CN103816544A - Composition containing enrofloxacin hexahydrate and application of same in preparation of drugs used for treating or preventing diseases of domestic animals - Google Patents
Composition containing enrofloxacin hexahydrate and application of same in preparation of drugs used for treating or preventing diseases of domestic animals Download PDFInfo
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Abstract
The invention relates to a composition containing enrofloxacin hexahydrate and application of the same in preparation of drugs used for treating or preventing bacterial diseases and mycoplasma infection diseases of domestic animals. The composition provided by the invention has the characteristics of high plasma concentration and peak concentration in domestic animals, high bioavailability and superiority in the aspects of pharmacokinetics and clinical effects compared with enrofloxacin composition drugs, can be used to replace enrofloxacin and a composition thereof, is applied to preparation of clinical drugs widely used by veterinarians and has wide market prospects and values.
Description
Technical field
The present invention relates to a kind of containing the hexahydrated compositions of enrofloxacin and preparation treatment prevention domestic animal is bacillary or the medicine of mycoplasma infection disease in application, belong to field of veterinary.
Background technology
Quinolone antibiotic is to apply clinically one of maximum class antibacterials modern age, and quinolone antibiotic is existing semicentennial application and development so far, and many quinolone antibiotics with new feature constantly come out, and are widely used by clinical.Enrofloxacin (ENR) is the special fluorine of first domestic animal caye promise ketone medicine, and first succeeded in developing the eighties by Bayer A.G, and China succeeded in developing in 1993 years.Enrofloxacin is broad spectrum antibiotic, has that has a broad antifungal spectrum, bactericidal activity are strong, widely distributed in body, without features such as cross resistances, is now widely used in veterinary clinic with other antimicrobial drugs.
Enrofloxacin hexahydrate is the novel crystal forms of enrofloxacin, and its has a broad antifungal spectrum, bactericidal activity are strong.The existing research about the hexahydrated Preparation and identification method of enrofloxacin at present, but shortage enrofloxacin hexahydrate and compositions thereof are used for the treatment of or prevent the research of medicine stability, drug metabolism, biochemical test and the challenge test of the disease of domestic animals.Especially for common domestic animal bacterial disease and mycoplasma infection diseases, as: mycoplasma pneumonia, Bacillus pasteurii disease, colibacillosis, salmonellosis, streptococcicosis, actinomycetes property pleuropneumonia, mastitis, colibacillosis, Bacillus pasteurii disease and mastitis etc., the suffer for want of medical supplies research of stability, drug metabolism, biochemical test and challenge test, cannot conclude whether enrofloxacin hexahydrate can substitute at present at the enrofloxacin of veterinary clinic extensive use and the medicine of compositions thereof.
Summary of the invention
In view of this, it is a kind of containing the hexahydrated compositions of enrofloxacin that main purpose of the present invention is to provide, and described compositions comprises effective dose:
A: enrofloxacin hexahydrate;
B: pharmaceutically acceptable carrier.
Preferably, compositions of the present invention comprises:
A) in the enrofloxacin hexahydrate of enrofloxacin 2% to 15%W/V;
B) 0.4% to 3%W/V cosolvent;
C) 3% to 7%W/V antiseptic;
D) pharmaceutically acceptable carrier.
Preferably, compositions of the present invention comprises:
A) in the enrofloxacin hexahydrate of enrofloxacin 5%W/V;
B) potassium hydroxide of 1%W/V;
C) n-butyl alcohol of 3%W/V;
D) water is to full dose.
Preferably, compositions of the present invention comprises:
A) in the enrofloxacin hexahydrate of enrofloxacin 10%W/V;
B) potassium hydroxide of 2%W/V;
C) n-butyl alcohol of 3%W/V;
D) water is to full dose.
Preferably, cosolvent of the present invention is the mixture of any one or any two in potassium hydroxide, sodium hydroxide, arginine, potassium carbonate, sodium carbonate and ethanolamine.
Preferably, antiseptic of the present invention is the mixture of any one or any two in n-butyl alcohol, benzyl alcohol and phenylpropanol.
Preferably, carrier of the present invention is selected from water for injection or 15%-25%W/V aqueous solution of propylene glycol.
Another aspect of the present invention is to provide a kind of purposes of the hexahydrated compositions of enrofloxacin in the medicine of preparation treatment or prevention domestic animal bacterial disease and mycoplasma infection diseases that contain.
Preferably, domestic animal bacterial disease of the present invention and mycoplasma infection diseases comprise: mycoplasma pneumonia, Bacillus pasteurii disease, colibacillosis, salmonellosis, streptococcicosis, actinomycetes property pleuropneumonia, mastitis, colibacillosis, Bacillus pasteurii disease and mastitis.
Preferably, domestic animal of the present invention comprises pig and cattle.
Preferably, drug dose of the present invention is every kg body weight 1-20mg; More preferably, every kg body weight 1-10mg; Most preferably, every kg body weight 2.5-5mg; Be used in conjunction 2-3 days.
Technique effect
The invention provides a kind ofly containing the hexahydrated compositions of enrofloxacin, the mixture that wherein contains in potassium hydroxide, sodium hydroxide, arginine, potassium carbonate, sodium carbonate and ethanolamine any one or any two forms cosolvent.The cosolvent that the present invention uses not only can help to be dissolved into fast in medicine acceptable carrier containing enrofloxacin hexahydrate compositions, and absorb and utilize in can promoting to be in carcass containing enrofloxacin hexahydrate, drug metabolism and effect of drugs are all significantly better than the compositions of independent use enrofloxacin hexahydrate and conventional carrier thereof.
