CN1907261A - Long-acting carbostyril family antibacterial drugs suspension injection - Google Patents
Long-acting carbostyril family antibacterial drugs suspension injection Download PDFInfo
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- CN1907261A CN1907261A CN 200610044296 CN200610044296A CN1907261A CN 1907261 A CN1907261 A CN 1907261A CN 200610044296 CN200610044296 CN 200610044296 CN 200610044296 A CN200610044296 A CN 200610044296A CN 1907261 A CN1907261 A CN 1907261A
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- 238000002347 injection Methods 0.000 title claims abstract description 61
- 239000007924 injection Substances 0.000 title claims abstract description 61
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 239000000725 suspension Substances 0.000 title claims description 36
- 229940124350 antibacterial drug Drugs 0.000 title claims description 8
- 239000003814 drug Substances 0.000 claims abstract description 41
- 229940079593 drug Drugs 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003963 antioxidant agent Substances 0.000 claims abstract 3
- 230000003078 antioxidant effect Effects 0.000 claims abstract 3
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 claims description 33
- 229960000740 enrofloxacin Drugs 0.000 claims description 33
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 28
- 210000004369 blood Anatomy 0.000 claims description 22
- 239000008280 blood Substances 0.000 claims description 22
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 18
- 229960003405 ciprofloxacin Drugs 0.000 claims description 14
- 230000000844 anti-bacterial effect Effects 0.000 claims description 8
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 8
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 8
- -1 hydroxypropyl Chemical group 0.000 claims description 7
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 5
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001087 glyceryl triacetate Substances 0.000 claims description 4
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 4
- 229960003415 propylparaben Drugs 0.000 claims description 4
- 229960002622 triacetin Drugs 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- XBHBWNFJWIASRO-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 claims 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims 2
- 229920000858 Cyclodextrin Polymers 0.000 claims 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims 2
- 241001597008 Nomeidae Species 0.000 claims 2
- QIPQASLPWJVQMH-DTORHVGOSA-N Orbifloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(F)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F QIPQASLPWJVQMH-DTORHVGOSA-N 0.000 claims 2
- NJCJBUHJQLFDSW-UHFFFAOYSA-N Rufloxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 claims 2
- 230000002421 anti-septic effect Effects 0.000 claims 2
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 claims 2
- 229950001733 difloxacin Drugs 0.000 claims 2
- 229960002549 enoxacin Drugs 0.000 claims 2
- 229960003376 levofloxacin Drugs 0.000 claims 2
- 229960002422 lomefloxacin Drugs 0.000 claims 2
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 claims 2
- 229960003702 moxifloxacin Drugs 0.000 claims 2
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims 2
- 229960001180 norfloxacin Drugs 0.000 claims 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims 2
- 229960001699 ofloxacin Drugs 0.000 claims 2
- 229960004780 orbifloxacin Drugs 0.000 claims 2
- 229960004236 pefloxacin Drugs 0.000 claims 2
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 claims 2
- 229960001732 pipemidic acid Drugs 0.000 claims 2
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 claims 2
- 229920000642 polymer Polymers 0.000 claims 2
- 229960004062 rufloxacin Drugs 0.000 claims 2
- 229950007734 sarafloxacin Drugs 0.000 claims 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 229960004954 sparfloxacin Drugs 0.000 claims 2
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 claims 2
- 241000894006 Bacteria Species 0.000 claims 1
- 101100493820 Caenorhabditis elegans best-1 gene Proteins 0.000 claims 1
- 101100004280 Caenorhabditis elegans best-2 gene Proteins 0.000 claims 1
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 claims 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims 1
- 229920003091 Methocel™ Polymers 0.000 claims 1
- 229920000881 Modified starch Polymers 0.000 claims 1
- 239000004698 Polyethylene Substances 0.000 claims 1
