CN1927201B - Antibiotic compound recipe comprising piperacillin - Google Patents

Antibiotic compound recipe comprising piperacillin Download PDF

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Publication number
CN1927201B
CN1927201B CN200610015440XA CN200610015440A CN1927201B CN 1927201 B CN1927201 B CN 1927201B CN 200610015440X A CN200610015440X A CN 200610015440XA CN 200610015440 A CN200610015440 A CN 200610015440A CN 1927201 B CN1927201 B CN 1927201B
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avocin
prescription
sodium
sulbactam
edta
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CN1927201A (en
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张和胜
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Ganzhou Hemay Pharmaceutical Co Ltd
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TIANJIN HEMEI BIOTECHNOLOGY CO Ltd
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Priority to PCT/CN2006/003020 priority patent/WO2008028347A1/en
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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

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  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention involves antibiotic compound recipe containing piperacillin, sulbactam or clavulanic acid, ion chelator which can inhibit the formation of particles chelator, the recipe can be further added in buffering ingredient as stability system, the characteristics of the recipe is that it can be prepared to stable pharmaceutical solutions, and with aminoglycoside antibiotics in the same container are re-prepared to drugs used for complex anti-microbial infection.

Description

The antibiotic compound of recipe comprising piperacillin
Invention field:
The present invention relates to the antibiotic compound formed by piperacillin, sulbactam or clavulanic acid, ion chelating agent and/or buffer components, the characteristics of this compound recipe are to be made into stable pharmaceutical solutions, and can be re-dubbed the medicine that stable pharmaceutical solutions infects as controlling microbial in same container with aminoglycoside antibiotics.
Technical background:
Piperacillin (Piperacillin) reaches by the activity that suppresses D-alanyl in the antibacterial-D-alanine transpeptidase (mucopeptide transpeptidase Peptidoglycan transpeptidase) and suppresses the synthetic of bacteria cell wall.Because being some, mucopeptide has cancellated high sugar content peptide, alternately form wire polysaccharide chains small peptide by N-acetyl-glucosamine (Glc-NAc) and N-acetyl wall propylhomoserin (Mur-NAc), these high polymers need change the peptide cross-linking reaction under the catalysis of mucopeptide transpeptidase, make the wire high polymer change into cross-linked structure, thereby finish the synthetic of cell wall.Piperacillin has irreversibly suppressed this mucopeptide transpeptidase and has made the antibacterial can't the synthetic cell wall.Acellular wall, intracellular hyperosmosis can not be finalized the design and bear to cell, causes bacteriolyze, causes antibacterial death.
Antibacterial is evolved into subsequently and can generates a kind of beta-lactamase, the amido link of β in the hydrolysis piperacillin--lactam nucleus, and piperacillin changed into the metabolite that does not have antibacterial activity.The human clavulanic acid of telling from the fermentation liquid of clavuligerus of finding had the activity of unique inhibition beta-lactamase in 1976, other beta-lactamase inhibitor subsequently, sulbactam especially wherein and lipid prodrug thereof, relax Ba Xilin and its TZB have obtained extensive use clinically.
Piperacillin and sulbactam compound recipe are one of most popular clinically at present injection of antibiotic preparations (piperazine relax preparation).It is widely used for treating hospital's type pneumonia (Nosocomial Pneumonia) of being caused by staphylococcus aureus, intra-abdominal infection, and especially appendicitis and the peritonitis that is caused by escherichia coli, the skin infection that comprises cellulitis and dermapostasis, ischemia/diabetes type foot infect and are the gynecological infection of representative with puerperal endometritis and pelvic inflammation.
The antibiotic of another kind of wide clinical application is aminoglycoside antibiotics (Aminoglycoside Antibiotics).Aminoglycoside antibiotics is the glycosides that is formed by amino sugar (monosaccharide or disaccharidase) and aminocyclitol.Owing to contain amino and other basic group, so chemical compound shows alkalescence.Since 1940 find first aminoglycoside antibiotics-streptomycin from Streptothrix since because this type of antibiotic has a broad antifungal spectrum, antibacterial activity are strong, use clinically more, existing so far more than 20 kind listing.
The antibacterial mechanisms of aminoglycoside antibiotics is different fully with piperacillin.After aminoglycoside antibiotics enters bacterial body,, cause that tRNA makes mistakes and synthetic non-functional protein, has suppressed the cell growth when the password of translation mRNA with the protein binding of 30S subunit.
Therefore, it is generally acknowledged that piperacillin and aminoglycoside antibiotics have share antibiotic preferably synergism.But because piperacillin is an acid compound, and aminoglycoside antibiotics is an alkaline matter, thereby, when this two classes antibiotic share in same container, can be because the two become salt formation precipitation, or the amino in the aminoglycoside antibiotics is with the reaction of the beta-lactam in piperacillin generation non-activity material and reduce tiring of the two greatly.So, in general forbid clinically piperacillin and aminoglycoside antibiotics are share in same container.
A problem of the easypro preparation of piperazine is this solution less stable at room temperature, and unsettled solution easily produces granule, especially relax piperazine that solution melts the back again or be prepared into freeze-dried powder of the piperazine of stored frozen relaxes preparation when being mixed with solution again, and the time of placing is long more, and granule generates manyly more.Granule in the solution of used for intravenous injection is deleterious to patient.Studies have shown that the granule content in infusion phlebitis and the transfusion closely related (Remmington ' s Pharmaceutical Science, 18Edition, Mark Publishing, 1990, page 1567).
Further discover, piperazine relax preparation and aminoglycoside antibiotics composite after easier generation granule, become clinically another problem that need solve that piperacillin and aminoglycoside antibiotics are share in same container.
Therefore, if can develop a kind of can being stabilized in aminoglycoside antibiotics and piperacillin in the same solution, can keep two class antibiotic drug effects not reduce simultaneously and the particulate compound preparation of difficult generation, not only more convenient in clinical use, and the Synergistic biocidal effect can utilize aminoglycoside antibiotics and piperacillin to share better the time, thereby will have enormous social meaning and economic worth.
Research and development can be stabilized in aminoglycoside antibiotics and piperacillin in the same solution, can keep simultaneously the key of the compound preparation that two class antibiotic drug effects do not reduce to be to find a stabilising system, can not only suppress aminoglycoside antibiotics and piperacillin and in same solution, form precipitation, also can suppress amino and the reaction of the beta-lactam in the piperacillin in the aminoglycoside antibiotics simultaneously fully.Through systematic study, we find when pH value is controlled between the 4-8, and aminoglycoside antibiotics and piperacillin in same solution salt-forming reaction take place and the amino and the beta-lactam in the piperacillin that form in deposited phenomenon and the aminoglycoside antibiotics react the inhibition that can obtain to a certain degree; When pH value was controlled between the 5-7.5, salt-forming reaction took place and forms the inhibition that amino in deposited phenomenon and the aminoglycoside antibiotics and the reaction of the beta-lactam in the piperacillin can obtain certain degree in aminoglycoside antibiotics and piperacillin in same solution; When pH value was controlled between the 6-7, salt-forming reaction took place and forms amino in deposited phenomenon and the aminoglycoside antibiotics and the reaction of the beta-lactam in the piperacillin can obtain the almost completely inhibition of degree in aminoglycoside antibiotics and piperacillin in same solution.
Further discover, but what bring in the ion chelating reagent complexation aminoglycoside antibiotics is the bivalence or the polyvalent cation of representative with the zinc ion, thereby can suppress the solution that piperacillin, sulbactam compound recipe are mixed with, and this solution forms granule with the solution that is re-dubbed that with the amikacin sulfate injection is the aminoglycoside antibiotics of representative.
Summary of the invention:
Correspondingly, the present invention discloses a kind of antibiotic compound, by piperacillin or its pharmaceutically acceptable salt or hydrate, at least a following beta-lactamase inhibitor: clavulanic acid or its pharmaceutically acceptable salt or hydrate, sulbactam or its pharmaceutically acceptable salt or hydrate and at least a ion chelating agent or at least a granule ion chelating agent that generates and the antibiotic compound that cushions the component composition of suppressing that suppresses the granule generation.The pharmaceutical solutions that this compound recipe is mixed with is as clear as crystal, do not form muddiness or precipitation, and can keep in this compound recipe piperacillin, beta-lactamase inhibitor to tire at least 8 hours not falling.The characteristics of further discovering this compound recipe be can with the composite use in same container of at least a aminoglycoside antibiotics, the gained combination solution is as clear as crystal, do not form muddiness or precipitation, and can keep in this compound recipe piperacillin and described aminoglycoside antibiotics to tire at least 8 hours not falling.