Secondly, provided by the invention containing enrofloxacin hexahydrate compositions, compared with enrofloxacin composition medicine, there is the interior blood drug level peak concentration of the carcass of being in high, bioavailability is high, pharmacokinetics and and clinical effectiveness aspect good feature, can substitute enrofloxacin and compositions thereof, be applied to preparation widely used medicine on veterinary clinic, there is wide market prospect and value.
Accompanying drawing explanation
Fig. 1 is enrofloxacin hexahydrate infrared spectrogram;
Fig. 2 is enrofloxacin hexahydrate X ray picture;
Fig. 3 is enrofloxacin raw material infrared spectrogram;
Fig. 4 is enrofloxacin raw material X ray picture;
Fig. 5 is for containing 5%W/V enrofloxacin hexahydrate composite injection curve when medicine in pig body;
Fig. 6 is containing 5%W/V enrofloxacin hexahydrate composite injection curve when medicine in cattle body.
The specific embodiment
In the embodiment of the present invention, by medicine stability test, prove containing enrofloxacin hexahydrate composition stable reliable; Learn test by the drug metabolism in pig and cattle body and medicine effect, prove to there is bioavailability containing enrofloxacin hexahydrate compositions high, serum drug level peak concentration is higher, the drug metabolism feature that the effect of drug absorption, distribution is better and absorb faster, and the pharmacodynamics feature of kill bacteria more effectively.
The bowel oedema disease therapeutic effect test that the swine enzootic pneumonia causing by mycoplasma hyopneumoniae infection and swine escherichia coli cause and the test of bovine pasteurellosis therapeutic effect, prove containing enrofloxacin hexahydrate composite injection compared with enrofloxacin injection, there is good effect by intramuscular injection for treating swine enzootic pneumonia and bowel oedema disease and sick infection of cattle Pasteur bar, can significantly improve effective percentage, cure rate, and not affect weightening finish.
Cosolvent described in the embodiment of the present invention is selected from potassium hydroxide, being selected from sodium hydroxide, arginine, potassium carbonate, sodium carbonate and ethanolamine the mixture of any one or any two with cosolvent, is same or analogous on, drug metabolism stable at medicine and effect of drugs.Preferably, the present invention selects 0.4% to 3%W/V cosolvent for the preparation containing enrofloxacin hexahydrate compositions.The cosolvent that the present invention uses is alkaline auxiliary solvent, not only can help to be dissolved into fast in medicine acceptable carrier containing enrofloxacin hexahydrate compositions, and absorb and utilize in can promoting to be in carcass containing enrofloxacin hexahydrate, drug metabolism and effect of drugs are significantly better than the medicine that uses enrofloxacin compositions, can effectively treat or prevent common domestic animal bacterial disease and mycoplasma infection diseases, can be applicable to the medicine of preparation treatment or prevention domestic animal bacterial disease and mycoplasma infection diseases.
Antiseptic described in the embodiment of the present invention is selected from n-butyl alcohol, is selected from n-butyl alcohol, benzyl alcohol and phenylpropanol the mixture of any one or any two with antiseptic, on, drug metabolism stable at medicine and effect of drugs, is same or analogous.Preferably, it is 3%-7%W/V that the present invention selects antiseptic content, for the preparation containing enrofloxacin hexahydrate compositions, can be applicable to treatment or prevention domestic animal bacterial disease and mycoplasma infection diseases.
Pharmaceutically acceptable carrier described in the embodiment of the present invention is selected from water for injection, aqueous solution of propylene glycol, and is selected from acceptable carrier on other drug, on, drug metabolism stable at medicine and effect of drugs, is same or analogous.Preferably, the pharmaceutically acceptable carrier of the present invention is selected from water or 15%-25%V/V aqueous solution of propylene glycol for the preparation containing enrofloxacin hexahydrate compositions, can be applicable to treatment or prevention domestic animal bacterial disease and mycoplasma infection diseases.
Compositions of the present invention can adopt dosage form conventional in veterinary, as peroral dosage form, injection dosage form, preferably uses injection Types of Medicine in the present embodiment.This implements described injection drug preparation method, can also adopt other conventional needle agent compounding method preparations of this area in the embodiment of the present invention.
In the embodiment of the present invention experimental examination learn feature and index containing the drug metabolism of enrofloxacin hexahydrate compositions in pig and cattle body and medicine effect, with containing enrofloxacin hexahydrate compositions other domestic animal as the drug metabolism in the bodies such as sheep, rabbit, donkey, horse, camel with medicine effect is learned feature and index is same or analogous; Because other domestic animals belong to warm-blooded mammals with pig and cattle as sheep, rabbit, donkey, horse, camel etc., and be all sterilization widely, the bacteriostasis based on containing enrofloxacin hexahydrate compositions containing the principle of drug action of enrofloxacin hexahydrate compositions.And based on containing the effect of bactericidal widely of enrofloxacin hexahydrate compositions, for common domestic animal bacterial disease and mycoplasma infection diseases, as: mycoplasma pneumonia, Bacillus pasteurii disease, colibacillosis, salmonellosis, streptococcicosis, actinomycetes property pleuropneumonia, mastitis, colibacillosis, Bacillus pasteurii disease and mastitis etc., also there is good effect, compared with enrofloxacin injection, can significantly improve effective percentage, cure rate, and not affect weightening finish.
In the embodiment of the present invention, tested and prepared drug dose, preferred every kg body weight 1-20mg, is used in conjunction 2-3 days; More preferably every kg body weight 1-10mg, is used in conjunction 2-3 days; Most preferably every kg body weight 2.5-5mg, is used in conjunction 2-3 days.Only use as statement with every kg body weight 2.5mg in embodiments of the present invention, other its effects of NM drug dose are similar to the consumption effect adopting in example of the present invention.
This area conventional means is the content with effective ingredient content statement effective ingredient different crystal forms, for avoiding misunderstanding, that in the embodiment of the present invention, prepares contains in the medicine of enrofloxacin hydrate compositions, and the content of enrofloxacin hydrate calculates with enrofloxacin.