- 239000004743 Polypropylene Substances 0.000 claims 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims 1
- 229920000615 alginic acid Polymers 0.000 claims 1
- 235000010443 alginic acid Nutrition 0.000 claims 1
- 239000003945 anionic surfactant Substances 0.000 claims 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 229960004385 danofloxacin Drugs 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims 1
- 229920002521 macromolecule Polymers 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 235000019426 modified starch Nutrition 0.000 claims 1
- 229960000210 nalidixic acid Drugs 0.000 claims 1
- 229920005615 natural polymer Polymers 0.000 claims 1
- 229920000573 polyethylene Polymers 0.000 claims 1
- 229940051841 polyoxyethylene ether Drugs 0.000 claims 1
- 229920000056 polyoxyethylene ether Polymers 0.000 claims 1
- 229920001155 polypropylene Polymers 0.000 claims 1
- 229920001296 polysiloxane Polymers 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 abstract 2
- 239000012190 activator Substances 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 54
- 238000010255 intramuscular injection Methods 0.000 description 29
- 239000007927 intramuscular injection Substances 0.000 description 29
- 241000287828 Gallus gallus Species 0.000 description 27
- 210000002381 plasma Anatomy 0.000 description 12
- 229940020010 ciprofloxacin injection Drugs 0.000 description 11
- 238000003756 stirring Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 238000010241 blood sampling Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a long-effective carbostyrile antibiotic drug injection, which comprises the following parts: 1-10% (W/V) carbostyrile antibiotic medicine, 1-10% (W/V) slow releasing carrier, 15-50% (W/V) alcohol, 1-20% (V/V) surface activator, 10-20% (W/V) water and 50-5% (V/V) and necessary conservative and antioxidant.
Description
This invention be about the bactericidal component of long-acting carbostyril family antibacterial drugs injection and its preparation technology with and The pharmacological results on target animals chicken and pig.
The multi-form preparation of carbostyril family antibacterial drugs is widely used in the anti-infective therapy of humans and animals.
Report in the past: once five and wait at " journal of animal science and veterinary medicine " 2002, their prepared enrofloxacin suspension of report is administered once at clinical practice 48h and still can keeps effective blood drug concentration to encountered pathogenic bacteria among 33 (1) 63-67, needs usually be administered once behind 48h in therapeutic process again.This is for keeping the longest enrofloxacin suspension injection of blood drug level in the report.
This patent characteristics: the suspension injection that this patent is invented is administered once at 96h through clinical practice still can keep effective blood drug concentration to encountered pathogenic bacteria, kinetic model at the intravital plasma drug level of chicken meets one-level absorption two-compartment model, and only need be administered once in treatment like this gets final product.
The present invention is a kind of new carbostyril family antibacterial drugs slow-release injection, and preparation process is:
1. Comprecin-encrusting substance and Comprecin body thing are mixed in proportion, promptly 50～90% through the bag quilt carbostyril family antibacterial drugs and 50～10% body carbostyril family antibacterial drugs uniform mixing,
2. surfactant is added water for injection, stirring and dissolving adds mixture in 1 again, stirs, and makes A liquid,
3. slow-released carrier is added in the ethanol and dissolve, adding methyl hydroxybenzoate, propylparaben are stirred to dissolving, glyceryl triacetate, benzyl alcohol are added again, and stir, and make B liquid after the filtration,
4. down stir B liquid, and add A liquid while stirring with high-shear emulsion machine at 8000～12000 rev/mins, stir about 15～30 minutes makes it become uniform emulsion.
Example one,
1, enrofloxacin injection
Contain in the 100ml injection:
Enrofloxacin: 5.0g
Sodium sulfite: 0.1g
Benzyl alcohol: 2.5ml
Water for injection is to 100ml
KOH transfers PH 10.5～11.5
2,0 Long-acting enrofloxacin suspension injection
Contain in the 100ml suspension:
A：EFX-β-CD(20％)：20g
EFX： 1g
F68： 3g
H2O： 20ml
B：EC 3g
Methyl hydroxybenzoate: 0.18g
Propylparaben: 0.02g
Ethanol: 15ml
Glyceryl triacetate: 50ml
Benzyl alcohol: 3ml
Mentioned component is made the 0 Long-acting enrofloxacin suspension injection according to preparation process.
