CN1526397A - Combined antibiotic medicine for inhibiting beta-lactamase - Google Patents
Combined antibiotic medicine for inhibiting beta-lactamase Download PDFInfo
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- CN1526397A CN1526397A CNA031433081A CN03143308A CN1526397A CN 1526397 A CN1526397 A CN 1526397A CN A031433081 A CNA031433081 A CN A031433081A CN 03143308 A CN03143308 A CN 03143308A CN 1526397 A CN1526397 A CN 1526397A
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Abstract
The combined antibiotic medicine for inhibiting beta-lactamase is prepared by combining Cefminox as one kind of the third generation of cephalosporin and beta-lactamase inhibitor in certain weight ratio. The Cefminox is in the form of its alkali metal salt or its free acid plus co-solvent; and the beta-lactamase inhibitor is Sulbactam, Clavulanic acid, tazobactam or their derivative, such as Sulperazon, tazobactam sodium, potassium Clavulanate, etc. The beta-lactamase inhibitor and Cefminox of the present invention have obvious synergistic antibiotic effect and this makes it possible to solve the increasing resistance of pathogenetic bacteria to Cefminox clinically.
Description
Technical field
The present invention relates to a kind of antibiotic combination drug that suppresses bacteriogenic beta-lactamase, specifically is the compound preparation that beta-lactamase inhibitor and third generation cephalosporins-cefminox (Cefminox) compatibility are formed.
Background technology
Cephalosporin antibacterial is extensive use of clinically, has obtained the unapproachable therapeutic effect of traditional antibiotics class medicine.But owing to be extensive use of for a long time clinically, even the abuse of antibiotics medicine, caused the drug resistance of bacterial antibiotic class medicine more and more stronger.Such as the penicillin of beta-lactam apoplexy due to endogenous wind, just take effect especially with 200,000 units clinically in the fifties at every turn, and now take effect with 800,000 units also difficulty at every turn.Tangible resistance has also appearred in the cephalosporins that belongs to beta-lactam together.Cefminox (Cefminox) is clinical third generation cephalosporins commonly used, and they once had a broad-spectrum antibacterial action, and is stable to the wide spectrum beta-lactamase (comprising penicillinase and cephalosporinase) that multiple gram positive bacteria and gram-negative bacteria produce.This product has the strong antibiotic effect to streptococcus (except the enterococcus), escherichia coli, klebsiella bacillus, Bacillus proteus, hemophilus influenza, bacteroid etc., stronger anti-beta-lactamase performance is arranged, and this product still generates lipoprotein to Peptidoglycan in the bacteria cell wall and plays blanketing.Lipoprotein structure is peculiar by gram-negative bacteria, and therefore, this product is strong to the effect of gram-negative bacteria than other similar medicines.But many in recent years pathogenic bacterium also increase sharply to their drug resistance, cause the clinical efficacy of cefminox to descend year by year.
Studies have shown that pathogen to beta-lactam antibiotic drug-fast approach is taken place and mainly contains three, first permeability of cell membrane changes, and stops antibiotic to enter in the cell by bacterial outer membrane; It two is changes of target site structure, comprises that target position structure or affinity change; It three is that cell membrane active efflux system and antibacterial produce inactivator, i.e. beta-lactamase, and hydrolysis destroys and enters endobacillary beta-lactam antibiotic.This thirdly is the principal mode that accounts for resistance mechanism 80%.This shows, producing beta-lactamase is the main resistance mechanism of antibacterial to Beta-lactam medicine, no matter pathogenic bacterium are by plasmid-mediated or chromosome mediation, the beta-lactamase that is produced is still beta-lactam antibiotic and produces drug-fast main mechanism, is the main cause of intractable infection.
For solving the enzyme drug resistance problem of producing, now existing multinomial example with some concrete antibacterials of cephalo-type and beta-lactamase inhibition combination compound preparation, as amoxicillin/clavulanate (Augmentin), cefoperazone/sulbactam sodium (Supleragon), piperacillin/Tazobactam Sodium (Tazocillin), for example application number is the bactericidal composition of CN98113282.0, it is ceftazidime to be mixed the back form compound preparation with beta-lactamase inhibitor, has solved ceftazidime long-term clinical application antibacterial and has produced the drug resistance problem.Though each concrete medicine can be described as has a broad antifungal spectrum in the cephalosporin antibacterial, antibacterial action is strong, and being actually can only be to a certain, or certain several antibacterial has high activity, and other antibacterials are only had general antibacterial action.Such as ceftazidime pseudomonas aeruginosa is had high activity, and other antibacterials are had only general antibacterial action.Like this, just different antibacterials had high activity, and has a broad antifungal spectrum, it is feasible that other concrete antibacterials of cephalo-type that antibacterial action is strong and beta-lactamase inhibitor are formed compound preparation, but when specifically being engaged in the combination of a certain medicine of cephalo-type, on the composition and ratio of prescription, toxicity, pharmacology, synergism, curative effect all will be carried out a large amount of very complicated, careful creative research and experimental works on the stability etc.
