CN101632677B - Suspension powder injection of cefoperazone sodium and tazobactam sodium pharmaceutical composition and new application thereof - Google Patents
Suspension powder injection of cefoperazone sodium and tazobactam sodium pharmaceutical composition and new application thereof Download PDFInfo
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- CN101632677B CN101632677B CN2009100179612A CN200910017961A CN101632677B CN 101632677 B CN101632677 B CN 101632677B CN 2009100179612 A CN2009100179612 A CN 2009100179612A CN 200910017961 A CN200910017961 A CN 200910017961A CN 101632677 B CN101632677 B CN 101632677B
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Abstract
The invention discloses a suspension powder injection with a cefoperazone sodium and tazobactam sodium pharmaceutical composition as an active ingredient, and comprises the following components: 4 parts of the cefoperazone sodium, 1 part of the tazobactam sodium, 5-30 parts of an emulsifier, 1-15 parts of an auxiliary emulsifier and 1-40 parts of a freeze-drying support agent. The invention further discloses an application thereof in preparing medicines for treating cystitis.
Description
Technical field
The present invention relates to suspension powder injection of cefoperazone sodium and tazobactam sodium pharmaceutical composition, further relate to its new application in the medicine of preparation treatment cystitis.
Background technology
Cystitis is clinical common, multiple infectious disease, has intractable and delay property, and treatment time is long, and relapse rate is high, main manifestations be frequent micturition, urine slowly, dysurea, hematuria, pyuria, waist abdomen ache etc.The cystitis clinical manifestation has acute and chronic two kinds, and chronic cystitis morbidity slowly, has burn feeling, and in urethral region, pain arranged while urinating, the time urgent micturition and frequent micturition are arranged, sustainable several weeks of symptom or intermittent attack, make the patient weak, become thin.Suddenly, symptom is to chronic similar in the acute cystitis morbidity, and the women is common, and it is weak unable that the patient feels, low grade fever is arranged, and high heat also can be arranged, and do not accommodate lumbago and backache on phalanx.Due to the relation of anatomical factors, the escherichia coli in women's vaginal secretions and stool are one of key factors of urinary tract infection recurrence, thus whether effective to the escherichia coli at this two place, the curative effect of the medicine of decision treatment cystitis.
Cefoperazone is the Third generation Cephalosporins antibiotic, by the biosynthesis that suppresses the sensitive bacterial cell wall, reaches bactericidal action.Tazobactam Sodium is except to Neisseriaceae and acinetobacter calcoaceticus, to other antibacterials without antibiotic activity, but Tazobactam Sodium has the inhibitory action of irreversibility to the most important beta-lactamase that is produced by the beta-lactam antibiotic Resistant strain.Tazobactam Sodium can prevent the destruction of fastbacteria to penicillins and cephalosporins, and Tazobactam Sodium and penicillins and cephalosporins have obvious synergism.
The domestic existing sale at present of cefoperazone sodium and tazobactam sodium compound preparation, for example patent documentation CN1868478A discloses the compound preparation that is comprised of the weight ratio cefoperazone sodium of 4: 1 and sodium-tazobactam.Compound formulation is the sterilized powder direct packaging and makes, and there is a common defect in it is exactly that preparation stabilization is poor, the prescription that can not satisfy the prescriptive period.
In the process of clinical practice, it is found that the compound formulation that contains cefoperazone sodium and beta-lactamase inhibitor is dissolved in transfusion often can find muddiness, the content of cefoperazone sodium descends, and therefore normal under a cloud is quality problems and stop using.Especially, in winter, the spring of the northern area of China, when temperature is starkly lower than 10 ℃, add in transfusion, the more frequent reversibility that cefoperazone sodium can occur is separated out and is produced insoluble or milky research of chaotic phenomenon so that have a strong impact on clinical use.
The stability of the compound formulation of cefoperazone sodium and beta-lactamase inhibitor content in solution and pH value height are in close relations.The pH value of the compound formulation of cefoperazone sodium and beta-lactamase inhibitor is the most stable when 4.5-6.5, and when pH＜4.5, the reversibility that has the part cefoperazone sodium is separated out and produces the outward appearance muddiness, and in solution, the cefoperazone sodium content descends rapidly, does not meet the pharmacopeia regulation and affects the treatment.And very easily decompose when pH value＞6.5, can destroy the lactam nucleus of cefoperazone sodium, the cefoperazone sodium content is descended and produce by-product, cause the generation of untoward reaction.
