CN105362219A - Preparation method of slow-release sparfloxacin injection - Google Patents
Preparation method of slow-release sparfloxacin injection Download PDFInfo
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- CN105362219A CN105362219A CN201510968098.4A CN201510968098A CN105362219A CN 105362219 A CN105362219 A CN 105362219A CN 201510968098 A CN201510968098 A CN 201510968098A CN 105362219 A CN105362219 A CN 105362219A
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- sparfloxacin
- injection
- preparation
- organic solvent
- fatty acid
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- 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 title claims abstract description 86
- 229960004954 sparfloxacin Drugs 0.000 title claims abstract description 86
- 238000002347 injection Methods 0.000 title claims abstract description 60
- 239000007924 injection Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 17
- 239000000194 fatty acid Substances 0.000 claims abstract description 17
- 229930195729 fatty acid Natural products 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 14
- 239000003381 stabilizer Substances 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 238000004090 dissolution Methods 0.000 claims abstract description 3
- 238000005374 membrane filtration Methods 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 8
- 238000010668 complexation reaction Methods 0.000 claims description 7
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 4
- 229960002622 triacetin Drugs 0.000 claims description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000005639 Lauric acid Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 3
- -1 polyoxyethylene Polymers 0.000 claims description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000006166 lysate Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 abstract description 12
- 210000004369 blood Anatomy 0.000 abstract description 12
- 239000008280 blood Substances 0.000 abstract description 12
- 239000000203 mixture Substances 0.000 abstract description 3
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 14
- 238000000034 method Methods 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 244000144977 poultry Species 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 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 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000204031 Mycoplasma Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000031295 Animal disease Diseases 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 206010061041 Chlamydial infection Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000003844 DNA helicases Human genes 0.000 description 1
- 108090000133 DNA helicases Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000204048 Mycoplasma hominis Species 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000202921 Ureaplasma urealyticum Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical group O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000009360 aquaculture Methods 0.000 description 1
- 244000144974 aquaculture Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 201000000902 chlamydia Diseases 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 208000012538 chlamydia trachomatis infectious disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003544 deproteinization Effects 0.000 description 1
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 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 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 229960001471 sodium selenite Drugs 0.000 description 1
- 235000015921 sodium selenite Nutrition 0.000 description 1
- 239000011781 sodium selenite Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a slow-release sparfloxacin injection and relates to a slow-release injection for animals. The sparfloxacin injection comprises components in percentage by weight as follows: 5%-20% of sparfloxacin, 1%-4% of fatty acid, 5%-35% of a stabilizer and the balance of an organic solvent. The sparfloxacin and the organic solvent are taken and stirred to be dissolved, the fatty acid is added to have a complex reaction with a dissolution product, the stabilizer is added and fully dissolved, the organic solvent is added until the mixture reaches a certain volume and is subjected to membrane filtration, and the slow-release sparfloxacin injection is prepared. New composition is formed after sparfloxacin, salt of sparfloxacin or hydrate of sparfloxacin has a reaction with the fatty acid, the release time of sparfloxacin can be prolonged, the effective blood concentration of the medicine in the animals is maintained for a long time, and accordingly, the purposes of reducing administration frequency and stress due to the medicine are achieved.
Description
Technical field
The present invention relates to a kind of preparation method of Injection for animals, especially relate to a kind of preparation method of slow release sparfloxacin injection.
Background technology
Sparfloxacin (sparfloxacin) has a broad antifungal spectrum, similar to ciprofloxacin to gram-negative bacteria antibacterial activity, strong and ciprofloxacin and ofloxacin to positive bacteria, to anaerobe, mycoplasma, chlamydia effect is strong, and also effective to multiple drug-resistant bacteria.High at intra-tissue concentration after oral absorption, long half time, for sensitive organism, anaerobe, mycoplasma and chlamydial infection.Except gram negative bacilli being had to height antibacterial activity, still to staphylococcus, there is good antibacterial action, slightly staphylococcus is worse than to the effect of streptococcus pneumoniae, Streptococcus.These product also have an inhibitory action to part mycobacteria, chlamydia trachomatis, U. urealyticum, mycoplasma hominis etc.The mechanism of action of this medicine and bacterial resistance situation are see norfloxacin.For antibacterial, now it is generally acknowledged that quinolones acts on the A subunit of bacterial cell DNA helicase, suppress the synthesis of DNA and copy and cause bacterial death.
Recent years, China's livestock and poultry breeding industry is frequently subject to the puzzlement of extensive respiratory tract and infectious disease of the digestive tract, and respiratory tract and digestive tract disease have usually, and sickness rate is high, the feature of course of disease length, needs long-time multiple dosing over the course for the treatment of.Sparfloxacin injection is common medicine and the specific drug of the large-scale cultivated animals such as chicken, pig, but the common sparfloxacin injection half-life is short, for meeting the Treatment need of ill poultry, need repetitively administered, improve the labor cost of modern livestock and poultry breeding industry and increase the stress of cultivated animals.Therefore the task of top priority that long-acting slow-release sparfloxacin injection becomes modern poultry industry is developed.
