CN101721366B - Components and preparation method of beta-lactam injection - Google Patents
Components and preparation method of beta-lactam injection Download PDFInfo
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- CN101721366B CN101721366B CN2010100301617A CN201010030161A CN101721366B CN 101721366 B CN101721366 B CN 101721366B CN 2010100301617 A CN2010100301617 A CN 2010100301617A CN 201010030161 A CN201010030161 A CN 201010030161A CN 101721366 B CN101721366 B CN 101721366B
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- China
- Prior art keywords
- injection
- beta
- lactam
- suspending agent
- fine powder
- Prior art date
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- 239000007924 injection Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
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- 239000000843 powder Substances 0.000 claims abstract description 36
- 239000000375 suspending agent Substances 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 15
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- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 239000000725 suspension Substances 0.000 claims description 19
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- 238000011835 investigation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- 229960000373 tazobactam sodium Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Images
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the components and preparation method of beta-lactam injection. The beta-lactam injection comprises 5 to 20 percent of beta-lactam antibiotics, 0.05 to 5 percent of suspending agent, 0.005 to 0.3 percent of antioxygen, 0.1 to 0.2 percent of nonionic surfactant and the balance of vegetable oil or grease for injection. The injection can be used for preventing and curing animal bacterial infectious diseases and can be injected hypodermically or in muscle and be applied through breast for a few times. The preparation method provided by the invention comprises: firstly, making the antibiotics and the antioxygen into micro powder and making the suspending agent into fine powder; secondly, adding the vegetable oil or grease for injection, which is sterilized at high temperature, into the fine powder of the suspending agent, heating the mixture, uniformly mixing the mixture and keeping the mixture in a sterile environment to cool the mixture to room temperature for later use; and finally, transferring the prepared oil or grease added with the suspending agent to a colloid mill, adding medicament micro powder, the antioxygen and the non-ionic surfactant with stirring, and performing uniform mixing and sterilization to obtain the beta-lactam injection.
Description
Technical field
The present invention relates to composition of a kind of beta-lactam injection and preparation method thereof.
Background technology
(β-lactams) means and comprises penicillium sp rope class, cephalosporins and atypia beta-lactam antibiotic etc. by a big class antibiotic that has beta-lactam nucleus in the chemical constitution beta-lactam antibiotic.This type of antibiotic has that bactericidal activity is strong, toxicity is low, indication extensively reaches the good advantage of clinical efficacy.Commercially available penicillins or cephalosporins injection be based on injectable powder, need now with the current, otherwise can very fast decomposition and lose its antibacterial activity.
Usually beta-lactam antibiotic is prevented and treated animal bacterial infection, when pharmaceutical dosage form adopts the powder pin, be independent packaging, need prepare back injection in time, once use up, injectable powder especially the packing charges of Penicillin antibiotics considerably beyond the price of its medicine itself, and in intensification is produced, injectable powder will dissolve the back injection, and it is very loaded down with trivial details to operate, and causes administration time to postpone easily.After the normal injection agent is injected to animal, typical situation be originally systemic drug concentration far above treatment concentration, be reduced to treatment concentration afterwards gradually, drop to invalid drug level at last, and the normal injection agent often needs 2 administrations every day, successive administration 3～5 days, this mode practical operation difficulty, and animal caused bigger stress.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of beta-lactam injection.This injection can reduce administration number of times, and what animal produced stress be little.
Another technical problem that the present invention will solve provides a kind of preparation method of beta-lactam injection.
Beta-lactam injection of the present invention, contain following weight and form:
Beta-lactam antibiotic 5%～20%
Suspending agent 0.05%～5%
Antioxidant 0.005%～0.3%
Non-ionic surface active agent 0.1～0.2%
Injection vegetable oil or grease add to 100%.