Patent documentation CN101129381A discloses the compound preparation that the cefoperazone sodium that contains pH adjusting agent and sodium-tazobactam form, but a large amount of uses of pH adjusting agent wherein cause cefoperazone sodium more easily degrade and be unfavorable for lyophilizing, the pH value regulator also has strong haemolysis, and side effect is larger.Patent documentation CN101348493A has disclosed a kind of employing column chromatography and has prepared high-purity cefoperazone sodium and sodium-tazobactam, then is made into the method for compound recipe injectable powder.The method has just been improved the purity of preparation to a certain extent, active component cefoperazone sodium and sodium-tazobactam is not protected accordingly, causes product stability poor, has had a strong impact on clinical efficacy.Patent documentation CN101036656 discloses a kind of cefoperazone tazobactam medicine compound preparation, cefoperazone acid, Tazobactam Sodium and cosolvent, consists of, and its three's weight ratio is 8-1: 1: 5.6-0.06.In the situation that being arranged, the cefoperazone sodium of authentication code and sodium-tazobactam crude drug sell, the present invention does not show the trend of progress forward, increase dissolubility by corresponding cefoperazone, sulbactam and cosolvent salify on the contrary and prepare compound preparation, preparation method complexity and cost are high, same poor stability.
At present, for insoluble or unstable and cause the low active component of bioavailability, it is added surfactant and makes Emulsion is common technique.
Patent documentation CN1857239A discloses a kind of coenzyme Q 10 injection emulsion, take coenzyme Q10 as the active drug composition, containing injection vegetable oil, emulsifying agent, isoosmotic adjusting agent, antioxidant, pH adjusting agent, coemulsifier, surplus is water for injection, this patent adopts the injection vegetable oil as dissolve medium, and shortcoming is that iodine number is high, and unsaturated bond is many, easy oxidation deterioration, easily become sour, produce low-molecular-weight aldehyde, ketone etc. and all can cause the zest of injection, also affect the stability of medicine simultaneously.
Patent documentation CN1418636A discloses a kind of Matrine Injection that contains Ovum Gallus domesticus Flavus lecithin, sodium deoxycholate, vitamin E, ethanol, adopt Ovum Gallus domesticus Flavus lecithin and sodium deoxycholate to make emulsifier combination, emulsifying effectiveness is poor, the complete emulsifying of kurarinone is dissolved, and easily become turbid in long-term put procedure.
Summary of the invention
The inventor is through long-term conscientious research, using emulsion suspendible technology is made injectable powder by lyophilization, not only solved the problem of cefoperazone sodium and tazobactam sodium poor stability, also be beneficial to its lyophilized formulations reconstruct good use afterwards, and be conducive to treat cystitis, completed thus the present invention.
The object of the present invention is to provide a kind of stable cefoperazone sodium and tazobactam sodium injectable powder, specifically, the combination of emulsifying agent, frozen-dried supporting agent and active component by certain content, adopt the emulsified mixed suspension technology to make cefoperazone sodium and tazobactam sodium suspension injection powder of the present invention, obtained gratifying technique effect.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of cefoperazone sodium and tazobactam sodium suspension injection powder, comprise the component of following weight portion meter: cefoperazone sodium 4-8 part, 1 part of sodium-tazobactam, emulsifying agent 5-30 part, co-emulsifier 1-15 part and frozen-dried supporting agent 1-40 part.
As the present invention's one preferred embodiment, cefoperazone sodium and tazobactam sodium suspension injection powder described above, comprise the component of following weight portion meter: cefoperazone sodium 4-8 part, 1 part of sodium-tazobactam, emulsifying agent 10-20 part, co-emulsifier 3-8 part and frozen-dried supporting agent 5-20 part.