Summary of the invention
The present invention is directed to and produce the problem that the beta-lactamase fastbacteria causes the cefminox curative effect to descend, a kind of antibacterial compound drug that suppresses beta-lactamase is provided.Do not destroyed with the protection cefminox, strengthen its curative effect again, solve antibacterial the drug-fast problem of cefminox by bacteriogenic beta-lactamase.
Cefminox sodium is the cephamycin derivant, is produced by semi-synthesis method, and its interaction property and third generation cephalosporin are close, and manufactured goods are heptahydrate.Structural formula is as follows:
Antibacterial compound drug of the present invention is combined by cefminox (Cefminox) and beta-lactamase inhibitor, and cefminox and beta-lactamase inhibitor be by active acid, their weight ratio be 1 to 10: 10 to 1.
The above cefminox is sodium salt (Cefminox Sodium) or its hydrate of cefminox, also can be other alkali metal salt or its hydrate of cefminox.
Beta-lactamase inhibitor among the present invention is sulbactam (Sulbactam) or derivatives thereof, or clavulanic acid (Clavulanic acid) or derivatives thereof, or Tazobactam Sodium (Tazobactam) or derivatives thereof.
Sulbactam derivant among the present invention comprises the alkali metal salt as the sulbactam of sulbactam sodium, and the clavulanic acid derivant comprises the alkali metal salt as the clavulanic acid of clavulanate potassium, and the Tazobactam Sodium derivant then comprises the alkali metal salt as the Tazobactam Sodium of sodium-tazobactam.
Usually, cefminox is with the form administrated by injection of their sodium salt.Quiet notes 0.5g or 1g, blood drug level is 50ug/ml, 100ug/ml respectively.Distributing with concentration in ascites, endometrium, the bile in the body is height, and apoplexy due to phlegm concentration is low.Mainly, higher concentration is also arranged in urine through renal excretion.The drainage of renal dysfunction person this product is obstructed, about 2.5 hours of t1/2.
After the cefminox composition of medicine of the present invention administration, it is wide to distribute in vivo, content is the highest in abdominal cavity, endometrium, lung, kidney, the bile, secondly be spleen and the intestines and stomach etc., also can see through blood brain barrier, content is very low in the normal brain activity spinal fluid, but when meninges had inflammatory activity, the amount that penetrates blood brain barrier increased.
Beta-lactamase inhibitor sulbactam among the present invention is semi-synthetic beta-lactamase inhibitor, and the sulbactam of 1000mg/L and 100g/L concentration is stored in various buffer (PH2.6-8.0), human serum and the urine very stable, half-life at 37 ℃ and surpasses 100h more.This product has strong antibacterial activity to gonococcus and meningococcus, and its MIC is respectively 0.1-3.2mg/L and 0.1-0.2mg/L, and is very poor to the effect of other antibacterials.And the beta-lactamase of golden Portugal bacterium and the generation of most gram negative bacilli is had very strong irreversible inhibitory action.2mg/L concentration is extremely strong to the inhibitory action of II, III, IV and V-type beta-lactamase, but I type beta-lactamase there is not effect, the latter is Enterobacter, not labor ground citron bacillus, the positive Bacillus proteus of indole, the beta-lactamase of the chromosome mediation that Pu Luofei stool Pseudomonas etc. produce.It is wider than clavulanic acid that it presses down zymogram.So only suppress meter and use not as antibacterials usually as beta-lactamase.
Blood peak concentration of drug behind sulbactam intramuscular injection 0.25g and the 0.5g is respectively 7mg/L and 13mg/L, and serum half-life is 1.1-1.3h.Behind intravenous drip 0.5g and the 1g, the blood peak concentration of drug is respectively 30mg/L and 68mg/L, and serum half-life is 1h.The dosage of 70-80% is converged through urine row.Sulbactam concentration in interstitial fluid and the peritoneum juice is suitable with the concentration in the blood.The permeable meninges that inflammation is arranged of this product, behind the intravenous drip 1g, concentration is 0.1-10mg/L in the cerebrospinal fluid.After giving mouse mainline this product, medicine is distributed to each tissue rapidly, and haemoconcentration is the highest, kidney time this, in internal organs such as spleen, lung, liver, the heart, higher concentration is arranged all, thus from medicine for characteristics and tissue distribution aspect, sulbactam can have good synergetic antibacterial effect with cefminox in vivo.