Example two, 0 Long-acting enrofloxacin suspension injection (example 1) are in the intravital pharmacokinetics experiment of chicken
The yellow chicken of 20 health, male and female has concurrently, and about 11 ages in week, body weight is 1.7～2.5kg, is bought at random by market.Random packet is raised in cages, and raises routinely, freely drink water and searches for food, and feedstuff is adequate diet (not containing antibacterials), raises the back test of 1 week before the test in advance, and taboo is raised 12h before the administration, and taboo is raised 4h after the administration.Weigh before the administration, number, be divided into 2 groups of enrofloxacin injection (example 1), 0 Long-acting enrofloxacin suspension injections (example-2) at random, press 10mg/kg dosage intramuscular administration for every group 10, chicken Baoding of lying on one's side, separate vein under the wing, adopt venous blood before the administration 1 time, after this by the certain time interval blood sampling, each about 2mL of blood sampling volume.
Actual measurement plasma drug level-time data that chicken intramuscular injection enrofloxacin injection (example 1) and intramuscular injection 0 Long-acting enrofloxacin suspension injection (example 1) back obtain adopts 3p87 pharmacokinetic parameter calculation procedure.Use computer to handle automatically.Model Selection is handled by this Automatic Program.Calculate the pharmacokinetic parameter of every chicken respectively, further obtain the meansigma methods and the standard error of each parameter.
1. the characteristics of pharmacokinetics of chicken intramuscular injection enrofloxacin injection (example 1)
After 10 healthy chicken intramuscular injection enrofloxacin injection (example 1), the measured value of different time plasma drug level sees Table 1.3p87 routine processes plasma drug level time data shows that enrofloxacin injection (example 1) is that one-level absorbs two-compartment model at the intravital plasma drug level optimal drug of chicken kinetic model.Curve during according to medicine, the main pharmacokinetic parameters of calculating every chicken respectively sees Table 3.
2. the characteristics of pharmacokinetics of chicken intramuscular injection 0 Long-acting enrofloxacin suspension injection (example 1)
Behind 9 healthy chicken intramuscular injection 0 Long-acting enrofloxacin suspension injections (example 1), the measured value of different time plasma drug level sees Table 2.3p87 routine processes plasma drug level time data shows that enrofloxacin is that one-level absorbs two Room open models at the intravital plasma drug level optimal drug of chicken kinetic model.Curve during according to medicine, the main pharmacokinetic parameters of calculating every chicken respectively sees Table 4.
