacillin sodium, clavulanic acid (clavulanic acid) potassium or sulbactam sodium, buffer solution plus ion chelating agent, and can be formulated into a solution preparation for cryopreservation or preparation into powder, lyophilized powder. The needle is stored and used as a solution before use. The solution preparation prepared by the compound is mixed with at least one aminoglycoside antibiotic solution preparation in the same container to obtain a clear and transparent preparation solution which does not form turbidity or precipitate, and can maintain the piperacillin and aminoglycoside antibiotics therein. The titer does not fall. The compound representative formula (unit dosage) is composed of 0.1-5 g of piperacillin, 0.1-5 g of sulbactam sodium, 0.01-5 g of sodium citrate, and 0.1-100 mg of EDTA.

 In addition, antibiotics consisting of piperacillin sodium, clavulanic acid (clavulanic acid) potassium or sulbactam sodium, buffer solution can be formulated into a solution preparation for cryopreservation or preparation into powder needles, freeze-dried powder, preserved before use. Used as a solution. The solution preparation prepared by the compound is mixed with at least one aminoglycoside antibiotic solution preparation in the same container to obtain a clear and transparent preparation solution which does not form turbidity or precipitate, and can maintain the piperacillin and aminoglycoside antibiotics therein. The titer does not fall. The compound representative formula (unit dosage) is composed of 0.1-5 g of piperacillin sodium, 0.1-5 g of sulbactam sodium, 0.01-5 g of sodium citrate; or the direct addition of aminoglycoside antibiotics has been recovered. Formulated with piperacillin sodium and aminoglycoside antibiotics (unit dose) from 0.1-5 grams of piperacillin sodium, 0.01-5 grams of sulbactam sodium, 0.01-5 grams of aminoglycoside antibiotics, 0.01- 5 grams of sodium citrate;

 Possible embodiments of the antibiotic combination of the present invention include the following formulations:

Formulation 1-1 : piperacillin 0.1-5g, sulbactam 0.1-5g, amikacin 0.01-5g, EDTA O.l-lOOmgc

Formulation 1-2: Piperacillin 0.1-5 g, sulbactam 0.1-5 g, gentamicin 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-3: piperacillin 0.1-5 g, sulbactam 0.1-5 g, tobramycin 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-4: Piperacillin 0.1-4 g, sulbactam 0.1-5 g, etimicin 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-5: piperacillin 0.1-5 g, sulbactam 0.1-5 g, dibekacin 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-6: Piperacillin 0.1-5 g, sulbactam 0.1-5 g, arbekacin 0.01-5 g, EDTA 0.1 -100 mg.

Formulation 1-7: piperacillin 0.1-5 g, sulbactam 0.1-5 g, kanamycin 0.01-5 g, EDTA 0.1 -100 mg.

Formulation 1-8: piperacillin 0.1-5 g, sulbactam 0.1-5 g, sagasidine 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-9: Piperacillin 0.1-5 g, sulbactam 0.1-5 g, isepamicin 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-10: piperacillin 0.1-5 g, sulbactam 0.1-5 g, neomycin 0.01-5 g, EDTA 0.1 -100 mg.

Formulation 1-11: piperacillin 0.1-5 g, sulbactam 0.1-5 g, paromomycin 0.01-5 g, EDTA 0.1_100 mg.

 Formulation 1-12: piperacillin 0.1-5 g, sulbactam 0.1-5 g, sisoka star 0.01-5 g, EDTA 0.1 -100 mg.

Formulation 1-13: piperacillin 0.1-5 g, sulbactam 0.1-5 g, netilmicin 0.01-5 g, and EDTA 0.1-100 mg. Formulation 1-14: Piperacillin sodium 0.1-5g, sodium clavulanate 0. Amikacin 0.0 EDTA Ol-lOOmgc Formulation 1-15: Piperacillin sodium 0.1-5g, sodium clavulanate 0. -5g Dacmycin 0.0 EDTA Ol-lOOmgc Formulation 1-16: Piperacillin sodium 0.1-5g, sodium clavulanate 0. -5g Tobramycin 0.0 -5g, EDTA Ol-lOOmgc Formulation 1-17: Piperacillin sodium 0.1-5g, potassium clavulanate 0. "5g etimicin 0.0 -5g, EDTA Ol-lOOmgc Formulation 1-18: Piperacillin sodium 0.1-5g, sodium clavulanate 0. -5g Dibekacin 0.0 -5g, EDTA 0.1-100mg Formulation 1-19: Piperacillin sodium 0.1-5g, sodium clavulanate 0. -5g Abbekacin 0.0 -5g, EDTAO.l-lOOmgo Formulation 1-20: Piperacillin Sodium 0.1-5g, sodium clavulanate 0. -5g kanamycin 0.0 -5g, EDTA 0.1-100mg. Formulation 1-21: piperacillin sodium 0.1-5g, sodium clavulanate 0. -5g 0.0-5g, EDTA Ol-lOOmg. Formulation 1-22: Piperacillin sodium 0.1-5g, sodium clavulanate 0. -5g Isepamicin 0.0 -5g, EDTA Ol-lOOmgc Formulation 1-23 : Pipera Xilin sodium 0.1-5g, sodium clavulanate 0. -5g neomycin 0.01 - g, EDTA Ol-lOOmgc formula 1-24: piperacillin sodium 0.1-5g, g Sodium citrate 0. -5g Paromomycin 0.0 g, EDTA Ol-lOOmgo Formulation 1-25: Piperacillin sodium 0.1-5 g, sodium clavulanate 0. Soxacin 0.0 g, EDTA Ol-lOOmgo Formulation 1 -26: piperacillin sodium 0.1-5 g, sodium clavulanate 0-5 g, netilmicin 10-5000 mg, EDTA Ol-lOOmgc, formula 1-27: piperacillin sodium 0.1-5 g, sulbactam 0.1- 4 g, amikacin sulfate 0.01-5 g, citric acid 0.01-5 g, sodium citrate 10-5000 mg, EDTA 0.1-100 mg.

Formulation 1-28: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, gentamicin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA O.l-lOOmgc

Formulation 1-29: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, tobramycin 0.01-5g, citric acid 0.01-5g, sodium citrate

10-5000mg, EDTA O.l-lOOmgc

Formulation 1-30: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, etimicin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA 0.1-100mg _o

Formulation 1-31 : Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, pebekacin 0.01-5g, citric acid 0.01-5g, uranyl citrate

0.01-5g, EDTA O.l-lOOmgc

Formulation 1-32: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, arbekacin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA O.l-lOOmgo

Formulation 1-33 : Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, kanamycin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-34: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, salicin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-35 : Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, isepamicin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA O.l-lOOmgc

Formulation 1-36: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g Neomycin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA O.l-lOOmgc

Formulation 1-37: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, paromomycin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA O.l-lOOmgc

Formulation 1-38: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, soxacin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA Ol-lOOmgc Formula 1-39: piperacillin sodium 0.1-5g, sulbactam 0.1-4g, netilmicin 0.01-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA 0.1-1 OOmgc

Formulation 1-40: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, EDTA O.l-lOOmgo

Formulation 1-41: piperacillin sodium 0.1-5 g, sulbactam 0.1-4 g, etimicin 0.01-5 g, sodium dihydrogen phosphate 0.01-5 g, sodium monohydrogen phosphate 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-42: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, gentamicin 0.01-5g, sodium phosphate monophosphate 0.01-5g, sodium monohydrogen phosphate 0.01-5g, EDTA O.l-lOOmgo

Formulation 1-43: piperacillin sodium 0.1-5g, sulbactam 0.1-4g, gentamicin 0.01-5g, sodium acetate 0.01-5g, acetic acid 0.01-5g,

EDTA O.l-lOOmgo

Formulation 1-44: Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, gentamicin 0.01-5g, benzoic acid 0.02-5g, EDTA 0.1-lOOmgo

Formulation 1-45: Piperacillin sodium 0.1-5 g, potassium clavulanate 0.1-4 g, gentamicin 0.01-5 g, benzoic acid 0.02-5 g, EDTA 0.1-100 mg.

Formulation 1-46: piperacillin sodium 0.1-5 g, sulbactam sodium 0.1-4 g, arginine 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-47: Piperacillin sodium 0.1-5g, sulbactam sodium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-lOOmgo

Formulation 1-48: Piperacillin sodium 0.1-5g, sulbactam sodium 0.1-4g, levulose 0.02-5g, citric acid 0.01-5g, sodium citrate

0.01-5g, EDTA O.l-lOOmgo

Formulation 1-49: Piperacillin sodium 0.1-5 g, sulbactam sodium 0.1-4 g, levulose 0.02-5 g, EDTA 0.1-100 mg.