Summary of the invention
The present invention is intended to the defect for prior art, a kind of preparation method that can extend the sparfloxacin injection half-life is provided, need repeated multiple times medication to solve in prior art in long course of disease Animal diseases therapeutic process, increase animal and meet an urgent need and increase the problem of aquaculture cost.
For realizing above technical purpose, the present invention by the following technical solutions:
A preparation method for slow release sparfloxacin injection, described sparfloxacin infusion pump is containing following composition by weight percentage;
Sparfloxacin 5-20%
Fatty acid 1-4%
Stabilizing agent 5-35%
Surplus is organic solvent
The preparation steps of described preparation method is as follows:
5) sparfloxacin and organic solvent stirring and dissolving is got;
6) lysate adding fatty acid and step 1 carries out complex reaction;
7) stabilizing agent is added;
8) slow release sparfloxacin injection is namely obtained with membrane filtration after organic solvent standardize solution.
The present invention prepares the method for sparfloxacin injection, and described sparfloxacin is salt or its hydrate of the form such as hydrochlorate, lactate, methanesulfonic acid, malic acid of the former medicine of sparfloxacin or sparfloxacin.
The present invention prepares the method for sparfloxacin injection, described organic solvent is that dissolve each other with water, pharmaceutically acceptable organic solvent, preferred organic solvent is on this basis: N,N-dimethylacetamide, propylene glycol, 2-Pyrrolidone, glycerol triacetate arbitrary.
The present invention prepares the method for sparfloxacin injection, and described fatty acid is C
9-C
18between containing the fatty acid of even number of carbon atoms, preferred fatty acid is further on this basis: n-caproic acid, lauric acid, Palmic acid, stearic arbitrary.
The present invention prepares the method for sparfloxacin injection, described stabilizing agent be fatty glyceride, fatty acid glyceride, PVP, polyoxyethylene hydrogenated Oleum Ricini arbitrary.
The present invention prepares the method for sparfloxacin injection, and described sparfloxacin organic solvent dissolution product and fatty acid complexation time are 1-4h.
Owing to have employed technique scheme, the present invention has following beneficial effect:
Traditional sparfloxacin injection is mainly sparfloxacin hydrochlorate or lactate aqueous solution, its half-life is in animal body 4-10 hour, clinical administration needs 2 times/day and continuous use 3-5d, the sparfloxacin injection disclosed by the invention half-life is in animal body 20-24h, every day, single-dose can meet clinical application requirement, greatly reduced the emergency reaction of medication animal while significantly reducing clinical treatment workload.Meanwhile, sparfloxacin injection provided by the invention, due to sparfloxacin and fatty acid complexation, extends sparfloxacin release time in animal body, its can in 3-10 days continuous release of active compounds.
Accompanying drawing explanation
Fig. 1 is that slow release sparfloxacin injection compares with the blood drug level of traditional sparfloxacin injection in piglet body.
In figure: 1, the change of traditional sparfloxacin injection blood drug level in piglet body; 2, the change of sparfloxacin n-caproic acid saline injection blood drug level in piglet body; 3, the change of sparfloxacin laruate injection blood drug level in piglet body; 4, the change of sparfloxacin palmitate injection blood drug level in piglet body; 5, the change of sparfloxacin stearate injection blood drug level in piglet body.
Detailed description of the invention
Below will be described in detail the specific embodiment of the present invention.In order to avoid too much unnecessary details, in the examples below to belonging to known structure or function will not be described in detail.
Embodiment 1
The preparation of 5% sparfloxacin n-caproic acid saline injection
Get 5g sparfloxacin (pure) and 40gN, N-dimethyl acetylamide, stirring and dissolving is to clarification, add after 1g n-caproic acid slowly stirs complexation 1h, add 5g fatty glyceride to continue to stir to clarify, N,N-dimethylacetamide is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 5% sparfloxacin injection.
Embodiment 2
The preparation of 10% sparfloxacin laruate injection
Get 10g sparfloxacin (pure) and 40g propylene glycol, stirring and dissolving is to clarification, add after 2g lauric acid slowly stirs complexation 2h, add 10g fatty acid glyceride to continue to stir to clarify, propylene glycol is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 10% sparfloxacin laruate injection.
Embodiment 3
The preparation of 15% sparfloxacin palmitate injection
Get 15g sparfloxacin (pure) and 40g2-ketopyrrolidine, stirring and dissolving is to clarification, add after 3g Palmic acid slowly stirs complexation 3h, add 20g PVP to continue to stir to clarify, 2-Pyrrolidone is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 15% sparfloxacin palmitate injection.
