CN103271875A - Marbofloxacin freeze-dried powder for injection and preparation method and application thereof - Google Patents
Marbofloxacin freeze-dried powder for injection and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses marbofloxacin freeze-dried powder for injection and a preparation method and application thereof. The marbofloxacin freeze-dried powder consists of the following components: 250g of marbofloxacin, an appropriate amount of lactic acid, 4.8g of injectable activated carbon and the balance of water for injection, wherein the solution is 5000ml in total. The preparation process disclosed by the invention comprises the following steps of: (1) preparing the water for injection; (2) sterilizing rubber plugs; (3) purifying penicillin bottles; and (4) preparing the marbofloxacin freeze-dried powder. The marbofloxacin freeze-dried powder has the advantages of no influence by quality of water in application regions, accuracy in dosage, convenience for use and the like; and the defect that marbofloxacin is water-insoluble is overcome.
Description
Technical field
The invention belongs to the veterinary drug preparation technical field, more specifically relate to a kind of injection marbofloxacin lyophilized powder and preparation method thereof and application.
Background technology
Marbofloxacin (Marbofloxacin) is another third generation fluoroquinolone antibacterial agent thing after enrofloxacin (Enrofloxacin), danofloxacin (Danofloxacin), sarafloxacin (Sarafloxacin), difloxacin (Difloxacin), developed by Switzerland Roche Holding Ag the earliest, Vetoquinol company further exploitation and in nineteen ninety-five first in Britain's listing, subsequently in succession in France, US and European listing and be listed in the animal specific medicine.Approval at present is used for dog, cat and milch cow.
Marbofloxacin has characteristics such as has a broad antifungal spectrum, antibacterial activity is strong, effective half-life is long.Its activity to aerobe is similar to ofloxacin or slightly strong, and most anaerobe are demonstrated the activity higher than ofloxacin.Some produce the chemical sproof pathogen of part to erythromycin, lincomycin, chloromycetin, doxycycline and sulphonamides, and are still responsive to marbofloxacin.In vivo, marbofloxacin shows than the stronger more lasting antibacterial activity of enrofloxacin.The elimination half-life in Canis familiaris L. and cat body was respectively 10～12 hours and 8～10 hours, and calf is being ruminated or do not ruminated to marbofloxacin and the cattle that grows up all shows similar absorption feature, and bioavailability is near 100%.Marbofloxacin has bigger distribution volume (more than 1.3 l/kg), except the central nervous system, the drug level of all analyzed tissues all is higher than blood plasma, and this feature makes this medicine can become the drug of first choice of the infection for the treatment of deep tissue, pulmonary infection and pyoderma.The most attractive characteristics of pharmacokinetics of marbofloxacin is its elimination long half time, and medicine long period in blood plasma and each tissue is kept valid density, does not also have the report of cumulative toxicity at present about these metabolites.Be suitable for administration once-a-day.Safe, have a extensive future.
Quinolone antibiotic for animals listing in 1990～2000 years has enrofloxacin, danofloxacin, difloxacin, sarafloxacin, orbifloxacin, ibafloxacin and marbofloxacin etc.Marbofloxacin (marbofloxacin, marbofloxacin) is a kind of novel fluoroquinolone antibacterial agent of animal specific, is developed by Switzerland Roche Holding Ag, and goes on the market in Britain first in nineteen ninety-five, and approval at present is used for dog, cat and milch cow; The infectious disease of preventing and treating poultry at home is its main uses, and chemotherapeutic accounts for more than 60% of veterinary drug market.Marbofloxacin has characteristics such as has a broad antifungal spectrum, antibacterial activity is strong, effective half-life is long.Its activity to aerobe is similar to ofloxacin or slightly strong, and most anaerobe are demonstrated the activity higher than ofloxacin.Some produce the chemical sproof pathogen of part to erythromycin, lincomycin, chloromycetin, doxycycline and sulphonamides, and are still responsive to marbofloxacin.In vivo, marbofloxacin shows than the stronger more lasting antibacterial activity of enrofloxacin.The elimination half-life in Canis familiaris L. and cat body was respectively 10～12 hours and 8～10 hours, and bioavailability is near 100%.It is excellent that marbofloxacin is used for the treatment of various skins, urethra, digestive tract, respiratory tract infection and the postoperative infection curative effect of dog, cat.Postoperative infection also there is the excellent prevention effect; Aspect of respiratory disease the treatment cattle has better future; Also can be used for treating the mastitis of cattle, sheep, further widen the range of application of marbofloxacin.Marbofloxacin also has the advantage for pig, cattle, sheep disease.Marbofloxacin is own as one of 15 kinds of structure antibacterials for animals of going on the market the nineties.Put on market and will obtain bigger economic benefit and social benefit.
Clinically oneself deep and the shallow epidermis skin that are used to treat dog infect, urinary tract infection, the skin of cat and soft tissue infection, acute upper respiratory tract infection, the pharmacokinetic studies of marbofloxacin cattle, sheep, pig shown also this medicine has great potential aspect digestive tract, respiratory tract, urogenital tract and the skin infection for the treatment of poultry.
Marbofloxacin has has a broad antifungal spectrum, feature that antibacterial activity is strong, its activity to aerobe is similar to ofloxacin or slightly strong, most anaerobe are demonstrated the activity higher than ofloxacin, be lower than ofloxacin as the MIC to Gram-negative and positive bacillus cereus, especially to the latter.Spreng etc. (1995) have measured marbofloxacin and have caused the external activity of dog, cat disease antibacterial to show that it has stronger antibacterial activity to most gram positive bacterias to 816 strains of clinical separation, and more responsive to gram negative bacteria, most of enterobacterias are comprised the MIC of escherichia coli, Cray Bai Shi bacillus, Bacillus proteus
90Be 0.08ug/ml～0.28ug/ml, to the MIC of pasteurella multocida
90Be 0.04ug/ml, to bacillus pyocyaneus MIC
90Be 0.94ug/ml, to staphylococcus aureus and Staphylococcus intermedius MIC
90Be respectively 0.2ug/ml and 0.23ug/ml, be better than ofloxacin, suitable with ciprofloxacin, enrofloxacin, but to streptococcus m IC
50Be worth higherly, be 3.8ug/ml.In addition, marbofloxacin also has greater activity to some pathogenic bacterium of cattle as pasteurella haemolytica, pasteurella multocida and lethargy haemophilus.
According to (1998) such as Pellerin, some produce the chemical sproof pathogen of part such as Staphylococcus intermedius to erythromycin, lincomycin, chloromycetin, doxycycline and sulphonamides, still responsive to marbofloxacin, so this medicine can be used as the drug of first choice of dog pyoderma due to this bacterium for the treatment of.Also find no the pass pathogen at present marbofloxacin is produced chemical sproof report.
In the simulation antibacterial activity in vivo test that dog carries out, marbofloxacin and enrofloxacin are respectively with 24h after 2mg/kg and the 5mg/kg administration, marbofloxacin still can effectively suppress Staphylococcus intermedius and bacillus pyocyaneus, and this moment, enrofloxacin can not stop above-mentioned antibacterial to regrow, this shows, though at external marbofloxacin the activity of middle staphylococcus and bacillus pyocyaneus is compared inferiorly slightly with enrofloxacin, under the condition, marbofloxacin shows stronger, more lasting bacteriostatic activity in analogue body.Spehnet etc. (1996) discover that marbofloxacin also can strengthen macrophage activity by regulating the inflammatory reaction that macrophage participates in, and promotes the non-specific immunity of body.