Formulation 1-50: piperacillin sodium 0.1-5 g, potassium clavulanate 0.1-4 g, citric acid 0.01-5 g, sodium citrate 0.02-5 g, EDTA

Formulation 1-51 : Piperacillin sodium 0.1-5g, potassium clavulanate 0.1-4g, EDTA O.l-lOOmgo

Formulation 1-52: piperacillin sodium 0.1-5 g, potassium clavulanate 0.1-4 g, levulose 0.01-5 g, citric acid 0.01-5 g, sodium citrate 0.01-5 g, EDTA 0.1-100 mg.

Formulation 1-53: piperacillin sodium 0.1-5 g, potassium clavulanate 0.1-4 g, levulose 0.01-5 g, EDTA 0.1 -100 mg. Formulation 1-54: Piperacillin sodium 0.1-5 g, sulbactam sodium 0.1-4 g, amikacin sulfate 0.01-5 g, citric acid 0.01-5 g, and sodium citrate 0.01-5 g.

Formulation 1-55: Piperacillin sodium 0.1-5 g, sulbactam sodium 0J-4 g, gentamicin 0.01-5 g, citric acid 0.01-5 g, sodium citrate 0.01-5 g.

Formulation 1-56: Piperacillin sodium 0.1-5 g, sulbactam sodium 0.1-4 g, tobramycin 0.01-5 g, citric acid 0.01-5 g, sodium citrate 0.01-5 g.

Formulation 1-57: Piperacillin sodium 0.1-5 g, sulbactam sodium 0.1-4 g, etimicin 0.01-5 g, citric acid 0.01-5 g, sodium citrate 0.01-5 g.

Formulation 1-58: piperacillin sodium 0.1-5 g, sulbactam sodium 0.1-4 g, debekacin 0.01-5 g, citric acid 0.01-5 g, and sodium citrate 0.01-5 g.

Formula 1-59: piperacillin sodium 0.1-5g, sulbactam sodium 0.1-4g, arbekacin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5go Formulated piperacillin sodium, sulbactam sodium, kanamycin, citric acid, sodium citrate.

Formulation piperacillin sodium, sulbactam sodium, sagamycin, citric acid, sodium citrate

Formulation Piperacillin sodium, sulbactam sodium, isepamicin, citric acid, sodium citrate.

Formulation Piperacillin sodium, sulbactam sodium, neomycin, citric acid, sodium citrate.

Formulation Piperacillin sodium, sulbactam sodium, paromomycin, citric acid, sodium citrate.

Formulation Piperacillin sodium, sulbactam sodium, saxacin, citric acid, sodium citrate.

Formulation Piperacillin sodium, sulbactam sodium, netilmicin, citric acid, sodium citrate.

Formulation Piperacillin sodium, sulbactam sodium, citric acid, sodium citrate.

Formulation Piperacillin sodium, sulbactam sodium, citric acid, sodium citrate, levulose.

Formulation Piperacillin sodium, potassium clavulanate, citric acid, sodium citrate. Formulation Piperacillin sodium, potassium clavulanate, amikacin sulfate, citric acid, sodium citrate.

Formulation Piperacillin sodium, potassium clavulanate, gentamicin, citric acid, sodium citrate.

Formulation piperacillin sodium, clavulanate potassium, tobramycin, citric acid, sodium citrate

Formulation Piperacillin sodium, potassium clavulanate, etimicin, citric acid, sodium citrate.

Formulation Piperacillin sodium, potassium clavulanate, citric acid, sodium citrate, and levulose.

 The antibiotic combination of the present invention is representative of specific formulations that can be directly used in clinical practice (all unit dosages) including but not limited to:

Formulation Piperacillin sodium, sulbactam sodium, EDTA disodium lmg.

Formulation 2-2: Piperacillin sodium 4 g, sulbactam sodium lg, EDTA disodium lmg.

Formulation 2-3: piperacillin sodium 4 g, sulbactam sodium 2 g, EDTA disodium lmg.

 Formulation 2-4: Piperacillin sodium 4g, sulbactam sodium 4g, EDTA disodium lmg.

 Formulation 2-5: piperacillin sodium 4 g, sulbactam sodium lg, EDTA disodium lmg, sodium citrate 0.25 g.

 Formulation 2-6: Piperacillin sodium 4g, sulbactam sodium 0.5g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-7: piperacillin sodium 4 g, sulbactam sodium 2 g, EDTA disodium 1 mg, and sodium citrate 0.25 g. Formulation 2-8: piperacillin sodium 4 g, sulbactam uranium 4 _g , EDTA disodium l mg, sodium citrate 0.25 g.

Formulation 2-9: piperacillin sodium 4 g, sulbactam sodium 0.5 g, etimicin sulfate 0.2 g, EDTA disodium lmg.

Formulation 2-10: piperacillin sodium 4g, sulbactam sodium lg, etimicin sulfate 0.2g, EDTA disodium lmg.

Formulation 2-11: piperacillin sodium 4 g, sulbactam sodium 2 g, etimicin sulfate 0.2 g, EDTA disodium lmg.

Formulation 2-12: piperacillin sodium 4 g, sulbactam sodium 4 g, etimicin sulfate 0.2 g, EDTA disodium lmg.

Formulation 2-13: piperacillin sodium 4g, sulbactam sodium lg, etimicin sulfate 0.2g, EDTA disodium 1mg, sodium citrate formula 2-14: piperacillin sodium 4g, sulbactam sodium 0.5g , etimicin sulfate 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.

Formulation 2-15: piperacillin sodium 4g, sulbactam sodium 2g, etimicin sulfate 0.2g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-16: piperacillin sodium 4g, sulbactam sodium 4g, etimicin sulfate 0.2g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-17: piperacillin sodium 4g, sulbactam sodium 0.5g, amikacin sulfate 0.5g, EDTA disodium lmg.

Formulation 2-18: piperacillin sodium 4g, sulbactam sodium lg, amikacin sulfate 0.5g, EDTA disodium lmg.

Formulation 2-19: piperacillin sodium 4g, sulbactam sodium 2g, amikacin sulfate 0.5g, EDTA disodium lmg.

Formulation 2-20: piperacillin sodium 4g, sulbactam sodium 4g, amikacin sulfate 0.5g, EDTA disodium lmg.

Formulation 2-21: piperacillin sodium 4g, sulbactam sodium lg, amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate formula 2-22: piperacillin sodium 4g, sulbactam sodium 0.5g , amikacin sulfate 0.5g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-23: piperacillin sodium 4g, sulbactam sodium 2g, amikacin sulfate 0.5g, EDTA disodium lmg, sodium citrate formula 2-24: piperacillin sodium 4g, sulbactam sodium 4g, Amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate formula 2-25: piperacillin sodium 4g, sulbactam sodium 0.5g, gentamicin sulfate 0.16g, EDTA disodium lmg.

Formulation 2-26: piperacillin sodium 4g, sulbactam sodium lg, gentamicin sulfate 0.16g, EDTA disodium lmg.

Formulation 2-27: piperacillin sodium 4g, sulbactam sodium 2g, gentamicin sulfate 0.16g, EDTA disodium lmg.

Formulation 2-28: piperacillin sodium 4g, sulbactam sodium 4g, gentamicin sulfate 0.16g, EDTA disodium lmg.

Formulation 2-29: piperacillin sodium 4g, sulbactam sodium lg, gentamicin sulfate 0.16g, EDTA disodium lmg, sodium citrate 0.25g _o

Formulation 2-30: piperacillin sodium 4 g, sulbactam sodium 0.5 g, gentamicin sulfate 0.16 g, EDTA disodium lmg, sodium citrate 0.25 g.

Formulation 2-31: Piperacillin sodium 4g, sulbactam sodium 2g, gentamicin sulfate 0.16g, EDTA disodium lmg, sodium citrate 0.25g.

Formula 2-32: piperacillin sodium 4g, sulbactam sodium 4g, gentamicin sulfate 0.16g, EDTA disodium lmg, sodium citrate Formula 2-33: piperacillin sodium 4 g, sulbactam sodium 0.5 g, tobramycin 0.2 g, and EDTA disodium 1 mg.

Formula 2-34: piperacillin sodium 4 g, _t- sulbactam sodium lg, tobramycin 0.2 g, EDTA disodium 1 mg.

