CN103239497B - 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 ENR, enrofloxacin, grace fluorine quinoline carboxylic acid, belong to the chemosynthesis antibacterial of Fluoroquinolones (Fluoroquinolones), for micro-yellow or light yellow crystalline powder, water insoluble, be soluble in the organic solvents such as sodium hydroxide solution, methanol and cyanogen methane.This product is broad-spectrum sterilization medicine, and mycoplasma is had to specially good effect.Escherichia coli, klebsiella bacillus, Salmonella, Bacillus proteus, bacillus pyocyaneus, haemophilus, pasteurella multocida, pasteurella haemolytica, golden Portugal bacterium, streptococcus etc. are had to sterilization effectiveness.Can be used as animal-use drug product, long half time in animal body, has good tissue distribution, belongs to 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.Meanwhile, the elimination half-life of enrofloxacin in poultry body is relatively short, needs continuous several times administration can reach therapeutic purposes, and frequent medication brings very big inconvenience to clinical use, and that also more easily causes animal simultaneously stress.Meanwhile, because enrofloxacin dissolution is low, the enrofloxacin preparation technology of high concentration is more difficult, and constant product quality cannot be ensured.And the enrofloxacin of low concentration must cause drug effect to weaken, in order to address this problem, seek new technique, 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, dissolution is high, and stability is high, strong drug action, formula rationally, not only can reduce difficulty of processing, also can reach good slow releasing function.
Another object of the present invention is to provide the preparation method of this enrofloxacin clathrate, and its process is coherent, and technological parameter science is applicable to industrialization promotion.
The technical scheme that realizes above-mentioned purpose is:
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: enrofloxacin 10-15 part, Semen Trigonellae 8-12 part, hydroxypropyl emthylcellulose 5-8 part, mannitol 2-4 part, HP-β-CD 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 to 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 DEG C of heating lixiviate 2-4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add gelatin quality 40-60 distilled water doubly in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 45 DEG C-55 DEG C, regulate pH value to 3.2-3.5, add acetone, make emulsion cohesion, then add 2-4 part formaldehyde, regulate pH value to 8.0, at 4-6 DEG C, solidify, wash away formaldehyde with 100-200 part distilled water, then vacuum drying gets product.
Semen Trigonellae: Latin is called Trigonella foenum-graecum L., is the dry mature seed of leguminous plant Semen Trigonellae.Nature and flavor hardship, temperature, return kidney channel, and effect is warming the kidney to activate YANG, and dispersing cold for relieving pain is mainly used in 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 in the present invention is a kind of novel enrofloxacin slow releasing preparation, by by compatible to enrofloxacin and Semen Trigonellae extract, when strengthening drug effect, reduce difficulty in process, again through slow-release auxiliary material hydroxypropyl emthylcellulose, sweeting agent mannitol enclose, by chemical bond by compound medicine enclose in inside, again successively through HP-β-CD, the adjuvant enclose such as gelatin form stay-in-grade clathrate, delay drug release to reaching, reduce clinical administration number of times, improve product stability and improve the object of the palatability of medicine, thereby the shortcoming overcoming and make up traditional enrofloxacin preparation is with not enough.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is described further, to help understanding content of the present invention.
Embodiment 1:
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts, mannitol, 37 parts of HP-β-CD, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts, gelatin, 4 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 50 DEG C, regulate pH value to 3.3, add acetone, make emulsion cohesion, then add 3 parts of formaldehyde, regulate pH value to 8.0, at 5 DEG C, solidify, wash away formaldehyde with 165 parts of distilled water, then vacuum drying gets product.
Embodiment 2
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 10 parts of enrofloxacins, 8 parts of Semen Trigonellaes, 5 parts of hydroxypropyl emthylcelluloses, 2 parts, mannitol, 30 parts of HP-β-CD, 3 parts of Polyethylene Glycol, 1 part of propylene glycol, 8 parts, gelatin, 3 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 2h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 40 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 45 DEG C, regulate pH value to 3.2, add acetone, make emulsion cohesion, then add 2 parts of formaldehyde, regulate pH value to 8.0, at 4 DEG C, solidify, wash away formaldehyde with 100 parts of distilled water, then vacuum drying gets product.