For making the present invention easier to understand, below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described, in the following example, NM specific experiment method, carries out according to normal experiment method conventionally.
1. the hexahydrated preparation of enrofloxacin
The isopropanol/water 8L that gets volume ratio 1:1 is added in 10L reaction bulb, add enrofloxacin (Zhejiang Province Guobang Pharmaceutical Co., Ltd, lot number: 091122-6) 400g, stirring at room temperature suspendible one week, filter filter cake cold water washing 2 times, each 4L, filter cake is placed under room temperature and naturally dries, and obtains enrofloxacin hexahydrate.
The hexahydrated Structural Identification of enrofloxacin: adopt infrared spectrometry and X-ray diffraction method to identify, infrared spectrum and X ray diffracting spectrum are shown in that respectively (vertical coordinate represents absorption intensity to Fig. 1, abscissa represents wave number), Fig. 2 (vertical coordinate represents intensity, and abscissa represents 2 θ); Enrofloxacin raw material infrared spectrum and X ray diffracting spectrum are shown in respectively Fig. 3 (vertical coordinate represents absorption intensity, and abscissa represents wave number), Fig. 4 (vertical coordinate represents intensity, and abscissa represents 2 θ).Enrofloxacin raw material and enrofloxacin hexahydrate X ray data are in table 1, table 2.
Table 1 enrofloxacin raw material X ray tables of data 2 enrofloxacin hexahydrate X ray data
2. contain the preparation of 5%W/V enrofloxacin hexahydrate compositions and medicine thereof
1) containing the preparation of 5%W/V enrofloxacin hexahydrate compositions
Enrofloxacin hexahydrate: 5%W/V
Cosolvent: KOH3%W/V
Antiseptic: n-butyl alcohol 3%W/V
Carrier: water for injection to full dose is 1000ml
Preparation process:
1) preparation of KOH solution: take KOH10g, add water for injection 50ml, be settled to 100ml after stirring and dissolving;
2) get water for injection 600ml and mix homogeneously with n-butyl alcohol 30g, when mixing, control 20 ℃-30 ℃ of temperature;
3) add enrofloxacin hexahydrate 67.6g to be uniformly mixed;
4) slowly add above-mentioned KOH solution, mix homogeneously;
5) water for injection is settled to 1000ml, mixes, and 0.45um filter membrane static pressure filters and obtains containing 5%W/V enrofloxacin hexahydrate compositions.
2) containing the preparation of the injection drug of 5%W/V enrofloxacin hexahydrate compositions
To after filtration after degerming, under lucifuge condition, fill nitrogen fill in injection bottle, lucifuge preservation containing 5%W/V enrofloxacin hexahydrate compositions.
3. contain the stability test of 5%W/V enrofloxacin hexahydrate compositions
1) high light impact test
Test apparatus: the light cupboard that illumination is 4500Lx ± 500Lx, avoid the impact of natural light.
Process of the test: will, containing 5%W/V enrofloxacin hexahydrate, be to place 10 days under 4500Lx ± 500Lx condition in illumination, and in sampling in the 5th, 10 days, investigate character, content, pH value, with the testing result contrast of original state, result of the test be as following table:
Table 3 highlight test result
| |
1 |
5 |
10 days |
| Character | Yellow clear liquid | Yellow clear liquid | Brown color clear liquid |
| Content | 99.7% | 98.8% | 98.3% |
| PH value | 10.0 | 10.0 | 10.1 |
Conclusion: the character of sample is without significant change, and pH value is without significant change, and content slightly declines, illustrates that test sample is more stable.
2) accelerated test
Test apparatus: SPX-250IC growth cabinet.Process of the test: will place 6 months under 40 ± 2 ℃ of conditions containing 5%W/V enrofloxacin hexahydrate,, test initial in test carries out the the 1st, 2,3, sampling in June, investigate character, pH value, content related item, the testing result contrast when initial with test, result of the test table 4:
Table 4 accelerated test result
Conclusion: contain the character of 5%W/V enrofloxacin hexahydrate sample without significant change, pH value is without significant change, and content slightly declines, and illustrates that test sample is more stable.
4. containing 5%W/V enrofloxacin hexahydrate composite injection and containing the pharmacokinetics comparison of 5%W/V enrofloxacin injection in pig body
12 Landraces (planting name), be divided at random two groups, with 2.5mg/kg body weight administered intramuscular, fasting 16h before test, 0.083h, 0.16h after first group of administration, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h vena cava anterior blood sampling 5mL, second group of 0.083h, 0.16h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h vena cava anterior blood sampling 5mL, the blood sample of collection is all used heparin sodium anticoagulant, centrifuging and taking blood plasma ,-20 ℃ of preservations.
Drug plasma extracting method: 500 μ L blood plasma add 25 μ L phosphoric acid and 100 μ L perchloric acid, 3000rpm vortex 5min, the centrifugal 10min of 15000rpm, draws supernatant, and 0.22 μ m filters sample introduction.
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica be filler,
ultra Performance Liquid Chromatography, BEH C18 chromatographic column (1.7 μ m2.1 × 50mm).Take acetonitrile-phosphoric acid solution (by triethylamine adjust pH to 3.0 for the phosphoric acid of 0.025mol/L) as mobile phase, detection wavelength is 278nm, 0～10min acetonitrile-phosphoric acid solution ratio 7:93,10～15min ratio 13:87,15～17min ratio 7:93, number of theoretical plate is higher than 1500,35 ℃ of column temperatures, flow velocity 0.2mL/min, 5 ℃ of specimen discs, sample size 10 μ L.Curve when medicine (the time dependent curve of blood drug level) as shown in Figure 5.Containing the pharmacokinetic parameter in enrofloxacin hexahydrate composite injection and the pharmacokinetics process of enrofloxacin injection in pig body in table 5.