Formulation 2-35: Piperacillin sodium 4g, sulbactam sodium 2g, tobramycin 0.2g, EDTA disodium lmg.

Formulation 2-36: Piperacillin sodium 4g, sulbactam sodium 4g, tobramycin 0.2g, EDTA disodium lmg.

Formulation 2-37: Piperacillin sodium 4g, sulbactam sodium lg, tobramycin 0.2g, EDTA disodium lmg, sodium citrate 0.25g. Formulation 2-38: piperacillin sodium 4 g, sulbactam sodium 0.5 g, tobramycin 0.2 g, EDTA disodium lmg, sodium citrate 0.25 g. Formulation 2-39: Piperacillin sodium 4 g, sulbactam sodium 2 g, tobramycin 0.2 g, EDTA disodium lmg, sodium citrate 0.25 g. Formulation 2-40: piperacillin sodium 4 g, sulbactam sodium 4 g, tobramycin 0.2 g, EDTA disodium lmg, sodium citrate 0.25 g. Formulation 2-41: Piperacillin sodium 3⁄4, . Sulbactam sodium 0.25g, EDTA disodium lmg.

Formulation 2-42: Piperacillin sodium 2g, . Sulbactam sodium 0.5g, EDTA disodium lmg.

Formulation 2-43: Piperacillin sodium 2g, sulbactam sodium lg, EDTA disodium lmg.

Formulation 2-44: Piperacillin sodium 2g, sulbactam sodium 2g, EDTA disodium lmg.

Formulation 2-45: Piperacillin sodium 2g, sulbactam sodium 0.5g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-46: Piperacillin sodium 2g, sulbactam sodium 0.25g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-47: Piperacillin sodium 2g, sulbactam sodium lg, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-48: piperacillin sodium 2 g, sulbactam sodium 2 g, EDTA disodium 1 mg, sodium citrate 0.25 _g .

Formulation 2-49: Piperacillin sodium lg, sulbactam sodium 0.5g, EDTA disodium lmg.

Formulation 2-50: Piperacillin sodium lg, sulbactam sodium lg, EDTA disodium lmg.

Formulation 2-51 : Piperacillin sodium lg, sulbactam sodium 0.25g, EDTA disodium lmg.

Formulation 2-52: Piperacillin sodium lg, sulbactam sodium 1.25g, EDTA disodium lmg.

Formulation 2-53 : Piperacillin sodium lg, sulbactam sodium lg, EDTA disodium lmg, sodium citrate 0.2g.

Formulation 2-54: Piperacillin sodium lg, sulbactam sodium 0.5g, EDTA disodium lmg, sodium citrate 0.2g.

Formulation 2-55: Piperacillin sodium lg, sulbactam sodium 0.25g, EDTA disodium lmg, sodium citrate 0.2g.

Formulation 2-56: Piperacillin sodium lg, sulbactam sodium 0.125 g, EDTA disodium lmg, sodium citrate 0.2 g.

Formulation 2-57: Piperacillin sodium 4g-, potassium clavulanate 0.5g, disodium EDTA lmg.

Formulation 2-58: Piperacillin sodium 4g-, potassium clavulanate lg, disodium EDTA lmg.

Formulation 2-59: Piperacillin sodium 4g-, potassium clavulanate 2g, disodium EDTA lmg.

Formulation 2-60: Piperacillin sodium 4g-, potassium clavulanate 4g, disodium EDTA lmg.

 Formulation 2-61 : Piperacillin sodium 4g., Clavulanate potassium lg, EDTA disodium lmg, Sodium citrate 0.25g.

 Formulation 2-62: Piperacillin sodium 4g., Clavulanate potassium 0.5g, EDTA disodium lmg, Sodium citrate 0.25g.

 Formulation 2-63 : Piperacillin sodium 4g., Clavulanate potassium 2g, EDTA disodium lmg, Sodium citrate 0.25g.

 Formulation 2-64: Piperacillin sodium 4g. Potassium clavulanate 4g, disodium EDTA lmg, sodium citrate 0.25g.

 Formulation 2-65: Piperacillin sodium 4g. Potassium clavulanate 0.5g, etimicin sulfate 0.2g, EDTA disodium lmg. Formulation 2-66: Piperacillin sodium 4g. Potassium clavulanate lg, etimicin sulfate 0.2g, sodium EDTA lmg.

 Formulation 2-67: Piperacillin sodium 4 g Potassium clavulanate 2 g, etimicin sulfate 0.2 g, sodium EDTA 1 mg.

 Formulation 2-68: Piperacillin sodium 4 g Potassium clavulanate 4 g, etimicin sulfate 0.2 g, sodium EDTA 1 mg.

Formulation 2-69: Piperacillin sodium 4g Potassium clavulanate lg, etimicin sulfate 0.2g, EDTA sodium 1mg, sodium citrate 0

Formulation 2-70: piperacillin sodium 4g, clavulanate potassium 0.5g, etimicin sulfate 0.2g, EDTA sodium lmg, sodium citrate 0.25g.

Formulation 2-71: piperacillin sodium 4g, clavulanate potassium 2g, etimicin sulfate 200mg, EDTA sodium lmg, sodium citrate 0.25g.

Formulation 2-72: piperacillin sodium 4g, clavulanate potassium 4g, etimicin sulfate 0.2g, EDTA sodium lmg, sodium citrate 0.25g.

Formulation -73 : Piperacillin sodium 4g, potassium clavulanate 0.5g, amikacin sulfate 0.5g, EDTA sodium lmg.

Formulation 2-74: Piperacillin sodium 4g, potassium clavulanate lg, amikacin sulfate 0.5g, EDTA sodium lmg.

Formulation 2-75: piperacillin sodium 4g, clavulanate potassium 2g, amikacin sulfate 0.5g, EDTA sodium lmg.

Formulation 2-76: piperacillin sodium 4g, clavulanate potassium 4g, amikacin sulfate 0.5g, EDTA sodium lmg.

Formulation 2-77: piperacillin sodium 4g, clavulanate potassium lg, amikacin sulfate 0.5g, EDTA sodium lmg, sodium citrate 0.25g.

Formulation 2-78: piperacillin sodium 4g, clavulanate potassium 0.5g, amikacin sulfate 0.5g, EDTA sodium lmg, sodium citrate 0.25g.

Formula 2-79: Piperacillin sodium 4g, Clavulanate potassium 2g, Amikacin sulfate 0.5g, EDTA sodium 1mg, Sodium citrate formula 2-80: Indocillin sodium 4g, Clavulanate potassium 4g, Sulfuric acid Amikacin 0.5g, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-81 : Piperacillin sodium 4g, potassium clavulanate 0.5g, gentamicin 80mg, EDTA sodium 1mg.

Formulation 2-82: piperacillin sodium 4g, clavulanate potassium lg, gentamicin sulfate 80mg, EDTA sodium lmg.

Formulation 2-83: piperacillin sodium 4g, clavulanate potassium 2g, gentamicin sulfate 80mg, EDTA disodium lmg.

Formulation 2-84: piperacillin sodium 4g, clavulanate potassium 4g, gentamicin sulfate 80mg, EDTA disodium lmg.

Formulation 2-85: Piperacillin sodium 4g, potassium clavulanate lg, gentamicin 80mg, EDTA disodium lmg, citric acid nano 0.25g.

Formulation 2-86: Piperacillin sodium 4g, potassium clavulanate 0.5g, gentamicin 80mg, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-87: piperacillin sodium 4g, clavulanate potassium 2g, gentamicin sulfate 80mg, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-88: piperacillin sodium 4g, clavulanate potassium 4g, gentamicin sulfate 80mg, EDTA disodium lmg, sodium citrate 0.25g.

Formulation 2-89: Piperacillin sodium 4 g, potassium clavulanate 0.5 g, tobramycin 0.2 g, EDTA: disodium lmg.

Formulation 2-90: piperacillin sodium 4g, clavulanate potassium lg, tobramycin 200mg, EDTA disodium lmg.

Formulation 2-91 : Piperacillin sodium 4g, potassium clavulanate 2g, tobramycin 200mg, EDTA. disodium lmg.

Formulation 2-92: Piperacillin sodium 4g, potassium clavulanate 4g, tobramycin 200mg, EDTA disodium lmg.