Wherein, emulsifying agent is selected from one or more in lecithin, Tween 80, PLURONICS F87, PVP K30, polyvinyl alcohol, sodium lauryl sulphate, cholesterol, peregal, gelatin, polyoxyethylene hydrogenated Oleum Ricini, glyceryl monostearate, preferably lecithin and PLURONICS F87 weight ratio are the combination of 5: 1～2: 1, and more preferably soybean lecithin and PLURONICS F87 weight ratio are the combination of 3: 1.，
Wherein, co-emulsifier is selected from one or more in n-butyl alcohol, ethylene glycol, ethanol, propylene glycol, glycerol, polyglycerin ester, mono-octyl phosphate sodium salt, NaGC, sodium deoxycholate, is preferably sodium deoxycholate.
Wherein, frozen-dried supporting agent is selected from one or more in mannitol, lactose, trehalose, glucose, sucrose, sorbitol, sodium chloride, glycine, is preferably mannitol and trehalose weight ratio and is the combination of 1: 1.
As another concrete preferred embodiment of the present invention, cefoperazone sodium and tazobactam sodium suspension injection powder described above, comprise the component of following weight portion meter: cefoperazone sodium 4-8 part, 1 part of sodium-tazobactam, emulsifying agent 10-20 part, sodium deoxycholate 3-8 part, frozen-dried supporting agent 5-20 part; Wherein emulsifying agent is selected from the combination of soybean lecithin and the PLURONICS F87 of 3: 1 weight ratios, and freeze drying protectant is selected from the combination of mannitol and the trehalose of 1: 1 weight ratio.
, as one of most preferred embodiment of the present invention, by following component, make 100 bottles of cefoperazone sodium and tazobactam sodium suspension injection powders: cefoperazone sodium 160g, sodium-tazobactam 40g, soybean lecithin 450g, PLURONICS F87 150g, sodium deoxycholate 200g, mannitol 240g and trehalose 240g.
, as two of most preferred embodiment of the present invention, by following component, make 100 bottles of cefoperazone sodium and tazobactam sodium suspension injection powders: cefoperazone sodium 80g, sodium-tazobactam 20g, soybean lecithin 150g, PLURONICS F87 50g, sodium deoxycholate 60g, mannitol 50g and trehalose 50g.
, as three of most preferred embodiment of the present invention, by following component, make 100 bottles of cefoperazone sodium and tazobactam sodium suspension injection powders: cefoperazone sodium 400g, sodium-tazobactam 50g, soybean lecithin 750g, PLURONICS F87 250g, sodium deoxycholate 400g, mannitol 500g and trehalose 500g.
The present invention further provides a kind of method for preparing the cefoperazone sodium and tazobactam sodium suspension injection powder, comprised the steps:
(1) emulsifying agent and co-emulsifier are added in water for injection, then add cefoperazone sodium and sodium-tazobactam mix homogeneously, 70-90 ℃ of heating in water bath is stirred to molten condition;
(2) aforesaid liquid is incubated under 70-90 ℃ of condition and adopts tissue mincer's shear agitation, obtain colostric fluid, then, through high pressure dispersing emulsification machine circulating emulsion, obtain emulsion;
(3) add frozen-dried supporting agent in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
Wherein, the selection of the amount of water for injection is the ordinary skill in the art, dissolves above material and gets final product, and is preferably the 3-5 of all supplementary material weight summations doubly, be above whole active component and excipient the weight summation 3-5 doubly.
Tissue mincer is JJ-2B type high-speed tissue mashing machine, and rotating speed is 10000-15000r/min, shear agitation 10-20 minute; High pressure dispersing emulsification machine model is NS1001L, by the import of Italian GEA Niro Soavi company, maximum working pressure (MWP) 1500bar, output 10L/hr, circulating emulsion 4-5 time.Above tissue mincer and high pressure dispersing emulsification machine and operation thereof are to enumerate explanation not limit, and equipment and operation well known in the art that this area has identical function can make the present invention.
The present invention also provides a kind of cefoperazone sodium and tazobactam sodium suspension injection powder in the application for the treatment of in cystitis, adopts intravenous drip, each 2g, and every day 3 times, every day 2 times after 3 days, 5 is a course for the treatment of.
The present invention also provides the application of described cefoperazone sodium and tazobactam sodium suspension injection powder in the medicine of preparation treatment cystitis.