And the beta-lactamase inhibitor clavulanic acid among the present invention (Clavulanic acid, clavulanic acid) is to separate to obtain in the culture fluid of mycete (Streptomyces clavuligerus ATCC27064), and has finished complete synthesis in 1977 years.But its sodium salt instability, its potassium salt of clinical use.The clavulanic acid antibacterial activity is very poor, only uses as beta-lactamase inhibitor.Influence bacterial growth jointly with the low concentration beta-lactam antibiotic, it is the wide spectrum enzyme inhibitor, not only can suppress II, III, IV and V-type beta-lactamase, and can act on specific part on the bacterial cell membrane, influence bacterial growth jointly with the antibiotic of low concentration, be higher than sulbactam so press down enzymatic activity.
It should be noted that clavulanic acid has very big-difference to the inhibitory action of various beta-lactamases, beta-lactamase that golden Portugal bacterium is produced and the plasmid-mediated enzyme that extensively is present in enterobacteriaceae lactobacteriaceae, hemophilus influenza, gonococcus and mucositis Bradley Chinese bacterium have powerful inhibitory action; The beta-lactamase that the chromosome that pneumobacillus, proteus mirabilis, proteus vulgaris and bacteroides fragilis are produced mediates also has rapid inhibitory effect; And the beta-lactamase of chromosomes such as bacterium morgani, thunder utmost point bacillus, Serratia, Enterobacter and pseudomonas aeruginosa mediations pressed down enzymatic activity what for poor.
In a word, by the inhibitory action of clavulanic acid to beta-lactamase, can make the antimicrobial spectrum augmentation of cefminox, antibacterial action is significantly strengthened, thereby the antibacterial of multiple product beta-lactamase is produced obvious synergism.
Behind the intravenous drip clavulanic acid, be distributed to rapidly and respectively organize in the body fluid, the vein dosage of 200mg can obtain blood peak concentration of drug 11mg/L.After giving the dosage of child's intravenous injection 5mg/kg, the blood peak concentration of drug is 19mg/L.The blood peak concentration of oral clavulanic acid is 3.1mg/L on an empty stomach, and serum half-life is 62.7min, and output is 46.0% in the 8h urine.Be difficult to see through normal blood brain barrier, after a large amount of administrations of meningitis patient, concentration can reach 1mg/L in the cerebrospinal fluid.Behind the intravenous injection clavulanic acid 200mg, concentration is 2.3mg/kg in the lung tissue.Concentration can be the 46%-91% of blood peak concentration of drug in the oral hydrothorax, and concentration is 66% of blood drug level in the ascites.At gallbladder antiperspirant, can obtain to hand over treatment concentration in middle ear effusion and the tonsil.After the intravenous injection, the suitable concentration of clavulanic acid of Cortex Lycii layer and sponge layer is respectively 2.3mg/kg and 1.6mg/kg.Clavulanic acid can see through Placenta Hominis, all can record this product in Cord blood and the amniotic fluid.So for characteristics and tissue distribution aspect, clavulanic acid can have good synergetic antibacterial effect with cefminox in vivo from its medicine.
Clavulanic acid and cefminox use in conjunction there is no new or serious adverse reaction occurs.Dermoreaction is used the clavulanic acid of 3 250mg every day and can be suffered from diarrhoea with similar with the cefminox person separately, feels sick.
(Tazobactam TAZ) is the sulbactam derivant to beta-lactamase inhibitor Tazobactam Sodium among the present invention.Inhibitor for irreversible competitive beta-lactamase, penicillinase to important clinically beta-lactamase such as the generation of golden Portugal bacterium, the TEM that gram negative bacilli produced, OXA, SHV, the strong inhibitory action of the equal tool of enzyme of chromosomes that antibacterial produces such as beta-lactamase that HMS and PSE etc. are plasmid-mediated and Bacillus proteus, Bacteroides, Klebsiella mediation.It presses down the enzyme effect and is better than clavulanic acid, sulbactam, and the I type enzyme of chromosome dyad mediation is also had inhibitory action, and has better chemical stability, is therefore paid attention to deeply.Existing Tazobactam Sodium and the listing of piperacillin (PIP) (1: 8) mixture, trade name Zosyn.
Tazobactam Sodium also has good antibacterial action to PIP drug resistance bacillus, proteus mirabilis, acinetobacter calcoaceticus etc., but very little to pseudomonas such as bacillus pyocyaneus and the effect of husky thunder bacterium.Usually do not make antibacterials separately and use, and only as beta-lactamase inhibitor, TAZ can recover because of the drug-fast golden Portugal of product beta-lactamase bacterium, hemophilus influenza, moraxelle catarrhalis, bacillus and bacteroides fragilis be not to the sensitivity of PIP.