Table 1: chicken single dose intramuscular injection enrofloxacin injection (example 1) is the drug level (ug/ml) of back in the blood plasma (10mg/kg)
| Time (h) | Chicken number | X±S.E | |||||||||
| a | b | c | d | e | f | g | H | i | j | ||
| 0.17 0.34 0.5 0.75 1 2 4 8 12 16 24 36 48 72 | 4.74 7.09 9.11 9.26 4.78 3.11 2.55 1.91 1.70 1.50 0.09 ND ND ND | 4.78 7.53 12.71 11.27 8.59 4.35 2.98 2.44 1.24 1.04 0.76 ND ND ND | 5.26 7.14 8.97 11.23 10.77 9.09 4.51 1.91 1.64 0.76 0.40 ND ND ND | 3.46 7.91 9.01 9.79 8.12 5.07 2.60 1.31 1.03 0.59 0.21 ND ND ND | 3.11 7.84 9.65 9.87 8.17 5.35 3.49 2.59 1.08 0.64 ND ND ND ND | 3.29 5.48 8.49 11.89 9.56 6.78 4.65 2.37 1.25 0.78 0.32 ND ND ND | 6.14 7.43 9.23 10.46 8.78 5.21 3.42 2.18 1.07 0.64 0.41 ND ND ND | 6.16 6.89 9.66 10.19 7.47 6.81 4.24 2.87 2.26 1.45 0.07 ND ND ND | 3.01 7.18 8.83 9.79 7.36 5.47 4.92 1.66 1.37 0.81 0.16 ND ND ND | 4.66 8.21 8.68 9.88 8.66 6.97 3.91 2.20 1.21 0.19 ND ND ND ND | 4.4±1.13 7.27±0.71 9.4±1.15 10.3±0.79 8.23±1.48 5.82±1.57 3.73±0.81 2.14±0.44 1.39±0.36 0.84±0.37 0.33±0.10 |
" ND ": can not record (Not Detectable)
Table 2: the plasma drug level (ug/ml) behind the chicken single dose intramuscular injection 0 Long-acting enrofloxacin suspension injection (10mg/kg) (example 1)
| Time (h) | Chicken number | X±S.E | ||||||||
| b | c | d | e | f | g | h | i | j | ||
| 0.17 0.34 0.5 | 1.35 1.83 2.17 | 1.08 1.35 1.53 | 1.52 1.85 2.75 | 1.83 2.61 2.89 | 1.77 1.79 2.41 | 1.10 1.43 2.02 | 1.62 1.87 2.31 | 1.27 1.29 2.49 | 1.59 2.72 3.15 | 1.46±0.26 1.86±0.48 2.41±0.46 |
| 0.75 1 2 4 8 12 16 24 36 48 72 84 96 120 | 3.13 3.33 4.39 5.37 3.95 3.03 2.49 - 1.01 ND ND ND ND ND | 2.30 2.86 4.05 6.32 4.75 3.96 3.08 2.23 2.07 1.29 0.47 ND ND ND | 3.74 4.18 4.88 5.61 3.31 2.65 2.33 1.64 1.19 1.01 0.57 ND ND ND | 3.64 3.86 3.93 - 2.94 2.15 2.01 1.82 1.76 1.26 0.86 0.44 ND ND | 2.57 3.74 4.01 4.87 3.86 3.06 2.56 1.92 0.96 0.55 0.56 ND ND ND | 2.56 2.97 3.56 3.97 2.98 2.37 1.43 1.36 1.05 0.96 0.83 0.52 ND ND | 2.74 5.67 9.99 12.58 7.03 6.25 4.78 4.55 5.02 1.81 1.08 0.31 0.04 ND | 4.18 5.02 6.08 6.75 6.03 5.37 4.57 3.76 1.73 0.71 0.41 ND ND ND | 3.22 4.51 4.81 6.06 5.62 4.84 4.16 3.28 2.17 0.48 0.12 0.06 ND ND | 3.12±0.59 4.02±0.88 5.07±1.87 6.44±1.02 4.49±1.37 3.74±1.36 3.04±1.12 2.57±1.07 1.88±1.19 1.01±0.41 0.61±0.28 0.33±0.11 0.04±0.00 |
" ND ": can not record (Not Detectable) "-": sample is lost
Table 3 chicken intramuscular injection single dose enrofloxacin injection (example 1) pharmacokinetic parameters (10mg/kg)
| Parameter | Unit | Chicken number | X±S.E | |||||||||
| a | b | c | d | e | f | g | h | i | j | |||