Prior art document: the people such as Hou Dongzhi. the behavior study of mifepristone solid lipid nanoparticle. Chinese Journal of Pharmaceuticals, 2004:35 (10) disclose and had used 1: 1: 1: 2 Tween 80: PLURONICS F87: NaTDC: lecithin system the solid lipid nanoparticle of mifepristone.But, and the concrete composition of unexposed lecithin, often according to raw material sources, it being divided into soybean lecithin, peanut lecithin, Ovum Gallus domesticus Flavus lecithin, Semen Allii Tuberosi lecithin etc. at present, it is comprised of a great difference, for example shown in following table:
| Soybean lecithin | Semen Allii Tuberosi lecithin | Peanut lecithin | Ovum Gallus domesticus Flavus lecithin | |
| Phosphatidylcholin (PC) | 22 | 37 | 23 | 73 |
| Phospholipid phthalein ethanolamine (PE) | 23 | 29.7 | 8 | 17 |
| Phospholipid phthalein serine (PS) | 2 | - | - | - |
| Phospholipid phthalein inositol (PI) | 20 | 14 | 17 | 1 |
| Phosphatidic acid (PA) | 5 | - | 2 | - |
| Sphingomyelin (SPH) | - | - | - | 3 |
| Phytoglycolipid (PGL) | 13 | 20 | 38 | 0 |
| Other phospholipid | 12 | - | 12 | - |
Select different lecithin will produce different effects, the combination of preferably soya lecithin of the present invention, PLURONICS F87 and sodium deoxycholate, emulsifying effectiveness is best, adding Tween 80 is disadvantageous for the present invention, and reason is that Tween 80 has very strong haemolysis, and side effect is larger, and the present invention is lyophilized injectable powder, add liquid tween series, be unfavorable for the removal of moisture in freezing dry process, cause injectable powder to be shaped bad.
Cefoperazone sodium and tazobactam sodium suspension injection powder provided by the invention, compared with prior art, have beyond thought effect, and major advantage is as follows:
(1) improve cefoperazone sodium and the sodium-tazobactam stability in preparation, prevented the generation of granule, guaranteed qualified product in effect duration;
(2) suspension injection powder of the present invention slowly administration for a long time in vivo, improved bioavailability greatly;
(3) emulsifying agent used and co-emulsifier degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(4) production technology is simple, and cost is low, can industrial-scale production.
The specific embodiment
Further illustrate by the following examples the present invention, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder
Prescription (100 bottles):
Cefoperazone sodium 160g
Sodium-tazobactam 40g
Soybean lecithin 450g
PLURONICS F87 150g
Sodium deoxycholate 200g
Mannitol 240g
Trehalose 240g
Preparation technology
(1) 450g soybean lecithin, 150g PLURONICS F87 and 200g sodium deoxycholate are added in 4500ml water for injection, then add 160g cefoperazone sodium and 40g sodium-tazobactam mix homogeneously, 70 ℃ of heating in water bath are stirred to molten condition;
(2) aforesaid liquid is incubated under 70-90 ℃ of condition and adopts the shear agitation 20min of tissue mincer, rotating speed 10000r/min, obtain colostric fluid, then, through high pressure dispersing emulsification machine circulating emulsion 4 times, obtain emulsion;
(3) add 240g mannitol and 240g trehalose in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
Comparative Examples 1
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder
Prescription (100 bottles):
Cefoperazone sodium 160g
Sodium-tazobactam 40g
Ovum Gallus domesticus Flavus lecithin 400g
PLURONICS F87 200g
Sodium deoxycholate 200g
Tween 80 200g
Mannitol 240g
Trehalose 240g
Preparation technology is with embodiment 1, choose the people such as Hou Dongzhi. the behavior study of mifepristone solid lipid nanoparticle. Chinese Journal of Pharmaceuticals, the combination that formulated component in 2004:35 (10) is made the not preferred component of the present invention, make the piperacillin sodium and tazobactam sodium suspension injection powder.