Marbofloxacin also shows antimicrobial drug after effect (PAE).Spreng etc. (1995) report, marbofloxacin is respectively 1.6～2.4h and l.0～1.7h to the PAE value of several The main pathogenic fungi of dog, cat.Because marbofloxacin has PAE preferably, its antibacterial activity in various body fluid, tissue can be kept 24h or longer time.Although the PAE meaning is not illustrated as yet in the body of marbofloxacin, the tissue concentration that medicine is higher and long PAE are the keys that obtains good efficacy, and this is for working out rational dosage regimen clinically, better bringing into play drug effect epochmaking meaning is arranged.
In recent years, abroad marbofloxacin is studied at the pharmacokinetics of dog, cat, cattle, sheep, pig, each pharmacokinetic parameters is as shown in table 1.
Table 1 marbofloxacin is at pharmacokinetic parameters/2mgkg of several animals
-1
According to table 1, marbofloxacin absorbs rapidly and fully in for oral administration, the intramuscular injection of nonruminant and calf, be more than 100% in the bioavailability of not ruminating calf and ruminate calf, be about 80% at cat, pregnancy and lactating sow, be higher than enrofloxacin, ciprofloxacin, norfloxacin, ofloxacin.Calf is being ruminated or do not ruminated to marbofloxacin and the cattle that grows up all shows similar absorption feature, bioavailability all reaches more than 100%, and enrofloxacin, danofloxacin are very poor in the oral absorption of ruminating beast or having ruminated in the calf body of growing up, bioavailability is lower than 10%, and marbofloxacin advantage in this respect is apparent.
Marbofloxacin has bigger distribution volume (more than 1.3 l/kg), except the central nervous system, the drug level of all analyzed tissues all is higher than blood plasma, and this feature makes this medicine can become the drug of first choice of the infection for the treatment of deep tissue, pulmonary infection and pyoderma.Reports such as Schneider, dog with 2mg/ (kgd), 4mg/ (kgd) and 6mg/ (kgd) oral administration 13d, 24h after the last administration, skin and plasma drug level ratio is respectively 1.40, l.65 with 1.76, approach in inflammatory exudate Chinese medicine concentration and blood plasma, this is beneficial to and prevents postoperative infection.Marbofloxacin concentration in the liver of dog and Mus, lung, kidney all is higher than blood plasma, is 1.4 at muscle, skin Chinese medicine concentration and the plasma drug level ratio of dog, and is 2.5 and 2.31 liver and this ratio of kidney, shows the favorable tissue permeability.Milch cow, namely surpass blood drug level with 2h Ruzhong drug level after 2～4mg/kg administration, 12h Ruzhong drug level still maintains more than the MIC value of marbofloxacin to most breast pathogen after the administration.
The plasma protein binding rate of marbofloxacin is lower, and people, experimental animal and dog, the marbofloxacin plasma protein binding rate is lower than 10%, and then higher cattle is 30%.
The most attractive characteristics of pharmacokinetics of marbofloxacin is its elimination long half time, and medicine long period in blood plasma and each tissue is kept valid density, is suitable for administration once-a-day.Be 5～6 times of enrofloxacin as the elimination half-life dog.Marbofloxacin is oral and subcutaneous administration with 2mg/kg, behind the 24h in dog plasma concentration be 0.3ug/ml and 0.22ug/ml, this value approaches or surpasses marbofloxacin to the MIC value of most of gram negative bacterias.Marbofloxacin is converted into two kinds of non-activity metabolites at liver: N-demethylation marbofloxacin and N-oxygen marbofloxacin.
From urine, drain with original shape at dog, 35%～40% marbofloxacin, so the concentration of marbofloxacin in urethra is enough to suppress to cause the various pathogen of urinary tract infection, and its activity is subjected to the acidity of urine and high concentration cation environmental effect little.The drainage of marbofloxacin in Lac Bovis seu Bubali is less than 1% of total amount; From the drainage of bile, do not ruminate calf and account for 10%, ruminate calf and account for 45%; From urine, drain and account for 75% and 45% respectively.It is slower than ruminating calf to the elimination of marbofloxacin not ruminate calf, CI
BDividing is 0.15 1/ (hkg) and 0.31 1/ (hkg) in addition.
Two kinds of metabolites of marbofloxacin are also mainly through renal excretion.Its clearance rate is higher than the original shape medicine, does not also have the report of cumulative toxicity at present about these metabolites.
Marbofloxacin residue in the muscle of pig and fat all is the original shape medicine almost, and then part is its metabolite in liver, kidney.The residual quantity of marbofloxacin all is lower than 8.5ug/kg in cattle administration (2mg/kg, 5d continuously) the various tissues of back 192h.73%～89% left drug is the marbofloxacin original shape in milk.With radiolabeled marbofloxacin subcutaneous injection (2mg/kg) administration, after the last administration of pig the 4th day, the liver Chinese medicine is residual to be lower than 49ug/kg, is lower than 82ug/kg in kidney, behind the last administration 2d, the injection site drug residue only is 21～88ug/kg.
Some factors can influence marbofloxacin dynamic process in animal body, as lactogenic and gestation, and behind the oral marbofloxacin of sow, the t of pregnant pig
1/2 β(10.09h) obviously be longer than lactogenic pig (5.74h), medicine the body clearance rate of lactogenic pig also higher (3.27ml/ (minkgbw), so, answer escalated dose when marbofloxacin is used for treatment between lactation period.Under dog injury of kidney state, the medicine kinetic parameter of marbofloxacin changes little, prompting runs into the dosage regimen that slight renal dysfunction can be adjusted marbofloxacin when clinical practice, and the people cures when using fluoroquinolones, then need prolong dosing interval as renal insufficiency and reduce consumption, cause side effect to avoid drug accumulation.Thomas(1994) the marbofloxacin intramuscular injection is infected the pharmacokinetic studies of ruminating calf health and pasteurella haemolytica and is found that marbofloxacin all has high bioavailability at both, but sick cattle is to the absorption of medicine with eliminate speed all less than healthy cattle.
The side effect of marbofloxacin poison is little, and untoward reaction is light, seldom causes such as side effect such as nausea,vomiting,diarrhea, spasm.
The toxicity of marbofloxacin is low, to the oral LD of mice
50Being 1781mg/kg, is 3772mg/kg to rat, hypodermic LD
50Be the 972mg/kg(mice) and the 2094mg/kg(rat), the Mus poisoning symptom comprise movable reduce, tremble, spasm.Fool proof to dog, can not cause joint and cartilage injury in 3 months with the 6mg/kg successive administration every day pup.
Can cause human or animal's spasm or epilepsy symptom when some fluoroquinolones and NSAID (non-steroidal anti-inflammatory drug) use in conjunction, and marbofloxacin and NSAID (non-steroidal anti-inflammatory drug) Tolfenamic acid be studies show that in the use in conjunction of dog, even marbofloxacin still toxic reaction can not occur with 10 times of recommended dose administrations, illustrate that marbofloxacin has bigger safety.
The homergy that can suppress theophylline slows down its elimination, and blood drug level raises, and uses simultaneously and should note.Marbofloxacin also should not be obeyed together with antacid such as magnesium hydroxide or aluminium hydroxide, in order to avoid influence the absorption of marbofloxacin.