Also find in the research by piperacillin or its pharmaceutically acceptable salt or hydrate, clavulanic acid or sulbactam or their pharmaceutically acceptable salts or hydrate, the pharmaceutical solutions that the antibiotic compound of forming with at least a buffering component is mixed with is as clear as crystal, do not form muddiness or precipitation, and can at least 8 hours, keep piperacillin in this compound recipe, beta-lactamase inhibitor is tired and is not fallen, and can with the composite use in same container of at least a aminoglycoside antibiotics, the gained combination solution is as clear as crystal, do not form muddiness or precipitation, and can at least 8 hours, keep in this compound recipe piperacillin and described aminoglycoside antibiotics to tire not falling.
Selected three kinds of aminoglycoside antibioticss commonly used at present in the research process of the present invention: etimicin, gentamycin, amikacin, these three kinds of antibiotic have been represented three subgroups of aminoglycoside antibiotics, thereby have the representativeness of wide model.Therefore, aminoglycoside antibiotics in the antibiotic compound of the present invention can be any aminoglycoside antibiotics, includes but not limited to streptomycin (Streptomycin), dibekacin (Dibekacin), kanamycin (Kanamycin), tobramycin (Tobramycin), amikacin (Kanamycin A Sulfate), arbekacin (Arbekacin), gentamycin (Gentamicin), sagamicin (Sagamicin), isepamicin (Isopamicin), sisomicin (Sisomicin), netilmicin (Netilmicin), neomycin (Neomycin), paromomycin (Paromoycin), etimicin (Etimicin), astromicin (Astromicin), ribostamycin (Ribostamycin), micronomicin (Micronomicin), spectinomycin (Spectinomycin).
Selected two kinds of beta-lactamase inhibitors commonly used at present in the research process of the present invention: clavulanic acid (clavulanic acid) potassium salt and sulbactam sodium salt carry out prescription research.
Selected three kinds of present the most frequently used buffer solution systems in the research process of the present invention: citric acid/citrate system, phosphoric acid/phosphate system, acetic acid/acetate systems, thereby have the representativeness of wide model.Therefore, buffer solution in the above-mentioned antibiotic compound can be any buffer solution system, includes but not limited to citric acid/citrate system and other polyacid system, phosphoric acid/phosphate system and other mineral acid system, acetic acid/acetate systems and other organic acid system, arginine system and other aminoacid system, boric acid system; More suitable buffer solution system is citric acid/citrate system, phosphoric acid/phosphate system, acetic acid/acetate systems, arginine, carbonic acid/carbonate system, citric acid/citrate system, Tris-HCl system.Use sodium citrate as representational buffering component in the concrete prescription of embodiments of the invention.
The pH value scope of the buffer solution in the antibiotic compound of the present invention is 4-8, and the pH value scope of proper buffer solution is 5.5-7.5, and the pH value scope of only buffer solution is 6-6.75.
Buffer solution proper concentration in the antibiotic compound of the present invention is 1-500mM, and the concentration range of proper buffer solution is 5-100mM, and the concentration range of only buffer solution is 10-60mM.
The ion chelating agent that suppresses the granule generation of the present invention can be ethylenediaminetetraacetic acid (EDTA), diethylene triamine pentacetic acid (DTPA) (DTPA), Hedta (HEDTA), complexon I (NTA), or their pharmaceutically acceptable salts or hydrate; More suitable ion chelating agent is EDTA and HEDTA and their sodium salt; Only ion chelating agent is EDTA and its salt or hydrate.
Antibiotic compound of the present invention includes but not limited to four kinds of concrete application modes when clinical practice: first kind of mode by avocin, clavulanic acid (clavulanic acid) potassium salt or sulbactam sodium salt, at least a aminoglycoside antibiotics and buffering solution add ion chelating agent forms antibiotic compound and can be mixed with the freezing preservation of pharmaceutical solutions or be prepared into the powder pin, freeze-dried powder is preserved, with before being mixed with the solution use.The pharmaceutical solutions that this compound recipe is mixed with is as clear as crystal, do not form muddiness or precipitation, and can keep that piperacillin and tiring of aminoglycoside antibiotics do not fall in this compound recipe.The representative formulations of described compound recipe (unit using dosage) is made up of 0.1-5 gram avocin, 0.1-5 gram sulbactam sodium, 0.1-100 milligram EDTA, 0.01-5 gram sodium citrate and 0.01-5 gram aminoglycoside antibiotics.
The second way is formed antibiotic compound by avocin, clavulanic acid (clavulanic acid) potassium salt or sulbactam sodium salt, at least a aminoglycoside antibiotics and ion chelating agent and can be mixed with the freezing preservation of pharmaceutical solutions or be prepared into powder pin, freeze-dried powder preservation, uses with before being mixed with solution.When being mixed with solution, this compound recipe need transfer pH to 6-7 with buffer components (only buffer components is a citric acid/citrate), the gained preparation is as clear as crystal, do not form muddiness or precipitation, and can keep that piperacillin and tiring of aminoglycoside antibiotics do not fall in this compound recipe.Described compound recipe representative formulations (unit using dosage) is made up of 0.1-5 gram avocin, 0.1-5 gram sulbactam sodium, 0.1-100 milligram EDTA, 0.01-5 gram aminoglycoside antibiotics.
The third mode by avocin, clavulanic acid (clavulanic acid) potassium salt or sulbactam sodium salt add that ion chelating agent forms antibiotic compound and can be mixed with the freezing preservation of pharmaceutical solutions or be prepared into the powder pin, freeze-dried powder is preserved, with before being mixed with the solution use.After the agent of this compound recipe wiring solution-forming as will with the use that in same container, is mixed of at least a aminoglycoside antibiotics pharmaceutical solutions, need with buffer components (only buffer components is a citric acid/citrate) transfer pH to 6-7 can obtain as clear as crystal, do not form muddiness or sedimentary combination solution preparation, and can keep wherein tiring of piperacillin and aminoglycoside antibiotics.The representative formulations of described compound recipe (unit using dosage) is made up of 0.1-5 gram avocin, 0.1-5 gram sulbactam sodium, 0.1-100 milligram EDTA.
The 4th kind of mode by avocin, clavulanic acid (clavulanic acid) potassium or sulbactam sodium, buffer solution add ion chelating agent form antibiotic compound and can be mixed with the freezing preservation of pharmaceutical solutions or be prepared into the powder pin, freeze-dried powder is preserved, with before being mixed with the solution use.Pharmaceutical solutions that this compound recipe is mixed with and at least a aminoglycoside antibiotics pharmaceutical solutions in same container, be mixed obtain as clear as crystal, do not form muddy or sedimentary combination solution preparation, and can keep wherein that piperacillin and tiring of aminoglycoside antibiotics do not fall.Described compound recipe representative formulations (unit using dosage) is made up of 0.1-5 gram piperacillin, 0.1-5 gram sulbactam sodium, 0.01-5 gram sodium citrate and 0.1-100 milligram EDTA.