Pharmacokinetic parameter result of calculation after table 5 pig muscle injection
Note: AUC: area under the drug-time curve, T
(1/2) Ka: absorption halftime, T
(1/2) Ke: eliminate the half-life, T
max: peak time, C
max: plasma drug level peak concentration.
Shown in Fig. 5, two kinds of injecting fluid internal procedures all meet absorption one-compartment model, but the drug metabolism of two kinds of injection is different with pharmacodynamic index, and absorption, distribution and the bactericidal effect in pig body is obviously different.
First, the AUC of enrofloxacin injection is 45.1% with the ratio of the AUC containing enrofloxacin hexahydrate composite injection, illustrates that the bioavailability of enrofloxacin injection is only for containing 45.1% of enrofloxacin hexahydrate composite injection; Containing enrofloxacin hexahydrate composite injection plasma drug level peak concentration (C
max) than the plasma drug level peak concentration (C of enrofloxacin injection medicine
max) ratio be 1.27, illustrate containing enrofloxacin hexahydrate composite injection in pig body, plasma drug level peak concentration is enrofloxacin injection 1.27 times.。
Secondly, the curative effect of antibacterials depends on that can medicine reach in vivo valid density and remove the pathogen in focus of infection.The medicine of doses reaches and suppresses or the concentration of kill bacteria growth in blood, body fluid and tissue, and maintains related a series of physiological dispositions of regular hour and be pharmacokinetics (pharmacokinetics, PK) process.Because the body-fluid concentration of organizing of antibacterials is usually less than blood drug level, be only 1/10～1/2 of blood drug level, therefore, for guaranteeing that infection site drug level reaches effectively antibacterial or bacteriocidal concentration, plasma drug level should at least reach 8～12 times of MIC value.Enrofloxacin and enrofloxacin hexahydrate are to gram negative bacteria pasteurella multocida and colibacillary MIC
90(suppressing the required minimal inhibitory concentration MIC of 90% tested bacterium) is 0.03 μ g/mL.Known by table 4 result, containing the C of enrofloxacin hexahydrate composite injection and enrofloxacin injection
max/ MIC
90be respectively 23.9 ± 5.9 and 18.8 ± 9.7, illustrating will be higher than enrofloxacin injection, containing the drug absorption of enrofloxacin hexahydrate compositions in pig body, the better effects if of distribution containing pharmacokinetic parameter (PK) index of enrofloxacin hexahydrate composite injection.
Finally, quinolones is concentration dependent form medicine, its drug effect (pharmacodynami-cs, PD) parameter is: the ratio of area (AUC) and minimal inhibitory concentration (MIC) under 24h drug level time graph, not only rapid-action while being AUC/MIC>125～250h, and kill bacteria and suppress Resistant strain and produce effectively, clinical effective rate is greater than 90% containing the AUC/MIC of enrofloxacin hexahydrate composite injection and enrofloxacin injection
90value is respectively 2257.3 ± 45.8h and 116.1 ± 42.8h.Illustrate in pig body, to be absorbed sooner than enrofloxacin injection medicine containing enrofloxacin hexahydrate composite injection, and kill bacteria more effectively, is better than the pharmacodynamic index of enrofloxacin containing the pharmacodynamic index of enrofloxacin hexahydrate compositions.
Therefore, contain 5%W/V enrofloxacin hexahydrate composite injection compared with enrofloxacin injection, it is high that Pharmacokinetic Characteristics in pig body has bioavailability, plasma drug level peak concentration is higher, the better feature of effect of drug absorption, distribution, and pharmacodynamic profile have be absorbed faster, and the feature of kill bacteria more effectively.
5, containing 5%W/V enrofloxacin hexahydrate composite injection and the pharmacokinetics comparison of common enrofloxacin injection in cattle body
12 healthy Luxi Yellow cattle, average weight 90kg, the 2-3 month.Be divided at random two groups, feed concentrate feed and Radix Glycyrrhizae mixture, containing any antibiotic.Not water restriction, in process of the test, guaranteeing to test cattle is healthy animal.
Fasting 16h before test, first group of subcutaneous injection 5.0mg/kg injection, second group of subcutaneous injection 5.0mg/kg injection.After first group of administration 0,0.17,0.33,0.50,0.75,1,1.5,2,3,4,6,8,10 and 24h, jugular vein blood sampling 5mL, after second group of medicine 0,0.17,0.33,0.50,0.75,1,1.5,2,3,4,6,8,10 and 24h, jugular vein blood sampling 5mL, the blood sample of collection is all used heparin sodium anticoagulant, centrifuging and taking blood plasma ,-20 ℃ of preservations.(blood sample of collection carries out medicine for identifying in January)
Drug plasma extracting method: 500 μ L blood plasma add 25 μ L phosphoric acid and 100 μ L perchloric acid, 3000rpm vortex 5min, the centrifugal 10min of 15000rpm, draws supernatant, and 0.22 μ m filters sample introduction.
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica be filler,
ultra Performance Liquid Chromatography, BEH C18 chromatographic column (1.7 μ m2.1 × 50mm).Take acetonitrile-phosphoric acid solution (by triethylamine adjust pH to 3.0 for the phosphoric acid of 0.025mol/L) as mobile phase, detection wavelength is 278nm, 0～10min acetonitrile-phosphoric acid solution ratio 7:93,10～15min ratio 13:87,15～17min ratio 7:93, number of theoretical plate is higher than 1500,35 ℃ of column temperatures, flow velocity 0.2mL/min, 5 ℃ of specimen discs, sample size 10 μ L.Result as shown in Figure 6.Pharmacokinetic parameter is in table 6
Pharmacokinetic parameter result of calculation after table 6 Corii Bovis seu Bubali hemostasis
| Parameter | Enrofloxacin hexahydrate injection | Enrofloxacin injection |
| AUC（h·μg/mL） | 6.67±0.800 | 3.69±0.52 |
| T (1/2)Ka（h） | 0.429±0.312 | 0.508±0.082 |
| T (1/2)Ke（h） | 4.158±2.386 | 3.902±2.363 |
| T max（h） | 1.56±0.528 | 1.711±0.453 |
| C max（μg/mL） | 0.874±0.287 | 0.497±0.290 |
Note: AUC: area under the drug-time curve, T
(1/2) Ka: absorption halftime, T
(1/2) Ke: eliminate the half-life, T
max: peak time, C
max: plasma drug level peak concentration.