The clinical pharmaceutical quantities of recommending of marbofloxacin is 2～4mg/kg, and be administered once every day, can carry out oral, intramuscular injection, subcutaneous injection or intravenous drip as required, the course for the treatment of 3～5d, external existing commercially available various concentration (2%～10%) marbofloxacin injection at present.In view of the high feature of its oral administration biaavailability, to the intensive culture animal, can consider with mixed feeding or drinking-water administration, but this respect report is not arranged at present as yet.
The antibacterial activity of some fluoroquinolones can reduce in urine, and marbofloxacin can be kept 2～5d to some sensitive organism bactericidal activities after with the 2mg/kg single dose administration in urine, so generally speaking, escherichia coli and Staphylococcus intermedius to cat, dog infect, and with 2mg/kg single dose administration (oral or subcutaneous injection), better curative effect are arranged namely, as the need long-term treatment, then can the per 3～4d of 2～4mg/kg once, and E .faecalis is infected, then need every day with the 2mg/kg administration.Clinical practice when the various inflammation of dog can with some NSAID (non-steroidal anti-inflammatory drug) such as Fenbufen and tolfenamic acid use in conjunction, and needn't neurotoxicity can appear worry.
Marbofloxacin has been used for the treatment of various skins, urethra, digestive tract, respiratory tract infection and the postoperative infection of dog, cat at present, studies show that Drugein(1997), marbofloxacin is better than enrofloxacin with the Staphylococcus intermedius of 2mg/kg treatment dog and the curative effect of charrin's disease, the pyoderma of the dog that is caused by Staphylococcus intermedius and escherichia coli in treatment and to go out the pyoderma curative effect of the cat that staphylococcus aureus causes excellent.Dossin etc. (1998) are respectively with marbofloxacin (2mg/kg, once a day, continuous 5d) with the acute upper respiratory tract infection of amoxicillin+clavulanic acid treatment cat, cure rate is respectively 87.8% and 77.8%, and the urinary tract infection that Cotard etc. (1995) treat dog with marbofloxacin and amoxicillin+clavulanic acid respectively, cure rate is 96.2% and 85.0%.
For the postoperative infection of dog, cat, marbofloxacin also has the excellent prevention effect, and with the quiet notes of 2～4mg/kg, the drug level in blood plasma and the inflammatory exudate reaches 12～24h more than maintaining the MIC value of some main infectious bacterias (enterobacteria and staphylococcus).
Marbofloxacin is to the multiple calling road pathogen of cattle, as pasteurella multocida, pasteurella haemolytica, lethargy haemophilus and Mycoplasma bovis better activity is arranged, make its aspect of respiratory disease the treatment cattle that better future be arranged, in addition, can infiltrate the Ruzhong rapidly and widely after the marbofloxacin administration, reach higher concentration, and keep the long period, also can be used for treating the mastitis of cattle, sheep.
The marbofloxacin parenterai administration can be used for treating mastitis, metritis, the agalactia syndrome of sow.
At present external marbofloxacin is approved for dog, cat, has accumulated more experience in recent years in this respect, facts have proved, marbofloxacin convenient drug administration, curative effect are certain, is accepted and approves.Marbofloxacin becomes the another animal specific fluoroquinolone kind new medicine after enrofloxacin, is widely used abroad, and it shows in vivo than the stronger more lasting antibacterial activity of enrofloxacin, and bioavailability all is higher than product of the same type.At home, as the product of animal specific veterinary drug seldom, and just more rare as the veterinary drug of house pet special use, the adding of marbofloxacin will be filled up a blank of domestic house pet medication, believe future house pet diseases prevention and treatment field be bound to bring into play its important function.
Tablet and injection dosage form have abroad been arranged at present, we are through having researched and developed the injection marbofloxacin, target animals is pets dog, cat etc., advantage such as its lyophilized powder has easy preservation, do not used the influence of region water quality, dosage is accurate, easy to use, and the water-fast characteristics of marbofloxacin have been overcome, at present this dosage form product that still do not go on the market.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, a kind of injection marbofloxacin lyophilized powder is provided.
Another object of the present invention is to provide the preparation method of this injection marbofloxacin lyophilized powder.
It is for the application on the medicine of the diseases such as respiratory tract, digestive tract, urinary tract and skin infection of the dog due to the treatment sensitive organism, cat with this injection marbofloxacin lyophilized powder that the present invention also has a purpose.
For achieving the above object, the present invention has taked following technical scheme:
A kind of injection marbofloxacin lyophilized powder is grouped into by following one-tenth:
Marbofloxacin: 250g
Lactic acid: an amount of
Needle-use activated carbon: 4.8g
Water for injection adds to: 5000ml;
Wherein, the addition of lactic acid is 4.5～5.2 for the pH that adjusts preparation; Preferred addition is that the pH of adjustment preparation is 4.8～4.9.
The preparation technology of described injection marbofloxacin lyophilized powder comprises the steps:
1, producing of water for injection:
(1) will make purified water after the drinking water process reverse osmosis ion exchange;
(2) purified water gets final product to such an extent that make water for injection after distillation;
2, the sterilization of plug:
Before wash bottle, carry out the plug sterilization earlier; After plug removed outer package, import into and send into sterilization tank between fine purifiation, 125 ℃ of dry sterilizations 3 hours are chilled to 40 ℃, and it is standby to take out cooling under hundred grades of laminar flows protections of bottling department.
Plug after the sterilization should use immediately or clean and deposit.Storage must not surpass 12 hours, as surpassing, then must sterilize again.
Sterilization finishes, and plug and next procedure that sterilization is good join.
3, the decontamination procedure of cillin bottle:
Cillin bottle is removed reason bottle after the outer package, import between fine purifiation, place and send on bottle machine, at first with purified water bottle is carried out ultrasonic waves for cleaning slightly washing the district, the inside and outside Fouling Cleaning of bottle is clean with being attached to; When bottle ran to the fine purifiation district, to use through the aperture be the water for injection that filters of 0.22 μ m filter membrane carried out continuously every flushing the bottle inside and outside wall, and using at last through the aperture is that the compressed air that 0.22 μ m filter membrane filters blows off the globule inside and outside the bottle.
Cillin bottle after the cleaning is sent into sterilization tank, 200 ℃ of dry sterilizations 2 hours, and sterilization finishes, and is chilled to 40 ℃.It is standby to take out cooling under hundred grades of laminar flow protections of bottling department.
Cillin bottle after the sterilization should use immediately or clean and deposit.Storage must not surpass 12 hours, as surpassing, then must return and relaunder sterilization between wash bottle.
4, the preparation of marbofloxacin lyophilized powder
(1) weighing;
(2) dense joining: getting 70% water for injection, add marbofloxacin, active carbon, stirred 20 minutes, is 0.45 μ m membrane filtration (doing bubble point test before and after using) with the aperture; Squeeze into rare filling of joining through pipeline.
(3) rare joining: regulate pH value to 4.5～5.2 with lactic acid, water for injection adds to full dose, is 0.22 μ m membrane filtration (doing bubble point test before and after using) with the aperture, fill in and ask verification certificate, do content, pH value, clarity, color, related substance inspection, after the passed examination, the notice embedding.The medicinal liquid preparation should be finished in 4 hours.Preparation finishes, and medicinal liquid and the next procedure for preparing joined.
(4) with the fill of filling liquid stopper-adding machine, regulate and send a bottle rotary speed, adjust shake plug unit frequency, connect fill head, filling tube, begin fill, half tamponade after getting rid of the latex inner air tube earlier, loading amount is the 2.0ml/ bottle, and content uniformity is controlled ± 10%, check a loading amount every 30 minutes, choose defective work.