During intravenously administrable, the blood peak concentration of drug (Cmax) of Tazobactam Sodium is directly proportional with dosage, distribution volume (Vss) and eliminate half life and also increase with the increase of dosage.Plasma protein binding rate is respectively 20%-30%.Intramuscular injection (0.25g) artifact availability is 84%, peak concentration (Cmax) 7.3mg/L.Tazobactam Sodium all can reach higher concentration in gastrointestinal tract, gallbladder, bile, skin, prostatic fluid.Measure in the meningitis patient, TAZ can reach 32.5%.And the TAZ penetrance increases with dosage and improves (23.4%-43.8%).TAZ has 50%-60% to discharge through tubular secretion and glomerular filtration with original shape, and all the other approach outside kidney are eliminated.About 29.8% patient TAZ hydrolysis non-activity metabolite in vivo discharges.When patient's decreased renal function, the half life of TAZ, all significantly rise, and therefore when interior granulation promoting acid anhydride elimination factor＜0.33ml/s, the administration interval should prolong 2h, and＜during 20ml/min, the administration interval, should prolong 2h again.Liver function injury is less to this product metabolic effect, can not make dose titration.So for characteristics and tissue distribution aspect, Tazobactam Sodium can have good synergetic antibacterial effect with cefminox in vivo from its medicine.
Prove that through internal and external test composition of medicine of the present invention is stronger than the antibacterial activity of single cefminox composition medicine, antimicrobial spectrum is wider, the results are shown in Table 1～4.
Table 1: various pathogen are to cefminox, the contrast of cefminox/clavulanic acid (1: 1) sensitivity
| Pathogen | The strain number | MIC (ug/ml) scope | |
| Cefminox/clavulanic acid | Cefminox | ||
| Staphylococcus epidermidis * | 42 | ????32 | ????256 |
| Staphylococcus aureus | 16 | ????0.25 | ????16 |
| Streptococcus hemolyticus | 28 | ????0.125 | ????32 |
| Methicillin-resistant gold Portugal bacterium | 16 | ????2-12.5 | ????＞256 |
| Escherichia coli | 16 | ????0.1-5 | ????32 |
| Salmonella typhi | 20 | ????0.5-12.5 | ????12.5-＞25 |
| The Lei Shi Bacillus proteus | 18 | ????1-25 | ????＞8 |
| Bacillus pyocyaneus | 20 | ????32 | ????＞128 |
| Bacillus cloacae | 32 | ????16 | ????128 |
| Cray Bai Shi pneumobacillus | 8 | ????0.25 | ????8 |
| Hemophilus influenza | 16 | ????0.5-12.5 | ????16 |
| Bacteroides fragilis | 20 | ????1 | ????128 |
* fastbacteria
Table 2: various pathogen are to cefminox, the contrast of cefminox/sulbactam (1: 1) sensitivity
| Pathogen | The strain number | MIC (ug/ml) scope | |
| Cefminox/sulbactam (1: 1) | Cefminox | ||
| Pneumobacillus * | 18 | ???16 | ????＞256 |
| Staphylococcus aureus | 24 | ???0.5 | ????4 |
| Hemolytic streptococcus | 24 | ???0.25 | ????64 |
| Escherichia coli * | 32 | ???0.125 | ????＞128 |
| Proteus mirabilis | 16 | ???0.25 | ????4 |
| The husky thunder bacterium of Shore | 16 | ???0.25 | ????4 |
| Cray Bai Shi pneumobacillus | 32 | ???0.125 | ????32 |
| The Lei Shi Bacillus proteus | 16 | ???2～8 | ????16 |
| The Fu Shi citrobacter | 20 | ???8 | ????128 |
| Bacillus pyocyaneus | 16 | ???16 | ????256 |
* fastbacteria
Table 3: various pathogen are to cefminox, the contrast of cefminox/Tazobactam Sodium (2: 1) sensitivity
| Pathogen | The strain number | MIC (ug/ml) scope | |
| Cefminox/Tazobactam Sodium | Cefminox | ||
| Methicillin-resistant gold Portugal bacterium | 24 | ????2-8 | ????＞128 |
| Staphylococcus epidermidis | 40 | ????4 | ????256 |
| Streptococcus hemolyticus | 16 | ????0.25 | ????16 |
| Staphylococcus aureus | 32 | ????0.5 | ????32 |
| Bacteroides fragilis * | 6 | ????0.125 | ????128 |
| Escherichia coli | 16 | ????0.1-2 | ????16 |
| Hemophilus influenza | 8 | ????1-16 | ????4 |
| The Lei Shi Bacillus proteus | 16 | ????4 | ????＞8 |
| Pneumobacillus * | 24 | ????4 | ????＞128 |
| Salmonella typhi | 24 | ????0.5-8 | ????12.5-＞25 |
| Cray Bai Shi pneumobacillus | 8 | ????0.125 | ????8 |
| Bacillus pyocyaneus | 22 | ????8 | ????＞256 |
| Bacillus cloacae | 16 | ????16 | ????128 |
* fastbacteria
Table 4. cefminox, cefminox/clavulanic acid (1: 1), cefminox/sulbactam (1: 1), cephalo