Described beta-lactam antibiotic comprises penicillins, cephalosporins.Wherein penicillins comprises: penicillin, benzathine benzylpenicillin, ampicillin, ampicillin, amoxicillin, oxazacillin or cloxacillin and salt thereof etc.; Cephalosporins comprises: cefalotin, ceftiofur, cefquinome, cefotaxime, cefazolin, Cefquinome, cefoxitin, cefuroxime, cefepime or ceftriaxone and salt thereof etc.
Described suspending agent can be aluminium stearate, castor oil hydrogenated, sodium carboxymethyl cellulose, Lututrin or polyvinylpyrrolidone etc., preferred aluminium stearate.
Described antioxidant is oil-soluble antioxidant, comprises a-tocopherol, propyl gallate, butylated hydroxyarisol (BHA) or dibutyl phenol (BHT) etc.
Described non-ionic surface active agent can be span, tween, pluronic or peregal etc.
Described injection vegetable oil or grease are injection soybean oil, Semen Maydis oil, Oleum Gossypii semen, Oleum Ricini or glyceryl triacetate, benzyl benzoate etc., preferred injection soybean oil or glyceryl triacetate.
Injection of the present invention can be prepared by following method:
A. beta-lactam antibacterials and antioxidant are prepared into the micropowder of 1-10 μ m, suspending agent is prepared into the fine powder of 30-75 μ m;
B. oil for injection or grease add the suspending agent fine powder behind 150～160 ℃ of high temperature sterilizes, heat and stir, and are placed to room temperature under gnotobasis, and be standby;
C. above-mentioned oil that adds suspending agent or the grease for preparing is transferred to colloid mill, adds beta-lactam antibacterials micropowder, antioxidant and non-ionic surface active agent while stirring, mixing, packing, sterilization, promptly.
Injection of the present invention can be used for the control that the animal bacteria sexuality is dyed disease, but percutaneous injection, intramuscular injection down, also can administration in breast.
In the injection of the present invention, except mentioned component,, can also add beta-lactamase inhibitor in order to improve the antibacterial effect of beta-lactam antibiotic, comprise: clavulanic acid, sulbactam or Tazobactam Sodium and the salt that is formed by them, addition are 1%～5% of above-mentioned total quantity.
Beta-lactam injection provided by the invention is a kind of oil-based suspension, the beta-lactam antibiotic that in the past only was prepared into the solid injectable powder is prepared into injection after, prolong duration of efficacy, reduced production cost when reducing administration number of times.Because of this injection administration number of times is few, what animal produced stress be little.Said preparation can be with getting with usefulness, and it is simple relatively to operate; An independent packaging can be carried out many animals administers, has saved the expense of packing greatly.
Description of drawings
Fig. 1 curve chart that is the Cefquinome sulfate suspension injection when the intravital pharmacokinetics medicine of pig.
Fig. 2 curve chart that is Cefquinome sulfate powder pin when the intravital pharmacokinetics medicine of pig.
The specific embodiment
A. get amoxicillin 45g and sulbactam sodium 15g, a-tocopherol and be prepared into micropowder in right amount respectively; Aluminium stearate is prepared into fine powder, crosses 150 mesh sieves;
B. with the injection soybean oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add aluminium stearate fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned soybean oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and just to be added amoxicillin and sulbactam sodium micropowder, a-tocopherol 0.6g, tween 80 0.3g, mixing, and packing, sterilization is promptly.
A. get amoxicillin 35g and clavulanate potassium 10g, propyl gallate and be prepared into micropowder in right amount respectively; Aluminium stearate is prepared into fine powder;
B. with the injection soybean oil at 150～160 ℃ of high temperature sterilize 2h, get 300ml and add aluminium stearate fine powder 15g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned soybean oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and just to be added amoxicillin and clavulanate potassium micropowder, propyl gallate 0.15g, tween 80 0.6g, mixing, and packing, sterilization is promptly.
Embodiment 3, scotcil suspension injection
A. get scotcil 60g, propyl gallate and be prepared into micropowder in right amount respectively; Aluminium stearate is prepared into fine powder;
B. with the injection soybean oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add aluminium stearate fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned soybean oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added scotcil micropowder, propyl gallate 0.3g, tween 80 0.4g, mixing, and packing, sterilization is promptly.