Fill should be finished in 6 hours.Fill finishes, and cillin bottle and next procedure that fill is good join.
(5) lyophilizing gland:
Use the vacuum freeze drier lyophilization, open refrigeration machine, will freeze the product temperature and be down to-45 ℃, constant temperature 2 hours reaches-50 ℃ with the temperature of condenser, opens vacuum earlier, when vacuum reached 20Pa, beginning subliming by heating drying made and freezes the product temperature and rise to-30 ℃, constant temperature 10 hours continues to heat to about 0 ℃ constant temperature 8 hours to freezing product, reheat to 45 ℃ later constant temperature 2 hours, import filtrated air after the EP (end of program), gland, outlet.
The lyophilizing gland finishes, and cillin bottle and next procedure that the lyophilizing gland is good join.
(6) aluminium lid sterilization: with the sterilization of ozone sterilization cabinet, send into sterilization tank after aluminium lid removed outer package, through ozone concentration 〉=120ppm, sterilization in 1 hour stops the back and waits for 10-15 minute, takes out for rolling the lid use in 100,000 grades of districts.Sterilization finishes, and aluminium lid and next procedure that sterilization is good join.
(7) roll lid: roll lid with the centrifugal Cover-rolling machine of three cuttves, qualified semi-finished product of packing are sealed with aluminium lid.At any time observe to prick and cover situation, choose defective work.Roll lid and finish, will roll cillin bottle and the next procedure of building and join.
(8) lamp inspection: will roll the cillin bottle that covered lamp inspection one by one, and choose the product that detects poor qualities such as rolling lid is disorderly hindered, distortion, a spray bottle tomography, atrophy.Lamp inspection finishes, and cillin bottle and next procedure that lamp inspection is qualified join.
(9) outer package: vanning: at first piece together case, adorn this batch product then.The preceding front-back at big case of vanning respectively labels printed product batch number, date of manufacture and an expiry date.Check errorless after, put into work certificate, with adhesive tape the case mouth is sealed.Seal the gap and be not more than 5mm.
(10) warehouse-in: the depositary management personnel handle the formality of finished product warehouse-in according to finished product acceptance test report.
Compared with prior art, the present invention has following beneficial effect:
Product of the present invention is not used advantages such as the influence of region water quality, dosage be accurate, easy to use, and has overcome the water-fast weak point of marbofloxacin.
Description of drawings
Fig. 1 is preparation technology's flow chart of the present invention.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment.
Embodiment 1
A kind of injection marbofloxacin lyophilized powder is grouped into by following one-tenth:
Marbofloxacin: 250g; Zhejiang Province Guobang Pharmaceutical Co., Ltd, product batch number: 090705 lactic acid (analytical pure): an amount of; Shanghai spark chemical industry in morning company limited, lot number: 20100611 injection-use activated carbons: 4.8g; The logical carbon leaching material company limited lot number of Shandong letter: 20100812
Water for injection adds to: 5000ml;
Wherein, the addition of lactic acid is 4.8～4.9 for the pH that adjusts preparation.
The preparation technology of described injection marbofloxacin lyophilized powder comprises following technical step:
(1) producing of water for injection:
(a) will make purified water after the drinking water process reverse osmosis ion exchange;
(b) purified water gets final product to such an extent that make water for injection after distillation;
(2) sterilization of plug:
Before wash bottle, carry out the plug sterilization earlier; After plug removed outer package, import into and send into sterilization tank between fine purifiation, 125 ℃ of dry sterilizations 3 hours are chilled to 40 ℃, and it is standby to take out cooling under hundred grades of laminar flows protections of bottling department;
Plug after the sterilization should use immediately or clean and deposit.Storage must not surpass 12 hours, as surpassing, then must sterilize again; Sterilization finishes, and plug and next procedure that sterilization is good join;
(3) decontamination procedure of cillin bottle:
Cillin bottle is removed reason bottle after the outer package, import between fine purifiation, place and send on bottle machine, at first with purified water bottle is carried out ultrasonic waves for cleaning slightly washing the district, the inside and outside Fouling Cleaning of bottle is clean with being attached to; When bottle ran to the fine purifiation district, to use through the aperture be the water for injection that filters of 0.22 μ m filter membrane carried out continuously every flushing the bottle inside and outside wall, and using at last through the aperture is that the compressed air that 0.22 μ m filter membrane filters blows off the globule inside and outside the bottle;
Cillin bottle after the cleaning is sent into sterilization tank, 200 ℃ of dry sterilizations 2 hours, and sterilization finishes, and is chilled to 40 ℃, and it is standby to take out cooling under hundred grades of laminar flows protections of bottling department;
Cillin bottle after the sterilization should use immediately or clean and deposit.Storage must not surpass 12 hours, as surpassing, then must return and relaunder sterilization between wash bottle;
(4) preparation of marbofloxacin lyophilized powder
(a) weighing;
(b) dense joining: getting 70% water for injection, add marbofloxacin, active carbon, stirred 20 minutes, is 0.45 μ m membrane filtration with the aperture; Squeeze into rare filling of joining through pipeline;
(c) rare joining: regulate pH value to 4.8～4.9 with lactic acid, water for injection adds to full dose, is 0.22 μ m membrane filtration with the aperture, fills in and asks verification certificate, does content, pH value, clarity, color, related substance inspection, after the passed examination, and the notice embedding; The medicinal liquid preparation should be finished in 4 hours; Preparation finishes, and medicinal liquid and the next procedure for preparing joined;
(d) with the fill of filling liquid stopper-adding machine, regulate and send a bottle rotary speed, adjust shake plug unit frequency, connect fill head, filling tube, begin fill, half tamponade after getting rid of the latex inner air tube earlier, loading amount is the 2.0ml/ bottle, and content uniformity is controlled ± 10%, check a loading amount every 30 minutes, choose defective work;
Fill should be finished in 6 hours; Fill finishes, and cillin bottle and next procedure that fill is good join;
(e) lyophilizing gland:
Use the vacuum freeze drier lyophilization, open refrigeration machine, will freeze the product temperature and be down to-45 ℃, constant temperature 2 hours reaches-50 ℃ with the temperature of condenser, opens vacuum earlier, when vacuum reached 20Pa, beginning subliming by heating drying made and freezes the product temperature and rise to-30 ℃, constant temperature 10 hours continues to heat to about 0 ℃ constant temperature 8 hours to freezing product, reheat to 45 ℃ later constant temperature 2 hours, import filtrated air after the EP (end of program), gland, outlet;
The lyophilizing gland finishes, and cillin bottle and next procedure that the lyophilizing gland is good join;
(f) aluminium lid sterilization: with the sterilization of ozone sterilization cabinet, send into sterilization tank after aluminium lid removed outer package, through ozone concentration 〉=120ppm, sterilization in 1 hour stops the back and waits for 10-15 minute, takes out for rolling the lid use in 100,000 grades of districts.Sterilization finishes, and aluminium lid and next procedure that sterilization is good join;
(g) roll lid: roll lid with the centrifugal Cover-rolling machine of three cuttves, qualified semi-finished product of packing are sealed with aluminium lid; At any time observe to prick and cover situation, choose defective work; Roll lid and finish, will roll cillin bottle and the next procedure of building and join;
(h) lamp inspection: will roll the cillin bottle that covered lamp inspection one by one, and choose the product that detects poor qualities such as rolling lid is disorderly hindered, distortion, a spray bottle tomography, atrophy; Lamp inspection finishes, and cillin bottle and next procedure that lamp inspection is qualified join;
(i) outer package: vanning: at first piece together case, adorn this batch product then; The preceding front-back at big case of vanning respectively labels printed product batch number, date of manufacture and an expiry date; Check errorless after, put into work certificate, with adhesive tape the case mouth is sealed; Seal the gap and be not more than 5mm;
(j) warehouse-in: the depositary management personnel handle the formality of finished product warehouse-in according to finished product acceptance test report.