Formula 2-93: Piperacillin sodium 4g, potassium clavulanate lg, tobramycin 200mg, disodium EDTA lmg, sodium citrate

0.25g. Formulation 2-94: 4 g of piperacillin sodium, 0.5 g of potassium clavulanate, 200 mg of tobramycin, 1 mg of disodium EDTA, and 0.25 g of sodium citrate.

Formulation 2-95: piperacillin sodium 4g, clavulanate potassium 2g, tobramycin 200mg, EDTA disodium lmg, sodium citrate formula 2-96: piperacillin sodium 4g, clavulanate potassium 4g, refractory 200 mg of mycin, 1 mg of disodium EDTA, and 0.25 g of sodium citrate.

Formulation 2-97: Piperacillin sodium 2g, clavulanate potassium 0.25g, EDTA disodium lmg.

Formulation 2-98: Piperacillin sodium 2g, potassium clavulanate 0.5g, disodium EDTA lmg.

Formulation 2-99: Piperacillin sodium 2g, potassium clavulanate lg, disodium EDTA lmg.

Formulation 2-100: Piperacillin sodium 2g, Clavulanate potassium 2g, EDTA disodium lmg.

Formulation 2-101 : Piperacillin sodium 2g, potassium clavulanate 0.5g, sodium EDTA lmg, sodium citrate 0.25g.

Formulation 2-102: Piperacillin sodium 2g, potassium clavulanate 0.25g, sodium EDTA lmg, sodium citrate 0.25g.

Formulation 2-103: Piperacillin sodium 2g, potassium clavulanate lg, sodium EDTA lmg, sodium citrate 0.25g.

Formulation 2-104: Piperacillin sodium 2g, potassium clavulanate 2g, sodium EDTA lmg, sodium citrate 0.25g.

Formulation 2-105: Piperacillin sodium lg, potassium clavulanate 0.5g, sodium EDTA lmg.

Formulation 2-106: Piperacillin sodium lg, potassium clavulanate lg, disodium EDTA lmg.

Formulation 2-107: Piperacillin sodium lg, potassium clavulanate 0.25g, disodium EDTA lmg.

Formulation 2-108: Piperacillin sodium lg, potassium clavulanate 0.125 g, disodium EDTA lmg.

Formulation 2-109: Piperacillin sodium lg, potassium clavulanate lg, disodium EDTA lmg, sodium citrate 0.2g.

Formulation 2-110: Piperacillin sodium lg, potassium clavulanate 0.5g, disodium EDTA lmg, sodium citrate 0.2g.

Formulation 2-111 : Piperacillin sodium lg, potassium clavulanate 0.25g, sodium EDTA lmg, sodium citrate 0.2g.

Formulation 2-112: Piperacillin sodium lg, potassium clavulanate 0.125 g, disodium EDTA lmg, citric acid 0.2 g.

Formulation 2-113 : Piperacillin sodium 4 g, potassium clavulanate lg, sodium citrate 0.2 g.

Formulation 2-114: Piperacillin sodium 4g, potassium clavulanate 0.5g, sodium citrate 0.2g.

Formulation 2-115: Piperacillin sodium 4g, potassium clavulanate 2g, sodium citrate 0.2g.

Formulation 2-116: Piperacillin sodium lg, potassium clavulanate 0.125 g, sodium citrate 0.2 g.

Formulation 2-117: Piperacillin sodium lg, potassium clavulanate 0.25g, sodium citrate 0.2g.

Formulation 2-118: Piperacillin sodium lg, potassium clavulanate 0.5g, sodium citrate 0.2g.

Formulation 2-119: Piperacillin sodium 2 g, potassium clavulanate 0.25 g, sodium citrate 0.2 g.

Formulation 2-120: Piperacillin sodium 2g, potassium clavulanate 0.5g, sodium citrate 0.2g.

Formulation 2-121 : Piperacillin sodium 2 g, potassium clavulanate 1.0 g, sodium citrate 0.2 g.

Formulation 2-122: Piperacillin sodium 4g, sulbactam sodium lg, sodium citrate 0.2g.

Formulation 2-123 : Piperacillin sodium 4g, sulbactam sodium 0.5g, sodium citrate 0.2g.

Formulation 2-124: Piperacillin sodium 4g, sulbactam sodium 2g, sodium citrate 0.2g.

 Formulation 2-125: Piperacillin sodium lg, sulbactam sodium 0.125 g, sodium citrate 0.2 g.

 Formulation 2-126: Piperacillin sodium lg, sulbactam sodium 0.25g, sodium citrate 0.2g.

Formulation 2-127: piperacillin sodium lg, sulbactam sodium 0.5 g, sodium citrate 0.2 g. Formulation 2-128: 2 parts of piperacillin sodium, 0.25 g of sulbactam sodium, and 0.2 g of sodium citrate.

Formulation 2-129: Piperacillin sodium 2g, sulbactam sodium 0.5g, sodium citrate 0.2g.

Formulation 2-130: Piperacillin sodium 2 g, sulbactam sodium 1.0 g, sodium citrate 0.2 g.

Formulation 2-131 : Piperacillin sodium 4g, sulbactam sodium lg, gentamicin sulfate 0.16g, sodium citrate 0.2g.

Formulation 2-132: Piperacillin sodium 4g, sulbactam sodium 0.5g, gentamicin sulfate 0.16g, sodium citrate 0.2g.

Formulation 2-133 : Piperacillin sodium 4 g, sulbactam sodium 2 g, gentamicin sulfate 0.16 g, and sodium citrate 0.2 g.

Formulation 2-134: Piperacillin sodium 4g, sulbactam sodium lg, amikacin sulfate 0.5g, sodium citrate 0.2g.

Formulation 2-135 : Piperacillin sodium 4g, sulbactam sodium 0.5g, amikacin sulfate 0.5g, sodium citrate 0.2g.

Formulation 2-136: Piperacillin sodium 4g, sulbactam sodium 2g, amikacin sulfate 0.5g, sodium citrate 0.2g.

Formulation 2-137: Piperacillin sodium 4g, sulbactam sodium l g, etimicin sulfate 0.2g, sodium citrate 0.2g.

Formulation 2-138: Piperacillin sodium 4 g, sulbactam sodium 0.5 g, etimicin sulfate 0.2 g, sodium citrate 0.2 g.

Formulation 2-139: Lasilizine sodium 4g, sulbactam sodium 2g, etimicin sulfate 0.2g, sodium citrate 0.2g.

 The antibiotic combination of the present invention can be used as an injection solution by using an isotonic solution for injection, including but not limited to a levosaccharide solution, a glucose solution and physiological saline. The amount of levulose, glucose or sodium chloride used in the unit dosage is 0.1-20 g; the concentration in the injection is 0.1-10%.

 Any combination of gentamicin, amikacin, etimicin and piperacillin sodium, clavulanic acid potassium or sulbactam sodium can be arbitrarily selected in three possible formulations and preservation methods. Component compatibility and stability studies were performed. The results show that the prepared solution preparation is used after being prepared for use, formulated into a solution preparation, frozen and thawed, added with aminoglycoside antibiotics, or prepared into a lyophilized powder needle, then stored at a low temperature and then reconstituted into a solution preparation. After adding aminoglycoside antibiotics, the content of piperacillin, sulbactam or clavulanic acid and aminoglycoside antibiotics can be maintained in more than 90% in three ways, some of which can make the content of each component above More than 95%, reached the index of clinical use of multiple drugs. In addition, the results of the study indicate that EDTA can significantly inhibit the formation of particles in the solution after the formulation of the present invention is formulated into a solution preparation, thereby enabling the patient to use the antibiotic formula of the present invention to treat diseases of microbial infections by intravenous injection. Safe, while patients and doctors have the option of using both piperacillin and aminoglycoside antibiotics, thus not only making the treatment more effective, but also potentially avoiding the possibility of resistance to a single type of antibiotic Sex, so there is a greater possibility of avoiding the first treatment failure.

 When the antibiotic compound of the present invention is prepared into a solution preparation, it can be used as a microorganism for controlled use as an injection solution, an eye drop, a nasal drop, an ear drop, a genital tract drop or lotion, or a topical solution.

 When the antibiotic compound prepared by the invention is prepared into a solution preparation, it can be prepared immediately before use, or prepared and packaged in advance for cryopreservation, and is used after being melted at room temperature and raised to room temperature.

 The antibiotic compound of the invention can also be prepared into a powder needle or a freeze-dried powder needle for refrigerated storage, and can be used as a solution immediately after use.

