CN103239497A - Enrofloxacin clathrate compound and preparation method thereof - Google Patents
Enrofloxacin clathrate compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an enrofloxacin clathrate compound and a preparation method thereof. The enrofloxacin clathrate compound is prepared by taking enrofloxacin and fenugreek as raw materials, performing clathration treatment on auxiliary materials such as a slow release formulation, a flavoring agent, a plasticizer, a curing agent and a flocculant, and drying the materials. The enrofloxacin clathrate compound has the advantages that the delay medicines are released, the clinical administration frequency is reduced, the product stability is improved and the palatability of the medicines is improved.
Description
Technical field
The present invention relates to the field of Chinese medicines for animals, be specifically related to a kind of enrofloxacin clathrate and preparation method thereof.
Background technology
Enrofloxacin (Enrofloxacin), have another name called ethyl ciprofloxacin, enrofloxacin, grace fluorine quinoline carboxylic acid, the chemosynthesis antibacterial that belongs to Fluoroquinolones (Fluoroquinolones), be little yellow or light yellow crystalline powder, water insoluble, be soluble in organic solvents such as sodium hydroxide solution, methanol and cyanogen methane.This product is the broad-spectrum sterilization medicine, and mycoplasma is had specially good effect.Escherichia coli, klebsiella bacillus, Salmonella, Bacillus proteus, bacillus pyocyaneus, haemophilus, pasteurella multocida, pasteurella haemolytica, golden Portugal bacterium, streptococcus etc. there is sterilization effectiveness.Can be used as the animal-use drug product, long half time in animal body has good tissue distribution, belongs to the broad-spectrum antibacterial, has bacteriostasis for gram positive bacteria, negative bacterium and mould slurry.
Enrofloxacin taste hardship is not suitable for oral administration, has so not only limited its administering mode, also makes it can not bring into play in the high advantage of the oral bioavailability of nonruminant.Simultaneously, the elimination half-life of enrofloxacin in the poultry body is shorter relatively, needs the continuous several times administration can reach therapeutic purposes, and frequent medication brings very big inconvenience for clinical use, simultaneously also easier cause animal stress.Simultaneously, because the enrofloxacin dissolution is low, the enrofloxacin preparation technology of high concentration is difficulty relatively, and constant product quality can't be guaranteed.And the enrofloxacin of low concentration must cause drug effect to weaken, and in order to address this problem, seeks new technology, and new combination formula seems particularly important.
Summary of the invention
The object of the present invention is to provide a kind of enrofloxacin clathrate, its good palatability, the dissolution height, stability is high, strong drug action, prescription rationally not only can reduce difficulty of processing, also can reach the good slow release effect.
Another object of the present invention provides the preparation method of this enrofloxacin clathrate, and its process links up, and the technological parameter science is fit to industrialization promotion.
The technical scheme that realizes above-mentioned purpose is:
The enrofloxacin clathrate is made by the following weight proportion raw material: enrofloxacin 10-15 part, Semen Trigonellae 8-12 part, hydroxypropyl emthylcellulose 5-8 part, mannitol 2-4 part, HP-30-45 part, Polyethylene Glycol 3-5 part, propylene glycol 1-3 part, gelatin 8-12 part, acetone 3-5 part;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add Semen Trigonellae quality 10-15 distilled water doubly, in 60-80 ℃ of heating lixiviate 2-4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of enrofloxacin quality 20-30 1mol/L doubly, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add gelatin quality 40-60 distilled water doubly in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 45 ℃-55 ℃, regulate pH value to 3.2-3.5, add acetone, make the emulsion cohesion, add 2-4 part formaldehyde again, regulate pH value to 8.0, solidify down at 4-6 ℃, with 100-200 part distilled water flush away formaldehyde, vacuum drying gets product again.
Semen Trigonellae: Latin is called Trigonella foenum-graecum L., is the dry mature seed of leguminous plant Semen Trigonellae.Nature and flavor hardship, temperature are returned kidney channel, and effect is warming the kidney to activate YANG, and dispersing cold for relieving pain is mainly used in the kidney cold caused by deficiency, cold and pain in the lower abdomen, inguinal hernia, the disturbance of lower legs due to pathogenic cold and dampness.