In above-described embodiment, the performance indications of the injection marbofloxacin lyophilized powder that makes are as follows:
1, dosage form: injection
2, character: this product is the loose block of the lyophilizing of white or off-white color.
3, effect and purposes: quinolone antibiotic.Be used for the dog due to the sensitive organism, the infection such as respiratory tract, digestive tract, urinary tract and skin of cat.
4, specification: 0.1g.
5, storage: lucifuge, airtight, preserve at cold place.
To the summary of the main result of study of the injection marbofloxacin lyophilized powder that makes among the embodiment and estimate as shown below:
1, study of pharmacy data
1.1 preparation prescription
| Supplementary material | Consumption |
| Marbofloxacin | 250g |
| Lactic acid | In right amount |
| Activated carbon (pin is used) | 4.8g |
| Water for injection adds to | 5000ml |
1.2 quality research and quality standard
1.2.1 with reference to European Pharmacopoeia standard and domestic like product standard, determine content format and the test item of quality standard, comprise title (Chinese name, English name, the Chinese phonetic alphabet), content, character, discriminating, inspection (acidity, solution appearance, moisture, aseptic, other, related substance), assay, indication, usage and consumption, specification, storage, effect duration etc. project.
1.2.2 carried out methodology checking research at inspection item, comprised stability of solution checking, detection method of content checking etc.
1.2.3 stability study
1.2.3.1 the factors influencing result of this product shows that this product is under the condition of high light, product appearance, related substance change greatly, and interpret sample need keep in Dark Place.Under super-humid conditions, moisture absorption weightening finish is about 15%, interpret sample have draw moist, but in the band Packing Condition in the moisture absorption weightening finish below 1%; The basic no change of other investigation projects of sample.
1.2.3.2 the acceleration result of this product shows that this product was placed 6 months under the accelerated test condition, the clarity of the appearance character of sample, acidity, solution and color, moisture, related substance and content are all up to specification.
Long-term placement is in the time of 18 months under 25 ± 2 ℃ of temperature, RH60% ± 10% condition 1.2.3.3 long-term test results shows this product, and the clarity of the appearance character of sample, acidity, solution and color, moisture, related substance and content are all up to specification.
1.2.3.4 this product long-term stable experiment still in the middle of further carrying out, according to the long-term stable experiment result of accelerated test and 18 months, with this product effect duration tentative be 2 years.
2, pharmacological toxicology research
2.1 main pharmacodynamics
2.1.1 the mechanism of action: the antibacterial action mechanism of fluoroquinolone antibiotics mainly is to suppress the gyrase (Gyrase claims II type topoisomerase again, Topoisomerase II) of one of bacteria dna (DNA) synzyme.Gyrase has two subunits of A, B, fluoroquinolones mainly acts on its A subunit, gyrase makes copying of DNA of bacteria, ribonucleic acid (RNA) and the synthetic of protein disturbed by suppressing, and bacterial cell can not be divided again, and then play the effect of sterilization.Marbofloxacin is except suppressing Topoisomerase II, and is also inhibited to the IV star topoisomerase in the bacterial cell.The mechanism of action of marbofloxacin is different from other antimicrobial drugs, therefore the probability very little (especially being non-Comprecin) of crossing drug resistant between generation and other drug.
2.1.2 the scope of application and clinical practice
Usefulness oral doses such as Paradis are that the marbofloxacin (commodity are called Zeniquin) of 2.75mg/kg is treated 72 dogs that suffer from shallow table or deep layer pyoderma, successive administration 21d and 28d, the result wherein has 62 examples (86.1%) to cure, 6 examples (8.3%) sx, 4 examples (5.6%) are invalid.Reports such as Horspool, the oral daily dose of dog of suffering from shallow table or deep layer Pyoderma is the ibafloxacin therapeutic equivalence of 15mg/kg.People such as Harry discover, 2.75mg/kg the distributed density of marbofloxacin in the dog pulmonary macrophage than height in serum and bronchus top layer liquid, its concentration can reach marbofloxacin to the MIC value of dog easy infection pathogenic bacteria, and visible marbofloxacin can be used for treating in the cell and the relevant bacterial infection of macrophage infiltration.
2.2 safety pharmacology research
2.2.1 marbofloxacin has low acute oral toxicity, acute oral LD
50Value is the 1781mg/kg(male ICR mouse) to the 3772mg/kg(male Sprague-Dawley rat).The LD of acute subcutaneous administration
50Be 972 mg/kg(male ICR mouses) to 2094 mg/kg(male Wistar rats).
2.2.2 in the research of a 13 all repeated doses, adult dog per kilogram every day oral 1,4 or 40mg marbofloxacin (gelatine capsule), the dosage at 40mg/kg/ days is observed the variation of the articular cartilage that typical quinolinones causes.Observing has a sperm tube atrophy takes place in 4 Canis familiaris L.s that give 40mg/kg/ days medicines, one sperm granuloma takes place.
2.2.3 to teenage Canis familiaris L. give≤the repeated doses research in 13 weeks of 6mg/kg/ days marbofloxacin in, find no the influence relevant with this material.
2.2.4 in a teratology research, do not find at other teratogenesis evidence of any dosage level.
2.2.5 other fluoroquinolone is not carcinogenic, so groundless is suspected marbofloxacin.
2.3 microorganism sensitivity tests
2.3.1 Hu Gongzheng etc. " the husky star of numb ripple is to the antibacterial activity of dog cat isolate "
2.3.1.1 compare with other antimicrobial drug, the antibacterial range of fluoroquinolones enlarges, antibacterial activity strengthens, and has the similar medicine of bibliographical information to compare with other, and marbofloxacin has similar or better antibacterial activity.
2.3.1.2 marbofloxacin has similar bactericidal activity with enrofloxacin to two kinds of bacterial strains testing.
2.3.1.3 after the medication of dog single dose, the sterilization persistent period of medicine in urine prolongs with the increase of dosage (1,2 and 4mg/kg), and be oral and the subcutaneous injection result is very approaching.
2.3.1.4 marbofloxacin and enrofloxacin are basic identical to the PAE of three kinds of pathogenic strains of dog (to be 1.6～2.4h) when 4 times of MIC.
2.3.2 Chen Jun etc. " progress of fluoroquinolone antibacterial agent Marbofloxacin "
2.3.2.1 antibacterial activity in vitro research: marbofloxacin has stronger antibacterial activity to gram positive bacteria, and is also relatively more responsive to gram negative bacteria, even also effective to some Mycoplasma, anaerobe.
2.3.2.2 the bactericidal activity of marbofloxacin: Ganiere etc. studies show that, marbofloxacin is 2～4 times of its corresponding MIC to the MBC of colon bacillus, staphylococcus aureus, streptococcus uberis, streptococcus dysgalactiae.It is suitable with danofloxacin that Schneider etc. record marbofloxacin minimum bactericidal concentration MBC.
