WO2008028347A1 - Préparation associant plusieurs antibiotiques - Google Patents

Préparation associant plusieurs antibiotiques Download PDF

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Publication number
WO2008028347A1
WO2008028347A1 PCT/CN2006/003020 CN2006003020W WO2008028347A1 WO 2008028347 A1 WO2008028347 A1 WO 2008028347A1 CN 2006003020 W CN2006003020 W CN 2006003020W WO 2008028347 A1 WO2008028347 A1 WO 2008028347A1
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Prior art keywords
sodium
piperacillin
formulation
sulbactam
edta
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PCT/CN2006/003020
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English (en)
Chinese (zh)
Inventor
Hesheng Zhang
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Tianjin Hemay Bio-Tech Co. Ltd
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Publication of WO2008028347A1 publication Critical patent/WO2008028347A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • 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.
  • Piperacillin inhibits bacterial cell wall synthesis by inhibiting the activity of the D-alanylalanine transpeptidase in bacteria.
  • 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.
  • clavulanic acid isolated from the fermentation broth of Streptomyces faecalis has a unique activity of inhibiting ⁇ -lactamase, followed by other ⁇ -lactamase inhibitors, especially sulbactam and its Lipid prodrugs, sulindac and tazobactam are widely used clinically.
  • 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.
  • 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.
  • Aminoglycoside Antibiotics 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.
  • aminoglycoside antibiotics 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.
  • 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.
  • 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 ⁇ -lactam in piperacillin.
  • 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 ⁇ -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 ⁇ -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 ⁇ -lactam in piperacillin can be almost completely inhibited.
  • 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.
  • the present invention discloses an antibiotic combination consisting of piperacillin or a pharmaceutically acceptable salt or hydrate thereof, at least one of the following ⁇ -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 ⁇ -lactamase inhibitor in the compound for at least 8 hours.
  • 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 ⁇ -lactamase inhibitor in the compound for at least 8 hours, and can be combined with at least one aminoglycoside antibiotic.
  • 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.
  • 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.
  • clavulanic acid clavulanic acid
  • sulbactam sodium salt Two currently used ⁇ -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.
  • 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.
  • arginine systems and other amino acid systems are suitable buffer solutions
  • 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.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • HEDTA hydroxyethylethylenediaminetriacetic acid
  • NTA nitrilotriacetic acid
  • 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 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 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 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.
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.
  • 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
  • Formulation 1-29 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, tobramycin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-30 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, etimicin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-31 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, pebekacin 0.01-5g, citric acid 0.01-5g, uranyl citrate
  • Formulation 1-32 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, arbekacin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-33 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, kanamycin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-34 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, salicin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-35 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, isepamicin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-36 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g Neomycin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-37 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, paromomycin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • Formulation 1-38 Piperacillin sodium 0.1-5g, sulbactam 0.1-4g, soxacin 0.01-5g, citric acid 0.01-5g, sodium citrate
  • 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
  • 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,
  • 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
  • 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, potassium clavulanate, citric acid, sodium citrate Formulation Piperacillin sodium, potassium clavulanate, amikacin sulfate, citric acid, sodium citrate.
  • 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 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • the antibiotic compound of the present invention 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.
  • the antibiotic compound prepared by the invention 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.
  • antibiotic compound of the present invention 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
  • 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
  • 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.
  • 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 ⁇ . 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.
  • 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 ⁇ . 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
  • 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.
  • 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 ⁇ m), 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.
  • 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 ⁇ m), 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.
  • 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 (0.2 ⁇ ), 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.
  • 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 ⁇ m), 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.
  • 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 (0.2 ⁇ ), 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.
  • 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 ⁇ ), 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.
  • 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.
  • 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.
  • 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 ⁇ m), 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.
  • valacillin sodium 4g sulbactam sodium 1.0g
  • EDTA disodium lmg sodium citrate 0.20g.
  • 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.
  • 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 ⁇ ), 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.
  • Example 15 100 mL of the solution of Example 15 was filtered (0.2 ⁇ m), 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.
  • 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 15 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.
  • 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 ⁇ ), 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.
  • 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 ⁇ m), 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.
  • Example 19 100 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.
  • 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 ⁇ m). 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.
  • 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.
  • 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 ⁇ m). 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.
  • 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 ⁇ m). 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.
  • 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 ⁇ m). 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.
  • 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
  • Example 4 G (0.4) 0.005 15 0 26 0
  • Example 5 Y (1.0) 0.005 21 0 43 1
  • Implementation Example 15 Y (1.0) - a 86 2 328 6
  • Example 16 - One - 23 3 91 2
  • Example 17 A (2.5) - 68 3 1958 12
  • 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.

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Abstract

L'invention concerne une préparation associant plusieurs antibiotiques, comprenant de la pipéracilline, du sulbactame ou de l'acide clavulanique, des chélateurs ioniques et/ou des substances tampon, pouvant servir à préparer une solution stable, ainsi qu'une solution stable et des antibiotiques de type aminoglycosides dans un contenant.
PCT/CN2006/003020 2006-08-25 2006-11-10 Préparation associant plusieurs antibiotiques WO2008028347A1 (fr)

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CN111110627A (zh) * 2018-10-30 2020-05-08 齐鲁制药有限公司 一种硫酸阿米卡星注射液及其制备方法
CN118340728A (zh) * 2024-06-18 2024-07-16 山东天宇生物科技有限公司 一种复合盐酸林可霉素可溶性粉及其制备方法

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CN101269072B (zh) * 2008-05-09 2010-06-02 郑飞雄 含量稳定的含β-内酰胺酶抑制剂和哌拉西林钠的药物组合物及其制备方法
GB201208080D0 (en) * 2012-05-09 2012-06-20 Norton Healthcare Ltd Tobramycin formulation
CN102940636A (zh) * 2012-11-01 2013-02-27 哈药集团制药总厂 一种哌拉西林舒巴坦钠药物组合物注射剂及其制备方法
WO2016056527A1 (fr) * 2014-10-08 2016-04-14 沢井製薬株式会社 Procédé de production de préparation lyophilisée
CN105887030B (zh) * 2016-06-30 2018-07-31 光驰科技(上海)有限公司 堆栈式溅射镀膜装置及其镀膜方法

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US6207661B1 (en) * 1999-02-22 2001-03-27 Baxter International Inc. Premixed formulation of piperacillin sodium and tazobactam sodium injection
CN1802179A (zh) * 2003-04-14 2006-07-12 惠氏控股公司 含有哌拉西林和三唑巴坦的注射用组合物

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US6207661B1 (en) * 1999-02-22 2001-03-27 Baxter International Inc. Premixed formulation of piperacillin sodium and tazobactam sodium injection
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CN111110627A (zh) * 2018-10-30 2020-05-08 齐鲁制药有限公司 一种硫酸阿米卡星注射液及其制备方法
CN111110627B (zh) * 2018-10-30 2022-12-02 齐鲁制药有限公司 一种硫酸阿米卡星注射液及其制备方法
CN118340728A (zh) * 2024-06-18 2024-07-16 山东天宇生物科技有限公司 一种复合盐酸林可霉素可溶性粉及其制备方法

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