 When the antibiotic compound of the present invention is prepared into a solution preparation, a powder needle or a lyophilized powder needle, other pharmaceutically acceptable pharmaceutical excipients may be added.

The present invention includes a method for preparing the antibiotic lyophilized powder needle: dissolving piperacillin sodium, sulbactam sodium or potassium clavulanate, EDTA disodium, and other excipients of the antibiotic compound of the present invention in water for injection or The pH of the solution is adjusted to 6-6.75 by using 2.5% aqueous solution of levoose or 5% normal saline for injection; the prepared solution is divided into the above-mentioned possible specific formula 2-1 To the unit shown in the specific formula 2-139, the dosage of the drug solution is placed in a container and placed in a freeze dryer, the temperature of the freeze dryer is adjusted to minus 35 ° C; the vacuum of the freeze dryer is pumped to 40 Pa The following: Adjust the temperature of the freeze dryer to 3-5 °C to remove the water; adjust the temperature of the freeze dryer to 40-50 °C to dry the obtained frozen powder needle, and fill it with dry nitrogen and then cover it aseptically. Store at a temperature below 5 °C in the dark.

 Table 1 lists some of the HIAC test results. The test data demonstrates that EDTA is effective in inhibiting the production of particles when the antibiotic combination of the present invention is formulated into a solution formulation. DETAILED DESCRIPTION OF THE INVENTION - The contents of piperacillin sodium, sulbactam sodium and potassium clavulanate are determined by C18 reverse phase liquid chromatography using a UV detector (Tianjin Hemei Biotechnology Co., Ltd. Analytical Method No.: Analytical Method HM-K -02); The content of aminoglycoside antibiotics was determined by acid-resistant reversed-phase high pressure liquid chromatography using an evaporation-light scattering detector (ELSD detector) (Tianjin Hemei Biotechnology Co., Ltd. Analytical Method No.: Analytical Method HM-K -08). The content of antibiotics in the compound at each time point in the solution is characterized by the percentage of the average concentration of the sample with the same concentration of three components of each component (the content is defined as 100%), and the antibiotic components in the compound are at each time. The relative amount of dots is defined by the ratio of the corresponding peak areas in the chromatogram.

 Example 1

Formulation: Piperacillin sodium 4g, sulbactam sodium 0.5g, gentamicin 80mg/2mL injection.

Preparation method: Piperacillin sodium and sulbactam sodium were dissolved in lOOmL water for injection, and gentamicin injection was added to immediately produce a large amount of white precipitate. After 15 minutes of ultrasound, the precipitate did not disappear. Example 2

 Piperacillin sodium 40 mg, sulbactam sodium 5 mg was dissolved in 2 mL of various pH and strength buffers, and gentamicin 80 mg / 2 mL injection solution was added dropwise 20 μί. Ultrasound was observed for 5 minutes to observe the presence or absence of precipitation. As a result, the pH of the buffer was not more than 6 and a clear solution was obtained. The type of the buffer had little effect on the results. See the table below for the results.

 Buffer Type Buffer pH Buffer Concentration (mM) Observations

 Citric Acid / Sodium Citrate 5 10 ***

 Citric acid / sodium citrate 5.5 10

 Citric Acid / Sodium Citrate 6 10 OK

 Citric Acid / Sodium Citrate 6 20 OK

 Citric acid / sodium citrate 6.5 10 O

 Citric Acid / Sodium Citrate 7 10 OK

 Citric Acid / Sodium Citrate 6 30 OK

 Acetic acid / sodium acetate 6.5 20 OK

 Phosphoric acid / disodium hydrogen phosphate 6.5 20 OK

 *The solution becomes slightly turbid **The solution becomes cloudy. ***The solution is cloudy. OK clear solution Example 3A

Piperacillin sodium 40 mg, sulbactam sodium 5 mg, EDTA sodium O.Olmg were dissolved in 2 mL of various pH and strength buffers, and gentamicin 80 mg / 2 mL injection solution was added dropwise to 20 μί. Ultrasound for 5 minutes, observe the presence or absence of precipitation, the result is slow When the pH of the flushing liquid is above 6 and no precipitation is formed, a clear solution can be obtained, and the type of the buffer solution has little effect on the result. See the table below for the results.

 Buffer Type : Buffer pH Buffer Concentration (mM) Observations

 Citric Acid / Sodium Citrate 5.5 10 **

 Citric Acid / Sodium Citrate 6 10 OK

 Citric Acid / Sodium Citrate 6.5 10 OK

 Citric Acid / Sodium Citrate 7 10 OK

 Citric Acid / Sodium Citrate 6.5 20 OK

 *The solution becomes slightly turbid **The solution becomes cloudy. ***The solution is turbid. OK Clear solution Example 3B

 Piperacillin sodium 40 mg, potassium clavulanate 5 mg, sodium EDTA O. Olmg was dissolved in 2 mL of various pH and strength buffers, and 20 L of gentamicin 80 mg / 2 mL injection was added dropwise. After 5 minutes of ultrasound, the presence or absence of precipitation was observed. As a result, the pH of the buffer was above 6 without precipitation, and a clear solution was obtained. The type of the buffer had little effect on the results. The results are shown in the table below.

 Buffer Type Buffer pH Buffer Concentration (mM) Observation

 Citric Acid / Sodium Citrate 6 10 OK

 Citric Acid / Sodium Citrate 6.5 10 OK

 Citric Acid / Sodium Citrate 7 10 OK

 *The solution becomes slightly turbid **The solution becomes cloudy and the solution is cloudy. OK clear liquid

 Example 4

 Formulation: piperacillin sodium 4g, sulbactam sodium 0.5g, EDTA disodium lmg, sodium citrate 0.20g, gentamicin 80mg/2mL injection.

实施例 5 Preparation method: Piperacillin sodium, sulbactam sodium and sodium citrate are dissolved in 200mL of water for injection, pH is adjusted to 6.5 with citric acid or sodium hydroxide aqueous solution, and gentamicin sulfate injection is added dropwise during shaking to produce a small amount. A flocculent white precipitate was obtained, and after 5 minutes of sonication, the white precipitate was dissolved to obtain a clear solution. Store in a drop bottle or drip bag and store at room temperature. Determine the HIAC data for 1 and 20 hours (see Table 1). Observe the presence of precipitate at 0, 1, 2, 4, 6 hours, and sample and analyze piperacillin. The contents of sodium and sulbactam sodium are shown in the table below.

Example 5

 Formulation: Piperacillin sodium 4g, sulbactam sodium 0.5g, EDTA disodium lmg, sodium citrate 0.20g, etimicin sulfate 200mg.

Preparation method: piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 200mL water for injection, pH adjusted to 6.0 with citric acid or sodium hydroxide solution, add etimicin sulfate 200mg, sonication for 10 minutes Transparent solution Liquid. After filtration (0.2 μm), packaged in a drop bottle or drip bag and stored at room temperature. Determine the HIAC data for 1 and 20 hours (see Table 1). Observe the presence or absence at 0, 1, 2, 4, 6, 8 hours. The sample was analyzed and sampled and analyzed for piperacillin and sulbactam sodium content (% content). The results are shown in the table below.

实施例 6

Example 6

 Formulation: Piperacillin sodium 4g, sulbactam sodium 1.0g, sodium citrate 0.20g, etimicin sulfate 200mg.

 Preparation method: Piperacillin sodium, sulbactam sodium and sodium citrate are dissolved in 200mL of water for injection, pH is adjusted to 6.0 with citric acid or sodium hydroxide solution, and etimicin sulfate 200mg is added, and ultrasonication is performed for 10 minutes to obtain transparency. Solution. After filtration (0.2 μm), it was stored in a drop bottle or a drip bag and stored at room temperature (22 °C). The precipitation was observed at 0, 1, 2, 4, 6, 8 hours, and piperacillin was sampled and analyzed. The contents of sulbactam sodium and etimicin are shown in the table below.

实施例 7

Example 7

 Formulation: Piperacillin sodium 4 g, sulbactam sodium 2.0 g, EDTA disodium lmg, sodium citrate 0.20 g, etimicin sulfate 200 mg.

实施例 8 Preparation method: piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 200mL water for injection, pH adjusted to 6.0 with citric acid or sodium hydroxide solution, add etimicin sulfate 200mg, ultrasound 10 A clear solution was prepared in minutes. After filtration (0.2 μπι), it was stored in a drop bottle or drip bag and stored at room temperature (22 °C). The precipitation was observed at 0, 1, 2, 4, 6, 8 hours, and the piperacillin was sampled and analyzed. The results of etimicin content are shown in the table below.