Embodiment 2
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder
Prescription (100 bottles):
Cefoperazone sodium 80g
Sodium-tazobactam 20g
Soybean lecithin 150g
PLURONICS F87 50g
Sodium deoxycholate 60g
Mannitol 50g
Trehalose 50g
Preparation technology
(1) 150g soybean lecithin, 50g PLURONICS F87 and 60g sodium deoxycholate are added in 2000ml water for injection, then add 80g cefoperazone sodium and 20g sodium-tazobactam mix homogeneously, 80 ℃ of heating in water bath are stirred to molten condition;
(2) aforesaid liquid is incubated under 70-90 ℃ of condition and adopts the shear agitation 10min of tissue mincer, rotating speed 15000r/min, obtain colostric fluid, then, through high pressure dispersing emulsification machine circulating emulsion 5 times, obtain emulsion;
(3) add 50g mannitol and 50g trehalose in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
Comparative Examples 2
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder
Prescription (100 bottles):
Cefoperazone sodium 80g
Sodium-tazobactam 20g
Soybean lecithin 210g
PLURONICS F87 420g
Sodium deoxycholate 310g
Mannitol 410g
Trehalose 410g
Preparation technology, with embodiment 2, chooses the extraneous components by weight percent of preferred ingredient of the present invention and forms, and makes the cefoperazone sodium and tazobactam sodium suspension injection powder.
Embodiment 3
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder
Prescription (100 bottles):
Cefoperazone sodium 400g
Sodium-tazobactam 50g
Soybean lecithin 750g
PLURONICS F87 250g
Sodium deoxycholate 400g
Mannitol 500g
Trehalose 500g
Preparation technology
(1) 750g soybean lecithin, 250g PLURONICS F87 and 400g sodium deoxycholate are added in 11000ml water for injection, then add 400g cefoperazone sodium and 50g sodium-tazobactam mix homogeneously, 90 ℃ of heating in water bath are stirred to molten condition;
(2) aforesaid liquid is incubated under 70-90 ℃ of condition and adopts the shear agitation 10min of tissue mincer, rotating speed 13000r/min, obtain colostric fluid, then, through high pressure dispersing emulsification machine circulating emulsion 5 times, obtain emulsion;
(3) add 500g mannitol and 500g trehalose in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
Comparative Examples 3
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder (preparation technology is different)
Prescription (100 bottles):
Cefoperazone sodium 400g
Sodium-tazobactam 50g
Soybean lecithin 750g
PLURONICS F87 250g
Sodium deoxycholate 400g
Mannitol 500g
Trehalose 500g
Preparation technology
(1) 750g soybean lecithin, 250g PLURONICS F87,400g sodium deoxycholate, 400g cefoperazone sodium and 50g sodium-tazobactam are added in 11000ml water for injection, be uniformly dispersed, stirring at room 60min;
(2) will adopt the shear agitation 10min of tissue mincer under the aforesaid liquid room temperature condition, rotating speed 13000r/min, obtain emulsion;
(3) add 500g mannitol and 500g trehalose in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
Comparative Examples 4
The preparation of cefoperazone sodium and tazobactam sodium suspension injection powder (freeze drying protectant is different)
Prescription (100 bottles):
Cefoperazone sodium 400g
Sodium-tazobactam 50g
Soybean lecithin 750g
PLURONICS F87 250g
Sodium deoxycholate 400g
Glucose 500g
Lactose 500g
Preparation technology, with embodiment 3, selects the combination that is different from the preferred freeze drying protectant glucose of the present invention and lactose, makes the cefoperazone sodium and tazobactam sodium suspension injection powder, and outward appearance has part to subside as a result, and character is bad.
Test example 1
The distribution of particle diameter
Suspension injection powder water for injection dissolved dilution with embodiment of the present invention 1-3 and Comparative Examples 1-4 preparation, with the suspension injection powder granular size homogeneous of JSM-5900 sem observation to embodiment of the present invention 1-3 preparation, be irregular spherical or oval spherical, and the suspension injection powder granular size heterogeneity of Comparative Examples 1-4 preparation, present various shapes, disorderly and unsystematic.