Enrofloxacin clathrate among the present invention is a kind of novel enrofloxacin slow releasing preparation, by enrofloxacin and Semen Trigonellae extract is compatible, when strengthening drug effect, reduce difficulty in process, again through the slow-release auxiliary material hydroxypropyl emthylcellulose, sweeting agent mannitol enclose, by chemical bond with the compound medicine enclose in inside, again successively through HP-, adjuvant enclose such as gelatin form stay-in-grade clathrate, delay drug release in the hope of reaching, reduce the clinical administration number of times, the purpose that improves product stability and improve the palatability of medicine, thus overcome and the shortcoming that remedies traditional enrofloxacin preparation with not enough.
Specific embodiment
The present invention is described further below in conjunction with specific embodiment, to help understanding content of the present invention.
Embodiment 1:
The enrofloxacin clathrate is made by the following weight proportion raw material: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts in mannitol, 37 parts of HP-, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts in gelatin, 4 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 13 times of Semen Trigonellae quality, in 68 ℃ of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 25 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 50 ℃, regulate pH value to 3.3, add acetone, make the emulsion cohesion, add 3 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 5 ℃, with 165 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Embodiment 2
The enrofloxacin clathrate is made by the following weight proportion raw material: 10 parts of enrofloxacins, 8 parts of Semen Trigonellaes, 5 parts of hydroxypropyl emthylcelluloses, 2 parts in mannitol, 30 parts of HP-, 3 parts of Polyethylene Glycol, 1 part of propylene glycol, 8 parts in gelatin, 3 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 10 times of Semen Trigonellae quality, in 60 ℃ of heating lixiviate 2h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 20 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 40 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 45 ℃, regulate pH value to 3.2, add acetone, make the emulsion cohesion, add 2 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 4 ℃, with 100 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Embodiment 3
The enrofloxacin clathrate is made by the following weight proportion raw material: 15 parts of enrofloxacins, 12 parts of Semen Trigonellaes, 8 parts of hydroxypropyl emthylcelluloses, 4 parts in mannitol, 45 parts of HP-, 5 parts of Polyethylene Glycol, 3 parts of propylene glycol, 12 parts in gelatin, 5 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 15 times of Semen Trigonellae quality, in 80 ℃ of heating lixiviate 4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 30 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 60 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 55 ℃, regulate pH value to 3.5, add acetone, make the emulsion cohesion, add 4 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 6 ℃, with 200 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Embodiment 4
The enrofloxacin clathrate is made by the following weight proportion raw material: 8 parts of enrofloxacins, 7 parts of Semen Trigonellaes, 4 parts of hydroxypropyl emthylcelluloses, 2 parts in mannitol, 26 parts of HP-, 2 parts of Polyethylene Glycol, 1 part of propylene glycol, 8 parts in gelatin, 2 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 9 times of Semen Trigonellae quality, in 55 ℃ of heating lixiviate 2-4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 18 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 38 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 45 ℃, regulate pH value to 3.2, add acetone, make the emulsion cohesion, add 2 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 4 ℃, with 90 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Embodiment 5
The enrofloxacin clathrate is made by the following weight proportion raw material: 18 parts of enrofloxacins, 15 parts of Semen Trigonellaes, 9 parts of hydroxypropyl emthylcelluloses, 5 parts in mannitol, 48 parts of HP-, 6 parts of Polyethylene Glycol, 4 parts of propylene glycol, 15 parts in gelatin, 6 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 18 times of Semen Trigonellae quality, in 85 ℃ of heating lixiviate 5h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 33 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 62 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 60 ℃, regulate pH value to 3.5, add acetone, make the emulsion cohesion, add 5 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 6 ℃, with 210 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Comparative Examples 1
The enrofloxacin clathrate is made by the following weight proportion raw material: 20 parts of enrofloxacins, 6 parts of hydroxypropyl emthylcelluloses, 3 parts in mannitol, 37 parts of HP-, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts in gelatin, 4 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The preparation of elementary complex: with hydroxypropyl emthylcellulose, the abundant mixing of mannitol, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 25 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 50 ℃, regulate pH value to 3.3, add acetone, make the emulsion cohesion, add 3 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 5 ℃, with 165 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Comparative Examples 2
The enrofloxacin clathrate is made by the following weight proportion raw material: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts in mannitol, 37 parts of HP-, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts in gelatin, 4 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 13 times of Semen Trigonellae quality, in 68 ℃ of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
Enrofloxacin pretreatment: enrofloxacin is dissolved in the NaOH solution of 1mol/L of 25 times of enrofloxacin quality, gets pretreated enrofloxacin solution for standby;