| C max A K e K a T 1/2α T 1/2β T 1/2Ka T 1/2Ke T (peak) V d(atea) Cl B AUC | Ug/ml Ug/ml h -1 h -1 h h h h L/kg L/kg L/kg/h Mg/L*h | 1.55 7.75 0.16 15.98 0.04 4.31 0.22 8.91 0.29 1.30 0.21 47.66 | 1.76 15.74 0.53 4.99 0.14 1.30 0.23 8.73 0.50 0.71 0.39 26.43 | 1.75 15.86 0.28 2.51 0.28 2.51 0.28 8.67 0.98 0.71 0.19 51.19 | 1.24 11.88 0.39 6.18 0.11 1.78 0.27 9.01 0.48 0.89 0.35 28.62 | 1.16 10.54 0.25 8.33 0.08 2.75 0.24 8.54 0.43 0.98 0.25 40.51 | 1.16 10.54 0.25 8.33 0.08 2.75 0.26 9.21 0.43 0.98 0.25 40.51 | 2.21 11.89 0.29 4.56 0.15 2.36 0.21 8.74 0.64 0.89 0.26 37.85 | 2.69 9.85 0.15 5.90 0.12 4.47 0.25 8.87 0.63 1.04 0.16 61.88 | 3.58 9.72 0.20 7.83 0.08 3.40 0.37 9.12 0.48 1.06 0.21 46.43 | 1.25 10.96 0.23 5.92 0.12 3.04 0.18 8.56 0.57 0.95 0.22 46.22 | 1.84±0.75 11.48±2.44 0.27±0.11 7.05±3.43 0.12±0.06 2.87±0.95 0.25±0.05 8.86±0.21 0.54±0.17 0.95±0.16 0.25±0.06 42.73±9.93 |
The pharmacokinetic parameters of table 4 chicken intramuscular injection single dose 0 Long-acting enrofloxacin suspension injection (10mg/kg) (example 1)
| Parameter | Unit | Chicken number | X±S.E | ||||||||
| a | b | c | d | e | f | g | h | i | |||
| C max A Ka Ke T 1/2α T 1/2β T 1/2Ka T 1/2Ke T (peak) V d(atea) Cl B AUC | Ug/ml Ug/ml h -1 h -1 h h h h L/kg L/kg L/kg/h Mg/L*h | 0.98 6.398 0.917 0.057 0.756 12.07 1.27 18.76 3.223 1.667 0.096 104.4 | 0.53 6.899 0.636 0.0413 1.089 16.743 2.01 17.52 4.593 1.550 0.064 155.82 | 0.84 5.955 1.309 0.053 0.529 13.21 1.24 19.64 2.549 1.75 0.093 107.39 | 0.59 3.749 3.691 0.026 0.188 26.023 1.07 22.10 1.346 2.687 0.072 139.71 | 0.69 5.059 1.076 0.04 0.643 17.27 2.51 20.31 3.174 2.053 0.082 121.4 | 0.55 4.059 1.369 0.039 0.506 17.77 2.64 21.24 2.674 2.536 0.098 101.1 | 0.71 11.816 0.814 0.038 0.852 18.372 1.34 18.64 3.957 0.887 0.033 298.66 | 0.97 8.382 0.930 0.039 0.745 17.35 1.84 18.46 3.535 1.246 0.049 200.7 | 1.04 8.374 0.595 0.044 1.165 15.76 1.58 19.24 4.729 1.289 0.056 176.3 | 0.76±0.18 * 6.74±2.37 1.26±0.89 0.04±0.01 0.67±0.28 17.17±3.71 1.72±0.54 * 19.54±1.36 ** 3.31±0.99 * 1.74±0.56 0.07±0.02 156.18±59.51 ** |
" * ": with remarkable (p＜0.05) " the * * " of intramuscular injection normal injection agent comparing difference and the poor heteropole of intramuscular injection normal injection agent remarkable (p＜0.01)
Healthy chicken single dose intramuscular injection enrofloxacin injection (example 1) and 0 Long-acting enrofloxacin suspension injection (example 1) blood drug level one time graph after (10mg/kg) is seen Fig. 1.
After showing that according to the result chicken muscle injection 0 Long-acting enrofloxacin suspension injection (example 1) (10mg/kg), absorb rapidly, absorb half-life t1/2
KaBe that (0.25 ± 0.05h) relatively is significant difference for 1.72 ± 0.54h and intramuscular injection same dose enrofloxacin injection (example 1).