Minot/Tazobactam Sodium (2: 1) is to the therapeutic effect of bacterial infection mice
| Infection strain | Challenging dose (bacterium number/Mus) | ????????????????????????????ED50(mg/kg) | |||
| Cefminox | Cefminox/clavulanic acid | Cefminox/sulbactam | Cefminox/Tazobactam Sodium | ||
| Bacillus pyocyaneus | 5×10 5 | ????400 | ????190 | ???205 | ????190 |
| Escherichia coli | 2×10 4 | ????240 | ????12 | ???10 | ????8.4 |
| Pneumobacillus | 4×10 7 | ????＞800 | ????35 | ???45 | ????40 |
| Acinetobacter calcoaceticus | 7×10 5 | ????45 | ????5 | ???- | ????- |
| Staphylococcus aureus | 5×10 8 | ????200 | ????10 | ???9 | ????6 |
Table 5. injected in mice gives the acute toxicity test of cefminox, cefminox/Tazobactam Sodium (2: 1)
The result
| Test and medicine | ????LD50(g/kg) | 95% confidence limit (g/kg) |
| Cefminox/Tazobactam Sodium (intravenous injection) | ????5.2 | ????4.5-6.0 |
| Cefminox/Tazobactam Sodium (lumbar injection) | ????9.5 | ????9.0-11.2 |
| Cefminox (intravenous injection) | ????6.3 | ????6.0-6.9 |
| Sodium-tazobactam (intravenous injection) | ????3.2 | ????2.9-3.6 |
Table 5 is after injected in mice gives cefminox, cefminox, cefminox/Tazobactam Sodium (2: 1) and cefminox/Tazobactam Sodium (4: 1), the acute toxicity data that calculates with the Bliss statistic law.Smyth method or Keplinger method with the synergy Y-factor method Y are estimated above result, and the acute toxicity of judging cefminox/Tazobactam Sodium is the summation action of its constituent cefminox, cefminox and sodium-tazobactam acute toxicity, i.e. the summation of its constituent cefminox, cefminox and sodium-tazobactam acute toxicity individual effect.The toxicity that pharmaceutical composition of the present invention is described does not increase.
The injectable powder of composition of medicine of the present invention or lyophilized injectable powder are because its main effective ingredient is to have the antibiotic cefminox now to mix with beta-lactamase inhibitor respectively, be specially adapted to treat infected by microbes to the beta-lactam antibiotic sensitivity, also effective to some penicillin resistant microorganisms, the same with the single component cefminox, can be used for the responsive microbial following infection that is used for due to the sensitive organism: site infections such as tonsil, respiratory tract, urinary tract, biliary tract, abdominal cavity, uterus also can be used for septicemia.The cefminox composition of medicine is particularly useful for catching of immunologic hypofunction, as urinary tract infection, respiratory tract infection, gonorrhea etc.Composition of medicine of the present invention also is applicable to the infection of the animal that is caused by above-mentioned commonly encountered diseases substance, thereby also can be used for the zoogenetic infection treatment of diseases.
The unit dose of medicine of the present invention is generally drug administration by injection, can do intravenous injection, intravenous drip or intramuscular injection.Because of cefminox sodium for injection, cefminox sodium for injection, injection clavulanate potassium, injection sulbactam sodium and injection sodium-tazobactam are the medicine that goes on the market, the also injectable powder that cefminox and beta-lactamase inhibitor can be made respectively, during clinical application again with the injection of the injection of cefminox and beta-lactamase inhibitor by administration after the mixed of the present invention or administration respectively, wherein cefminox suitable accumulated dose every day is 4000 milligrams.
The less generation of the untoward reaction of medicine of the present invention, about 3.2% patient has diarrhoea, and 0.4% has nauseatingly, and 2.3% skin pruritus or erythra occur, and other untoward reaction of 2%-4% are still arranged.Serum transaminase, BUN, creatinine, laboratory abnormalities persons such as alkali phosphatase and prothrombin time are 0.4%-4.6%, and 6.5% the direct Coombs test of the patient positive is still arranged.Because these goods concentration in feces is very low, so it is less to the intestinal microbial population influence.
Clinical it should be noted that to penicillin and (or) inhibitor of cephalosporin or beta-lactamase has allergies person's forbidding.