The preparation of elementary complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, pretreated enrofloxacin solution, hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that elementary complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, it is standby to make gelatin solution, and elementary complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 50 ℃, regulate pH value to 3.3, add acetone, make the emulsion cohesion, add 3 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 5 ℃, with 165 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Comparative Examples 3
The enrofloxacin clathrate is made by the following weight proportion raw material: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts in mannitol, 37 parts of HP-, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts in gelatin, 4 parts in acetone;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 13 times of Semen Trigonellae quality, in 68 ℃ of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with HP-, hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 25 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, it is standby to make gelatin solution, and elementary complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 50 ℃, regulate pH value to 3.3, add acetone, make the emulsion cohesion, add 3 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 5 ℃, with 165 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
Comparative Examples 4
The enrofloxacin clathrate, the medicament of being made by the following weight proportion raw material: enrofloxacin 10-15 part, HP-30-45 part, 0.1mol/L sodium hydroxide 8-12 part;
The preparation method that above-mentioned each component is made enrofloxacin clathrate of the present invention is: enrofloxacin and HP-according to the 1:1 molar ratio weighing, are at first used enrofloxacin the 0.1mol/L dissolution of sodium hydroxide; In addition the HP-of remainder is added in 40 ℃ the distilled water and make saturated solution, under the electronic stirring of magnetic force, enrofloxacin solution is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continues to be stirred to room temperature, gets white suspension, after putting refrigerator and cooled Tibetan 24h, sucking filtration, with enrofloxacin quality 6-12 chloroform washing doubly 3 times, 60 ℃ are drying to obtain.
The test example
1, drug release determination
Precision takes by weighing the enrofloxacin clathrate of 30mg embodiment 1-5 and Comparative Examples 1-4 preparation respectively, render to respectively in nine stripping rotors that respectively contain 900 mL release medium, dissolution method second method by 98 pages of first appendix of " People's Republic of China's veterinary drug allusion quotation " version in 2005 is measured, 0.5 ℃ of 37 ℃ of scholar of release medium temperature change slurry rotating speed 50 r/min.Self-preparing agent contact release medium plays 1min, 2min, 4min, 6min and samples respectively, each time point 5 mL that from each stripping rotor, take a sample, through 0.45 μ m filtering with microporous membrane, in the stripping rotor of sampling, mend release medium 5 mL immediately simultaneously, sampling solution is measured with the chromatographic condition of assay, precision takes by weighing enrofloxacin crude drug 18.4 mg simultaneously, in above-mentioned same test conditions down-sampling in contrast, calculate the sample concentration that each time point is gathered, with the crude drug release conditions in contrast, investigate the slow release effect of clathrate.The results are shown in Table 1:
Table 1 slow release effect relatively
As seen from the above table: compare with crude drug, each experimental group all has tangible slow releasing function, wherein embodiment 1-3 is better than embodiment 4-5, embodiment 4-5 is better than Comparative Examples 1-4, wherein embodiment 1 effect optimum, as seen factors such as prescription, each supplementary material proportioning, technology and technological parameter, all can influence the slow release effect of product, have only four to complement each other, reasonable compatibility can get a desired effect.
2, stability test
Get the enrofloxacin clathrate of embodiment 1-5 and Comparative Examples 1-4 preparation respectively, press commercially available back (plastic bag sealing packing, every bag of 100g), 2 ℃ of temperature 40 scholars, placed 6 months under relative humidity 75% scholar's 5% the condition, take a sample respectively once the 1st, 2,3,6 the end of month, investigate the test sample cosmetic variation, and carry out assay, investigate the stability of test sample.Assay: the accurate enrofloxacin clathrate that takes by weighing 25.0mg embodiment 1-5 and Comparative Examples 1-4 preparation places the 100mL volumetric flask respectively, add the sodium hydroxide solution 10mL dissolving of 0.1mol/L and add the tri-distilled water standardize solution, dilution is 10 times behind 0.45 μ m filtering with microporous membrane, get need testing solution, inject high performance liquid chromatograph and measure, the results are shown in Table 2:
Table 2 stability relatively
As seen from the above table: because each experimental group supplementary material proportioning difference, cause its determining enrofloxacin content difference, preserve down through the high humidity hot environment, the determining enrofloxacin content of each experimental group all has fluctuation in various degree, wherein embodiment 1-3 fluctuation is less, stability obviously is better than embodiment 4-5 and Comparative Examples 1-4, and embodiment 1 effect optimum.4 fluctuations of Comparative Examples 1, Comparative Examples are bigger, this with its prescription in only to contain enrofloxacin and enclose adjuvant and technology relevant, the high concentration enrofloxacin causes product stability to reduce, difficulty of processing increases simultaneously, as seen reasonable composite addressing this problem.
