CN105395479A - Preparation method of sustained-release ciprofloxacin injection - Google Patents
Preparation method of sustained-release ciprofloxacin injection Download PDFInfo
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- CN105395479A CN105395479A CN201510959989.3A CN201510959989A CN105395479A CN 105395479 A CN105395479 A CN 105395479A CN 201510959989 A CN201510959989 A CN 201510959989A CN 105395479 A CN105395479 A CN 105395479A
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- Prior art keywords
- ciprofloxacin
- injection
- preparation
- organic solvent
- slow release
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- 229940020010 ciprofloxacin injection Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000013268 sustained release Methods 0.000 title abstract 5
- 239000012730 sustained-release form Substances 0.000 title abstract 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 claims abstract description 89
- 229960003405 ciprofloxacin Drugs 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 16
- 229930195729 fatty acid Natural products 0.000 claims abstract description 16
- 239000000194 fatty acid Substances 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 13
- 239000003381 stabilizer Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims abstract description 4
- 238000005374 membrane filtration Methods 0.000 claims abstract description 3
- -1 glycerol formal Chemical compound 0.000 claims description 11
- 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
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 7
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-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
- 229940074076 glycerol formal Drugs 0.000 claims description 4
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 4
- 229960002622 triacetin Drugs 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- 239000005720 sucrose 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
- 238000004090 dissolution Methods 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
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229940090044 injection Drugs 0.000 abstract description 21
- 238000002347 injection Methods 0.000 abstract description 21
- 239000007924 injection Substances 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 16
- 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 2
- 230000000536 complexating effect Effects 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 244000144977 poultry Species 0.000 description 5
- 238000005352 clarification Methods 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229940049964 oleate Drugs 0.000 description 4
- 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
- 238000001727 in vivo Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 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
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 244000144972 livestock Species 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
- 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 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 108010035947 CPLX inhibitor Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical group O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 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
- 230000037396 body weight Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 1
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 description 1
- 229960004055 ciprofloxacin lactate Drugs 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
- 230000000694 effects Effects 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
- 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
- 229960001699 ofloxacin Drugs 0.000 description 1
- 238000004321 preservation Methods 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
- 239000006228 supernatant Substances 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a sustained-release ciprofloxacin injection, and relates to a sustained-release injection used for animals. The sustained-release ciprofloxacin injection comprises, by weight, 5 to 20% of ciprofloxacin, 1 to 4% of a fatty acid, 5 to 35% of a stabilizing agent, and the balance an organic solvent. The preparation method comprises following steps: ciprofloxacin is dissolved in the organic solvent, and stirring is carried out until dissolving is realized; the fatty acid is added for complexing with an obtained dissolving product; the stabilizing agent is added; after complete dissolving is realized, an obtained solution is diluted to a constant volume with the organic solvent; and the sustained-release ciprofloxacin injection is obtained via membrane filtration. A novel composition is obtained via reaction of ciprofloxacin, or a ciprofloxacin salt or a ciprofloxacin aquo-complex with fatty acid, so that release time of ciprofloxacin is prolonged, effective blood concentration of drugs in animal bodies is maintained for a long time, and the number of drug adminstration times is reduced, and drug stress reaction is reduced.
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 ciprofloxacin injection.
Background technology
Ciprofloxacin (Ciprofloxaein, CPLX), have another name called ciprofloxacin, it is the medicine that in third generation fluoroquinolone antibacterial agent, antibacterial action is stronger, all having very strong antibacterial activity to gram negative bacteria, gram positive bacteria, mycoplasma etc., is one the strongest to gram negative bacteria antibacterial activity in the fluoroquinolones of current veterinary clinic application.Due to ciprofloxacin there is fat-soluble height, the feature such as the antibacterial after effect time is longer, distribution in vivo is wide and adverse reaction rate is low, and be widely used in the control of the infectious disease such as poultry, aquatic product.
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.Ciprofloxacin injection is common medicine and the specific drug of the large-scale cultivated animals such as chicken, pig, but the common ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin 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 ciprofloxacin injection, described ciprofloxacin injection comprises following composition by weight percentage;
Ciprofloxacin 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) ciprofloxacin 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 ciprofloxacin injection is namely obtained with membrane filtration after organic solvent standardize solution.
The present invention prepares the method for ciprofloxacin injection, and described ciprofloxacin is salt or its hydrate of the form such as hydrochlorate, lactate, methanesulfonic acid, malic acid of the former medicine of ciprofloxacin or ciprofloxacin.
The present invention prepares the method for ciprofloxacin 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, N-Methyl pyrrolidone, glycerol formal, glycerol triacetate arbitrary.
The present invention prepares the method for ciprofloxacin 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, capric acid, oleic acid, stearic arbitrary.