From comparison, can find out the t of long-acting suspension
MaxBe 3.31 ± 0.99h, the t of contrast injection
MaxBe 0.54 ± 0.17h, the peak time of the blood drug level of long-acting injection is obviously delayed, and there were significant differences between the two; The elimination of intramuscular injection long-acting injection is slower, and eliminating the half-life is 19.54 ± 1.36; And the elimination half-life of the enrofloxacin injection of intramuscular injection same dose (example 1) is 8.86 ± 0.21, is its 2.21 times, and relatively there were significant differences for the two, illustrates that the slow release effect of 0 Long-acting enrofloxacin suspension injection (example 1) is very obvious.
Chicken is pressed 10mg/kg single dose intramuscular injection 0 Long-acting enrofloxacin suspension injection (example 1), and blood drug level begins slow rising, reaches behind the peak concentration slowly to descend, and the blood drug level of 10min and 30min is respectively 1.46 ± 0.26ug/ml after the administration; With 3.34 ± 3.11ug/ml, the average blood drug level of 24h, 48h and 96h is respectively 2.57 ± 1.07ug/ml, 1.01 ± 0.41ug/ml, 0.04 ± 0.00ug/ml this shows, said preparation not only can reach the above concentration of MIC very soon. but also long-acting is preferably arranged, and the blood drug level in the 48h of intramuscular injection 0 Long-acting enrofloxacin suspension injection (example 1) back maintains more than the 1.01ug/ml.96h still can keep the effective blood drug concentration to encountered pathogenic bacteria after the administration.
Example three,
1, ciprofloxacin injection
Contain in the 100ml injection:
Ciprofloxacin: 5.0g
Sodium sulfite: 0.1g
Benzyl alcohol: 2.5ml
Water for injection is to 100ml
KOH transfers PH 10.5～11.5
2, long-acting ciprofloxacin suspension injection
Contain in the 100ml suspension:
A：CFX-β-CD(20％)： 15g
CFX： 1.5g
F68： 3g
H2O： 20ml
B：EC： 3g
Methyl hydroxybenzoate: 0.18g
Propylparaben: 0.02g
Ethanol: 15ml
Glyceryl triacetate: 50ml
Benzyl alcohol: 3ml
Example four, long-acting ciprofloxacin suspension injection (according to example three-2) are in the intravital pharmacokinetics experiment of pig
12 of health pig, about age in male and female half and half, 7 week, average weight 44.30 ± 2.96kg.Clinical health, duration of test is raised routinely, freely drinks water and searches for food, and feedstuff is adequate diet (not containing antibacterials)
Weigh before the test pig administration, numbering is divided into 2 groups of intramuscular injection ciprofloxacin injection (according to example three-1), long-acting ciprofloxacin suspension injections (according to example three-2) at random, and dosage is 10mg/kg.The primary blank blood sample from the vena cava anterior blood sampling, is adopted in pig Baoding of only lying on the back before the administration.After this take a blood sample at interval by certain hour, separated plasma is preserved in-20 ℃ of refrigerators, and is to be measured.
Behind health pig single dose intramuscular injection ciprofloxacin injection (according to example three-1), the long-acting ciprofloxacin suspension injection (according to example three-2), the measured value of different time blood drug level the results are shown in Table 5.
Table 5: the blood drug level (ug/mL) of pig intramuscular injection ciprofloxacin injection (according to example three-1), long-acting ciprofloxacin suspension injection (according to example three-2)
| Time (h) | Normal injection | Long-acting injection |
| 0.1 0.25 0.5 0.75 1 2 4 8 12 24 36 48 72 96 | 0.66±0.14 0.98±0.27 1.22±0.21 1.24±0.33 1.15±0.13 0.97±0.09 0.62±0.07 0.32±0.03 0.21±0.04 0.09±0.02 | 0.88±0.29 1.02±0.28 1.46±0.31 1.75±0.37 1.15±0.09 1.04±0.06 0.94±0.02 0.76±0.08 0.51±0.01 0.30±0.07 0.18±0.04 0.12±0.04 0.09±0.01 0.07±0.02 |
Actual measurement plasma drug level-the time data that obtains adopts 3P
87Medicine pharmacokinetic parameters calculation procedure.The processing that uses a computer because computer is selected best model automatically, meets two Room open models, carries out linear fit, calculates relevant medicine kinetic parameter.