3, animal experiment
Broiler, without the pasteurellosis bacillus vaccine immunity, male and female has concurrently, raises routinely, feeds complete feed, free choice feeding and drinking-water.Carry out clinical observation before the test, healthy person is selected for use.During test, chicken length of time is 40 ages in days, and body weight 445 ± 10g, is equally divided into 11 groups, 30 every group at random by 330.
Spawn culture: before the use, the strong toadstool kind of preservation is the inoculation blood agar plate earlier, is incubated at 37 ℃, behind the 24h, selects colonies typical and is inoculated in the meat soup, takes out behind 37 ℃ of cultivation 18h again.With this broth culture inoculation chicken, also the inoculation chicken can be caused death in the hope of its pathogenicity rejuvenation, separate pasteurellosis bacillus and inoculate the blood agar plate cultivation from the liver of dead chicken, selecting colonies typical at last cultivates with ordinary broth, and be diluted to counteracting toxic substances bacterium liquid with meat soup, cultivating counting method with flat board and measure its growth turbidity unit, is 0.5 hundred million CFU/ml.
Inoculum concentration and bacterial population: the above-mentioned bacterium liquid of the broiler intramuscular inoculation 0.05ml by every 100g body weight contains 2,500,000 CFU viable bacterias approximately.
Reaction is observed: the clinical symptoms that chicken is observed in before the inoculation and inoculation back, mainly comprise the mental status, appetite, feces etc., and record respectively.Dead chicken is carried out necropsy, get liver and carry out the antibacterial separation and Culture.
5h behind test method: the 1-8 group chicken inoculation bacterium liquid gives embodiment 1-5, Comparative Examples 1-4 the enrofloxacin clathrate of preparation respectively, and the clathrate mixing is in broiler fodder, and (every 1kg feedstuff adds the 10g clathrate) be 3d continuously.Another group does not infect not administration, and as the normal healthy controls group, last group infects not administration as infecting matched group.Observation period is observed the various clinical manifestations of chicken every day for inoculation back 15d, and dead chicken is carried out necropsy, makes the antibacterial separation and Culture, determines the cause of the death.And to every chicken before and after testing weighing and body condition is observed.The results are shown in Table 3.
The therapeutic evaluation standard:
1) death: at duration of test, classical symptom and the death of chicken Bacillus pasteurii disease occur, necropsy has typical characteristics of lesion, and separation and Culture goes out chicken source pasteurella multocida from liver, is judged to be to infect death.Calculate the mortality rate of each group according to dead chicken number.
2) cure: at duration of test, the mental status, appetite recover normal behind for oral administration or intramuscular administration, clinical symptoms no longer occurs and all belong to healing.The ratio that accounts for test group according to the healing chicken calculates cure rate.
3) effective: through take orally or intramuscular administration after, the chicken of Zhi Yuing and do not have death but have the symptom shower to be " effectively " fully; The percentage rate that the chicken number of every group of survival accounts for the test chicken number during off-test is effective percentage.
4) weightening finish: the body weight of every chicken during according to on-test and off-test, calculate the gain in weight of every chicken, calculate average weight gain and the standard deviation of every group of test chicken then accordingly.The relative weight gain rate is to calculate by the ratio of each medication treatment group with the average weight gain of normal healthy controls group, and wherein the normal healthy controls group is made as 100%.
Table 3 enrofloxacin clathrate is to the curative effect situation of test chicken Bacillus pasteurii disease
As seen from the above table: embodiment 1-3 group, up to 100%, and the relative weight gain rate also is higher than other test group to the effective percentage of test chicken Bacillus pasteurii disease, wherein especially with embodiment 1 effect optimum, this with embodiment 1 in each set of dispense than science, technology is rationally closely related.Embodiment 4-5 effect is slightly inferior to embodiment 1-3, and this ratio range with two groups is unreasonable relevant, and Comparative Examples 1-4 effect illustrates and has only prescription, technology to complement each other inferior to embodiment 1-5, just can bring into play maximum efficacy.