Test example 2
The size of particle diameter
Suspension injection powder water for injection dissolved dilution with embodiment of the present invention 1-3 and Comparative Examples 1-4 preparation, measure size with the zetasizer3000HS laser particle size analyzer, embodiment 1-3 sample is in the 200-250nm left and right, and Comparative Examples 1-4 sample size heterogeneity, do not have stable scope.The results are shown in Table 1:
Table 1 particle size determination result
Test example 3
Study on the stability
Cefoperazone Sodium and Tazobactam (Hainan GeneralSanyang Pharmaceutical Co., Ltd's production with the sample of above each embodiment and Comparative Examples preparation and listing, lot number 20071016) place under 60 ℃ of high temperature, illumination 4500Lx condition and carried out the influence factor in 10 days and test investigation, the results are shown in Table 2; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 3; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 12 months, carry out long term test and investigate, detect the variation of every quality index, the results are shown in Table 4.
Table 2 influence factor result
Table 3 accelerated test result
Table 4 long-term test results
Accelerated March, June by above found that, during long-term December, the cefoperazone sodium and tazobactam sodium injectable powder clarity of Comparative Examples and listing is against regulation, and pH value descends larger, and content reduces obviously, and related substance raises; And in the scope of the invention, sample appearance character, clarity, pH value, content and the related substance of the preparation of supplementary material proportioning all change less than obvious.The sample stable quality after long time storage that the present invention's preparation is described is better.
The generation of test example 4 granules relatively
The granule production of embodiment 1-3 and Comparative Examples 1-4 after relatively redissolving, in Table 5.
The generation of table 5 granule relatively
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 | Comparative Examples 4 | |
| Produce the situation of granule after redissolving | Produce without granule, be clear and bright solution | Produce without granule, be clear and bright solution | Produce without granule, be clear and bright solution | Have more granule to produce, clarity is against regulation | Have more granule to produce, clarity is against regulation | Have more granule to produce, clarity is against regulation | Have more granule to produce, clarity is against regulation |
By above result as can be known, produce without granule after the sample of embodiment of the present invention preparation redissolves, be clear and bright solution; And the sample of Comparative Examples preparation has more granule to produce after redissolving, and clarity is against regulation.Special superiority of the present invention has been described.
Test example 5
Clinical trial is prepared
1, object choice
Admittance standard: without General Symptoms, and lower urinary tract disorder group (frequent micturition, urgent micturition, dysurea or bladder area pain) is arranged all, and sentence following patient: 1. anemia of pregnant woman or the upper urinary tract infection evidence is arranged, as body temperature 〉=37.5 ℃ companion's waist hypochondriac pain or tenderness; Medical history or evidence that 2. urinary tract function or anatomic abnormalities are arranged; 3. the urinary tract infection symptom surpassed for 3 weeks; 4. to sulfanilamide, Du-6859a is irritated; 5. gastrointestinal upset or once made gastrointestinal procedures, affect medicine and fully absorb; 6. once took antibacterials person in 30 days.
2, drug use method
(1) treatment group: give the embodiment 1 cefoperazone sodium and tazobactam sodium suspension injection powder of preparation, intravenous drip, each 2g, every day 3 times, every day 2 times after 3 days, 5 is a course for the treatment of.
(2) matched group: give Gatifloxacin, oral, each 0.2g, 2 times/days, 5 is a course for the treatment of.
(3) listing sample matched group: give the Cefoperazone Sodium and Tazobactam (lot number 20071016) of the general Sanyo in Hainan Pharmaceutical, intravenous drip, each 2g, every day 3 times, every day 2 times after 3 days, 5 is a course for the treatment of.
3, the standard of curative effect evaluation
Recovery from illness: frequent micturition, dysurea, symptoms of urgency disappear, and routine urinalysis is normal, without hematuria;
Produce effects: frequent micturition, dysurea, symptoms of urgency alleviate, without hematuria, heating;
Invalid: frequent micturition, dysurea, symptoms of urgency are without alleviating or aggravation, and the systemic infection symptom is accompanied in heating.
4, statistical procedures
Relatively with t, checking of measurement data people's mean ± standard deviation (X ± 5) measurement data, relatively with X2, the checking of enumeration data, P＜0.05 has been considered as statistical significance.