Ciprofloxacin injection (according to example three-1) is in the intravital pharmacokinetics feature of pig
Computer Processing blood drug level-time data shows that the pharmacokinetics optimum mathematics model of quiet notes ciprofloxacin injection (according to example three-1) is not for there being the two-compartment model of absorption, and theoretical equation is: C=Ae-α t+Be-β t.The data best fit model is that one-level absorbs two Room open models during the medicine of intramuscular injection ciprofloxacin injection, and theoretical equation is C=A1e-α t+A2e-β t+A3e-Kat.The pharmacokinetic parameters of quiet notes, intramuscular injection ciprofloxacin injection (according to example three-1) sees Table 6.
Table 6: the pharmacokinetic parameters of pig intramuscular injection ciprofloxacin injection (according to example three-1), long-acting ciprofloxacin suspension injection (according to example three-2)
| Parameter | Unit | Parameter value (mean+SD) | |
| Normal injection | Long-acting injection | ||
| 0 A B α β Ka Ke t 1/2Ka t 1/2α t 1/2β T max C max Vl Vd C 1B AUC | μg/mL μg/mL μg/mL h -1 h -1 h -1 h -1 h h h h μg/mL L/kg L/kg L/kg -1.h -1 mg.L -1.h | 5.60±0.541 3.56±0.276 2.04±0.346 1.02±0.473 0.08±0.004 0.34±0.021 0.171±0.01 0.94±0.87 0.67±0.24 6.074±1.101 1.78±0.53 1.55±0.09 1.735±0.141 4.234±0.515 0.316±0.053 17.94±6.59 | 3.50±0.055 3.74±0.943 0.42±0.308 0.24±0.065 0.03±0.006 2.05±1.124 2.03±0.030 2.42±0.175 3.018±0.723 30.91±0.83 5.64±0.378 4.531±0.152 3.264±0.761 9.531±0.134 2.376±0.043 166.96±49.89 |
Health pig single dose intramuscular injection ciprofloxacin injection (according to example three-1), long-acting ciprofloxacin suspension injection (according to example three-2) blood drug level-time graph after (10mg/kg) is seen Fig. 2.
Show that according to the result the long-acting ciprofloxacin suspension injection of pig intramuscular injection (according to example three-2) (10mg/kg) absorbs half-life t
1/2Ka2.42 ± 0.175h and intramuscular injection same dose normal injection (according to example three-1) 0.94 ± 0.87h comparing difference are remarkable, peak time Tmax 5.64 ± 0.378 is significant prolongation also, and AUC normal injection and long-acting injection that we surveyed are respectively 17.94 ± 6.59mg.L
-1.h with 166.96 ± 49.89mg.L
-1.h significant difference (P＜0.05) illustrates that the interior blood drug level of long-acting ciprofloxacin suspension injection unit interval in this patent is evident as height, and has higher AUC and eliminate slower characteristics, can bring into play its long-acting.
Annotate: EFX: enrofloxacin
EFX-β-CD: enrofloxacin-beta-schardinger dextrin-
CFX-β-CD: ciprofloxacin-beta-schardinger dextrin-
CFX: ciprofloxacin
EC: ethyl cellulose
F68: propylene glycol polyoxyethylene poly-oxygen propylene aether
Description of drawings: Fig. 1 is healthy chicken single dose intramuscular injection enrofloxacin injection (example 1) and 0 Long-acting enrofloxacin suspension injection (the example 1) blood drug level-time plot after (10mg/kg); Fig. 2 is the blood drug level-time plot behind long-acting ciprofloxacin suspension injection of intramuscular injection (according to example three-2) and the ciprofloxacin injection (according to example three-1).