2.3.3 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " marbofloxacin antibacterial activity in vitro mensuration "
The bacteriostatic test that this test is undertaken by clinical SEPARATION OF GOLD Staphylococcus aureus and escherichia coli to separate sources, the result shows that marbofloxacin has fungistatic effect preferably to each bacterial strain, and its MIC is 0.125～1ug/ml(staphylococcus aureus) and 0.0625～0.5ug/ml(escherichia coli); Two enrofloxacins are respectively 0.25～2ug/ml(staphylococcus aureus) and 0.25～1ug/ml(escherichia coli).
2.4 pharmacokinetics
2.4.1 Chen Jun etc. " progress of fluoroquinolone antibacterial agent Marbofloxacin ", main pharmacokinetic parameter is as shown in the table.
2.4.2 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " pharmacokinetic studies of marbofloxacin lyophilized powder in the dog body "
Behind the healthy domesticated dog subcutaneous injection marbofloxacin (2mg/kg), the absorption half-life is 1.70h, and the elimination half-life is 8.33h, and 0.89h reaches peak concentration, shows that the injection back absorbs rapidly under this coating, eliminates slowly.Similar to most of quinolones, the concentration of marbofloxacin in tissue surpasses blood drug level, and the medicine of the phagocyte guiding quinolones of inflammation part arrives areas of inflammation, so marbofloxacin can show more antimicrobial effect.Marbofloxacin is between 0.008～4ug/ml to the common pathogenic bacterium of dog such as the MIC of staphylococcus, streptococcus, escherichia coli, pasteurellosis bacillus, Bacillus proteus and pseudomonas, therefore dog is by per kilogram of body weight 2mg subcutaneous injection 1 time (extremely sensitive bacterium), 2 times (sensitive organism) can reach effective blood drug level.
2.5 acute toxicity
2.5.1 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " studies on acute toxicity of marbofloxacin "
This experiment obtains the oral LD of marbofloxacin
50Be 887.8mg/Kg b.w., LD
5095% credible 793.0～994.0mg/kg b.w. that is limited to, can be judged as the lower toxicity material by acute toxicity grading criteria.
2.5.3 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " studies on acute toxicity of injection marbofloxacin "
This experiment obtains the LD of injection marbofloxacin
50Be 441.6mg/Kg b.w., LD
5095% credible 397.2～490.9mg/kg b.w. that is limited to, can be judged as poisoning class material by acute toxicity grading criteria.The dog injected dose that Vetoquinol company is recommended is 2mg/kg/ days, and our company also is the 2mg/kg body weight to the hypodermic dosage of dog, once-a-day, is used in conjunction 3.
2.5.4 according to " mutagenicity of Marbofloxacin and the researchs of teratogenesis shape " such as Shen Jianzhong, the LD that marbofloxacin is oral to kunming mouse
50Be 1000 mg/kg b.w, its 95% credible 776.2～1288.2 mg/kg b.w that are limited to.
2.5.5 point out that marbofloxacin has low acute oral toxicity, acute oral LD in European drug evaluation mechanism (EMEA) in to marbofloxacin final report (2)
50The value scope is the 1781mg/kg(male ICR mouse) to the 3772mg/kg(male Sprague-Dawley rat).The LD of acute subcutaneous administration
50Be 972 mg/kg(male ICR mouses) to 2094 mg/kg(male Wistar rats).
2.6 subchronic toxicity
Animal medicine institute of trust Agricultural University Of Nanjing of our company has carried out the subchronic toxicity test to mice, marbofloxacin is given mice continuous irrigation stomach 30 days by every kg body weight 177.6mg, 88.8mg, 17.8 mg (be equivalent to the maximum using dosage of clinical recommendation 32,16,3 times), and experimental result shows that marbofloxacin is safe according to the clinical use of recommended dose (2.75 ~ 5.5mg/Kg b.w.).
2.7 mutagenesis
2.7.1 reports such as loyalty are built in Shen
[1]Marbofloxacin has been carried out mutagenicity research, and result of the test shows that marbofloxacin does not have mutagenic action to Salmonella typhimurium.
2.7.2 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out Salmonella reversion test, carries out analytical test by Nanjing Medical University health analyzing and testing center, result of the test shows that marbofloxacin does not have mutagenic action to Salmonella typhimurium.
2.7.3 reports such as loyalty are built in Shen
[1]Marbofloxacin has been carried out mutagenicity research, and result of the test shows, marbofloxacin does not cause that mouse bone marrow cells MNPCE leads and increases.
2.7.4 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out micronucleus test, marbofloxacin is negative to mouse bone marrow cells micronucleus test result, shows that it does not have a mutagenic action to somatic cell.
2.8 genotoxicity
Shen Jianzhong " mutagenicity of Marbofloxacin and teratogenecity research ", according to the result can think 20,100 and 500mg/kg b.w. dosage marbofloxacin the reproduction function of conceived rat and the growth promoter of tire Mus are not all had obvious influence, do not cause tire Mus outward appearance, internal organs and skeleton deformity, can think that marbofloxacin does not have tangible teratogenecity.
Our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out sperm malformation test, and result of the test shows that the former powder of marbofloxacin does not have the toxicity that causes mouse sperm deformity.
2.9 chronic toxicity
2.9.1 the prosperous grade of Li Ji " enrofloxacin is to acute toxicity and the cumulative toxicity research of young machine chicken ", similar medicine enrofloxacin is carried out the fixed dosage method of contaminating continuously, 4 result of the tests show that cumulative coefficient is 5.8, and according to the evaluation criterion of cumulative action as can be known, it belongs to slightly accumulates.
2.9.2 according to European drug evaluation mechanism (EMEA) to concluding that other fluoroquinolones are not carcinogenic, so groundless is suspected marbofloxacin in the veterinary drug marbofloxacin final report content.
2.10 part or whole body specific safety testing data
Our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " the subcutaneous irritation test of marbofloxacin lyophilized powder "
This test is carried out subcutaneous injection after the marbofloxacin lyophilized powder is diluted, from subcutaneous zests of aspect overall merit medicine such as outward appearance observation, gross anatomy and histopathological examinations.The result shows, does not cause the abnormal response of the visible medicine-feeding part of outward appearance and the change of animal behavior during the subcutaneous injection marbofloxacin, simultaneously by dissecting and histological examination shows that medicine-feeding part compares zero difference with contrast.In conjunction with the different aspect check result, nonirritant when judging marbofloxacin lyophilized powder subcutaneous injection, safety is good, the clinical subcutaneous injection that can be used for.
3, to the summary of clinical research
3.1 Wang Zhiqiang etc. " animal specific fluoroquinolone antibacterial agent---marbofloxacin "
Marbofloxacin has been used for the treatment of various skins, urethra, digestive tract, respiratory tract infection and the postoperative infection of dog, cat at present, studies show that of Drugein etc. (1997), marbofloxacin is better than enrofloxacin with the Staphylococcus intermedius of 2mg/kg treatment dog and the curative effect of charrin's disease, and the pyoderma curative effect of the dog pyoderma that is caused by Staphylococcus intermedius and escherichia coli in treatment and the cat that caused by staphylococcus aureus is excellent.For the postoperative infection of dog, cat, marbofloxacin also has the excellent prevention effect, and with the quiet notes of 2～4mg/kg, the drug level in blood plasma and the inflammatory exudate reaches 12～24h more than maintaining the MIC value of some main infectious bacterias (enterobacteria and staphylococcus).
3.2 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " marbofloxacin is to the therapeutic effect of dog vaginitis/acrobystitis---phase ii clinical trial report "
In the data variation before and after " treatment ", we mainly consider to judge " curative effect " of each group with regard to the variation of WBC, PC and bacterial number etc. in routine blood test, serum biochemistry, vagina or the preputial pouch endocrine.