In addition, form antibiotic compound by avocin, clavulanic acid (clavulanic acid) potassium or sulbactam sodium, buffer solution and also can be mixed with the freezing preservation of pharmaceutical solutions or be prepared into powder pin, freeze-dried powder preservation, use with before being mixed with solution.Pharmaceutical solutions that this compound recipe is mixed with and at least a aminoglycoside antibiotics pharmaceutical solutions in same container, be mixed obtain as clear as crystal, do not form muddy or sedimentary combination solution preparation, and can keep wherein that piperacillin and tiring of aminoglycoside antibiotics do not fall.Described compound recipe representative formulations (unit using dosage) is made up of 0.1-5 gram avocin, 0.1-5 gram sulbactam sodium, 0.01-5 gram sodium citrate; Or the prescription (unit using dosage) that directly adds composite good recipe comprising piperacillin sodium of aminoglycoside antibiotics composition and aminoglycoside antibiotics restrains sodium citrate by 0.1-5 gram avocin, 0.01-5 gram sulbactam sodium, 0.01-5 gram aminoglycoside antibiotics, 0.01-5;
The possible embodiment of antibiotic compound of the present invention comprises following prescription:
Prescription 1-1: piperacillin 0.1-5g, sulbactam 0.1-5g, amikacin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-2: piperacillin 0.1-5g, sulbactam 0.1-5g, gentamycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-3: piperacillin 0.1-5g, sulbactam 0.1-5g, tobramycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-4: piperacillin 0.1-4g, sulbactam 0.1-5g, etimicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-5: piperacillin 0.1-5g, sulbactam 0.1-5g, dibekacin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-6: piperacillin 0.1-5g, sulbactam 0.1-5g, arbekacin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-7: piperacillin 0.1-5g, sulbactam 0.1-5g, kanamycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-8: piperacillin 0.1-5g, sulbactam 0.1-5g, sagamicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-9: piperacillin 0.1-5g, sulbactam 0.1-5g, isepamicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-10: piperacillin 0.1-5g, sulbactam 0.1-5g, neomycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-11: piperacillin 0.1-5g, sulbactam 0.1-5g, paromomycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-12: piperacillin 0.1-5g, sulbactam 0.1-5g, western cable clamp star 0.01-5g, EDTA 0.1-100mg.
Prescription 1-13: piperacillin 0.1-5g, sulbactam 0.1-5g, netilmicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-14: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, amikacin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-15: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, gentamycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-16: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, tobramycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-17: avocin 0.1-5g, clavulanate potassium 0.1-5g, etimicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-18: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, dibekacin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-19: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, arbekacin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-20: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, kanamycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-21: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, sagamicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-22: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, isepamicin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-23: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, neomycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-24: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, paromomycin 0.01-5g, EDTA 0.1-100mg.
Prescription 1-25: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, western cable clamp star 0.01-5g, EDTA 0.1-100mg.
Prescription 1-26: avocin 0.1-5g, clavulanic acid sodium 0.1-5g, netilmicin 10-5000mg, EDTA 0.1-100mg.
Prescription 1-27: avocin 0.1-5g, sulbactam 0.1-4g, amikacin sulfate 0.01-5g, citric acid 0.01-5g, sodium citrate 10-5000mg, EDTA 0.1-100mg.
Prescription 1-28: avocin 0.1-5g, sulbactam 0.1-4g, gentamycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-29: avocin 0.1-5g, sulbactam 0.1-4g, tobramycin 0.01-5g, citric acid 0.01-5g, sodium citrate 10-5000mg, EDTA 0.1-100mg.
Prescription 1-30: avocin 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.
Prescription 1-31: avocin 0.1-5g, sulbactam 0.1-4g, dibekacin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-32: avocin 0.1-5g, sulbactam 0.1-4g, arbekacin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-33: avocin 0.1-5g, sulbactam 0.1-4g, kanamycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-34: avocin 0.1-5g, sulbactam 0.1-4g, sagamicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-35: avocin 0.1-5g, sulbactam 0.1-4g, isepamicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-36: avocin 0.1-5g, sulbactam 0.1-4g, neomycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-37: avocin 0.1-5g, sulbactam 0.1-4g, paromomycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-38: avocin 0.1-5g, sulbactam 0.1-4g, western cable clamp star 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-39: avocin 0.1-5g, sulbactam 0.1-4g, netilmicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-40: avocin 0.1-5g, sulbactam 0.1-4g, EDTA 0.1-100mg.
Prescription 1-41: avocin 0.1-5g, sulbactam 0.1-4g, etimicin 0.01-5g, sodium dihydrogen phosphate 0.01-5g, disodium-hydrogen 0.01-5g, EDTA 0.1-100mg.
Prescription 1-42: avocin 0.1-5g, sulbactam 0.1-4g, gentamycin 0.01-5g, sodium dihydrogen phosphate 0.01-5g, disodium-hydrogen 0.01-5g, EDTA 0.1-100mg.
Prescription 1-43: avocin 0.1-5g, sulbactam 0.1-4g, gentamycin 0.01-5g, sodium acetate 0.01-5g, acetic acid 0.01-5g, EDTA 0.1-100mg.
Prescription 1-44: avocin 0.1-5g, sulbactam 0.1-4g, gentamycin 0.01-5g, smart peace sour 0.02-5g, EDTA0.1-100mg.
Prescription 1-45: avocin 0.1-5g, clavulanate potassium 0.1-4g, gentamycin 0.01-5g, smart peace sour 0.02-5g, EDTA 0.1-100mg.
Prescription 1-46: avocin 0.1-5g, sulbactam sodium 0.1-4g, arginine 0.01-5g, EDTA 0.1-100mg.
Prescription 1-47: avocin 0.1-5g, sulbactam sodium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-48: avocin 0.1-5g, sulbactam sodium 0.1-4g, levulose 0.02-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-49: avocin 0.1-5g, sulbactam sodium 0.1-4g, levulose 0.02-5g, EDTA 0.1-100mg.
Prescription 1-50: avocin 0.1-5g, clavulanate potassium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.02-5g, EDTA 0.1-100mg.
Prescription 1-51: avocin 0.1-5g, clavulanate potassium 0.1-4g, EDTA 0.1-100mg.
Prescription 1-52: avocin 0.1-5g, clavulanate potassium 0.1-4g, levulose 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g, EDTA 0.1-100mg.
Prescription 1-53: avocin 0.1-5g, clavulanate potassium 0.1-4g, levulose 0.01-5g, EDTA 0.1-100mg.
Prescription 1-54: avocin 0.1-5g, sulbactam sodium 0.1-4g, amikacin sulfate 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-55: avocin 0.1-5g, sulbactam sodium 0.1-4g, gentamycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-56: avocin 0.1-5g, sulbactam sodium 0.1-4g, tobramycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-57: avocin 0.1-5g, sulbactam sodium 0.1-4g, etimicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-58: avocin 0.1-5g, sulbactam sodium 0.1-4g, dibekacin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-59: avocin 0.1-5g, sulbactam sodium 0.1-4g, arbekacin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-60: avocin 0.1-5g, sulbactam sodium 0.1-4g, kanamycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-61: avocin 0.1-5g, sulbactam sodium 0.1-4g, sagamicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-62: avocin 0.1-5g, sulbactam sodium 0.1-4g, isepamicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-63: avocin 0.1-5g, sulbactam sodium 0.1-4g, neomycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-64: avocin 0.1-5g, sulbactam sodium 0.1-4g, paromomycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-65: avocin 0.1-5g, sulbactam sodium 0.1-4g, western cable clamp star 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-66: avocin 0.1-5g, sulbactam sodium 0.1-4g, netilmicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-67: avocin 0.1-5g, sulbactam sodium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-68: avocin 0.1-5g, sulbactam sodium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.01-5g, levulose 0.01-5g.
Prescription 1-69: avocin 0.1-5g, clavulanate potassium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-70: avocin 0.1-5g, clavulanate potassium 0.1-4g, amikacin sulfate 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-71: avocin 0.1-5g, clavulanate potassium 0.1-4g, gentamycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-72: avocin 0.1-5g, clavulanate potassium 0.1-4g, tobramycin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-73: avocin 0.1-5g, clavulanate potassium 0.1-4g, etimicin 0.01-5g, citric acid 0.01-5g, sodium citrate 0.01-5g.
Prescription 1-74: avocin 0.1-5g, clavulanate potassium 0.1-4g, citric acid 0.01-5g, sodium citrate 0.01-5g, levulose 0.01-5g.
Some representative concrete prescriptions (unit's of being using dosage) that can directly use in clinical practice of antibiotic compound of the present invention include but not limited to:
Prescription 2-1: avocin 4g, sulbactam sodium 0.5g, EDTA disodium 1mg.
Prescription 2-2: avocin 4g, sulbactam sodium 1g, EDTA disodium 1mg.
Prescription 2-3: avocin 4g, sulbactam sodium 2g, EDTA disodium 1mg.
Prescription 2-4: avocin 4g, sulbactam sodium 4g, EDTA disodium 1mg.
Prescription 2-5: avocin 4g, sulbactam sodium 1g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-6: avocin 4g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-7: avocin 4g, sulbactam sodium 2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-8: avocin 4g, sulbactam sodium 4g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-9: avocin 4g, sulbactam sodium 0.5g, Etimicin sulfate. 0.2g, EDTA disodium 1mg.