Example 8

 Formulation: Piperacillin sodium 4 g, sulbactam sodium 1.0 g, EDTA disodium 5 mg, sodium citrate 0.20 g, etimicin sulfate 200 mg.

Preparation method: piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 200mL water for injection, pH adjusted to 6.0 with citric acid or sodium hydroxide solution, add etimicin sulfate 200mg, ultrasound 10 After a minute, the white precipitate dissolved to give a clear solution. After filtering (0.2μπι), it is packaged in a drip bottle or drip bag and stored at room temperature, at 0, 1, 2, At 4, 6, and 8 hours, the presence or absence of precipitation was observed, and the contents of piperacillin, sulbactam, and etimicin were sampled and analyzed. The results are shown in the table below.

 Example 9

 Formulation: Piperacillin sodium 4 g, sulbactam sodium 4.0 g, EDTA disodium lmg, sodium citrate 0.20 g, etimicin sulfate 200 mg.

 Preparation method: piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 200mL water for injection, pH adjusted to 6.0 with citric acid or sodium hydroxide solution, add etimicin sulfate 200mg, ultrasound 10 After a minute, the white precipitate dissolved to give a clear solution. After filtration (0.2 μm), packaged in a drop bottle or drip bag and stored at room temperature. Observe the presence of precipitate at 0, 1, 2, 4, 6, 8 hours, and sample and analyze piperacillin, sulbactam and The results of etimicin content are shown in the table below.

 Example 10

 Formulation: 4 g of cililicillin sodium, 1.0 g of potassium clavulanate, 1 mg of disodium EDTA, 0.20 g of sodium citrate, and 200 mg of etimicin sulfate.

Preparation method: piperacillin sodium, clavulanate potassium, EDTA disodium and sodium citrate dissolved in 200mL water for injection, pH 6.5 with citric acid or sodium hydroxide solution, add etimicin sulfate 200mg, ultrasound 10 After a minute, the white precipitate dissolved to give a clear solution. After filtration (0.2μπι), it was stored in a drip bottle or drip bag and stored at room temperature (22 °C). At the 0, 1, 2, 4, 6 hour time point, the presence or absence of precipitation was observed, and piperacillin and clavulanic acid were sampled and analyzed. The potassium content, the results are shown in the table below.

 Example 11

 Formulation: Piperacillin sodium 4g, sulbactam sodium 0.5g, EDTA disodium lmg, sodium citrate 0.20g, amikacin sulfate 500mg.

Preparation method: piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 200mL water for injection, adjusted to pH 6.0 with lemon acid or sodium hydroxide aqueous solution, added amikacin sulfate 500mg, ultrasound After 10 minutes, the white precipitate dissolved to give a clear solution. 100 mL of the obtained solution was filtered (0.2 μιη), placed in a container and placed in a freeze dryer, the temperature of the freeze dryer was adjusted to minus 35 ° C, and the vacuum of the freeze dryer was pumped to 30 Pa, and the freeze dryer was placed. The temperature was adjusted to 3 ° C. After the water was dried, the temperature of the freeze dryer was adjusted to 40 ° C to obtain a freeze-dried powder needle, which was filled with dry nitrogen. Cover the bacteria and store in the refrigerator below 0 °C. After 7 days, the obtained lyophilized powder was formulated into a solution with 100 mL of water for injection, and the presence or absence of precipitation was observed at 0, 1, 2, 4, 6, 8 hours, and the contents of piperacillin and sulbactam were sampled and analyzed. See the table below for the results.

 Example 12

Formulation: piperacillin sodium 4g, sulbactam sodium 1.0g, EDTA disodium lm _g , sodium citrate 0.20g, amikacin sulfate 500mg.

Preparation method: Piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 200mL of water for injection, pH adjusted to 6.0 with citric acid or sodium hydroxide solution, 500mg of amikacin sulfate, ultrasonic for 10 minutes The white precipitate was dissolved to give a clear solution. After filtration (0.2 μm), it was stored in a drop bottle or a drip bag and stored at room temperature (22 ^Q C). At 0, 1, 2, 4, 6, 8 hours, the presence or absence of precipitation was observed, and piperacillin was sampled and analyzed. The contents of sulbactam sodium and amikacin sulfate are shown in the table below.

 Example 13

 Formulation: valacillin sodium 4g, sulbactam sodium 1.0g, EDTA disodium lmg, sodium citrate 0.20g.

实施例 14 Preparation method: Piperacillin sodium, sulbactam sodium, disodium EDTA and sodium citrate were dissolved in 200 mL of water for injection, and the pH was adjusted to 6.0 with citric acid or aqueous sodium hydroxide solution. After filtering (0.2 μm), take 100 mL of the solution into a drop bottle or a drip bag, freeze it to a solid and store it at a temperature below 0 ° C. After 7 days, take it out and let it cool at room temperature (22 ^D C) and warm to room temperature, and at 0. At 1, 2, 4, 6, 8 hours, the presence or absence of precipitation formation and sampling analysis of piperacillin and sulbactam sodium were observed. The results are shown in the table below.

Example 14

 Formulation: Piperacillin sodium 400g, sulbactam sodium 100g, EDTA disodium 100mg, sodium citrate 20g.

Preparation method: Piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate were ground into a uniform powder in a grinder and divided into 100 bottles. One bottle was dissolved in 100 mL of water for injection, and citric acid or sodium hydroxide was used. The pH of the aqueous solution was adjusted to 6.0, 10 mL was taken, and 20 mg of etimicin sulfate was added, and after 10 minutes of sonication, a clear solution was obtained. The presence or absence of precipitation was observed at 0, 1, 2, 4, 6, and 8 hours, and the contents of piperacillin, sulbactam, and etimicin were sampled and analyzed. The results are shown in the table below. Time (h) 0 1 2 4 6 8 Piperacillin sodium 107.4 105.8 108.1 103.4 105.6 107.2 Sulbactam sodium 98.3 96.7 97.2 96.5 98.3 95.9 etimicin sulfate 111.4 95.5 93.6 94.0 97.3 98.0 Example 15

 Formulation: Piperacillin sodium 4 g, sulbactam sodium 1.0 g, sodium citrate 0.20 g.

 Preparation method: Piperacillin sodium, sulbactam sodium, sodium citrate were dissolved in 200 mL of water for injection, and the pH was adjusted to 6.0 with citric acid or sodium hydroxide aqueous solution. After filtration (0.2 μηι), take 100 mL of the package into a drop bottle or a drop bag to freeze (solid). After 7 days of storage, melt at room temperature and warm to room temperature. Take 20 mL of HIAC data for 1 hour and 20 hours (see Table 1), and take another 20 mL. Ethylamine sulfate 20 mg was added, and after 10 minutes of sonication, a clear solution was obtained. At 0, 1, 2, 4, 6, 8 hours, observe the presence or absence of precipitation, determine the HIAC data for 1 and 20 hours (see Table 1), and sample and analyze the piperacillin and sulbactam sodium. The following table.

实施例 16

Example 16

实施例 17 100 mL of the solution of Example 15 was filtered (0.2 μm), placed in a container and placed in a freeze dryer, the temperature of the freeze dryer was adjusted to minus 40 ^Q C, and the vacuum of the freeze dryer was pumped to 50 Pa. The temperature of the freeze dryer was adjusted to 3 ° C. After the water was dried, the temperature of the freeze dryer was adjusted to 45 ° C to dry to obtain a freeze-dried powder needle, which was filled with dry gas and then aseptically sealed, and placed in a refrigerator at 0 °. C save. After 7 days, the obtained lyophilized powder needle was made into a solution with 100 mL of water for injection, and the HIAC data of 1 hour and 20 hours (see Table 1) was measured, and 60 mL of the obtained solution was added, and 20 mg of etimicin sulfate was added thereto, and ultrasonication was carried out for 10 minutes. A clear solution was obtained, and the HIAC data for 1 hour and 20 hours were measured (see Table 1), and the presence or absence of precipitation formation and sampling analysis of piperacillin and etimicin at 0, 1, 2, 4, 6, and 8 hours were observed. The content is shown in the table below.

Example 17

 20 mL of the thawing solution of Example 15 was added with 50 mg of amikacin sulfate, and after 10 minutes of sonication, a clear solution was prepared, and HIAC data of 1 and 20 hours (see Table 1) were measured, at 0, 1, 2, 4, 6 At 8 hours, the presence or absence of precipitation was observed, and the contents of piperacillin and amikacin were sampled and analyzed. The results are shown in the table below.