Shown in Fig. 6, two kinds of injecting fluid internal procedures all meet absorption one-compartment model, but the drug metabolism of two kinds of injection is different with pharmacodynamic index, and absorption, distribution and the bactericidal effect in cattle body is obviously different.
First, the AUC of enrofloxacin injection is 55.3% with the ratio of the AUC containing enrofloxacin hexahydrate composite injection, illustrates that the bioavailability of enrofloxacin injection is only for containing 55.3% of enrofloxacin hexahydrate composite injection; Containing enrofloxacin hexahydrate composite injection plasma drug level peak concentration C
maxplasma drug level peak concentration C with enrofloxacin injection medicine
maxratio be 1.76, illustrate containing enrofloxacin hexahydrate composite injection in cattle body, plasma drug level peak concentration is enrofloxacin injection 1.76 times.
Secondly, pharmacokinetics principle described in step 4, plasma drug level should at least reach 8～12 times of MIC value.Enrofloxacin is to gram negative bacteria pasteurella multocida and colibacillary MIC
90(suppressing the required minimal inhibitory concentration MIC of 90% tested bacterium) is 0.03 μ g/mL.Known by table 5 result, containing the C of enrofloxacin hexahydrate composite injection and enrofloxacin injection
max/ MIC
90be respectively 29.1 ± 9.6 and 16.5 ± 9.7, illustrating will be higher than enrofloxacin injection, containing the drug absorption of enrofloxacin hexahydrate compositions in cattle body, the better effects if of distribution containing pharmacokinetic parameter (PK) index of enrofloxacin hexahydrate composite injection.
Finally, pharmacodynamics described in step 4 (PD) principle, rapid-action when AUC/MIC>125～250h, bactericidal effect is good.AUC/MIC90 value containing enrofloxacin hexahydrate composite injection and enrofloxacin injection is respectively 222.3 ± 26.6h and 123.0 ± 17.3h.Illustrate in cattle body, to be absorbed sooner than enrofloxacin injection medicine containing enrofloxacin hexahydrate composite injection, and kill bacteria more effectively, is better than the pharmacodynamic index of enrofloxacin containing the pharmacodynamic index of enrofloxacin hexahydrate compositions.
Therefore, contain enrofloxacin hexahydrate composite injection compared with enrofloxacin injection, it is high that Pharmacokinetic Characteristics in cattle body has bioavailability, plasma drug level peak concentration is higher, the better feature of effect of drug absorption, distribution, and pharmacodynamic profile have be absorbed faster, and the feature of kill bacteria more effectively.
6, containing 5%W/V enrofloxacin hexahydrate composite injection and the therapeutic effect of enrofloxacin injection to manual-induced swine enzootic pneumonia
Containing enrofloxacin hexahydrate composite injection and enrofloxacin injection, manual-induced mycoplasma pneumoniae of swine is treated, observe the therapeutic effect of two kinds of injection to swine enzootic pneumonia.Experimental animal, 10 week age, 80 of health pig, were provided by country's medicine Engineering Technical Research Centre for animals, for mycoplasma hyopneumoniae infection.Mycoplasma hyopneumoniae S6 strain is purchased from China Veterinery Drug Inspection Office; The self-control of KM2 culture medium.
Respectively the strong virus mycoplasma S6 strain of preserving is inoculated in to KM2 culture medium, goes down to posterity 3 times, measuring change color unit by the method in (" animal Mycoplasma and research method ", Beijing: Chinese agriculture publishing house, 1998) such as Bi Dingren is 10
8cCU/mL.Test pig is divided into 4 groups at random, and 20 every group (every body weight difference is no more than 1.0kg), raises in cages, and all feeds and does not contain the mixed feed of any medicine.Through trial test after 1 week, except normal healthy controls group, other each group is directly injected 2.0mL mycoplasma bacterium liquid by larynx in trachea, after counteracting toxic substances, raises routinely, observe each group of test pig spirit, search for food, drink water, the clinical setting such as breathing, respectively organize disposition in table 6.
After test pig counteracting toxic substances, treat that Symptoms is that spirit is depressed, sagging, a stand a corner or crouch down on ground, frequency of respiration increases severely, and is obvious ventral breathing, cough number of times is few and overcast, sometimes also can there is spastic apasm of coughing etc., to contain enrofloxacin hexahydrate composite injection and enrofloxacin injection with administered intramuscular, 2.5mg/kg body weight, 1 time/d, be used in conjunction 3d.Record symptom, after treatment, observe 1 week pig clinical symptoms change, dead pig is cutd open to inspection and Isolation and culture of agent.
Table 7 is manually sent out the clinical trial grouping of swine enzootic pneumonia disease and is processed
Index of assessment of curative effect is cured: after medication treatment, clinical symptoms disappears completely, and it is normal that spirit and diet recover, and statistics is cured number, calculates cure rate.Effective: after medication treatment, clinical symptoms obviously alleviates, spirit and diet recover to take a turn for the better, and add up effective number, calculate obvious effective rate.Be effectively cure rate and obvious effective rate sum.Invalid: after medication treatment, clinical symptoms does not disappear, the state of an illness do not take a turn for the better and treat during because of primary disease death be all considered as invalidly, statistics invalid number, calculates inefficiency.The relative weight gain rate: calculate by each medication group and the ratio of the average weight gain of blank group.