Prescription 2-10: avocin 4g, sulbactam sodium 1g, Etimicin sulfate. 0.2g, EDTA disodium 1mg.
Prescription 2-11: avocin 4g, sulbactam sodium 2g, Etimicin sulfate. 0.2g, EDTA disodium 1mg.
Prescription 2-12: avocin 4g, sulbactam sodium 4g, Etimicin sulfate. 0.2g, EDTA disodium 1mg.
Prescription 2-13: avocin 4g, sulbactam sodium 1g, Etimicin sulfate. 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-14: avocin 4g, sulbactam sodium 0.5g, Etimicin sulfate. 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-15: avocin 4g, sulbactam sodium 2g, Etimicin sulfate. 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-16: avocin 4g, sulbactam sodium 4g, Etimicin sulfate. 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-17: avocin 4g, sulbactam sodium 0.5g, amikacin sulfate 0.5g, EDTA disodium 1mg.
Prescription 2-18: avocin 4g, sulbactam sodium 1g, amikacin sulfate 0.5g, EDTA disodium 1mg.
Prescription 2-19: avocin 4g, sulbactam sodium 2g, amikacin sulfate 0.5g, EDTA disodium 1mg.
Prescription 2-20: avocin 4g, sulbactam sodium 4g, amikacin sulfate 0.5g, EDTA disodium 1mg.
Prescription 2-21: avocin 4g, sulbactam sodium 1g, amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-22: avocin 4g, sulbactam sodium 0.5g, amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-23: avocin 4g, sulbactam sodium 2g, amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-24: avocin 4g, sulbactam sodium 4g, amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-25: avocin 4g, sulbactam sodium 0.5g, gentamycin sulfate 0.16g, EDTA disodium 1mg.
Prescription 2-26: avocin 4g, sulbactam sodium 1g, gentamycin sulfate 0.16g, EDTA disodium 1mg.
Prescription 2-27: avocin 4g, sulbactam sodium 2g, gentamycin sulfate 0.16g, EDTA disodium 1mg.
Prescription 2-28: avocin 4g, sulbactam sodium 4g, gentamycin sulfate 0.16g, EDTA disodium 1mg.
Prescription 2-29: avocin 4g, sulbactam sodium 1g, gentamycin sulfate 0.16g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-30: avocin 4g, sulbactam sodium 0.5g, gentamycin sulfate 0.16g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-31: avocin 4g, sulbactam sodium 2g, gentamycin sulfate 0.16g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-32: avocin 4g, sulbactam sodium 4g, gentamycin sulfate 0.16g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-33: avocin 4g, sulbactam sodium 0.5g, tobramycin 0.2g, EDTA disodium 1mg.
Prescription 2-34: avocin 4g, sulbactam sodium 1g, tobramycin 0.2g, EDTA disodium 1mg.
Prescription 2-35: avocin 4g, sulbactam sodium 2g, tobramycin 0.2g, EDTA disodium 1mg.
Prescription 2-36: avocin 4g, sulbactam sodium 4g, tobramycin 0.2g, EDTA disodium 1mg.
Prescription 2-37: avocin 4g, sulbactam sodium 1g, tobramycin 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-38: avocin 4g, sulbactam sodium 0.5g, tobramycin 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-39: avocin 4g, sulbactam sodium 2g, tobramycin 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-40: avocin 4g, sulbactam sodium 4g, tobramycin 0.2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-41: avocin 2g, sulbactam sodium 0.25g, EDTA disodium 1mg.
Prescription 2-42: avocin 2g, sulbactam sodium 0.5g, EDTA disodium 1mg.
Prescription 2-43: avocin 2g, sulbactam sodium 1g, EDTA disodium 1mg.
Prescription 2-44: avocin 2g, sulbactam sodium 2g, EDTA disodium 1mg.
Prescription 2-45: avocin 2g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-46: avocin 2g, sulbactam sodium 0.25g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-47: avocin 2g, sulbactam sodium 1g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-48: avocin 2g, sulbactam sodium 2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-49: avocin 1g, sulbactam sodium 0.5g, EDTA disodium 1mg.
Prescription 2-50: avocin 1g, sulbactam sodium 1g, EDTA disodium 1mg.
Prescription 2-51: avocin 1g, sulbactam sodium 0.25g, EDTA disodium 1mg.
Prescription 2-52: avocin 1g, sulbactam sodium 1.25g, EDTA disodium 1mg.
Prescription 2-53: avocin 1g, sulbactam sodium 1g, EDTA disodium 1mg, sodium citrate 0.2g.
Prescription 2-54: avocin 1g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.2g.
Prescription 2-55: avocin 1g, sulbactam sodium 0.25g, EDTA disodium 1mg, sodium citrate 0.2g.
Prescription 2-56: avocin 1g, sulbactam sodium 0.125g, EDTA disodium 1mg, sodium citrate 0.2g.
Prescription 2-57: avocin 4g, clavulanate potassium 0.5g, EDTA disodium 1mg.
Prescription 2-58: avocin 4g, clavulanate potassium 1g, EDTA disodium 1mg.
Prescription 2-59: avocin 4g, clavulanate potassium 2g, EDTA disodium 1mg.
Prescription 2-60: avocin 4g, clavulanate potassium 4g, EDTA disodium 1mg.
Prescription 2-61: avocin 4g, clavulanate potassium 1g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-62: avocin 4g, clavulanate potassium 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-63: avocin 4g, clavulanate potassium 2g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-64: avocin 4g, clavulanate potassium 4g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-65: avocin 4g, clavulanate potassium 0.5g, Etimicin sulfate. 0.2g, EDTA disodium 1mg.
Prescription 2-66: avocin 4g, clavulanate potassium 1g, Etimicin sulfate. 0.2g, EDTA sodium 1mg.
Prescription 2-67: avocin 4g, clavulanate potassium 2g, Etimicin sulfate. 0.2g, EDTA sodium 1mg.
Prescription 2-68: avocin 4g, clavulanate potassium 4g, Etimicin sulfate. 0.2g, EDTA sodium 1mg.
Prescription 2-69: avocin 4g, clavulanate potassium 1g, Etimicin sulfate. 0.2g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-70: avocin 4g, clavulanate potassium 0.5g, Etimicin sulfate. 0.2g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-71: avocin 4g, clavulanate potassium 2g, Etimicin sulfate. 200mg, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-72: avocin 4g, clavulanate potassium 4g, Etimicin sulfate. 0.2g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-73: avocin 4g, clavulanate potassium 0.5g, amikacin sulfate 0.5g, EDTA sodium 1mg.
Prescription 2-74: avocin 4g, clavulanate potassium 1g, amikacin sulfate 0.5g, EDTA sodium 1mg.
Prescription 2-75: avocin 4g, clavulanate potassium 2g, amikacin sulfate 0.5g, EDTA sodium 1mg.
Prescription 2-76: avocin 4g, clavulanate potassium 4g, amikacin sulfate 0.5g, EDTA sodium 1mg.
Prescription 2-77: avocin 4g, clavulanate potassium 1g, amikacin sulfate 0.5g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-78: avocin 4g, clavulanate potassium 0.5g, amikacin sulfate 0.5g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-79: avocin 4g, clavulanate potassium 2g, amikacin sulfate 0.5g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-80: avocin 4g, clavulanate potassium 4g, amikacin sulfate 0.5g, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-81: avocin 4g, clavulanate potassium 0.5g, gentamycin sulfate 80mg, EDTA sodium 1mg.
Prescription 2-82: avocin 4g, clavulanate potassium 1g, gentamycin sulfate 80mg, EDTA sodium 1mg.
Prescription 2-83: avocin 4g, clavulanate potassium 2g, gentamycin sulfate 80mg, EDTA disodium 1mg.
Prescription 2-84: avocin 4g, clavulanate potassium 4g, gentamycin sulfate 80mg, EDTA disodium 1mg.
Prescription 2-85: avocin 4g, clavulanate potassium 1g, gentamycin sulfate 80mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-86: avocin 4g, clavulanate potassium 0.5g, gentamycin sulfate 80mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-87: avocin 4g, clavulanate potassium 2g, gentamycin sulfate 80mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-88: avocin 4g, clavulanate potassium 4g, gentamycin sulfate 80mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-89: avocin 4g, clavulanate potassium 0.5g, tobramycin 0.2g, EDTA disodium 1mg.