 Time (h) 0 1 2 4 6 8

Piperacillin sodium 101.8 101.3 101.8 101.2 98.3 95.1 Amikacin sulfate 86.05 83.57 81.55 80.55 85.75 83.83 Example 18

 Formulation: Piperacillin sodium 4g, sulbactam sodium l g, EDTA disodium lmg, sodium citrate 0.20g.

取上述由冻干粉针配制的澄明溶液 10mL， 加入硫酸依替米星 20毫克， 超声 10分钟后 制得澄明溶液， 于 0， 1， 2， 4, 6, 8小时时间点观察有无沉淀生成， 并取样分析哌拉西林、 依替米星含量， 结果见下表。

实施例 19 Preparation method: piperacillin sodium, sulbactam sodium, EDTA disodium and sodium citrate dissolved in 10 mL of water for injection, the pH was adjusted to 6.0 with citric acid, ultrasonication for 10 minutes to obtain a clear solution, and the prepared solution was filtered ( 0.2 μηι), placed in a container and placed in a freeze dryer, the temperature of the freeze dryer is adjusted to minus 35 ° C, the vacuum of the freeze dryer is pumped to below 40 Pa, and the temperature of the freeze dryer is adjusted to 3 ^Q C After removing the water, adjust the temperature of the freezing dryer to 40 °C. Dry the obtained lyophilized powder needle, fill it with dry nitrogen, and cover it aseptically. Store at 0 °C or below. After 7 days, add 100 mL of water for injection to dissolve to obtain a clear solution, and then leave it at room temperature. Observe the presence of precipitate at 0, 1, 2, 4, 6, 8 hours, and analyze the content of piperacillin and sulbactam. See the table below.

Take 10mL of the clear solution prepared from the lyophilized powder needle, add 20 mg of etimicin sulfate, and obtain a clear solution after sonication for 10 minutes. Observe the precipitate at 0, 1, 2, 4, 6, 8 hours. The samples were generated and sampled and analyzed for the content of piperacillin and etimicin. The results are shown in the table below.

Example 19

 Formulation: piperacillin sodium 4g, sulbactam sodium 0.5 g, EDTA disodium lmg, sodium citrate 0.20 g.

 Preparation method: Piperacillin sodium, sulbactam sodium, disodium EDTA and sodium citrate were dissolved in 200 mL of a 2.5% aqueous solution of levonose for injection, and the pH was adjusted to 6.0 with citric acid or sodium hydroxide aqueous solution. After filtration (0.2 μm), take 100 mL of the package into a drop bottle or a drop bag to freeze (solid), and after 7 days, melt at room temperature and warm to room temperature, measure the HIAC data for 1 hour and 20 hours (see Table 1), and take the above-mentioned thawing solution 40 mL. Add lOOmg sulfate amylose, and obtain a clear solution after sonication for 10 minutes. Determine the HIAC data for 1 and 20 hours (see Table 1). Observe at 0, 1, 2, 4, 6, 8 hours. Precipitation was generated and samples were analyzed for piperacillin, sulbactam and amikacin. The results are shown in the table below.

实施例 20

Example 20

100 mL of the solution of Example 19 was placed in a container and placed in a freeze dryer, the temperature of the freeze dryer was adjusted to minus 35 ° C, and the vacuum of the freeze dryer was pumped to 30 Pa, and the temperature of the freeze dryer was set. After adjusting the water to 3 ° C, the water is dried and the temperature of the freeze dryer is adjusted to 40 ° C. The dried lyophilized powder needle is dried and filled with dry nitrogen, and then sealed under 0 °C. Save. After 7 days, add 100 mL of water for injection to dissolve to obtain a clear solution, add 100 mg of etimicin sulfate, and clarify the solution after sonication for 10 minutes and place at room temperature. Determine the HIAC data for 1 hour and 20 hours (see Table 1). At 1, 2, 4, 6, 8 hours, the presence or absence of precipitation was observed, and the contents of piperacillin, sulbactam and etimicin were sampled and analyzed. The results are shown in the table.

实施例 21

Example 21

Formulation: Piperacillin sodium 4g, sulbactam sodium L0g, sodium citrate 0.20 _g .

 Preparation method: Piperacillin sodium, sulbactam sodium and sodium citrate were dissolved in 10 mL of water for injection, and the pH was adjusted to 6.0 with citric acid. After 10 minutes of sonication, a clear solution was obtained, and the obtained solution was filtered (0.2 μm). Loading into a container and placing it in a freeze dryer, adjusting the temperature of the freeze dryer to minus 35 ° C, pumping the vacuum of the freeze dryer to below 40 Pa, and adjusting the temperature of the freeze dryer to 3 ° C. After the water is removed, the temperature of the freeze dryer is adjusted to 40 °C to dry the obtained lyophilized powder needle, filled with dry nitrogen, and then aseptically sealed, and stored in the refrigerator at below 0 °C. After 7 days, add 100 mL of water for injection to dissolve to obtain a clear solution, and then place at room temperature. Take 10 mL of the above clear solution prepared from lyophilized powder, add 40 mg of amikacin sulfate, and sonicate for 10 minutes to obtain a clear solution at 0, 1 At 2, 4, 6, 8 hours, the presence or absence of precipitation was observed, and the contents of piperacillin sodium, sulbactam sodium and amikacin were sampled and analyzed. The results are shown in the table below.

 Example 22

 Formulation: Piperacillin sodium 4g, sulbactam sodium 0.5g, sodium citrate 0.20g.

 Preparation method: Piperacillin sodium, sulbactam sodium and sodium citrate were dissolved in 10 mL of water for injection, and the pH was adjusted to 6.0 with citric acid. After 10 minutes of sonication, a clear solution was obtained, and the obtained solution was filtered (0.2 μm). Filled into a container and placed in a freeze dryer, the temperature of the freeze dryer is adjusted to minus 35 ° C, the vacuum of the freeze dryer is pumped to below 40 Pa, and the temperature of the freeze dryer is adjusted to 3 ° C. After drying, the temperature of the freeze dryer was adjusted to 40 ° C to dry the obtained lyophilized powder needle, filled with dry nitrogen, and then aseptically sealed, and stored in the refrigerator at below 0 °C. After 7 days, add 100 mL of water for injection to dissolve to obtain a clear solution, and then place at room temperature. Take 10 mL of the above clear solution prepared from lyophilized powder, add 40 mg of amikacin sulfate, and sonicate for 10 minutes to obtain a clear solution at 0, 1 At 2, 4, 6, 8 hours, the presence or absence of precipitation was observed, and the contents of piperacillin sodium, sulbactam sodium and amikacin were sampled and analyzed. The results are shown in the table below.

 Time ( 0 1 2 4 6 8

Piperacillin sodium 96.07 99.59 95.71 90.18 97.38 88.87 Sulbactam sodium 87.51 90.36 94.38 89.05 93.03 90.45 Amikacin sulfate 96.88 97.78 96.14 96.88 98.34 98.11 Example 23

 Formulation: valacillin sodium 4g, sulbactam sodium lg, sodium citrate 0.20g.

Preparation method: Piperacillin sodium, sulbactam sodium and sodium citrate were dissolved in 10 mL of water for injection, and the pH was adjusted to 6.0 with citric acid. After 10 minutes of sonication, a clear solution was obtained, and the obtained solution was filtered (0.2 μm). Filled into a container and placed in a freeze dryer, the temperature of the freeze dryer is adjusted to minus 35 ° C, the vacuum of the freeze dryer is pumped to below 40 Pa, and the temperature of the freeze dryer is adjusted to 3 ° C. After drying, the temperature of the freeze dryer was adjusted to 40 ° C to dry the obtained lyophilized powder needle, filled with dry nitrogen, and then aseptically sealed, and stored in the refrigerator at below 0 °C. After 7 days, add 100 mL of water for injection to dissolve to obtain a clear solution, and then place at room temperature. Take 10 mL of the clear solution prepared from the frozen powder needle, add 20 mg of etimicin sulfate, and sonicate for 10 minutes to obtain a clear solution at 0, 1 At 2, 4, 6, 8 hours, the presence or absence of precipitation was observed, and the content of etimicin was sampled and analyzed. The results are shown in the table below.

 Example 24

 Formulation: Piperacillin sodium 4g, sulbactam sodium 0.5g, sodium citrate 0.20g.