In a word, owing to have significant synergism between cefminox in the composition of medicine of the present invention and beta-lactamase inhibitor, the activity that can effectively suppress beta-lactamase helps its antibacterial action of the stable performance of cefminox, can significantly strengthen its antibacterial activity and antimicrobial spectrum.Thereby solve present antibacterial effectively and more and more cefminox is produced drug-fast problem, strengthened the clinical efficacy of existing medicine cefminox.What the preparation of medicine of the present invention was adopted is prior art, presses sterile powder injection preparation technology or freeze-dried powder preparation technology and produces, and the process equipment maturation is perfect, is easy to suitability for industrialized production.Because of the main component of composition of medicine of the present invention is the medicine that goes on the market, under same invention thinking instructs, the also injectable powder that cefminox and beta-lactamase inhibitor can be made respectively, again the injection of cefminox and the injection of beta-lactamase inhibitor are mixed in proportion back administration or administration respectively during clinical application, also can achieve good results easier applying.
The specific embodiment
Embodiment 1: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot) and clavulanate potassium 1 kilogram (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 2: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot) are mixed for 20 kilograms with clavulanate potassium (by active acid), press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 3: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), clavulanate potassium 2 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 4: under aseptic cleaning condition, with 10 kilograms of Cefminox sodiums (by the cephalo minot), 10 kilograms of mixing of clavulanate potassium (by active acid), press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 5: under aseptic cleaning condition, with 10 kilograms of Cefminox sodiums (by the cephalo minot), sulbactam sodium 2 kilograms of (by active acid) and mixing, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 6: under aseptic cleaning condition, 20 kilograms of Cefminox sodiums (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 7: under aseptic cleaning condition, 5 kilograms of Cefminox sodiums (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 5000 of injectable powder of the present invention.
Embodiment 8: under aseptic cleaning condition, with cefminox acid 10 kilograms of (by the cephalo minot), sulbactam sodium 10 kilograms of (by active acid) and 5.0 kilograms of mixing of L-arginine, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 9: under aseptic cleaning condition, 5 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 5000 of injectable powder of the present invention.
Embodiment 10: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 1.25 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 11: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 10 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 12: under aseptic cleaning condition, 10 kilograms of cefminox hydrates (by the cephalo minot), sodium-tazobactam 5 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 13: under aseptic cleaning condition, 10 kilograms of cefminox sodium hydrates (by the cephalo minot), sodium-tazobactam 2.5 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 14: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 1 kilogram (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 15: under aseptic cleaning condition, 8 kilograms of Cefminox sodiums (by the cephalo minot) and clavulanate potassium 1 kilogram (by active acid) are mixed, press the preparation of injection procedure operation, prepare 8000 of injectable powder of the present invention.
Embodiment 16: under aseptic cleaning condition, 10 kilograms of cefminox sodium hydrates (by the cephalo minot) are mixed for 1 kilogram with clavulanate potassium (by active acid), press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 17: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), clavulanate potassium 2 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 18: under aseptic cleaning condition, with 9 kilograms of Cefminox sodiums (by the cephalo minot), 1 kilogram of mixing of clavulanate potassium (by active acid), press lyophilized injectable powder preparation technology procedure operation, prepare 9000 of injectable powder of the present invention.
Embodiment 19: under aseptic cleaning condition, with 7 kilograms of cefminox sodium hydrates (by the cephalo minot), sulbactam sodium 2 kilograms of (by active acid) and mixing, press lyophilized injectable powder preparation technology procedure operation, prepare 7000 of injectable powder of the present invention.
Embodiment 20: under aseptic cleaning condition, 20 kilograms of Cefminox sodiums (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 20000 of injectable powder of the present invention.
Embodiment 21: under aseptic cleaning condition, with 5 kilograms of cefminox hydrates (by the cephalo minot), sulbactam sodium 10 kilograms of (by active acid) and 5.0 kilograms of mixing of L-arginine, press the preparation of injection procedure operation, prepare 5000 of injectable powder of the present invention.
Embodiment 22: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 23: under aseptic cleaning condition, 6 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 1 kilogram (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 6000 of injectable powder of the present invention.