Prescription 2-90: avocin 4g, clavulanate potassium 1g, tobramycin 200mg, EDTA disodium 1mg.
Prescription 2-91: avocin 4g, clavulanate potassium 2g, tobramycin 200mg, EDTA disodium 1mg.
Prescription 2-92: avocin 4g, clavulanate potassium 4g, tobramycin 200mg, EDTA disodium 1mg.
Prescription 2-93: avocin 4g, clavulanate potassium 1g, tobramycin 200mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-94: avocin 4g, clavulanate potassium 0.5g, tobramycin 200mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-95: avocin 4g, clavulanate potassium 2g, tobramycin 200mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-96: avocin 4g, clavulanate potassium 4g, tobramycin 200mg, EDTA disodium 1mg, sodium citrate 0.25g.
Prescription 2-97: avocin 2g, clavulanate potassium 0.25g, EDTA disodium 1mg.
Prescription 2-98: avocin 2g, clavulanate potassium 0.5g, EDTA disodium 1mg.
Prescription 2-99: avocin 2g, clavulanate potassium 1g, EDTA disodium 1mg.
Prescription 2-100: avocin 2g, clavulanate potassium 2g, EDTA disodium 1mg.
Prescription 2-101: avocin 2g, clavulanate potassium 0.5g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-102: avocin 2g, clavulanate potassium 0.25g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-103: avocin 2g, clavulanate potassium 1g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-104: avocin 2g, clavulanate potassium 2g, EDTA sodium 1mg, sodium citrate 0.25g.
Prescription 2-105: avocin 1g, clavulanate potassium 0.5g, EDTA sodium 1mg.
Prescription 2-106: avocin 1g, clavulanate potassium 1g, EDTA disodium 1mg.
Prescription 2-107: avocin 1g, clavulanate potassium 0.25g, EDTA disodium 1mg.
Prescription 2-108: avocin 1g, clavulanate potassium 0.125g, EDTA disodium 1mg.
Prescription 2-109: avocin 1g, clavulanate potassium 1g, EDTA disodium 1mg, sodium citrate 0.2g.
Prescription 2-110: avocin 1g, clavulanate potassium 0.5g, EDTA disodium 1mg, sodium citrate 0.2g.
Prescription 2-111: avocin 1g, clavulanate potassium 0.25g, EDTA sodium 1mg, sodium citrate 0.2g.
Prescription 2-112: avocin 1g, clavulanate potassium 0.125g, EDTA disodium 1mg, citric acid 0.2g.
Prescription 2-113: avocin 4g, clavulanate potassium 1g, sodium citrate 0.2g.
Prescription 2-114: avocin 4g, clavulanate potassium 0.5g, sodium citrate 0.2g.
Prescription 2-115: avocin 4g, clavulanate potassium 2g, sodium citrate 0.2g.
Prescription 2-116: avocin 1g, clavulanate potassium 0.125g, sodium citrate 0.2g.
Prescription 2-117: avocin 1g, clavulanate potassium 0.25g, sodium citrate 0.2g.
Prescription 2-118: avocin 1g, clavulanate potassium 0.5g, sodium citrate 0.2g.
Prescription 2-119: avocin 2g, clavulanate potassium 0.25g, sodium citrate 0.2g.
Prescription 2-120: avocin 2g, clavulanate potassium 0.5g, sodium citrate 0.2g.
Prescription 2-121: avocin 2g, clavulanate potassium 1.0g, sodium citrate 0.2g.
Prescription 2-122: avocin 4g, sulbactam sodium 1g, sodium citrate 0.2g.
Prescription 2-123: avocin 4g, sulbactam sodium 0.5g, sodium citrate 0.2g.
Prescription 2-124: avocin 4g, sulbactam sodium 2g, sodium citrate 0.2g.
Prescription 2-125: avocin 1g, sulbactam sodium 0.125g, sodium citrate 0.2g.
Prescription 2-126: avocin 1g, sulbactam sodium 0.25g, sodium citrate 0.2g.
Prescription 2-127: avocin 1g, sulbactam sodium 0.5g, sodium citrate 0.2g.
Prescription 2-128: avocin 2g, sulbactam sodium 0.25g, sodium citrate 0.2g.
Prescription 2-129: avocin 2g, sulbactam sodium 0.5g, sodium citrate 0.2g.
Prescription 2-130: avocin 2g, sulbactam sodium 1.0g, sodium citrate 0.2g.
Prescription 2-131: avocin 4g, sulbactam sodium 1g, gentamycin sulfate 0.16g, sodium citrate 0.2g.
Prescription 2-132: avocin 4g, sulbactam sodium 0.5g, gentamycin sulfate 0.16g, sodium citrate 0.2g.
Prescription 2-133: avocin 4g, sulbactam sodium 2g, gentamycin sulfate 0.16g, sodium citrate 0.2g.
Prescription 2-134: avocin 4g, sulbactam sodium 1g, amikacin sulfate 0.5g, sodium citrate 0.2g.
Prescription 2-135: avocin 4g, sulbactam sodium 0.5g, amikacin sulfate 0.5g, sodium citrate 0.2g.
Prescription 2-136: avocin 4g, sulbactam sodium 2g, amikacin sulfate 0.5g, sodium citrate 0.2g.
Prescription 2-137: avocin 4g, sulbactam sodium 1g, Etimicin sulfate. 0.2g, sodium citrate 0.2g.
Prescription 2-138: avocin 4g, sulbactam sodium 0.5g, Etimicin sulfate. 0.2g, sodium citrate 0.2g.
Prescription 2-139: avocin 4g, sulbactam sodium 2g, Etimicin sulfate. 0.2g, sodium citrate 0.2g.
The available in use injection isosmotic solution of antibiotic compound of the present invention includes but not limited to levulose solution, glucose solution and normal saline, is mixed with injection and uses.Wherein levulose, glucose or the sodium chloride consumption in the unit using dosage is the 0.1-20 gram; Concentration in injection is 0.1-10%.
Selected gentamycin, amikacin, etimicin to form different prescriptions arbitrarily and carried out component compatibility and stability study with three kinds of possible dosage forms and preserving type with piperacillin sodium salt, clavulanic acid potassium salt or sulbactam sodium salt.The result shows, the pharmaceutical solutions of joining, now with the current, be mixed with pharmaceutical solutions after stored frozen use after adding aminoglycoside antibiotics after thawing or be prepared into freeze-dried powder after cryopreservation use in three kinds of modes after adding aminoglycoside antibiotics after being mixed with pharmaceutical solutions again again and all can keep the content of piperacillin, sulbactam or clavulanic acid and aminoglycoside antibiotics more than 90%, the some of them prescription more can make above-mentioned each components contents more than 95%, has reached the index when multiple medicine clinically is composite to be used.In addition, result of study shows that EDTA can obviously suppress formulated described in the present invention and become particulate generation in the solution behind the pharmaceutical solutions, thereby make patient safer when using the disease of antibiotic formulation treatment infected by microbes class of the present invention in quiet notes mode, patient and doctor have had the selection of using piperacillin and aminoglycoside antibiotics simultaneously simultaneously, thereby not only make therapeutic scheme more effective, and might avoid to a greater extent because of using single kind antibiotic to run into drug-fast probability, thereby have and bigger may avoid treatment failure for the first time.
When being prepared into pharmaceutical solutions, antibiotic compound of the present invention can be used as injection, eye drop, nasal drop, ear drop, reproductive tract drop or lotion or externally used solution agent as the control of microorganisms purposes.
Antibiotic compound of the present invention is prepared into when pharmaceutical solutions uses and can prepares immediately before use, or prepares in advance and encapsulate freezing preservation, uses with preceding room temperature thawing and after rising to room temperature.
Antibiotic compound of the present invention also can be prepared into powder pin or freeze-dried powder stored refrigerated, is mixed with solution with injection liquid and uses immediately with preceding.
When being prepared into pharmaceutical solutions, powder pin or freeze-dried powder, antibiotic compound of the present invention can add pharmaceutic adjuvant acceptable on other pharmaceutics.