Test example 6
Clinical test results
1, object of study basic condition
100 routine patients are the women, do routine urianlysis, leukocyte 〉=10HP; The nitrite experiment is positive; Urine thin bacterium quantitative culture has true property bacteriuria.Be divided at random 3 groups, treatment group 33 people, 34.3 ± 5.9 years old mean age; Matched group 34 people, 35.8 ± 7.1 years old mean age; Listing sample matched group 33 people, 35.4 ± 8.9 years old mean age.Press the such scheme administration.Course of disease not statistically significant before three groups of ages and treatment, have comparability.
2, the result after treatment group, matched group and listing sample treatment of control group
2.1 clinical efficacy
Three groups of Clinical efficacy comparisons of table 6
Annotate: compare with matched group: ★ P＜0.05; Compare with the listing sample: △ P＜0.05.
The results are shown in Table 5, in table, the cure rate for the treatment of group and effective percentage are respectively 72.73%, 93.94%; Matched group be respectively 55.88%, 73.53%; Listing sample matched group is respectively 66.67%, 81.82%.Compare with matched group, cure rate and the effective percentage for the treatment of group and listing sample matched group have significant (P＜0.05); Compare with the listing sample, the effective percentage for the treatment of group has significant (P＜0.05).
2.2 the main adverse reaction of three kinds of medicines is gastrointestinal reaction, that common sympton has is nauseating, anorexia, vomiting, dizzy, headache is arranged partially, but all can recover normal after drug withdrawal.Untoward reaction is in Table 7.
Three groups of untoward reaction reactions of table 7 relatively
The untoward reaction rate of cefoperazone sodium and tazobactam sodium suspension injection powder of the present invention is 6.06%, and Gatifloxacin is 20.59%, and listing sample matched group is 12.12%, and the untoward reaction of cefoperazone sodium and tazobactam sodium is starkly lower than Gatifloxacin.
In sum, the cefoperazone sodium and tazobactam sodium suspension injection powder of the present invention's preparation is used for the treatment of the cystitis good results, untoward reaction is few, and this has shown that the cefoperazone sodium and tazobactam sodium suspension injection powder is better than prior art products in the clinical practice for the treatment of cystitis.
Claims (14)
1. a suspension powder injection of cefoperazone sodium and tazobactam sodium pharmaceutical composition, is characterized in that being made by the component of following weight portion: cefoperazone sodium 4-8 part, 1 part of sodium-tazobactam, emulsifying agent 5-30 part, co-emulsifier 1-15 part and frozen-dried supporting agent 1-40 part; The preparation method of described suspension injection powder comprises the steps:
(1) emulsifying agent and co-emulsifier are added in water for injection, then add cefoperazone sodium and sodium-tazobactam mix homogeneously, 70-90 ℃ of heating in water bath is stirred to molten condition;
(2) aforesaid liquid is incubated under 70-90 ℃ of condition and adopts tissue mincer's shear agitation, obtain colostric fluid, then, through high pressure dispersing emulsification machine circulating emulsion, obtain emulsion;
(3) add frozen-dried supporting agent in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
2. suspension injection powder according to claim 1, is characterized in that being made by the component of following weight portion: cefoperazone sodium 4-8 part, 1 part of sodium-tazobactam, emulsifying agent 10-20 part, co-emulsifier 3-8 part and frozen-dried supporting agent 5-20 part.
3. suspension injection powder according to claim 1 and 2, is characterized in that emulsifying agent is selected from one or more in lecithin, Tween 80, PLURONICS F87, PVP K30, polyvinyl alcohol, sodium lauryl sulphate, cholesterol, peregal, gelatin, polyoxyethylene hydrogenated Oleum Ricini, glyceryl monostearate.
4. suspension injection powder according to claim 3, is characterized in that it is the combination of 5: 1～2: 1 that emulsifying agent is selected from lecithin and PLURONICS F87 weight ratio.
5. suspension injection powder according to claim 3, is characterized in that it is the combination of 3: 1 that emulsifying agent is selected from soybean lecithin and PLURONICS F87 weight ratio.
6. suspension injection powder according to claim 1 and 2, is characterized in that co-emulsifier is selected from one or more in n-butyl alcohol, ethylene glycol, ethanol, propylene glycol, glycerol, polyglycerin ester, mono-octyl phosphate sodium salt, NaGC, sodium deoxycholate.
