CN103110644A - Powder injection of drug composition of cefoperazone sodium and sulbactam sodium for injection - Google Patents
Powder injection of drug composition of cefoperazone sodium and sulbactam sodium for injection Download PDFInfo
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- CN103110644A CN103110644A CN201310073963XA CN201310073963A CN103110644A CN 103110644 A CN103110644 A CN 103110644A CN 201310073963X A CN201310073963X A CN 201310073963XA CN 201310073963 A CN201310073963 A CN 201310073963A CN 103110644 A CN103110644 A CN 103110644A
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Abstract
The invention provides powder injection of a drug composition of cefoperazone sodium and sulbactam sodium for injection, relating to the fields of pharmaceutical preparations and preparation methods and mainly solving the problems that single preparations of cefoperazone sodium and sulbactam sodium and metronidazole in the prior art have great dosages, poor treatment effects after being combined and big side effects. The drug composition comprises cefoperazone sodium and sulbactam sodium and metronidazole lipid microspheres in a weight ratio of (300:12)-(300:40), wherein the weight of the metronidazole lipid microspheres is based on metronidazole. The drug composition is prepared into powder injection. The pH value of water solution of the drug composition is 4.5-6.0. The powder injection of the drug composition provided by the invention not only has high curative effect but also can reduce the dosage of metronidazole by over 80%, thus greatly reducing or avoiding the toxic and side effects, especially gastrointestinal reactions including nausea, emesis, anorexia, abdominal cramp and neurotoxicity, of metronidazole and further reducing the occurrence rate of adverse reactions.
Description
Technical field:
The present invention relates to pharmaceutical preparation and preparation method field, relate in particular to a kind of cefoperazone sodium and sulbactam sodium for injection pharmaceutical composition injectable powder and preparation method thereof.
Background technology:
In recent years, in clinical extensive use, the drug resistance phenomenon of antibacterial obviously increases along with antibacterials, and wherein due to beta lactamase, especially extended spectrum β lactamases, drug resistance is noticeable.It is reported, in the patient of gram-negative bacteria treatment of infection failure or recurrence approximately 25%～75%, caused by the Production by Bacteria beta lactamase.Therefore, the exploitation beta lactamase restrainer and with the compound formulation of beta-lactam class medicine, have important clinical significance.The compound formulation of cefoperazone sodium in injection/sulbactam sodium 2:1 is also successfully listing therefore.Clinical practice shows, this product clinical efficacy is obvious, and untoward reaction is low, anti-enzyme, and wide spectrum is subject to the approval that personnel are suffered from vast medical care.
1972, Tally found that first metronidazole has the effect of whole body anaerobe resistant, and was defined as the drug of first choice of anti anaerobic bacteria infection by World Health Organization (WHO) in 1978.In clinical extensive use, its purposes is widened day by day along with first nitre, and its advantage is: the scope of anaerobe resistant is wide, and sterilizing power is strong, and general avirulence has no drug resistance.It has tablet, injection, suppository, compound preparation, can be for oral, quiet notes and anus plug, also can be applied to intravenously administrable with other multiple antibacterials preparation, so, the requisite a kind of curative of clinical departments become.Recently studying its mechanism of action is, answers by its reduzate and bacterial cell DNA antisense, disturbs growth, the breeding of antibacterial, last kill bacteria.
Untoward reaction appears in nearly 15-30% case clinically, and is the most common with digestive tract reaction, comprises nauseating, vomiting, inappetence, abdominal colic, generally do not affect treatment; Neurological symptom has headache, dizzy, abnormal, the numb limbs and tense tendons of occasionally feeling, ataxia, polyneuritis etc., and heavy dose can cause tic.In the measles such as minority case generation, flushing, pruritus, cystitis, dysuria, mouth, metallic taste and leukopenia etc., all belong to reversibility, recovers voluntarily after drug withdrawal, and reviewing analysis shows that the main cause that untoward reaction occurs is the overdose medication.
infection in clinical operation usually is accompanied by the mixed infection that contains anaerobe and aerobe, rather than the infection of single anaerobe or aerobe, it is the clinical first-selected medication for the treatment of anaerobic infection because of metronidazole, cefoperazone sodium sulbactam sodium commonly used and metronidazole drug combination contain the MOI of anaerobe for preventing post-operation infection and treatment clinically, but cefoperazone sodium and sulbactam sodium for injection and injection metronidazole are all as single product, during the difference medication, the consumption of metronidazole is very large, the toxic and side effects of metronidazole is very strong, the metronidazole of normal therapeutic dosage can produce digestive tract reaction, the most common comprise nauseating, vomiting, inappetence, abdominal colic and higher neurotoxicity.To this for clinical provide a kind of safe and effective, medicine that toxic and side effects is low is extremely urgent, Given this, proposes the present invention.