The present invention includes the method for the described antibiotic compound freeze-dried powder of preparation: other adjuvant of antibiotic compound described in avocin, sulbactam sodium or clavulanate potassium, EDTA disodium and the present invention is dissolved in water for injection or injection 2.5% levulose aqueous solution or 5% normal saline, transfers pH to 6-6.75; Prepared solution is distributed into contains the above-mentioned 2-1 that may specifically fill a prescription to may specifically filling a prescription the medicinal liquid of the unit using dosage shown in the 2-139 in container and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃; The vacuum of freezer dryer is evacuated to below 40 handkerchiefs; The temperature of freezer dryer is transferred to 3-5 ℃ to be removed water and does; The temperature of freezer dryer is transferred to 40-50 ℃ of dry obtained freeze-drying powder pin, charge into aseptic closure behind the drying nitrogen, and keep in Dark Place 5 ℃ of following temperature.
Table 1 has been listed section H IAC test result.Particulate generation when test data proof EDTA can suppress antibiotic compound of the present invention effectively and is mixed with pharmaceutical solutions.
The specific embodiment:
The content of avocin, sulbactam sodium and clavulanate potassium C18 reversed phase liquid chromatography is measured (Tianjin Hemei Biotech Co., Ltd's analytical method numbering: analytical method HM-K-02) with UV-detector; The content usefulness anti-acid reversed-phase high pressure liquid chromatography of aminoglycoside antibiotics, usefulness evaporation-light scattering detector (ELSD detector) are measured (Tianjin Hemei Biotech Co., Ltd's analytical method numbering: analytical method HM-K-08).Antibiotic each time point content in solution characterizes in the mode of the percent of the mean concentration that is equivalent to the identical sample of three parts of concentration of its each component (this moment, content was defined as 100%) in the compound recipe, in the compound recipe each antibiotic component the relative amount of each time point by chromatograph in the definition of respective peaks area ratio.
Embodiment 1
Prescription: avocin 4g, sulbactam sodium 0.5g, gentamycin 80mg/2mL injection.
Compound method: avocin and sulbactam sodium are dissolved in 100mL water for injection, add injection liquid of gentamicin, produce a large amount of white precipitates immediately, and ultrasonic 15 minutes, precipitation did not disappear.
Embodiment 2
Avocin 40mg, sulbactam sodium 5mg are dissolved in the buffer of various different pH value of 2mL and intensity, splash into gentamycin 80mg/2mL injection 20 μ L.Ultrasonic 5 minutes, observe to have or not to precipitate generating, the result is that the buffer pH value generates in nothing precipitation more than 6, can obtain clear solutions, the kind of buffer influences not quite the result.The results are shown in following table.
Figure BYZ000001576096300181
* the more muddy OK clear liquid of the muddy * * * solution of solution becomes slight haze * * solution becomes
Embodiment 3A
Avocin 40mg, sulbactam sodium 5mg, EDTA sodium 0.01mg are dissolved in the buffer of various different pH value of 2mL and intensity, splash into gentamycin 80mg/2mL injection 20 μ L.Ultrasonic 5 minutes, observe to have or not to precipitate generating, the result is that the buffer pH value generates in nothing precipitation more than 6, can obtain clear solutions, the kind of buffer influences not quite the result.The results are shown in following table.
* the more muddy OK clear liquid of the muddy * * * solution of solution becomes slight haze * * solution becomes
Embodiment 3B
Avocin 40mg, clavulanate potassium 5mg, EDTA sodium 0.01mg are dissolved in the buffer of various different pH value of 2mL and intensity, splash into gentamycin 80mg/2mL injection 20 μ L.Ultrasonic 5 minutes, observe to have or not to precipitate generating, the result is that the buffer pH value generates in nothing precipitation more than 6, can obtain clear solutions, the kind of buffer influences not quite the result.The results are shown in following table.
Figure BYZ000001576096300192
* the more muddy OK clear liquid of the muddy * * * solution of solution becomes slight haze * * solution becomes
Embodiment 4
Prescription: avocin 4g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.20g, gentamycin sulfate 80mg/2mL injection.
Compound method: avocin, sulbactam sodium and sodium citrate are dissolved in 200mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.5, drip gentamicin injection liquid in shaking, produce a small amount of cotton-shaped white precipitate, white precipitate dissolving after ultrasonic 5 minutes and make clear solution.Be encapsulated into room temperature preservation after a drop bottle or the drip bag, measure 1,20 hour HIAC data (seeing Table 1), in 0,1,2,4,6 hours time points are observed and are had or not precipitation to generate, and the content of sample analysis avocin, sulbactam sodium, the results are shown in following table.
Time (h) 0 1 2 4 6
Avocin 98.6 99.1 99.9 98.8 97.5
Sulbactam sodium 99.2 98.9 100.4 97.6 97.0
Embodiment 5
Prescription: avocin 4g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.20g, Etimicin sulfate. 200mg.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, and regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, add Etimicin sulfate. 200mg, make clear solution in ultrasonic 10 minutes.Filter and to be encapsulated into room temperature preservation after a drop bottle or the drip bag after (0.2 μ m), measure 1,20 hour HIAC data (seeing Table 1), in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam sodium content (content %), the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 103.8 99.46 97.19 98.52 94.52 96.62
Sulbactam sodium 97.51 90.99 103.6 97.55 90.97 99.21
Etimicin sulfate. 108.9 100.2 100.5 100.4 100.4 97.50
Embodiment 6
Prescription: avocin 4g, sulbactam sodium 1.0g, sodium citrate 0.20g, Etimicin sulfate. 200mg.Compound method: avocin, sulbactam sodium and sodium citrate are dissolved in 200mL water for injection, and regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, adds Etimicin sulfate. 200mg, make clear solution in ultrasonic 10 minutes.Room temperature (22 ℃) is preserved after being encapsulated into a drop bottle or drip bag after the filtration (0.2 μ m), and in 0,1,2,4,6,8 hours time points are observed and had or not precipitation to generate, and the content of sample analysis piperacillin, sulbactam sodium and etimicin, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 101.8 101.3 101.8 101.2 98.25 95.07
Sulbactam sodium 94.10 97.38 96.40 97.67 96.91 97.06
Etimicin sulfate. 99.75 98.84 98.71 98.74 98.94 96.82
Embodiment 7
Prescription: avocin 4g, sulbactam sodium 2.0g, EDTA disodium 1mg, sodium citrate 0.20g, Etimicin sulfate. 200mg.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, and regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, adds Etimicin sulfate. 200mg, make clear solution in ultrasonic 10 minutes.Room temperature (22 ℃) is preserved after being encapsulated into a drop bottle or drip bag after the filtration (0.2 μ m), and in 0,1,2,4,6,8 hours time points are observed and had or not precipitation to generate, and sample analysis piperacillin and etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 98.8 100.3 99.2 97.7 101.5 98.1
Etimicin sulfate. 102.3 101.7 101.1 102.2 101.6 94.3
Embodiment 8
Prescription: avocin 4g, sulbactam sodium 1.0g, EDTA disodium 5mg, sodium citrate 0.20g, Etimicin sulfate. 200mg.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, add Etimicin sulfate. 200mg, white precipitate dissolving after ultrasonic 10 minutes and make clear solution.Filter and to be encapsulated into room temperature preservation after a drop bottle or the drip bag after (0.2 μ m), in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam sodium and etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 102.2 101.1 100.7 99.15 97.93 99.33
Sulbactam sodium 94.41 96.75 99.39 95.36 96.14 96.53
Etimicin sulfate. 99.46 99.63 99.45 99.45 100.2 100.2
Embodiment 9
Prescription: avocin 4g, sulbactam sodium 4.0g, EDTA disodium 1mg, sodium citrate 0.20g, Etimicin sulfate. 200mg.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, add Etimicin sulfate. 200mg, white precipitate dissolving after ultrasonic 10 minutes and make clear solution.Filter and to be encapsulated into room temperature preservation after a drop bottle or the drip bag after (0.2 μ m), in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam sodium and etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 99.8 102.4 98.6 100.1 97.8 99.5
Sulbactam sodium 101.4 98.5 100.7 98.6 97.4 99.3
Etimicin sulfate. 102.3 101.7 102.6 100.6 100.9 101.2
Embodiment 10
Prescription: avocin 4g, clavulanate potassium 1.0g, EDTA disodium 1mg, sodium citrate 0.20g, Etimicin sulfate. 200mg.