The clinical symptoms aspect, first group occur the mild symptoms micromodification kind 1 example arranged, according to the standard of curing in the test plan, belong to and fail to respond to any medical treatment.Cure 6 examples for second group, 4 examples are effectively cured 10 examples for the 3rd group, cure 10 examples for the 4th group, cure 9 examples for the 5th group, and 1 example effectively.
3.3 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " marbofloxacin is to dog vaginitis/acrobystitis therapeutic effect experiment--clinical examination laboratory reports of three phases (austral region) "
From result of the test, the cure rate of marbofloxacin is 100%, and the cure rate of enrofloxacin is 100%.Aspect toxic and side effects, this test is except having selected the blood routine index, considered liver function, renal function, muscle, skeleton and the glycometabolic influence of injection marbofloxacin to dog emphatically, the result proves that injection marbofloxacin and control drug enrofloxacin injection all do not produce toxic and side effects.
3.4 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " marbofloxacin is to dog vaginitis/acrobystitis therapeutic effect experiment--clinical examination laboratory report of three phases (north district) "
In the experiment of three phases, because the animal subject quantity of each experimental group has reached 40, so reliability will be higher than the second phase experiment far away.This experiment has further confirmed to be subjected to reagent thing marbofloxacin 2mg/kg subcutaneous injection to treatment effect and the clinical safety of dog vaginitis or acrobystitis.
3.5 the clinical trial of injection marbofloxacin is summed up
By pre-stage test, this project marbofloxacin recommended dose is 2mg/kg, and subcutaneous injection once-a-day, is used in conjunction three.
Phase ii clinical trial is the result show, the injection marbofloxacin should be 2mg/kg to the recommended dose of dog vaginitis/acrobystitis diagnosis and treatment, adopts subcutaneous injection, 1 time on the 1st, is used in conjunction 3.Its therapeutic effect is certain, does not have tangible untoward reaction, and animal livers, kidney, muscle and skeletal function are not caused unusually, and safety is higher.
The phase iii clinical trial result who carries out according to phase ii clinical trial dosage and test method shows that the injection marbofloxacin has tangible curative effect to China south, backlands district dog vaginitis/acrobystitis, and cure rate can reach 100%; Research finds that also the injection marbofloxacin does not cause tangible harmful effect to histoorgans such as the liver of natural cases dog, kidney, skeleton, muscle.
Conclusion:
(1) the injection marbofloxacin has significant curative effect to dog vaginitis/acrobystitis, and its using method is 2mg/kg.BW subcutaneous injection or intramuscular injection, once-a-day, is used in conjunction three.
(2) the above Therapeutic Method that adopts the injection marbofloxacin can not cause harmful effect to histoorgans such as the liver of natural cases dog, kidney, skeleton, muscle, and clinical trial is safe and reliable.
3.5 target animals safety testing data
3.5.1 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " the injection marbofloxacin is to the safety research of dog ", this test is pressed high, medium and low three dosage (22mg/kgbw, 11mg/kgbw, 5.5mg/kgbw) to the target animals intramuscular injection, be used in conjunction 7 days, every day 1 time.The result shows, except high dose group is occurring after the injection the of short duration pain reaction, clinically do not observe other any untoward reaction.And injection marbofloxacin blood physiology index, serum biochemistry index to dog in the scope of 5.5mg/kgbw～22mg/kgbw all do not have obvious influence, do not show toxic reaction.
3.5.2 our company entrusts animal medicine institute of Agricultural University Of Nanjing to carry out " the target animals tolerance test of injection marbofloxacin ", very big owing to dosage in this test, the sialorrhea that causes animal, appetite descends obviously, feces reduces and does black, other abnormal symptoms do not occur, the appetite and the spirit that stop the back experimental dog in administration are all recovered rapidly.By this test, can think that the injection marbofloxacin is safer to dog, have no adverse reaction by clinical recommended dose administration, the symptom of sialorrhea, loss of appetite only appears under 10 times of maximum recommended dosage, can recover after the drug withdrawal.
4, residual testing data
Because this product and preparation are applied to house pet, so require to exempt to report this part information according to declaration material.
5, eco-toxicity data
5.1 the king adds dragon, Liu Jianzhen etc. about " enrofloxacin residual is to the influence of soil microorganism function " test, this test finds that enrofloxacin is extremely remarkable to the soil nitrification influence.When enrofloxacin concentration reaches 1 μ g/ml, soil nitrification there is certain inhibitory action in 3-9 days.When enrofloxacin concentration reaches 10g/ml, the strong inhibition soil nitrification, when this off-test, its inhibitory action is not seen and is weakened, and may be that nitrobacteria is very sensitive to enrofloxacin, just is suppressed when relatively low concentration; Soil nitrification is the same with Ammonification, all is the important step of nitrogen cycle in the biosphere, so enrofloxacin residual then can destroy the nitrogen cycle of soil if keeping higher level for a long time in the soil.
5.2 adding dragon, Liu Jianzhen etc., the king reports about " enrofloxacin residual is to the influence of soil microorganism quantity and community function diversity ", the enrofloxacin residual of relatively low concentration is not obvious to the influence of soil microbial community multiformity, and the enrofloxacin residual of higher concentration has then reduced its microbiologic population's multiformity relatively.Drug level is more high, and the soil microorganism multiformity is just more low.
Claims (4)
1. an injection marbofloxacin lyophilized powder is characterized in that, is grouped into by following one-tenth:
Marbofloxacin: 250g;
Lactic acid: addition is 4.5～5.2 for the pH that adjusts preparation;
Needle-use activated carbon: 4.8g;
Water for injection adds to: 5000ml.
2. a kind of injection marbofloxacin lyophilized powder according to claim 1 is characterized in that, the addition of lactic acid is 4.8～4.9 for the pH that adjusts preparation.