Cure rate, obvious effective rate, effective percentage, the relative weight gain rate data are summarized in table 8 below.
Treatment situation and the result of the test of table 8 to test pig asthma
Note * represents significant difference (P<0.05)
As shown in Table 7, containing enrofloxacin hexahydrate composite injection group, artificial challenge is brought out cure rate, effective percentage significant difference (P<0.05) compared with enrofloxacin injection group of swine enzootic pneumonia; The relative weight gain rate containing enrofloxacin hexahydrate composite injection group is significantly higher than enrofloxacin injection group (P<0.05), not remarkable (P>0.05) of difference compared with normal healthy controls group.
According to this result of the test, prove to press 2.5mg/kg body weight containing enrofloxacin hexahydrate composite injection, 1 time/d, be used in conjunction 3d, can obtain good therapeutic effect to the infection of swine enzootic pneumonia.Compared with enrofloxacin injection group, use containing enrofloxacin hexahydrate composite injection group and infect and have good effect by intramuscular injection for treating swine enzootic pneumonia, can significantly improve effective percentage, cure rate, and not affect weightening finish.
7, contain 5%W/V enrofloxacin hexahydrate composite injection and enrofloxacin injection to manual-induced bowel oedema disease therapeutic test
Containing enrofloxacin hexahydrate composite injection and enrofloxacin injection, manual-induced bowel oedema disease is treated, observe the therapeutic effect of two kinds of injection to bowel oedema disease.Experimental animal, Du Luoke, long white, DABAI three way cross ablactational baby pig, 40 days ages in days, did not use vaccine after birth, and half and half, 80 pig of male and female divides 4 to be group at random.Before test, raise routinely, feed the not complete feed containing antibacterials, and carry out clinical observation.Each group disposition is in table 9.
Table 9 is sent out the clinical trial grouping of swine enzootic pneumonia and processes artificial
The strong toadstool kind of manual-induced bowel oedema disease is selected from Henan breaks out the isolated swine escherichia coli virulent strain of pathological material of disease of edema disease death, and through China Veterinary Drugs Supervisory Inst. identify) use before, cryodesiccated strong toadstool kind is first inoculated nutrient broth, cultivate 20 hours, subcutaneous injection white mice, separates swine escherichia coli from dead Liver of Mice, transplants in ordinary broth, cultivate after 18 hours for 37 ℃ and take out, calculate and often contain bacterial concentration by ordinary broth agar plate culture counting method.Diluting with ordinary broth is 3.8 × 10
9cFU/mL.
Every pig of inoculum concentration and viable count is all by every body weight intravenous inoculation swine escherichia coli, containing hundred million bacterium.Before inoculation is observed in reaction and after inoculation, all survey rectal temperature, observe the symptoms such as the mental status, appetite, feces and gait, and record respectively.Dead pig is all carried out necropsy, gets liver, spleen and mesenteric lymph node and carries out antibacterial separation and Culture.
When the colibacillary pig of Pigs Inoculated, occur that body temperature significantly raises, vomiting, appetite decline or useless absolutely, when the symptom such as dysentery, respectively enrofloxacin hexahydrate injection group and enrofloxacin injection group pig are treated by table 8, by 2.5mg/kg body weight, every day 1 time, be used in conjunction 3 days.Each medication pre-test body temperature and observation clinical symptoms.Observation period is medication for the first time day after tomorrow, and before and after every pig is tested weighing and body condition is observed.
Efficacy assessment standard:
Cure rate is all at experimental session, and pig body temperature, appetite after medication recover normal, no longer occurs that the symptoms such as dysentery, postscript row, posterior paralysis, ataxia all belong to healing.Calculate accordingly cure rate.
Obvious effective rate body temperature after medication reduces or recovers normal, and appetite increases, and dysentery stops, but occur pacing after the symptoms such as row, posterior paralysis, ataxia or medication and infect matched group comparison, death time significant prolongation, temperature decline, be all judged to effectively, calculates accordingly obvious effective rate.Effective percentage: be effectively cure rate and obvious effective rate sum.Body weight/test natural law that every pig of duration of test increases.Calculate again the average daily gain soil standard deviation of every treated animal.
Cure rate, obvious effective rate, effective percentage, the relative weight gain rate data are summarized in table 10 below.
Treatment situation and the result of the test of table 10 to bowel oedema disease
Note * represents significant difference (P<0.05)
As shown in Table 9, artificial challenge is brought out to cure rate, effective percentage significant difference (P<0.05) compared with enrofloxacin injection group of bowel oedema disease containing enrofloxacin hexahydrate composite injection group; The relative weight gain rate containing enrofloxacin hexahydrate composite injection group is significantly higher than enrofloxacin injection group (P<0.05), not remarkable (P>0.05) of difference compared with normal healthy controls group.
Infect and have good effect by intramuscular injection for treating bowel oedema disease containing enrofloxacin hexahydrate composite injection group, significantly improve effective percentage, cure rate with enrofloxacin injection group phase specific energy, and do not affect weightening finish.According to this result of the test, press 2.5mg/kg body weight containing enrofloxacin hexahydrate composite injection, 1 time/d, be used in conjunction 3d, can obtain good therapeutic effect to the infection of swine enzootic pneumonia.
1. the hexahydrated preparation of enrofloxacin, test method is referring to embodiment 1.