Compound method: avocin, clavulanate potassium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.5, add Etimicin sulfate. 200mg, white precipitate dissolving after ultrasonic 10 minutes and make clear solution.Filter be encapsulated into a drop bottle or drip bag after (0.2 μ m) after room temperature (22 ℃) preserve, in 0,1,2,4,6 hours time points are observed and are had or not precipitation to generate, and the content of sample analysis piperacillin, potassium clavulanate, the results are shown in following table.
Time (h) 0 1 2 4 6
Avocin 98.8 97.6 98.1 100.3 98.4
Clavulanate potassium 99.4 98.8 99.3 99.5 98.7
Embodiment 11
Prescription: avocin 4g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.20g, amikacin sulfate 500mg.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, add amikacin sulfate 500mg, white precipitate dissolving after ultrasonic 10 minutes and make clear solution.Filter 100mL gained solution in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to 30 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of dryings after doing and obtain freeze-dried powder, charge into aseptic closure behind the drying nitrogen, put in the refrigerator and preserve below 0 ℃.After 7 days with the freeze-dried powder of gained with 100mL water for injection wiring solution-forming, 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 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
Embodiment 12
Prescription: avocin 4g, sulbactam sodium 1.0g, EDTA disodium 1mg, sodium citrate 0.20g, amikacin sulfate 500mg.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, add amikacin sulfate 500mg, white precipitate dissolving after ultrasonic 10 minutes and make clear solution.Room temperature (22 ℃) is preserved after being encapsulated into a drop bottle or drip bag after the filtration (0.2 μ m), and in 0,1,2,4,6,8 hours time points are observed and had or not precipitation to generate, and the content of sample analysis piperacillin, sulbactam sodium and amikacin sulfate, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 93.25 99.69 92.42 83.82 94.95 94.24
Sulbactam sodium 97.38 93.40 92.65 86.94 93.95 91.47
Amikacin sulfate 98.69 98.34 97.54 97.56 98.87 98.95
Embodiment 13
Prescription: avocin 4g, sulbactam sodium 1.0g, EDTA disodium 1mg, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL water for injection, and regulating pH with citric acid or sodium hydrate aqueous solution is 6.0.Get after the filtration (0.2 μ m) and be frozen into solid and place 0 ℃ of following temperature to preserve after 100mL is encapsulated into a drop bottle or drip bag, take out after 7 days and place room temperature (22 ℃) to melt and be warming up to room temperature, and in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate and sample analysis piperacillin, sulbactam sodium content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 102.1 101.7 100.3 99.6 98.6 99.3
Sulbactam sodium 95.8 97.8 99.6 95.9 96.4 97.5
Embodiment 14
Prescription: avocin 400g, sulbactam sodium 100g, EDTA disodium 100mg, sodium citrate 20g.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate grind to uniform powder in grinder and are distributed into 100 bottles, get one bottle and be dissolved in 100mL water for injection, regulating pH with citric acid or sodium hydrate aqueous solution is 6.0, get 10mL, add Etimicin sulfate. 20mg, make clear solution after ultrasonic 10 minutes.In 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and the content of sample analysis piperacillin, sulbactam sodium and etimicin, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 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
Embodiment 15
Prescription: avocin 4g, sulbactam sodium 1.0g, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium, sodium citrate are dissolved in 200mL water for injection, regulate pH to 6.0 with citric acid or sodium hydrate aqueous solution.Filter and to get that 100mL is encapsulated into a drop bottle after (0.2 μ m) or drip bag freezing (one-tenth solid) is preserved after 7 days room temperature and melted and be warming up to and get 20mL after the room temperature and measure 1,20 hour HIAC data (seeing Table 1), other gets 20mL, add Etimicin sulfate. 20mg, make clear solution after ultrasonic 10 minutes.In 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and measure 1,20 hour HIAC data (seeing Table 1), and sample analysis piperacillin, sulbactam sodium content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 101.8 101.3 101.8 101.2 98.3 95.1
Sulbactam sodium 94.1 97.4 96.4 97.7 96.9 97.1
Embodiment 16
Filter the solution of the embodiment 15 of 100mL in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 40 ℃, the vacuum of freezer dryer is evacuated to 50 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 45 ℃ of dryings after doing and obtain freeze-dried powder, charge into aseptic closure behind the drying nitrogen, put 0 ℃ of preservation in the refrigerator.With the freeze-dried powder of gained 100mL water for injection wiring solution-forming, measure 1,20 hour HIAC data (seeing Table 1) after 7 days, other gets gained solution 60mL, add Etimicin sulfate. 20mg, make clear solution after ultrasonic 10 minutes, measure 1,20 hour HIAC data (seeing Table 1), and in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate and sample analysis piperacillin, etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 101.8 101.3 101.8 101.2 98.3 95.1
Etimicin sulfate. 94.81 99.66 100.9 101.5 96.97 94.44
Embodiment 17
Add amikacin sulfate 50mg in the solution that thaws of the embodiment 15 of 20mL, make clear solution after ultrasonic 10 minutes, measure 1,20 hour HIAC data (seeing Table 1), in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, amikacin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 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
Embodiment 18
Prescription: avocin 4g, sulbactam sodium 1g, EDTA disodium 1mg, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 10mL water for injection, with Fructus Citri Limoniae acid for adjusting pH to 6.0, make clear and bright solution after ultrasonic 10 minutes, filter the solution that makes in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to below 40 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of resulting freeze-dried powders of drying after doing, charge into aseptic closure behind the drying nitrogen, preserving below 0 ℃.After 7 days, add the dissolving of 100mL water for injection obtain clear and bright solution after room temperature place, in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam sodium content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 100.2 99.0 99.0 96.2 94.5 95.3
Sulbactam sodium 98.5 98.7 98.2 95.6 94.0 96.1
Get above-mentioned clear and bright solution 10mL, add 20 milligrams of Etimicin sulfate .s, make clear and bright solution after ultrasonic 10 minutes, in 0 by the freeze-dried powder preparation, 1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 100.2 99.0 99.0 96.2 94.5 95.3
Etimicin sulfate. 100.0 98.8 97.5 98.4 95.6 92.8
Embodiment 19
Prescription: avocin 4g, sulbactam sodium 0.5g, EDTA disodium 1mg, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium, EDTA disodium and sodium citrate are dissolved in 200mL injection 2.5% levulose aqueous solution, regulate pH to 6.0 with citric acid or sodium hydrate aqueous solution.Filter and to get that 100mL is encapsulated into a drop bottle or drip bag freezing (one-tenth solid) is preserved after (0.2 μ m), after 7 days room temperature melt and be warming up to room temperature after measure 1,20 hour HIAC data (seeing Table 1), get above-mentioned thawing solution 40mL, add amikacin sulfate 100mg, make clear and bright solution after ultrasonic 10 minutes, measure 1,20 hour HIAC data (seeing Table 1), in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam sodium and amikacin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 93.25 99.69 92.42 83.82 94.95 94.24
Sulbactam sodium 97.38 93.40 92.65 86.94 93.95 91.47
Amikacin sulfate 96.88 97.78 96.14 96.88 98.34 98.11
Embodiment 20
The solution of the embodiment 19 of 100mL is packed in the container and is placed freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to 30 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of resulting freeze-dried powders of drying after doing, charge into aseptic closure behind the drying nitrogen, preserving below 0 ℃.After 7 days, add the dissolving of 100mL water for injection and obtain clear and bright solution, add 100 milligrams of Etimicin sulfate .s, clear and bright solution after ultrasonic 10 minutes is also placed under room temperature, measure 1,20 hour HIAC data (seeing Table 1), in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis piperacillin, sulbactam sodium and etimicin content, the results are shown in Table.