The present invention prepares the method for ciprofloxacin injection, described stabilizing agent be sucrose ester, polyglyceryl fatty acid ester, PVP, polyoxyethylene castor oil arbitrary.
The present invention prepares the method for ciprofloxacin injection, and described ciprofloxacin 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 ciprofloxacin injection is mainly ciprofloxacin hydrochloride 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 ciprofloxacin 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, ciprofloxacin injection provided by the invention, due to ciprofloxacin and fatty acid complexation, extends ciprofloxacin 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 ciprofloxacin injection compares with the blood drug level of traditional ciprofloxacin injection in piglet body.
In figure: 1, the change of traditional ciprofloxacin injection blood drug level in piglet body; 2, the change of ciprofloxacin n-caproic acid saline injection blood drug level in piglet body; 3, the change of ciprofloxacin caprate injection blood drug level in piglet body; 4, the change of ciprofloxacin oleate injection blood drug level in piglet body; 5, the change of ciprofloxacin 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% ciprofloxacin n-caproic acid saline injection
Get 5g ciprofloxacin (pure) and 40gN, N-dimethyl acetylamide, stirring and dissolving is to clarification, add after 1g n-caproic acid slowly stirs complexation 1h, add 5g sucrose ester to continue to stir to clarify, N,N-dimethylacetamide is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 5% ciprofloxacin injection.
Embodiment 2
The preparation of 10% ciprofloxacin caprate injection
Get 10g ciprofloxacin (pure) and 40gN-methyl pyrrolidone, stirring and dissolving is to clarification, add after 2g capric acid slowly stirs complexation 2h, add 10g polyglyceryl fatty acid ester to continue to stir to clarify, N-Methyl pyrrolidone is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 10% ciprofloxacin caprate injection.
Embodiment 3
The preparation of 15% ciprofloxacin oleate injection
Get 15g ciprofloxacin (pure) and 40g glycerol formal, stirring and dissolving is to clarification, add after 3g oleic acid slowly stirs complexation 3h, add 20g PVP to continue to stir to clarify, glycerol formal is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 15% ciprofloxacin oleate injection.
Embodiment 4
The preparation of 20% ciprofloxacin stearate injection
Get 20g ciprofloxacin (pure) and 40g glycerol triacetate, stirring and dissolving is to clarification, add after 4g stearic acid slowly stirs complexation 4h, add 35g polyoxyethylene castor oil to continue to stir to clarify, glycerol triacetate is settled to 100ml, with 0.45 μm of organic membrane filter, obtain 20% ciprofloxacin stearate injection.
Embodiment 5
Slow release ciprofloxacin injection of the present invention compares with the blood drug level of traditional ciprofloxacin 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 ciprofloxacin injection: ciprofloxacin water for injection is mixed with 5% injection (in ciprofloxacin, lower same);
2) ciprofloxacin n-caproic acid saline injection: prepare by embodiment 1;
3) ciprofloxacin caprate injection: prepare by embodiment 2;
4) ciprofloxacin oleate injection; Prepare by embodiment 3;
5) ciprofloxacin 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 ciprofloxacin injection 10mg/kg ((in ciprofloxacin), 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 ciprofloxacin 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 ciprofloxacin injection holding time of effective blood drug concentration in experimental animals is significantly less than injection of the present invention, the time that tradition ciprofloxacin injection reaches peak plasma concentrations is in vivo about 2h, after this decay rapidly, and the injection of ciprofloxacin 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 ciprofloxacin injection, is characterized in that: described ciprofloxacin injection component and mass percent are:
The preparation steps of described preparation method is as follows:
1) ciprofloxacin 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 ciprofloxacin injection is namely obtained with membrane filtration after organic solvent standardize solution.
2. the preparation method of a kind of slow release ciprofloxacin injection according to claim 1, is characterized in that: described ciprofloxacin is salt or its hydrate of the form such as hydrochlorate, lactate, methanesulfonic acid, malic acid of the former medicine of ciprofloxacin or ciprofloxacin.
3. the preparation method of a kind of slow release ciprofloxacin injection according to claim 1, is characterized in that: described organic solvent be N,N-dimethylacetamide, N-Methyl pyrrolidone, glycerol formal, glycerol triacetate any one.
4. the preparation method of a kind of slow release ciprofloxacin injection according to claim 1, is characterized in that: described fatty acid be n-caproic acid, capric acid, oleic acid, stearic acid any one.
5. the preparation method of a kind of slow release ciprofloxacin injection according to claim 1, is characterized in that: described stabilizing agent be sucrose ester, polyglyceryl fatty acid ester, PVP, polyoxyethylene castor oil any one.
6. the preparation method of a kind of slow release ciprofloxacin injection according to claim 1, is characterized in that: described ciprofloxacin organic solvent dissolution product and fatty acid complexation time are 1-4h.
Priority Applications (1)
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