3. the preparation technology of the described injection marbofloxacin of claim 1 lyophilized powder is characterized in that, comprises following technical step:
(1) producing of water for injection:
(a) will make purified water after the drinking water process reverse osmosis ion exchange;
(b) purified water gets final product to such an extent that make water for injection after distillation;
(2) sterilization of plug:
Before wash bottle, carry out the plug sterilization earlier; After plug removed outer package, import into and send into sterilization tank between fine purifiation, 125 ℃ of dry sterilizations 3 hours are chilled to 40 ℃, and it is standby to take out cooling under hundred grades of laminar flows protections of bottling department;
Plug after the sterilization should use immediately or clean and deposit; Storage must not surpass 12 hours, as surpassing, then must sterilize again; Sterilization finishes, and plug and next procedure that sterilization is good join;
(3) decontamination procedure of cillin bottle:
Cillin bottle is removed reason bottle after the outer package, import between fine purifiation, place and send on bottle machine, at first with purified water bottle is carried out ultrasonic waves for cleaning slightly washing the district, the inside and outside Fouling Cleaning of bottle is clean with being attached to; When bottle ran to the fine purifiation district, to use through the aperture be the water for injection that filters of 0.22 μ m filter membrane carried out continuously every flushing the bottle inside and outside wall, and using at last through the aperture is that the compressed air that 0.22 μ m filter membrane filters blows off the globule inside and outside the bottle;
Cillin bottle after the cleaning is sent into sterilization tank, 200 ℃ of dry sterilizations 2 hours, and sterilization finishes, and is chilled to 40 ℃, and it is standby to take out cooling under hundred grades of laminar flows protections of bottling department;
Cillin bottle after the sterilization should use immediately or clean and deposit.Storage must not surpass 12 hours, as surpassing, then must return and relaunder sterilization between wash bottle;
(4) preparation of marbofloxacin lyophilized powder:
(a) weighing;
(b) dense joining: getting 70% water for injection, add marbofloxacin, active carbon, stirred 20 minutes, is 0.45 μ m membrane filtration with the aperture; Squeeze into rare filling of joining through pipeline;
(c) rare joining: regulate pH value to 4.5～5.2 with lactic acid, water for injection adds to full dose, is 0.22 μ m membrane filtration with the aperture, fills in and asks verification certificate, does content, pH value, clarity, color, related substance inspection, after the passed examination, and the notice embedding; The medicinal liquid preparation should be finished in 4 hours; Preparation finishes, and medicinal liquid and the next procedure for preparing joined;
(d) with the fill of filling liquid stopper-adding machine, regulate and send a bottle rotary speed, adjust shake plug unit frequency, connect fill head, filling tube, begin fill, half tamponade after getting rid of the latex inner air tube earlier, loading amount is the 2.0ml/ bottle, and content uniformity is controlled ± 10%, check a loading amount every 30 minutes, choose defective work;
Fill should be finished in 6 hours; Fill finishes, and cillin bottle and next procedure that fill is good join;
(e) lyophilizing gland:
Use the vacuum freeze drier lyophilization, open refrigeration machine, will freeze the product temperature and be down to-45 ℃, constant temperature 2 hours reaches-50 ℃ with the temperature of condenser, opens vacuum earlier, when vacuum reached 20Pa, beginning subliming by heating drying made and freezes the product temperature and rise to-30 ℃, constant temperature 10 hours continues to heat to 0 ℃ constant temperature 8 hours to freezing product, reheat to 45 ℃ later constant temperature 2 hours, import filtrated air after the EP (end of program), gland, outlet;
The lyophilizing gland finishes, and cillin bottle and next procedure that the lyophilizing gland is good join;
(f) aluminium lid sterilization: with the sterilization of ozone sterilization cabinet, send into sterilization tank after aluminium lid removed outer package, through ozone concentration 〉=120ppm, sterilization in 1 hour stops the back and waits for 10-15 minute, takes out in 100,000 grades of districts for rolling the lid use; Sterilization finishes, and aluminium lid and next procedure that sterilization is good join;
(g) roll lid: roll lid with the centrifugal Cover-rolling machine of three cuttves, qualified semi-finished product of packing are sealed with aluminium lid; At any time observe to prick and cover situation, choose defective work; Roll lid and finish, will roll cillin bottle and the next procedure of building and join;
(h) lamp inspection: will roll the cillin bottle that covered lamp inspection one by one, and choose the product that detects poor qualities such as rolling lid is disorderly hindered, distortion, a spray bottle tomography, atrophy; Lamp inspection finishes, and cillin bottle and next procedure that lamp inspection is qualified join;
(i) outer package: vanning: at first piece together case, adorn this batch product then; The preceding front-back at big case of vanning respectively labels printed product batch number, date of manufacture and an expiry date; Check errorless after, put into work certificate, with adhesive tape the case mouth is sealed; Seal the gap and be not more than 5mm;
(j) warehouse-in: the depositary management personnel handle the formality of finished product warehouse-in according to finished product acceptance test report.
4. the described injection marbofloxacin of claim 1 lyophilized powder is for the preparation of the application on the medicine of respiratory tract, digestive tract, urinary tract and the skin infection disease of the dog for the treatment of due to the sensitive organism, cat.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104071363A (en) * | 2014-07-04 | 2014-10-01 | 海南通用康力制药有限公司 | Arginine aspirin powder injection split filling process and automatic split filing system thereof |
| CN104706621A (en) * | 2015-03-19 | 2015-06-17 | 国邦医药化工集团有限公司 | Marbofloxacin micro-capsule and preparation method thereof |
| CN105147697A (en) * | 2015-10-28 | 2015-12-16 | 保定冀中药业有限公司 | Preparation method of marbofloxacin water solution |
| CN106138099A (en) * | 2016-07-12 | 2016-11-23 | 浙江华尔成生物药业股份有限公司 | Pharmaceutical composition, pharmaceutical preparation and preparation method thereof, purposes |
| CN106580887A (en) * | 2017-01-02 | 2017-04-26 | 江苏恒丰强生物技术有限公司 | Marbofloxacin soluble pulvis |
| CN107445977A (en) * | 2017-07-13 | 2017-12-08 | 江西傲新生物科技有限公司 | A kind of water-soluble Marbofloxacin and preparation method and application |
| CN107648192A (en) * | 2017-10-25 | 2018-02-02 | 佛山科学技术学院 | A kind of Marbofloxacin flavor piece and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101394936A (en) * | 2006-03-08 | 2009-03-25 | 富士胶片株式会社 | Coating apparatus |
| CN101405032A (en) * | 2006-01-24 | 2009-04-08 | 菲特其诺公司 | Anti-infective solution comprising a compound of pyrido(3,2,1-ij)-benzoxadiazine type |
-
2013
- 2013-07-01 CN CN2013101768269A patent/CN103271875A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101405032A (en) * | 2006-01-24 | 2009-04-08 | 菲特其诺公司 | Anti-infective solution comprising a compound of pyrido(3,2,1-ij)-benzoxadiazine type |
| CN101394936A (en) * | 2006-03-08 | 2009-03-25 | 富士胶片株式会社 | Coating apparatus |
Non-Patent Citations (2)
| Title |
|---|
| 崔福德: "《药剂学》", 29 February 2004, 人民卫生出版社 * |
| 张玲玲等: "国产麻保沙星的毒性及体外抗菌活性研究", 《西北农林科技大学学报(自然科学版)》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN104706621A (en) * | 2015-03-19 | 2015-06-17 | 国邦医药化工集团有限公司 | Marbofloxacin micro-capsule and preparation method thereof |
| CN104706621B (en) * | 2015-03-19 | 2017-08-15 | 国邦医药化工集团有限公司 | A kind of marbofloxacin micro-capsule and preparation method thereof |
| CN105147697A (en) * | 2015-10-28 | 2015-12-16 | 保定冀中药业有限公司 | Preparation method of marbofloxacin water solution |
| CN105147697B (en) * | 2015-10-28 | 2017-12-05 | 保定冀中药业有限公司 | A kind of preparation method of the Marbofloxacin aqueous solution |
| CN106138099A (en) * | 2016-07-12 | 2016-11-23 | 浙江华尔成生物药业股份有限公司 | Pharmaceutical composition, pharmaceutical preparation and preparation method thereof, purposes |
| CN106580887A (en) * | 2017-01-02 | 2017-04-26 | 江苏恒丰强生物技术有限公司 | Marbofloxacin soluble pulvis |
| CN107445977A (en) * | 2017-07-13 | 2017-12-08 | 江西傲新生物科技有限公司 | A kind of water-soluble Marbofloxacin and preparation method and application |
| CN107445977B (en) * | 2017-07-13 | 2019-08-09 | 江西傲新生物科技有限公司 | A kind of water solubility Marbofloxacin and the preparation method and application thereof |
| CN107648192A (en) * | 2017-10-25 | 2018-02-02 | 佛山科学技术学院 | A kind of Marbofloxacin flavor piece and preparation method thereof |
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