7. suspension injection powder according to claim 6, is characterized in that co-emulsifier is selected from sodium deoxycholate.
8. suspension injection powder according to claim 1 and 2, is characterized in that frozen-dried supporting agent is selected from one or more in mannitol, lactose, trehalose, glucose, sucrose, sorbitol, sodium chloride, glycine.
9. suspension injection powder according to claim 8, is characterized in that it is the combination of 1: 1 that frozen-dried supporting agent is selected from mannitol and trehalose weight ratio.
10. suspension injection powder according to claim 1 and 2, is characterized in that being made by the component of following weight portion: cefoperazone sodium 4-8 part, 1 part of sodium-tazobactam, emulsifying agent 10-20 part, sodium deoxycholate 3-8 part and frozen-dried supporting agent 5-20 part; Wherein emulsifying agent is selected from the combination of the weight ratio soybean lecithin of 3: 1 and PLURONICS F87, and freeze drying protectant is selected from the combination of the weight ratio mannitol of 1: 1 and trehalose.
11. the preparation method of the described suspension injection powder of claim 1-10, is characterized in that comprising the steps:
(1) emulsifying agent and co-emulsifier are added in water for injection, then add cefoperazone sodium and sodium-tazobactam mix homogeneously, 70-90 ℃ of heating in water bath is stirred to molten condition;
(2) aforesaid liquid is incubated under 70-90 ℃ of condition and adopts tissue mincer's shear agitation, obtain colostric fluid, then, through high pressure dispersing emulsification machine circulating emulsion, obtain emulsion;
(3) add frozen-dried supporting agent in emulsion, filter packing after dissolving, lyophilization, obtain the cefoperazone sodium and tazobactam sodium suspension injection powder.
12. suspension injection powder according to claim 1, is characterized in that making 100 bottles of cefoperazone sodium and tazobactam sodium suspension injection powders by following component: cefoperazone sodium 160g, sodium-tazobactam 40g, soybean lecithin 450g, PLURONICS F87 150g, sodium deoxycholate 200g, mannitol 240g and trehalose 240g.
13. suspension injection powder according to claim 1, is characterized in that making 100 bottles of cefoperazone sodium and tazobactam sodium suspension injection powders by following component: cefoperazone sodium 80g, sodium-tazobactam 20g, soybean lecithin 150g, PLURONICS F87 50g, sodium deoxycholate 60g, mannitol 50g and trehalose 50g.
14. suspension injection powder according to claim 1, is characterized in that making 100 bottles of cefoperazone sodium and tazobactam sodium suspension injection powders by following component: cefoperazone sodium 400g, sodium-tazobactam 50g, soybean lecithin 750g, PLURONICS F87 250g, sodium deoxycholate 400g, mannitol 500g and trehalose 500g.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101890022B (en) * | 2010-07-29 | 2012-05-23 | 王明 | Cefoperazone sodium and tazobactam sodium medicament composition liposome injection |
| CN103120692A (en) * | 2011-11-21 | 2013-05-29 | 辽宁海思科制药有限公司 | Preparation method for injection cefoperazone sodium tazobactam sodium composition |
| CN102512374A (en) * | 2011-12-16 | 2012-06-27 | 苏州二叶制药有限公司 | Preparation process for cefoperazone sodium and tazobactam sodium for injection |
| CN103948602B (en) * | 2014-04-30 | 2015-05-06 | 成都苑东药业有限公司 | Cefoperazone sodium and tazobactam sodium medicinal composition for injection and preparation method thereof |
| CN104013629B (en) * | 2014-06-18 | 2015-12-02 | 重庆福安药业集团庆余堂制药有限公司 | The compound medicament composition of cefoperazone sodium and tazobactam sodium and preparation technology thereof |
| CN107281187B (en) * | 2017-07-11 | 2020-11-17 | 苏州二叶制药有限公司 | Cefoperazone sodium and tazobactam sodium for injection and preparation method thereof |
| WO2023039947A1 (en) * | 2021-09-18 | 2023-03-23 | 湘北威尔曼制药股份有限公司 | Pharmaceutical composition containing cefoperazone sodium and tazobactam sodium and application thereof |
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