Claims (7)
1, a kind of long-acting carbostyril family antibacterial drugs suspension injection, it is characterized in that: said preparation is a kind of by antiseptic of antibacterial and double-layer sustained release carrier, surfactant, solvent and necessity and the suspension injection that antioxidant is formed, and antibacterial wherein is the part encrusting substance.
2, antibacterial according to claim 1 is that Comprecin comprises norfloxacin (Norfloxacin), enrofloxacin (Enorofloxacin), sarafloxacin (Sarafloxacin), difloxacin (Difloxacin), Dan Nuosha star (Danofloxacin), orbifloxacin (Orbifloxacin), pipemidic acid (Pipemidic Acid), ofloxacin (Ofloxacin), levofloxacin (Levofloxacin), enoxacin (Enoxacin), ciprofloxacin (Ciprofloxacin), lomefloxacin (Lomefloxacin), pefloxacin (Pefloxacin), rufloxacin (Rufloxacin), sparfloxacin (Sparfloxacin), moxifloxacin (Moxifloxacin), nalidixan (Nalidixic Acid) etc., wherein 50～100% antibacterial is had the quilt that carrier wraps in certain aperture, make it can form slow release mechanism in animal body, this bag suppressed by vector can be a natural polymer, semi-synthetic macromolecule and synthetic high polymer, as alginates, starch derivatives, cyclodextrin and derivant etc. thereof wherein are preferably cyclodextrin and derivant thereof.
3, the proper proportion of antibacterial body thing according to claim 1 and drug coated component is 50～10%: 50～90%, can make product behind the blood drug level that obtains a first kill bacteria excessively, and can continue to keep follow-up blood drug level.
4, be high molecular polymer water insoluble or that water solublity is minimum according to described its outer carrier of claim 1 as slow releasing function, insoluble framework material commonly used has: cellulose derivative such as ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxy methocel and Carboxymethyl cellulose sodium and polyethylene, polypropylene, polysiloxanes and polyoxyethylene and card pool mother etc. are preferably ethyl cellulose.Consumption can be 1～10%, best 1～5%.
5, when forming suspension, must add at least a surfactant according to claim 1 is described, this surfactant can be anion surfactant and non-ionic surface active agent as: alkylphenol polyoxyethylene, fatty alcohol-polyoxyethylene ether and copolyether etc., its HLB value should be not less than 8.Consumption can 1～20%, best 2～10%.
6, be ethanol 15～50% (V/V), glyceryl triacetate 50～5% (V/V) and water for injection 10～20% (W/V) according to the described solvent for use of claim 1.
7, be that benzyl alcohol and antioxidant are methyl hydroxybenzoate and propylparaben according to the described necessary antiseptic of claim 1.
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| CN 200610044296 CN1907261A (en) | 2006-05-22 | 2006-05-22 | Long-acting carbostyril family antibacterial drugs suspension injection |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697725A (en) * | 2012-06-07 | 2012-10-03 | 山东省健牧生物药业有限公司 | Veterinary ciprofloxacin lactate injection and preparation method thereof |
| CN114557961A (en) * | 2022-02-17 | 2022-05-31 | 四川永诺生物科技有限公司 | Slow-release enrofloxacin suspension and preparation method thereof |
| CN119405601A (en) * | 2024-11-25 | 2025-02-11 | 华南农业大学 | A kind of difloxacin microcrystalline suspension injection and preparation method thereof |
-
2006
- 2006-05-22 CN CN 200610044296 patent/CN1907261A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697725A (en) * | 2012-06-07 | 2012-10-03 | 山东省健牧生物药业有限公司 | Veterinary ciprofloxacin lactate injection and preparation method thereof |
| CN114557961A (en) * | 2022-02-17 | 2022-05-31 | 四川永诺生物科技有限公司 | Slow-release enrofloxacin suspension and preparation method thereof |
| CN119405601A (en) * | 2024-11-25 | 2025-02-11 | 华南农业大学 | A kind of difloxacin microcrystalline suspension injection and preparation method thereof |
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