Summary of the invention:
Technical problem to be solved by this invention is to overcome the defective of prior art, provide a kind of curative effect high, safe, good stability, the cefoperazone sodium sulbactam sodium pharmaceutical composition that toxic and side effects is low, the principal agent of this pharmaceutical composition is: cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere, said composition can effectively be treated the MOI that contains anaerobe.
Technical problem to be solved by this invention realizes by the following technical solutions.
A kind of cefoperazone sodium sulbactam sodium pharmaceutical composition, it is characterized in that, this pharmaceutical composition comprises cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere, the weight ratio of cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere is 300:12-300:40, the weight of metronidazole lipid microsphere is in metronidazole, this pharmaceutical composition is prepared into powder ampoule agent for injection, and the pH value of the aqueous solution of this pharmaceutical composition is 4.5-6.0.
In this pharmaceutical composition, the preferred weight ratio of cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere is 100:10, and the weight of metronidazole lipid microsphere is in metronidazole, and the preferred pH value of the aqueous solution of this pharmaceutical composition is 5.0-5.5.
Another object of the present invention is to provide a kind of method that cefoperazone sodium sulbactam sodium pharmaceutical composition is prepared into powder ampoule agent for injection, it is characterized in that, the concrete steps of the method are:
(1) preparation metronidazole lipid microsphere, after this goods rehydration, mean diameter is less than 120nm, and pH value is between 5.0-5.5, and the absolute value of Zeta-potential is greater than 20mV, and envelop rate is more than 80%.
The crude drug component of preparation metronidazole lipid microsphere is:
The step of preparation metronidazole lipid microsphere is:
A) glycerol for injection and the poloxamer F-68 with recipe quantity is dissolved in water for injection, be placed in 80 ℃ of water bath with thermostatic control magnetic stirring apparatuss and be stirred to whole dissolvings, make mixture A, the injection water yield can be with abundant fused the getting final product of glycerol for injection and poloxamer F-68;
B) recipe quantity oleic acid is added in the oil phase that is consisted of by long-chain fat acid glyceride and medium chain length fatty acid triglyceride, forms and mix oil phase;
C) fabaceous lecithin and the metronidazole with recipe quantity adds in dehydrated alcohol 200ml, is stirred to fabaceous lecithin and metronidazole under 80 ℃ all after dissolving, and decompression volatilizes dehydrated alcohol, then adds the mixing oil phase, stirs and makes mixture B;
D) mixture A is added in mixture B, be placed in the 8000r/min of high-speed tissue mashing machine and stir 3 times, each 3min;
E) regulate pH value to 5.0-5.5, water for injection is settled to 1000ml, adds in high pressure homogenizer 70MPa homogenizing 8 times;
F) bottling, gland, 100 ℃ of sterilization 30min, the rapid cooling of ice-water bath and get final product, standby;
(2) cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere are dropped into respectively in the efficient asymmetric mixer of V-type in proportion, mix after 1.5 hours, listen by the aluminum that drain hole is put into after sterilization; Aluminum is listened rolled lid, labeling, packing;
(3) will add in racking machine through cefoperazone sodium sulbactam sodium and the metronidazole lipid microsphere mixed material of outer cleaning/disinfecting, adjust loading amount according to batch production ordering, be distributed into cillin bottle, buckle butyl rubber plug, namely get the cefoperazone sodium sulbactam sodium pharmaceutical composition injectable powder of injection through rolling lid, lamp inspection, packing.
The specification that described cefoperazone sodium sulbactam sodium pharmaceutical composition is prepared into powder ampoule agent for injection is 0.75g/ bottle, 1.5g/ bottle, 225g/ bottle and 3.0g/ bottle, by cefoperazone sulbactam.
Pharmaceutical composition preparation technology of the present invention is simple, has guaranteed well the growth of related substance in the storage of the stability of active component and finished product.