Time (h) 0 1 2 4 6 8
Avocin 93.25 99.69 92.42 83.82 94.95 94.24
Sulbactam sodium 97.38 93.40 92.65 86.94 93.95 91.47
Etimicin sulfate. 99.75 98.84 98.71 98.74 98.94 96.82
Embodiment 21
Prescription: avocin 4g, sulbactam sodium 1.0g, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium and sodium citrate are dissolved in 10mL water for injection, with Fructus Citri Limoniae acid for adjusting pH to 6.0, make settled solution after ultrasonic 10 minutes, filter the solution that makes in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to below 40 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of resulting freeze-dried powders of drying after doing, charge into aseptic closure behind the drying nitrogen, put in the refrigerator and preserving below 0 ℃.After 7 days, room temperature was placed after the dissolving of adding 100mL water for injection obtained settled solution, got above-mentioned clear and bright solution 10mL by the freeze-dried powder preparation, add 40 milligrams of amikacin sulfates, make clear and bright solution after ultrasonic 10 minutes, in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis avocin, sulbactam sodium and amikacin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 93.25 99.69 92.42 83.82 94.95 94.24
Sulbactam sodium 97.38 93.40 92.65 86.94 93.95 91.47
Amikacin sulfate 98.69 98.34 97.54 97.56 98.87 98.95
Embodiment 22
Prescription: avocin 4g, sulbactam sodium 0.5g, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium and sodium citrate are dissolved in 10mL water for injection, with Fructus Citri Limoniae acid for adjusting pH to 6.0, make settled solution after ultrasonic 10 minutes, filter the solution that makes in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to below 40 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of resulting freeze-dried powders of drying after doing, charge into aseptic closure behind the drying nitrogen, put in the refrigerator and preserving below 0 ℃.After 7 days, room temperature was placed after the dissolving of adding 100mL water for injection obtained settled solution, got above-mentioned settled solution 10mL by the freeze-dried powder preparation, add 40 milligrams of amikacin sulfates, make clear and bright solution after ultrasonic 10 minutes, in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis avocin, sulbactam sodium and amikacin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 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
Embodiment 23
Prescription: avocin 4g, sulbactam sodium 1g, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium and sodium citrate are dissolved in 10mL water for injection, with Fructus Citri Limoniae acid for adjusting pH to 6.0, make settled solution after ultrasonic 10 minutes, filter the solution that makes in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to below 40 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of resulting freeze-dried powders of drying after doing, charge into aseptic closure behind the drying nitrogen, put in the refrigerator and preserving below 0 ℃.After 7 days, room temperature was placed after the dissolving of adding 100mL water for injection obtained settled solution, got above-mentioned clear and bright solution 10mL by the freeze-dried powder preparation, add 20 milligrams of Etimicin sulfate .s, make clear and bright solution after ultrasonic 10 minutes, in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Etimicin sulfate. 99.46 99.63 99.45 99.45 100.2 100.2
Embodiment 24
Prescription: avocin 4g, sulbactam sodium 0.5g, sodium citrate 0.20g.
Compound method: avocin, sulbactam sodium and sodium citrate are dissolved in 10mL water for injection, with Fructus Citri Limoniae acid for adjusting pH to 6.0, make settled solution after ultrasonic 10 minutes, filter the solution that makes in the container of packing into after (0.2 μ m) and place freezer dryer, the temperature of freezer dryer is transferred to subzero 35 ℃, the vacuum of freezer dryer is evacuated to below 40 handkerchiefs, the temperature of freezer dryer is transferred to 3 ℃ to be removed water and the temperature of freezer dryer is transferred to 40 ℃ of resulting freeze-dried powders of drying after doing, charge into aseptic closure behind the drying nitrogen, put in the refrigerator and preserving below 0 ℃.After 7 days, room temperature was placed after the dissolving of adding 100mL water for injection obtained settled solution, got above-mentioned settled solution 10mL by the freeze-dried powder preparation, add 20 milligrams of Etimicin sulfate .s, make clear and bright solution after ultrasonic 10 minutes, in 0,1,2,4,6,8 hours time points are observed and are had or not precipitation to generate, and sample analysis avocin, sulbactam sodium and etimicin content, the results are shown in following table.
Time (h) 0 1 2 4 6 8
Avocin 103.8 99.46 97.19 98.52 94.52 96.62
Sulbactam sodium 97.51 90.99 103.6 97.55 90.97 99.21
Etimicin sulfate. 108.9 100.2 100.5 100.4 100.4 97.50
The HIAC test
With HIAC-3000 type light transmission detector and American Pharmacopeia method (USP 788) pharmaceutical solutions of part Example formulations is carried out light transmission test (Light Obscuration Testing), wherein granule content characterizes with the granule number in every ml soln, the average that its result measures for secondary, same sample is measured when 1 hour and 20 hours respectively, and partial test the results are shown in table 1.
Table 1: section H IAC test result
G: gentamycin; Y: etimicin; A: amikacin.

Claims (14)

1. antibiotic compound, by piperacillin or its pharmaceutically acceptable salt, sulbactam or its pharmaceutically acceptable salt, at least a ion chelating agent that suppresses the granule generation, buffer components, form with at least a aminoglycoside antibiotics, described buffer components makes the pH value of described antibiotic compound be controlled at 6-7.
2. the antibiotic compound in the claim 1 is characterized by that described to suppress the ion chelating agent that granule generates be ethylenediaminetetraacetic acid, diethylene triamine pentacetic acid (DTPA), Hedta, or their pharmaceutically acceptable salts or hydrate.
3. the antibiotic compound in the claim 1 is characterized by that described to suppress the ion chelating agent that granule generates be ethylenediaminetetraacetic acid or disodium edta.
4. the antibiotic compound in the claim 1, the unit using dosage that it is characterized by described compound recipe comprises 0.1-5 gram avocin, 0.1-5 gram sulbactam sodium and 0.1-100 milligram ethylenediaminetetraacetic acid.
5. the antibiotic compound in the claim 1, it is characterized by described buffer components is citric acid/citrate, phosphoric acid/phosphate system, acetic acid/acetate, arginine or Tris-HCl.
6. the antibiotic compound in the claim 1, the unit using dosage that it is characterized by described compound recipe comprises 0.1-5 gram avocin, 0.1-5 gram sulbactam sodium, 0.01-5 gram sodium citrate and 0.1-100 milligram ethylenediaminetetraacetic acid.
7. the antibiotic compound in the claim 6 is characterized in that described antibiotic compound is prepared into the powder pin or freeze-dried powder is preserved.
8. the antibiotic compound in the arbitrary claim of claim 1-7, it is characterized by described aminoglycoside antibiotics is etimicin, gentamycin, tobramycin, amikacin, netilmicin, dibekacin, kanamycin, arbekacin, sagamicin, isepamicin, sisomicin, neomycin, paromomycin, streptomycin, spectinomycin, micronomicin, astromicin or ribostamycin, or they are at pharmaceutically acceptable salt.
9. the antibiotic compound in the arbitrary claim of claim 1-7, the unit using dosage that it is characterized by described aminoglycoside antibiotics are the 0.01-5 gram.
10. the antibiotic compound in the claim 1, the unit using dosage that it is characterized by described compound recipe restrains avocin, 0.1-5 gram sulbactam sodium, 0.01-5 gram sodium citrate, 0.1-100 milligram ethylenediaminetetraacetic acid and 0.05-2 gram Etimicin sulfate., amikacin sulfate or gentamycin sulfate by 0.1-5 and forms.
11. the antibiotic compound in claim 1-7 and the 10 arbitrary claim is characterized by to add in the described compound recipe to wait and oozes component.
12. the antibiotic compound in the claim 11 is characterized by described grade and oozes component and be selected from glucose, levulose and sodium chloride.
13. the antibiotic compound in the arbitrary claim of claim 1-7 is characterized by described compound recipe and uses with pharmaceutical solutions, powder pin or freeze-dried powder.
14. the preparation method of the freeze-dried powder of the antibiotic compound in the claim 13 is characterized by described method and is made up of the following step:
A, each component in the compound recipe is dissolved in the water for injection, regulates pH to 6-7, stir then and make it molten clear with buffer components;
B, will be filled in the freeze-dried powder bottle by required dosage branch by the solution that step a makes, place and be chilled to subzero 5 ℃ of freezer dryers in advance, the temperature with freezer dryer transfers to subzero 35 ℃ then;
C, the vacuum of freezer dryer is evacuated to below 40 handkerchiefs;
D, the temperature of freezer dryer is transferred to 3-5 ℃;
E, under these conditions water remove is done;
F, the temperature of freezer dryer is transferred to 40-50 ℃ of dry obtained freeze-drying powder pin;
G, charge into drying nitrogen,, place 5 ℃ of following temperature, keep in Dark Place the bottle capping to freezer dryer.
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