Embodiment 24: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 1.25 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 25: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 10 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 26: under aseptic cleaning condition, cefminox acid 10 kilograms of (by the cephalo minot), sodium-tazobactams 5 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 27: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 2.5 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 28: under aseptic cleaning condition, 10 kilograms of Cefminox sodiums (by the cephalo minot), sodium-tazobactam 1 kilogram (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 29: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection sulbactam sodium (specification: the 0.5g/ bottle) be dissolved in same 250 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 30: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 0.5g/ bottle) 2 and injection sulbactam sodium (specification: the 1.0g/ bottle) be dissolved in same 250 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 31: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection sodium-tazobactam (specification: the 0.5g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 32: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection sodium-tazobactam (specification: the 0.25g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 33: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection clavulanate potassium (specification: the 0.5g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 34: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 0.5g/ bottle) 1 and injection clavulanate potassium (specification: the 0.5g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 35: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection clavulanate potassium (specification: the 0.25g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 36: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection sulbactam sodium (specification: the 0.5g/ bottle) be dissolved in same 250 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 37: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 0.5g/ bottle) 2 and injection sulbactam sodium (specification: the 1.0g/ bottle) be dissolved in same 250 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 38: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection sodium-tazobactam (specification: the 0.5g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 39: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection sodium-tazobactam (specification: the 0.25g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 40: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection clavulanate potassium (specification: the 0.5g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 41: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 0.5g/ bottle) 1 and injection clavulanate potassium (specification: the 0.5g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 42: under aseptic cleaning condition, with cefminox sodium for injection (specification: the 1.0g/ bottle) 1 and injection clavulanate potassium (specification: the 0.25g/ bottle) be dissolved in same 100 milliliters of glucose infusion liquids, give quiet of sensitive organism infected patient.
Embodiment 43: under aseptic cleaning condition, 9 kilograms in cefminox potassium (by the cephalo minot) and clavulanate potassium 1 kilogram (by active acid) are mixed, press the preparation of injection procedure operation, prepare 9000 of injectable powder of the present invention.
Embodiment 44: under aseptic cleaning condition, 10 kilograms of cefminox potassium hydrates (by the cephalo minot) are mixed for 20 kilograms with clavulanate potassium (by active acid), press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 45: under aseptic cleaning condition, 10 kilograms in cefminox potassium (by the cephalo minot), clavulanate potassium 2 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 46: under aseptic cleaning condition, with 10 kilograms in cefminox potassium (by the cephalo minot), 10 kilograms of mixing of clavulanate potassium (by active acid), press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 47: under aseptic cleaning condition, with 10 kilograms of cefminox potassium hydrates (by the cephalo minot), sulbactam sodium 2 kilograms of (by active acid) and mixing, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 48: under aseptic cleaning condition, 20 kilograms in cefminox potassium (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 20000 of injectable powder of the present invention.
Embodiment 49: under aseptic cleaning condition, with 5 kilograms of cefminox hydrates (by the cephalo minot), sulbactam sodium 10 kilograms of (by active acid) and 5.0 kilograms of mixing of L-arginine, press the preparation of injection procedure operation, prepare 5000 of injectable powder of the present invention.
Embodiment 50: under aseptic cleaning condition, 10 kilograms in cefminox potassium (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 51: under aseptic cleaning condition, 5 kilograms in cefminox potassium (by the cephalo minot), sodium-tazobactam 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 5000 of injectable powder of the present invention.
Embodiment 52: under aseptic cleaning condition, 10 kilograms in cefminox potassium (by the cephalo minot), sodium-tazobactam 1.25 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 53: under aseptic cleaning condition, 10 kilograms of cefminox potassium hydrates (by the cephalo minot), sodium-tazobactam 10 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 54: under aseptic cleaning condition, 10 kilograms in cefminox potassium (by the cephalo minot) and clavulanate potassium 1 kilogram (by active acid) are mixed, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 55: under aseptic cleaning condition, 9 kilograms in cefminox potassium (by the cephalo minot) is mixed for 3 kilograms with clavulanate potassium (by active acid), press the preparation of injection procedure operation, prepare 9000 of injectable powder of the present invention.
Embodiment 56: under aseptic cleaning condition, 6 kilograms in cefminox potassium (by the cephalo minot), clavulanate potassium 1 kilogram (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 60000 of injectable powder of the present invention.
Embodiment 57: under aseptic cleaning condition, with 8 kilograms in cefminox potassium (by the cephalo minot), 1 kilogram of mixing of clavulanate potassium (by active acid), press lyophilized injectable powder preparation technology procedure operation, prepare 8000 of injectable powder of the present invention.
Embodiment 58: under aseptic cleaning condition, with 10 kilograms in cefminox potassium (by the cephalo minot), sulbactam sodium 2 kilograms of (by active acid) and mixing, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 59: under aseptic cleaning condition, 20 kilograms in cefminox potassium (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 20000 of injectable powder of the present invention.
Embodiment 60: under aseptic cleaning condition, 5 kilograms in cefminox potassium (by the cephalo minot), sulbactam sodium 10 kilograms (by active acid) are mixed, press the preparation of injection procedure operation, prepare 5000 of injectable powder of the present invention.