 Preparation method: Piperacillin sodium, sulbactam sodium and sodium citrate were dissolved in 10 mL of water for injection, and the pH was adjusted to 6.0 with citric acid. After 10 minutes of sonication, a clear solution was obtained, and the obtained solution was filtered (0.2 μm). Filled into a container and placed in a freeze dryer, the temperature of the freeze dryer is adjusted to minus 35 ° C, the vacuum of the freeze dryer is pumped to below 40 Pa, and the temperature of the freeze dryer is adjusted to 3 ° C. After drying, the temperature of the freeze dryer was adjusted to 40 ° C to dry the obtained lyophilized powder needle, filled with dry nitrogen, and then aseptically sealed, and stored in the refrigerator at below 0 °C. After 7 days, add 100 mL of water for injection to dissolve to obtain a clear solution, and then place at room temperature. Take 10 mL of the above clear solution prepared from lyophilized powder, add 20 mg of etimicin sulfate, and sonicate for 10 minutes to obtain a clear solution at 0, 1 At 2, 4, 6, 8 hours, the presence or absence of precipitation was observed, and the contents of piperacillin sodium, sulbactam sodium and etimicin were sampled and analyzed. The results are shown in the table below.

HIAC test

A light transmittance test was performed on a solution formulation of a part of the example formulation using a HIAC-3000 type light transmittance detector and a US Pharmacopoeia method (USP 788), wherein the particle content is characterized by the number of particles per ml of solution. The results are the average of the second measurements, and the same sample was measured at 1 hour and 20 hours, respectively, and some of the test results are shown in Table 1. Table 1: Partial HIAC test results

Sample Aminoglycosides Disodium EDTA Particles (ppm)

 Antibiotics 1(h) 20(h)

 (mg/ml) (mg/ml) ΙΟμηι 25μηι ΙΟμιη 25μΐΏ Example 4 G (0.4) 0.005 15 0 26 0 Example 5 Y (1.0) 0.005 21 0 43 1 Example 15 —- — 47 3 135 5 Implementation Example 15 Y (1.0) - a 86 2 328 6 Example 16 - One - 23 3 91 2 Example 16 Y (0.33) - - 117 3 689 8 Example 17 A (2.5) - 68 3 1958 12 Implementation Example 19 - - 0.005 5 1 19 1 Example 19 A (2.5) 0.005 13 0 159 4 Example 20 Y (1.0) 0.005 8 0 48 0

G: gentamicin; Y: etimicin; A: amikacin.

Claims

Claims, by valacillin or a pharmaceutically acceptable salt or hydrate thereof, at least one of the following beta-lactamase inhibitors: clavulanic acid or a pharmaceutically acceptable salt or hydrate thereof, sulbactam or An antibiotic combination comprising a pharmaceutically acceptable salt or hydrate thereof, and at least one ion chelating agent which inhibits the formation of granules, and a compound of the antibiotic formulated into a preparation and its use as an antimicrobial infectious agent. The antibiotic compound according to claim 1, wherein said ion chelating agent capable of inhibiting particle formation is ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylethylenediamine Acetic acid (HEDTA), or a pharmaceutically acceptable salt or hydrate thereof. The ion chelating agent capable of inhibiting particle formation according to claim 1, wherein said ion chelating agent capable of inhibiting particle formation is ethylenediaminetetraacetic acid (EDTA). The antibiotic compound according to claim 1, characterized in that a buffer compound component is added to the antibiotic compound to form a new compound. An antibiotic combination consisting of piperacillin or a pharmaceutically acceptable salt or hydrate thereof, clavulanic acid or sulbactam or a pharmaceutically acceptable salt or hydrate thereof, and at least one buffer component, and the antibiotic The compound is formulated into a preparation and its use as an antimicrobial infectious agent. The buffer component of claims 4 and 5, characterized in that said buffer component is citric acid/citrate, phosphoric acid/phosphate system, acetic acid/acetate, arginine, carbonic acid/carbonate , citric acid / citrate, Tris-HC1. The buffering component of claims 4 and 5, characterized in that said buffering component has a pH in the range of from 5.5 to 7.5. The buffering component of claims 4 and 5 wherein said buffering component has a pH in the range of from 6 to 6.75. The antibiotic combination according to claims 1, 4 and 5, characterized in that the antibiotic combination further comprises at least one aminoglycoside antibiotic to form a new compound, and its use as an antimicrobial infectious agent. 0. The aminoglycoside antibiotic of claim 9, wherein said aminoglycoside antibiotic is: etimicin, gentamicin, tobramycin, amikacin, netilmicin, ground Bekaxing, kanamycin, arbekacin, sagamycin, isepamicin, sisomicin, neomycin, paromomycin, streptomycin, spectinomycin, small noromycin , astemin, ribomycin, or a pharmaceutically acceptable salt or hydrate thereof. The antibiotic combination according to claim 1, wherein said compound is administered in a unit dose of 0.1 to 5 g of piperacillin sodium, 0.1 to 5 g of sulbactam sodium, and 0.1 to 100 mg of EDTA. 2. An antibiotic combination according to claim 4, characterized in that said unit is administered in a dosage of from 0.1 to 5 grams of piperacillin sodium, 0.1 to 5 clavulanate potassium, from 0.01 to 5 grams of sodium citrate and from 0.1 to 100. The composition of milligrams of EDTA. 3. The antibiotic combination of claim 4, wherein said compound is administered in a unit dosage of 0.1 to 5 grams of piperacillin sodium, 0.1 to 5 grams of sulbactam sodium, 0.01 to 5 grams of sodium citrate, and 0.1- Composition of 100 mg EDTA. A compound according to claim 9, wherein said aminoglycoside antibiotic is used in a unit dose of from 0.01 to 5 g. 5. The antibiotic combination according to claim 9, wherein said compound is administered in a unit dose of 0.1 to 5 g of piperacillin sodium, 0.1 to 5 g of sulbactam sodium, 0.01 to 5 g of sodium citrate, 0.1- 100 mg EDTA and 0.05-2 g of etimicin sulfate. 6. The antibiotic combination of claim 9 wherein said compound is administered in a unit dose of from 0.1 to 5 grams of piperacillin. Sodium, 0.1-5 g of sulbactam sodium, 0.01-5 g of sodium citrate, 0.1-100 mg EDTA and 0.05-2 g of amikacin sulfate. The antibiotic combination according to claim 9, characterized in that the unit dosage of the compound is from 0.1 to 5 g of piperacillin sodium, 0.1 to 5 g of sulbactam sodium, 0.01 to 5 g of sodium citrate, 0.1 to 100 Mg EDTA and 0.05-2 g of gentamicin sulfate. The antibiotic combination according to claim 5, characterized in that the unit dosage of the compound is composed of 0.1-5 g of piperacillin, 0.1-5 g of sulbactam sodium, 0.01-5 g of sodium citrate. The antibiotic combination according to claim 5, characterized in that the unit dosage of the compound is composed of 0.1-5 g of piperacillin, 0.1-5 g of clavulanate potassium, 0.01-5 g of sodium citrate. , claims 1, 4, 5, The antibiotic combination of 9, 11, 12, 13, 15, 16, 17, 18, 19 is characterized in that an isotonic component can be added to the compound. The isotonic component of claim 20, wherein said isotonic component is glucose, levulose, sodium chloride. The antibiotic combination according to claim 1, 4, 5, 9, 11, 12, 13, 15, 16, 17, 18, 19, 20, characterized in that the compound is in the form of a solution preparation, a powder needle or a lyophilized powder. Needle formulation application. The method for preparing an antibiotic lyophilized powder needle according to claim 22, wherein the method comprises the following steps:  a, the components in the compound are dissolved in water for injection, the pH is adjusted to 6-6.75 with sodium hydroxide / citric acid, and then stirred to dissolve; b. The solution prepared in step a is dispensed into the freeze-dried powder bottle at the required dosage, placed in a freeze dryer at 5 °C pre-cooled, and then the temperature of the freeze dryer is adjusted to minus 35 °. C _;  c. pumping the vacuum of the freeze dryer to below 40 Pa;  d, the temperature of the freeze dryer is adjusted to 3-5 ° C;  e. remove the water under the above conditions;  f, the temperature of the freeze dryer is adjusted to 40-50 ° C to dry the resulting freeze-dried powder needle; g. Fill the freeze dryer with dry nitrogen, cover the bottle, place it at a temperature below 5 ^Q C, and store it in the dark.