Embodiment 4
The preparation of 20% sparfloxacin stearate injection
Get 20g sparfloxacin (pure) and 40g glycerol triacetate, stirring and dissolving is to clarification, add after 4g stearic acid slowly stirs complexation 4h, add 35g polyoxyethylene hydrogenated Oleum Ricini to continue to stir to clarify, glycerol triacetate is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 20% sparfloxacin stearate injection.
Embodiment 5
Slow release sparfloxacin injection of the present invention compares with the blood drug level of traditional sparfloxacin injection in piglet body
1, laboratory animal
Select sodium selenite 15 in 6 week age, male and female has concurrently, average weight (14.0 ± 1.5) kg, carries out routine and raises, free choice feeding and drinking-water in dedicated experiments district, and feedstuff is not containing any antibacterials.
2, injection formula
1) traditional sparfloxacin injection: hydrochloric acid sparfloxacin water for injection is mixed with 5% injection (in sparfloxacin, lower same);
2) sparfloxacin n-caproic acid saline injection: prepare by embodiment 1;
3) sparfloxacin laruate injection: prepare by embodiment 2;
4) sparfloxacin palmitate injection; Prepare by embodiment 3;
5) sparfloxacin stearate injection: prepare by embodiment 4.
3, laboratory animal grouping and administration
15 healthy test pig are divided into 5 groups at random, often group 3 is parallel, numbers, weighs, by body weight intramuscular injection sparfloxacin injection 10mg/kg ((in sparfloxacin), take free choice feeding and drinking-water, feedstuff is complete feed (not containing antibiotics).
4, the collection of sample
Test pig is lain on the back Baoding by Baoding personnel, gathers blank blood sample before administration from vena cava anterior.After sparfloxacin injection intramuscular delivery 0.1,0.5,1,2,4,6,8,10,12,18,24,48,72,96,120,144,168,192h blood sampling.Each blood sampling 3ml, adds corresponding heparin sodium, through the centrifugal 10min of low-temperature and high-speed centrifuge 10000r/min, gets upper plasma in-20 DEG C of preservations.
5, the mensuration of blood drug level
Get blood plasma 0.5mL, add ofloxacin (interior mark) the 10 μ L of 50mg/L, high speed centrifugation after methanol Deproteinization, on supernatant, machine fluorescence detector detects.Chromatographic condition: Nova-PakC18 post (4 μm, 4.6mm × 200mm); Mobile phase is water-acetonitrile (92: 8), includes 0.015mol/L tetrabutyl ammonium bromide, and phosphoric acid adjusts pH to be 3.0; Flow velocity 1.0mL/min; Excitation wavelength 278nm, emission wavelength 465nm.Result as shown in Figure 1, tradition sparfloxacin injection holding time of effective blood drug concentration in experimental animals is significantly less than injection of the present invention, the time that tradition sparfloxacin injection reaches peak plasma concentrations is in vivo about 2h, after this decay rapidly, and the injection of sparfloxacin of the present invention reaches the time of peak plasma concentrations in vivo between 8-12 hour, holding time of effective blood drug concentration reaches more than 18h.
Claims (6)
1. a preparation method for slow release sparfloxacin injection, is characterized in that: described sparfloxacin injection component and mass percent are:
Sparfloxacin 5-20%
Fatty acid 1-4%
Stabilizing agent 5-35%
Surplus is organic solvent;
The preparation steps of described preparation method is as follows:
1) sparfloxacin and organic solvent stirring and dissolving is got;
2) lysate adding fatty acid and step 1 carries out complex reaction;
3) stabilizing agent is added;
4) slow release sparfloxacin injection is namely obtained with membrane filtration after organic solvent standardize solution.
2. the preparation method of a kind of slow release sparfloxacin injection according to claim 1, is characterized in that: described sparfloxacin is salt or its hydrate of the form such as hydrochlorate, lactate, methanesulfonic acid, malic acid of the former medicine of sparfloxacin or sparfloxacin.
3. the preparation method of a kind of slow release sparfloxacin injection according to claim 1, is characterized in that: described organic solvent be N,N-dimethylacetamide, propylene glycol, 2-Pyrrolidone, glycerol triacetate any one.
4. the preparation method of a kind of slow release sparfloxacin injection according to claim 1, is characterized in that: described fatty acid be n-caproic acid, lauric acid, Palmic acid, stearic acid any one.
5. the preparation method of a kind of slow release sparfloxacin injection according to claim 1, is characterized in that: described stabilizing agent be fatty glyceride, fatty acid glyceride, PVP, polyoxyethylene hydrogenated Oleum Ricini any one.
6. the preparation method of a kind of slow release sparfloxacin injection according to claim 1, is characterized in that: described sparfloxacin organic solvent dissolution product and fatty acid complexation time are 1-4h.
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Application publication date: 20160302 |