2. contain the preparation of 10%W/V enrofloxacin hexahydrate compositions and medicine
1) containing the preparation of 10%W/V enrofloxacin hexahydrate compositions
Enrofloxacin hexahydrate: 10%W/V
Cosolvent: KOH2%W/V
Antiseptic: n-butyl alcohol 3%W/V
Carrier: water for injection is to full dose 1000ml
Preparation process:
1) preparation of KOH solution: take KOH20g, add water for injection 100ml, be settled to 200ml after stirring and dissolving;
2) get water for injection 600ml and mix homogeneously with n-butyl alcohol 30g, when mixing, control 20 ℃-30 ℃ of temperature;
3) add enrofloxacin hexahydrate 135.1g to be uniformly mixed;
4) slowly add above-mentioned KOH solution, mix homogeneously;
5) water for injection is settled to 1000ml, mixes, and 0.45um filter membrane static pressure filters and obtains containing 10%W/V enrofloxacin hexahydrate compositions.
2) will after filtration after degerming, under lucifuge condition, fill nitrogen fill in injection bottle, lucifuge preservation containing 10%W/V enrofloxacin hexahydrate compositions containing the preparation of the injection drug of 10%W/V enrofloxacin hexahydrate compositions.
3, contain the stability test of 10%W/V enrofloxacin hexahydrate compositions
1) high light impact test, method is referring to embodiment 1, and result is with embodiment 1.
2) accelerated test, method, with embodiment 1, the results are shown in following table 11.
Table 11 accelerated test result
Conclusion: the character of sample is without significant change, and pH value is without significant change, and content slightly declines, illustrates that test sample is more stable.
4, containing 10%W/V enrofloxacin hexahydrate composite injection and the therapeutic test of enrofloxacin injection to bovine pasteurellosis
With containing 10%W/V enrofloxacin hexahydrate composite injection and the treatment of enrofloxacin injection to bovine pasteurellosis, observe the therapeutic effect of two kinds of injection to bovine pasteurellosis.
Experimental animal, the sick cattle of 80 hairs of infected cattle pasteurellosis bacillus, is divided into 2 groups, 40 every group at random.Test material: gather this cattle farm blood, and get the pathological changes internal organs such as the pulmonis Bovis seu Bubali of dying of illness, lymph node, spleen.
Antibacterial separates: from gathered pathological material of disease, isolate altogether 2 strain pasteurellosis bacilluss, the bacterial strain being separated to from lymph node is decided to be bacterium No. 1, and the bacterial strain being separated to from lung is decided to be bacterium No. 2.Antibacterial is well-grown on blood agar plate, and bacterium colony is light gray, circle, moistening, dewdrop sample petite, without haemolysis.In Mai Kangkai culture medium, No. 1 antibacterial does not grow, the good and neat smooth surface of colony edge of No. 2 bacterial growths.Dyeing microscopic examination: Bacterial stain is Gram-negative, single existence, the blunt circle in two ends, the two poles of the earth are dense dyes.Biochemical test result: isolated 2 strain pasteurellosis bacilluss are carried out to biochemical test evaluation, wherein No. 1 bacterial strain sucrose, carbamide, glucose, mannose ferment test are positive, and lactose, citric acid, maltose fermentation test, triple sugar iron test, urease test are all negative.No. 2 bacterial strain sucrose, carbamide, lactose, maltose, glucose, mannose ferment test are positive, and triple sugar iron test and urease test are positive, and mannose, citric acid fermentation test are negative.Can infer that according to each result of the test No. 1 for pasteurella multocida, be for No. 2 aerogenesis pasteurellosis bacillus.Each group disposition is in table 12.
Table 12 is to cattle pasteurellosis bacillus therapeutic effect test grouping and disposition
Contain 10%W/V enrofloxacin hexahydrate composite injection and enrofloxacin injection with the intramuscular injection of 2.5mg/kg body weight, 1 time/d, be used in conjunction 3d.
Index of assessment of curative effect.Cure: after medication treatment, clinical symptoms disappears completely, it is normal that spirit and diet recover, and statistics is cured number, calculates cure rate.Effective: after medication treatment, clinical symptoms obviously alleviates, spirit and diet recover to take a turn for the better, and add up effective number, calculate obvious effective rate.Be effectively cure rate and obvious effective rate sum.Invalid: after medication treatment, clinical symptoms does not disappear, the state of an illness do not take a turn for the better and treat during because of primary disease death be all considered as invalidly, statistics invalid number, calculates inefficiency.
Cure rate, obvious effective rate, effective percentage data are summarized in table 13 below.
Treatment situation and the result of the test of table 13 to bovine pasteurellosis
Treat bovine pasteurellosis infection containing 10%W/V enrofloxacin hexahydrate composite injection group by subcutaneous injection and have good effect, obviously improve effective percentage, cure rate with enrofloxacin injection group phase specific energy, contain enrofloxacin hexahydrate composite injection with the intramuscular injection of 2.5mg/kg body weight with 10%W/V, 1 time/d, be used in conjunction 3d, can effectively cure bovine pasteurellosis.
1. the hexahydrated preparation of enrofloxacin, test method is referring to embodiment 1.
2. contain the preparation of 2%W/V enrofloxacin hexahydrate compositions
Enrofloxacin hexahydrate: 2%W/V
Cosolvent: NaOH0.4%W/V
Antiseptic: n-butyl alcohol 5%W/V
Carrier: propylene glycol 25%V/V, water for injection are to 1000ml
Preparation process:
1) preparation of KOH solution: take NaOH4g, add water for injection 50ml, be settled to 100ml after stirring and dissolving;
2) get water for injection 600ml and mix homogeneously with n-butyl alcohol 50g, when mixing, control 20 ℃-30 ℃ of temperature;
3) add enrofloxacin hexahydrate 27.0g to be uniformly mixed;
4) slowly add above-mentioned NaOH solution, mix homogeneously;
5) add propylene glycol 250ml and mix, water for injection is settled to 1000ml, mixes, and 0.45um filter membrane static pressure filters and get final product.