Embodiment 61: under aseptic cleaning condition, with cefminox acid 9 kilograms of (by the cephalo minot), sulbactam sodium 1 kilogram of (by active acid) and 5.0 kilograms of mixing of L-arginine, press lyophilized injectable powder preparation technology procedure operation, prepare 9000 of injectable powder of the present invention.
Embodiment 62: under aseptic cleaning condition, 5 kilograms in cefminox potassium (by the cephalo minot), sodium-tazobactam 10 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 63: under aseptic cleaning condition, 10 kilograms in cefminox potassium (by the cephalo minot), sodium-tazobactam 1.25 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 64: under aseptic cleaning condition, 8 kilograms in cefminox potassium (by the cephalo minot), sodium-tazobactam 1 kilogram (by active acid) are mixed, press the preparation of injection procedure operation, prepare 8000 of injectable powder of the present invention.
Embodiment 65: under aseptic cleaning condition, with 10 kilograms of cefminox hydrates (by the cephalo minot), sodium-tazobactam 5 kilograms of (by active acid) and 5.0 kilograms of mixing of sodium bicarbonate, press the preparation of injection procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 66: under aseptic cleaning condition, 10 kilograms of cefminox potassium hydrates (by the cephalo minot), sodium-tazobactam 2.5 kilograms (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 67: under aseptic cleaning condition, 10 kilograms in cefminox potassium (by the cephalo minot), sodium-tazobactam 1 kilogram (by active acid) are mixed, press lyophilized injectable powder preparation technology procedure operation, prepare 10000 of injectable powder of the present invention.
Embodiment 68: under aseptic cleaning condition, with 5 kilograms of cefminox hydrates (by the cephalo minot), sulbactam sodium 2.5 kilograms of (by active acid) and 5.0 kilograms of mixing of sodium bicarbonate, press the preparation of injection procedure operation, prepare 5000 of injectable powder of the present invention.
Claims (8)
1. antibacterial compound drug that suppresses beta-lactamase, it is characterized in that by cefminox (Cefminox) and beta-lactamase inhibitor respectively by active acid weight ratio 1-10: 10-1 combines.
2. according to the antibacterial compound drug of the described inhibition beta-lactamase of claim 1, it is characterized in that by proportioning cefminox being mixed back administration or administration respectively with beta-lactamase inhibitor again when said mixing comprises clinical use.
3. according to the antibacterial compound drug of claim 1 or 2 described inhibition beta-lactamases, it is characterized in that said cefminox is the alkali metal salt (comprising its hydrate) of cefminox or the form that its free acid adds (comprising its hydrate) cosolvent.
4. according to the antibacterial compound drug of the described inhibition beta-lactamase of claim 3, the alkali metal salt that it is characterized in that said cefminox is Cefminox sodium (cefminoxsodium)
5. according to the antibacterial compound drug of the described inhibition beta-lactamase of claim 3, it is characterized in that said additives are the L-arginine, or sodium carbonate, or sodium bicarbonate.
6. according to the antibacterial compound drug of claim 1 or 2 described inhibition beta-lactamases, it is characterized in that said beta-lactamase inhibitor is clavulanic acid (Clavulanicacid) or derivatives thereof, or sulbactam (Sulbactam) or derivatives thereof, or Tazobactam Sodium (Tazobactam) or derivatives thereof.
7. according to the antibacterial compound drug of the described inhibition beta-lactamase of claim 6, it is characterized in that said clavulanic acid derivant is the alkali metal salt of clavulanic acid; Said sulbactam derivant is the alkali metal salt of sulbactam; Said Tazobactam Sodium derivant is the alkali metal salt of Tazobactam Sodium.
8. according to the antibacterial compound drug of the described inhibition beta-lactamase of claim 7, the alkali metal salt that it is characterized in that said clavulanic acid is a clavulanate potassium: the alkali metal salt of said sulbactam is a sulbactam sodium; The alkali metal salt of said Tazobactam Sodium is a sodium-tazobactam.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031433081A CN1526397A (en) | 2003-09-22 | 2003-09-22 | Combined antibiotic medicine for inhibiting beta-lactamase |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA031433081A CN1526397A (en) | 2003-09-22 | 2003-09-22 | Combined antibiotic medicine for inhibiting beta-lactamase |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101036656B (en) * | 2006-03-15 | 2010-08-11 | 广州白云山天心制药股份有限公司 | Stable cefoperazone tazobactam medicine compound preparation |
-
2003
- 2003-09-22 CN CNA031433081A patent/CN1526397A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101036656B (en) * | 2006-03-15 | 2010-08-11 | 广州白云山天心制药股份有限公司 | Stable cefoperazone tazobactam medicine compound preparation |
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