The present invention is directed to treatment clinically and contain the MOI of anaerobe and propose, a kind of cefoperazone sodium and sulbactam sodium for injection composition powder injection is provided.The every consumption per day of cefoperazone sodium sulbactam sodium list product preparation adult is the 3g left and right clinically, and the consumption that metronidazole list product preparation is grown up every day is the 2g left and right.in cefoperazone sodium sulbactam sodium pharmaceutical composition provided by the invention, cefoperazone sodium sulbactam sodium, metronidazole lipid microsphere (take metronidazole) weight ratio (W/W) is 300:12-300:40, therefore the every consumption per day of cefoperazone sodium sulbactam sodium is 3g, at twice during administration, the consumption of metronidazole every day is 120mg-400mg, each consumption is 60mg-200mg, be that 4000ml calculates by the normal adult total blood volume, after each administration, blood drug level is 15-50 μ g/ml, and the metronidazole effective blood drug concentration is 2-8 μ g/ml, the metronidazole lipid microsphere has slow releasing function, the effective blood drug concentration time can keep more than 12 hours in vivo.Pharmaceutical composition injectable powder provided by the invention not only has high curative effect thus, and can reduce metronidazole consumption (using more than 80% less), thereby greatly alleviate or avoided the toxic and side effects of metronidazole, digestive tract reaction particularly, comprise nauseating, vomiting, inappetence, abdominal colic and neurotoxicity, more reduced the incidence rate of untoward reaction.
The specific embodiment:
For technological means, creation characteristic that the present invention is realized, reach purpose and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention.
For the concordance of guarantee test result, the embodiment of the present invention has been used raw material, adjuvant, cillin bottle and the plug of same batch, and has adopted consistent production technology to prepare the cefoperazone sodium sulbactam sodium pharmaceutical composition injectable powder of injection.
Embodiment one, cefoperazone sodium and sulbactam sodium for injection composition powder injection are in 1000
Prescription (specification: the 0.75g/ bottle):
Cefoperazone sodium sulbactam sodium 750g
Metronidazole lipid microsphere (in metronidazole) 75g
Preparation technology:
Cefoperazone sodium sulbactam sodium, the metronidazole lipid microsphere (in metronidazole) of recipe quantity are dropped into respectively in the efficient asymmetric mixer of V-type in proportion, mix after 1.5 hours, listen by the aluminum that drain hole is put into after sterilization; Aluminum is listened rolled lid, labeling, packing; To add in racking machine through cefoperazone sodium sulbactam sodium and the metronidazole lipid microsphere mixed material of outer cleaning/disinfecting, adjust loading amount according to batch production ordering, be distributed into cillin bottle, buckle butyl rubber plug, namely get the cefoperazone sodium sulbactam sodium pharmaceutical composition injectable powder of injection through rolling lid, lamp inspection, packing.
Embodiment two, cefoperazone sodium and sulbactam sodium for injection composition powder injection are in 1000
Prescription (specification: the 1.5g/ bottle):
Cefoperazone sodium sulbactam sodium 1500g
Metronidazole lipid microsphere (in metronidazole) 150g
Preparation technology:
Cefoperazone sodium sulbactam sodium, the metronidazole lipid microsphere (in metronidazole) of recipe quantity are dropped into respectively in the efficient asymmetric mixer of V-type in proportion, mix after 1.5 hours, listen by the aluminum that drain hole is put into after sterilization; Aluminum is listened rolled lid, labeling, packing; To add in racking machine through cefoperazone sodium sulbactam sodium and the metronidazole lipid microsphere mixed material of outer cleaning/disinfecting, adjust loading amount according to batch production ordering, be distributed into cillin bottle, buckle butyl rubber plug, namely get the cefoperazone sodium sulbactam sodium pharmaceutical composition injectable powder of injection through rolling lid, lamp inspection, packing.
Clinical data
In the patient who makes a definite diagnosis anaerobe and aerobe (to the aerobe of cefoperazone sodium sulbactam sodium sensitivity) mixed infection, use A scheme (2 bottles/day of cefoperazone sodium and sulbactam sodium for injection composition powder injections (1.5g/ bottle)) and B scheme (cefoperazone sodium sulbactam sodium 3g/ day+metronidazole 2g/ day) GP TH, each is organized and divides equally 2 venoclysises every day, and its curative effect and untoward reaction are as follows:
The Comprehensive Clinical curative effect,
To curative effect judgement terminal point, total number of cases 42 examples of A scheme group, effective 40 examples, total effective rate is total number of cases 44 examples of 95.2%, B scheme group, effective 38 examples, total effective rate is 86.36%.
Adverse effect
Treat in 86 routine cases, the untoward reaction of varying degree appears in totally 15 examples, the untoward reaction rate is 17.4%, wherein gastrointestinal reaction appears in the routine patient of A scheme group 4, show as nauseating, vomiting, the side effect incidence rate be 9.5%, B scheme group totally 11 examples the untoward reaction of varying degree appears, the side effect incidence rate is 25%, it is nauseating to show as, vomiting, inappetence.A scheme group adverse reaction rate and degree are all lower than B scheme group.