Preparation, stability test and the drug metabolism in pig and cattle body and the effect of drugs test method reference example 1 and 2 that contain the medicine of 2%W/V enrofloxacin hexahydrate compositions, result of the test is similar with 2 to embodiment 1, is not repeated at this.
1. the hexahydrated preparation of enrofloxacin, test method is referring to embodiment 1.
2. contain the preparation of 15%W/V enrofloxacin hexahydrate compositions
Enrofloxacin hexahydrate: in enrofloxacin 15%W/V
Cosolvent: NaOH3%W/V
Antiseptic: n-butyl alcohol 7%W/V
Carrier: propylene glycol 25%V/V, water for injection are to 1000ml
Preparation process:
1) preparation of KOH solution: take NaOH30g, add water for injection 100ml, be settled to 200ml after stirring and dissolving;
2) get water for injection 400ml and mix homogeneously with n-butyl alcohol 70g, when mixing, control 20 ℃-30 ℃ of temperature;
3) add enrofloxacin hexahydrate 202.7g to be uniformly mixed;
4) slowly add above-mentioned NaOH solution, mix homogeneously;
5) add propylene glycol 250ml and mix, water for injection is settled to 1000ml, mixes, and 0.45um filter membrane static pressure filters and get final product.
Preparation, stability test and the drug metabolism in pig and cattle body and the effect of drugs test method reference example 1 that contain the medicine of 15%W/V enrofloxacin hexahydrate compositions, result of the test is similar to embodiment 1, is not repeated at this.
To sum up, the invention provides a kind ofly containing the hexahydrated compositions of enrofloxacin, the mixture that wherein contains in potassium hydroxide, sodium hydroxide, arginine, potassium carbonate, sodium carbonate and ethanolamine any one or any two forms cosolvent.The cosolvent that the present invention uses not only can help to be dissolved into fast in medicine acceptable carrier containing enrofloxacin hexahydrate compositions, and absorb and utilize in can promoting to be in carcass containing enrofloxacin hexahydrate, common domestic animal bacterial disease and mycoplasma infection diseases can effectively be treated or prevent to drug metabolism and effect of drugs all, significantly better than the pharmaceutical composition of independent use enrofloxacin and conventional carrier thereof.
Secondly, provided by the invention containing enrofloxacin hexahydrate compositions, compared with enrofloxacin and composition medicine thereof, there is the interior blood drug level peak concentration of the carcass of being in high, bioavailability is high, pharmacokinetics and and clinical effectiveness aspect good feature, can substitute enrofloxacin and compositions thereof, can prepare widely used medicine on veterinary clinic, there is wide market prospect and value.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (13)
1. containing the hexahydrated compositions of enrofloxacin, it is characterized in that, described compositions comprises effective dose:
A: enrofloxacin hexahydrate;
B: pharmaceutically acceptable carrier.
2. compositions as claimed in claim 1, is characterized in that, described compositions comprises:
A) in the enrofloxacin hexahydrate of enrofloxacin 2% to 15%W/V;
B) 0.4% to 3%W/V cosolvent;
C) 3% to 7%W/V antiseptic;
D) pharmaceutically acceptable carrier is to full dose.
3. compositions as claimed in claim 2, is characterized in that, the cosolvent described in composition component b is selected from potassium hydroxide, sodium hydroxide, arginine, potassium carbonate, sodium carbonate and ethanolamine the mixture of any one or any two.
4. compositions as claimed in claim 2, is characterized in that, the antiseptic described in composition component c is selected from n-butyl alcohol, benzyl alcohol and phenylpropanol the mixture of any one or any two.
5. compositions as claimed in claim 2, is characterized in that, the carrier described in composition component d is selected from water for injection or 15%-25%V/V aqueous solution of propylene glycol.
6. compositions as claimed in claim 1, is characterized in that, described compositions comprises:
A) in the enrofloxacin hexahydrate of enrofloxacin 5%W/V;
B) potassium hydroxide of 1%W/V;
C) n-butyl alcohol of 3%W/V;
D) water is to full dose.
7. compositions as claimed in claim 1, is characterized in that, described compositions comprises:
A) in the enrofloxacin hexahydrate of enrofloxacin 10%W/V;
B) potassium hydroxide of 2%W/V;
C) n-butyl alcohol of 3%W/V;
D) water is to full dose.
8. the application in the medicine of preparation treatment or prevention domestic animal bacterial disease and mycoplasma infection diseases containing the hexahydrated compositions of enrofloxacin described in any one in claims 1-7.
9. application as claimed in claim 8, it is characterized in that, described domestic animal bacterial disease and mycoplasma infection diseases comprise: mycoplasma pneumonia, Bacillus pasteurii disease, colibacillosis, salmonellosis, streptococcicosis, actinomycetes property pleuropneumonia, mastitis, colibacillosis, Bacillus pasteurii disease and mastitis.
10. the application described in claims 8, is characterized in that, described domestic animal comprises pig and cattle.
11. application as claimed in claim 1, described drug dose is every kg body weight 1-20mg; Be used in conjunction 2-3 days.
12. application as claimed in claim 10, described drug dose is every kg body weight 1-10mg; Be used in conjunction 2-3 days.
13. application as described in claims 12, described drug dose is every kg body weight 2.5-5mg; Be used in conjunction 2-3 days.
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| WO2008092576A1 (en) * | 2007-01-31 | 2008-08-07 | Bayer Animal Health Gmbh | Enrofloxacin-hexahydrate |
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| Title |
|---|
| 中国兽药典委员会编: "《兽药使用指南.化学药品卷：中华人民共和国兽药典：2005年版》", 30 April 2006, 中国农业出版社, article "第二章抗微生物药", pages: 78-80 * |
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