A. get ceftiofur 30g, butylated hydroxyarisol and be prepared into micropowder in right amount respectively; Castor oil hydrogenated is prepared into fine powder;
B. with the injection soybean oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add castor oil hydrogenated fine powder 0.15g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned soybean oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added ceftiofur micropowder, butylated hydroxyarisol 30mg, Arlacel-80 0.6g, mixing, and packing, sterilization is promptly.
A. get ceftiofur 30g, dibutyl phenol and be prepared into micropowder in right amount respectively; Castor oil hydrogenated is prepared into fine powder;
B. with the injection soybean oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add castor oil hydrogenated fine powder 7.5g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned soybean oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added ceftiofur micropowder, dibutyl phenol 15mg, Arlacel-80 0.3g, mixing, and packing, sterilization is promptly.
A. get procaine benzylpenicillin 60g, a-tocopherol and be prepared into micropowder in right amount respectively; Polyvinylpyrrolidone is prepared into fine powder;
B. with the injection soybean oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add polyvinylpyrrolidone fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned soybean oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added procaine benzylpenicillin micropowder, a-tocopherol 0.9g, Arlacel-80 0.3g, mixing, and packing, sterilization is promptly.
A. get ceftriaxone 30g and his azoles sulbactam sodium 7.5g, the a-tocopherol is prepared into micropowder respectively; Polyvinylpyrrolidone is prepared into fine powder;
B. with the injection Semen Maydis oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add polyvinylpyrrolidone fine powder 7.5g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned Semen Maydis oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added ceftriaxone-Ta azoles sulbactam sodium micropowder, a-tocopherol 0.9g, tween 80 0.6g, mixing, and packing, sterilization is promptly.
A. get Cefquinome sulfate 26.7g (in cefquinome 22.5g), propyl gallate is prepared into micropowder respectively; Aluminium stearate is prepared into fine powder;
B. with the injection Semen Maydis oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add aluminium stearate fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned Semen Maydis oil that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added Cefquinome sulfate micropowder, propyl gallate 0.15g, tween 80 0.6g, mixing, and packing is filled nitrogen, sterilization promptly.Batch number is 20080407.
Embodiment 9, ampicillin-sulbactam sodium suspension injection
A. get ampicillin 30g and sulbactam sodium 7.5g, a-tocopherol and be prepared into micropowder in right amount respectively; Aluminium stearate is prepared into fine powder;
B. with glyceryl triacetate 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add aluminium stearate fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned glyceryl triacetate that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added ampicillin-sulbactam sodium micropowder, a-tocopherol 0.6g, tween 80 0.6g, mixing, and packing, sterilization is promptly.
A. get Cefquinome 15g, a-tocopherol and be prepared into micropowder in right amount respectively; Aluminium stearate is prepared into fine powder;
B. with the injection Oleum Ricini 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add aluminium stearate fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned Oleum Ricini that adds suspending agent for preparing is transferred to colloid mill, the limit is stirred and is just added Cefquinome micropowder, a-tocopherol 0.6g, tween 80 0.3g, mixing, and packing, sterilization is promptly.
Embodiment 11, stability test
According to " chemicals stability test guideline " the Cefquinome sulfate suspension injection is carried out accelerated test.
Experimental condition
Test specimen: embodiment 8 preparation Cefquinome sulfate suspension injection (batch numbers: 20080407)
Test apparatus: the rich news in SPX-250IC micro computer growth cabinet Shanghai Medical Equipment Plant
Investigation project: character, content, sedimentation, granularity
Test site: Henan Province's veterinary drug Engineering Technical Research Centre
Process of the test: test specimen is placed 40 ± 2 ℃ of temperature, and the SPX-250IC micro computer growth cabinet of relative humidity 75% ± 5% was placed 6 months, detected in the 0th, 1,2,3,6 sampling at the end of month, and testing result sees Table 1.