Above demonstration and described ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and description is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1. cefoperazone sodium sulbactam sodium pharmaceutical composition, it is characterized in that, this pharmaceutical composition comprises cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere, the weight ratio of cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere is 300:12-300:40, the weight of metronidazole lipid microsphere is in metronidazole, this pharmaceutical composition is prepared into powder ampoule agent for injection, and the pH value of the aqueous solution of this pharmaceutical composition is 4.5-6.0.
2. cefoperazone sodium sulbactam sodium pharmaceutical composition according to claim 1, it is characterized in that, in this pharmaceutical composition, the preferred weight ratio of cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere is 100:10, the weight of metronidazole lipid microsphere is in metronidazole, and the preferred pH value of the aqueous solution of this pharmaceutical composition is 5.0-5.5.
3. the described pharmaceutical composition of claim 1 or 2 is prepared into the method for powder ampoule agent for injection, it is characterized in that, the concrete steps of the method are:
(1) preparation metronidazole lipid microsphere
The crude drug component of preparation metronidazole lipid microsphere is:
The step of preparation metronidazole lipid microsphere is:
A) glycerol for injection and the poloxamer F-68 with recipe quantity is dissolved in water for injection, be placed in 80 ℃ of water bath with thermostatic control magnetic stirring apparatuss and be stirred to whole dissolvings, make mixture A, the injection water yield can be with abundant fused the getting final product of glycerol for injection and poloxamer F-68;
B) recipe quantity oleic acid is added in the oil phase that is consisted of by long-chain fat acid glyceride and medium chain length fatty acid triglyceride, forms and mix oil phase;
C) fabaceous lecithin and the metronidazole with recipe quantity adds in dehydrated alcohol 200ml, is stirred to fabaceous lecithin and metronidazole under 80 ℃ all after dissolving, and decompression volatilizes dehydrated alcohol, then adds the mixing oil phase, stirs and makes mixture B;
D) mixture A is added in mixture B, be placed in the 8000r/min of high-speed tissue mashing machine and stir 3 times, each 3min;
E) regulate pH value to 5.0-5.5, water for injection is settled to 1000ml, adds in high pressure homogenizer 70MPa homogenizing 8 times;
F) bottling, gland, 100 ℃ of sterilization 30min, the rapid cooling of ice-water bath and get final product, standby;
(2) cefoperazone sodium sulbactam sodium and metronidazole lipid microsphere are dropped into respectively in the efficient asymmetric mixer of V-type in proportion, mix after 1.5 hours, listen by the aluminum that drain hole is put into after sterilization; Aluminum is listened rolled lid, labeling, packing;
(3) will add in racking machine through cefoperazone sodium sulbactam sodium and the metronidazole lipid microsphere mixed material of outer cleaning/disinfecting, adjust loading amount according to batch production ordering, be distributed into cillin bottle, buckle butyl rubber plug, namely get the cefoperazone sodium sulbactam sodium pharmaceutical composition injectable powder of injection through rolling lid, lamp inspection, packing.
4. cefoperazone sodium sulbactam sodium pharmaceutical composition according to claim 3 is prepared into the method for powder ampoule agent for injection, it is characterized in that: the specification that described cefoperazone sodium sulbactam sodium pharmaceutical composition is prepared into powder ampoule agent for injection is 0.75g/ bottle, 1.5g/ bottle, 225g/ bottle and 3.0g/ bottle, by cefoperazone sulbactam.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310073963XA CN103110644A (en) | 2013-03-08 | 2013-03-08 | Powder injection of drug composition of cefoperazone sodium and sulbactam sodium for injection |
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| CN201310073963XA CN103110644A (en) | 2013-03-08 | 2013-03-08 | Powder injection of drug composition of cefoperazone sodium and sulbactam sodium for injection |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250236A (en) * | 1991-08-05 | 1993-10-05 | Gasco Maria R | Method for producing solid lipid microspheres having a narrow size distribution |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250236A (en) * | 1991-08-05 | 1993-10-05 | Gasco Maria R | Method for producing solid lipid microspheres having a narrow size distribution |
Non-Patent Citations (4)
| Title |
|---|
| L.A.M. FERREIRA ET AL: "Vehicle influence on in vitro release of metronidazole:role of w/o/w multiple emulsion", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| YUTAKA MIZUSHIMA: "Lipid microspheres (lipid emulsions) as a drug carrier - An overview", 《ADVANCED DRUG DELIVERY REVIEW》 * |
| 冯大林等: "脂质微球给药系统的研究进展", 《现代医药卫生》 * |
| 杨艳芳: "头孢哌酮钠舒巴坦钠和甲硝唑联用治疗慢性胆囊炎的疗效分析", 《中国医药指南》 * |
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Application publication date: 20130522 |