Claims (5)
1. enrofloxacin clathrate, it is characterized in that: it is the medicament of being made by the following weight proportion raw material: enrofloxacin 10-15 part, HP-30-45 part, 0.1mol/L sodium hydroxide 8-12 part;
Preparation method is as follows: enrofloxacin and HP-according to the 1:1 molar ratio weighing, are at first used enrofloxacin the 0.1mol/L dissolution of sodium hydroxide; In addition the HP-of remainder is added in 40 ℃ the distilled water and make saturated solution, under the electronic stirring of magnetic force, enrofloxacin solution is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continues to be stirred to room temperature, gets white suspension, after putting refrigerator and cooled Tibetan 24h, sucking filtration, with enrofloxacin quality 6-12 chloroform washing doubly 3 times, 60 ℃ are drying to obtain.
2. enrofloxacin clathrate, it is characterized in that: it is the medicament of being made by the following weight proportion raw material: enrofloxacin 10-15 part, Semen Trigonellae 8-12 part, hydroxypropyl emthylcellulose 5-8 part, mannitol 2-4 part, HP-30-45 part, Polyethylene Glycol 3-5 part, propylene glycol 1-3 part, gelatin 8-12 part, acetone 3-5 part.
3. enrofloxacin clathrate according to claim 2, it is characterized in that: it is the medicament of being made by the following weight proportion raw material: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts in mannitol, 37 parts of HP-, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts in gelatin, 4 parts in acetone.
4. enrofloxacin clathrate according to claim 2, it is characterized in that: preparation method is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add Semen Trigonellae quality 10-15 distilled water doubly, in 60-80 ℃ of heating lixiviate 2-4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of enrofloxacin quality 20-30 1mol/L doubly, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add gelatin quality 40-60 distilled water doubly in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 45 ℃-55 ℃, regulate pH value to 3.2-3.5, add acetone, make the emulsion cohesion, add 2-4 part formaldehyde again, regulate pH value to 8.0, solidify down at 4-6 ℃, with 100-200 part distilled water flush away formaldehyde, vacuum drying gets product again.
5. enrofloxacin clathrate according to claim 3, it is characterized in that: preparation method is:
The extraction of Semen Trigonellae: get Semen Trigonellae and be crushed to 100 orders, add the distilled water of 13 times of Semen Trigonellae quality, in 68 ℃ of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is 1/5 of original volume, it is standby namely to get the Semen Trigonellae extracting solution;
The preparation of elementary complex: with hydroxypropyl emthylcellulose, mannitol, the abundant mixing of Semen Trigonellae extracting solution, it is standby that the interpolation distilled water is made the mixing saturated solution; Enrofloxacin is dissolved in the NaOH solution of 1mol/L of 25 times of enrofloxacin quality, and with mix saturated solution and fully mix, supersound process 1h, it is standby namely to get elementary complex;
The preparation of middle rank complex: make saturated solution in the distilled water with 40 ℃ of HP-addings, under the electronic stirring of magnetic force, elementary complex is joined in the HP-saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, get white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is standby in 60 ℃;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, it is standby to make gelatin solution, and intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; Under 50 ℃, regulate pH value to 3.3, add acetone, make the emulsion cohesion, add 3 parts of formaldehyde again, regulate pH value to 8.0, solidify down at 5 ℃, with 165 parts of distilled water flush away formaldehyde, vacuum drying gets product again.
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| CN109453390A (en) * | 2018-11-30 | 2019-03-12 | 佛山科学技术学院 | A kind of Enrofloxacin hydroxypropyl cyclodextrin inclusion and its preparation method and application |
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| CN104195095A (en) * | 2014-09-22 | 2014-12-10 | 云南省畜牧兽医科学院 | Cell culture medium with anti-pollution capacity |
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| CN109453390A (en) * | 2018-11-30 | 2019-03-12 | 佛山科学技术学院 | A kind of Enrofloxacin hydroxypropyl cyclodextrin inclusion and its preparation method and application |
| CN109453390B (en) * | 2018-11-30 | 2021-11-30 | 佛山科学技术学院 | Enrofloxacin hydroxypropyl cyclodextrin inclusion compound and preparation method and application thereof |
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Effective date of registration: 20160712 Address after: 330500 Jiangxi city of Nanchang province Anyi County Phoenix Industrial Park Road Patentee after: Jiangxi painI Biological Pharmaceutical Co. Ltd. Address before: 330096 hi tech Industrial Development Zone, Jiangxi, Nanchang Patentee before: Jiangxi New Century Minxing Animal Health Product Co., Ltd. |