Table 1 Cefquinome sulfate suspension injection accelerated test result
| Time | Character | Sedimentation * | Content | Granularity |
| 0 month | Off-white color is to light brown suspendible liquid | Up to specification | In cefquinome, be 98% of labelled amount | Up to specification |
| January | Off-white color is to light brown suspendible liquid | Up to specification | In cefquinome, be 98% of labelled amount | Up to specification |
| February | Off-white color is to light brown suspendible liquid | Up to specification | In cefquinome, be 95% of labelled amount | Up to specification |
| March | Off-white color is to light brown suspendible liquid | Up to specification | In cefquinome, be 94% of labelled amount | Up to specification |
| June | Off-white color is to light brown suspendible liquid | Up to specification | In cefquinome, be 92% of labelled amount | Up to specification |
*Settlement test method: get 1 bottle of this product, jolting 30 seconds is got test sample 10ml and is put that (internal diameter 1.0～1.2cm) must not precipitate in 10 minutes in the scale test tube.
Result of the test shows Cefquinome sulfate in 40 ± 2 ℃ of temperature, places 6 months under relative humidity 75% ± 5% condition, and color, character do not change; Sedimentation, granularity are all up to specification; Content descends slightly to some extent, but still labelled amount 90.0%～105.0% between, up to specification.
Test specimen: sample 1 (the Cefquinome sulfate suspension injection of embodiment 8 preparations is pressed, and content counts 7.5% with cefquinome), sample 2 (Cefquinome sulfate powder pin is mixed with 7.5% injection with water for injection, and content is in cefquinome)
Experimental animal and grouping: 12 healthy Landraces, body weight 10-15kg is divided into 2 groups at random, 6/group.
Test method: fasting 16h before the test, 1, the 2 group of musculi colli injected sample 2 of the 1st group of musculi colli injected sample, dosage is 0.033ml/kg.Two groups of pigs respectively at administration before and 5min, 15min, 30min, 1h after the administration, 2h, 4h, 8h, 12h, 24h, 36h, 48h, 72h time point through the vena cava anterior 5ml that takes a blood sample, blood is put into the centrifuge tube of handling through heparin sodium, the centrifugal 10min of 3000r/min, get blood plasma ,-20 ℃ of preservations.
Get plasma sample 0.2ml in the 1.5ml centrifuge tube, add acetonitrile 0.2ml, the 30s that on miniature whirlpool vortex mixer, vibrates, 4 ℃, the centrifugal 10min of 12000r/min get supernatant 20 μ l and carry out the HPLC analysis.Chromatographic condition: chromatographic column C18 (150mm * 4.6mm, 5 μ m); 25 ℃ of column temperatures; Mobile phase is that a perchloric acid hydrate sodium 3.45g is dissolved in the 1000ml water, adds phosphoric acid 12ml and acetonitrile 90ml, regulates pH to 3.6 with triethylamine; Flow velocity 1.0ml/min; Detect wavelength 270nm; Sample size 10 μ l.The result as shown in Figure 1 and Figure 2.Two kinds of injecting fluid internal procedures, Cefquinome sulfate suspension injection peak concentration in the pig body is less, the blood drug level length of holding time.
Claims (1)
1. the preparation method of a Cefquinome sulfate suspension injection, its concrete steps are:
A. get Cefquinome sulfate 26.7g, propyl gallate and be prepared into micropowder respectively; Aluminium stearate is prepared into fine powder;
B. with the injection Semen Maydis oil 150～160 ℃ of high temperature sterilizes 2 hours, get 300ml and add aluminium stearate fine powder 6g, 150～160 ℃ of heating also stir, and are placed to room temperature under gnotobasis;
C. the above-mentioned Semen Maydis oil that adds suspending agent for preparing is transferred to colloid mill, adds Cefquinome sulfate micropowder, propyl gallate 0.15g, tween 80 0.6g while stirring, mixing, packing is filled nitrogen, sterilization promptly.
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