Embodiment 3
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 15 parts of enrofloxacins, 12 parts of Semen Trigonellaes, 8 parts of hydroxypropyl emthylcelluloses, 4 parts, mannitol, 45 parts of HP-β-CD, 5 parts of Polyethylene Glycol, 3 parts of propylene glycol, 12 parts, gelatin, 5 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 60 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 55 DEG C, regulate pH value to 3.5, add acetone, make emulsion cohesion, then add 4 parts of formaldehyde, regulate pH value to 8.0, at 6 DEG C, solidify, wash away formaldehyde with 200 parts of distilled water, then vacuum drying gets product.
Embodiment 4
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 8 parts of enrofloxacins, 7 parts of Semen Trigonellaes, 4 parts of hydroxypropyl emthylcelluloses, 2 parts, mannitol, 26 parts of HP-β-CD, 2 parts of Polyethylene Glycol, 1 part of propylene glycol, 8 parts, gelatin, 2 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 2-4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 38 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 45 DEG C, regulate pH value to 3.2, add acetone, make emulsion cohesion, then add 2 parts of formaldehyde, regulate pH value to 8.0, at 4 DEG C, solidify, wash away formaldehyde with 90 parts of distilled water, then vacuum drying gets product.
Embodiment 5
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 18 parts of enrofloxacins, 15 parts of Semen Trigonellaes, 9 parts of hydroxypropyl emthylcelluloses, 5 parts, mannitol, 48 parts of HP-β-CD, 6 parts of Polyethylene Glycol, 4 parts of propylene glycol, 15 parts, gelatin, 6 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 5h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 62 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 60 DEG C, regulate pH value to 3.5, add acetone, make emulsion cohesion, then add 5 parts of formaldehyde, regulate pH value to 8.0, at 6 DEG C, solidify, wash away formaldehyde with 210 parts of distilled water, then vacuum drying gets product.
Comparative example 1
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 20 parts of enrofloxacins, 6 parts of hydroxypropyl emthylcelluloses, 3 parts, mannitol, 37 parts of HP-β-CD, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts, gelatin, 4 parts, acetone;
The preparation method that above-mentioned each component is made to enrofloxacin clathrate of the present invention is:
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 50 DEG C, regulate pH value to 3.3, add acetone, make emulsion cohesion, then add 3 parts of formaldehyde, regulate pH value to 8.0, at 5 DEG C, solidify, wash away formaldehyde with 165 parts of distilled water, then vacuum drying gets product.
Comparative example 2
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts, mannitol, 37 parts of HP-β-CD, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts, gelatin, 4 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
Enrofloxacin pretreatment: enrofloxacin is dissolved in the NaOH solution of 1mol/L of 25 times of enrofloxacin quality, obtains pretreated enrofloxacin solution for standby;
The preparation of elementary complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, pretreated enrofloxacin solution, hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that elementary complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, make gelatin solution for subsequent use, elementary complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 50 DEG C, regulate pH value to 3.3, add acetone, make emulsion cohesion, then add 3 parts of formaldehyde, regulate pH value to 8.0, at 5 DEG C, solidify, wash away formaldehyde with 165 parts of distilled water, then vacuum drying gets product.
Comparative example 3
Enrofloxacin clathrate, is made up of the raw material of following weight proportioning: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts, mannitol, 37 parts of HP-β-CD, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts, gelatin, 4 parts, acetone;
The preparation method that above-mentioned each component is made to 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 DEG C of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: HP-β-CD, hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, make gelatin solution for subsequent use, elementary complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 50 DEG C, regulate pH value to 3.3, add acetone, make emulsion cohesion, then add 3 parts of formaldehyde, regulate pH value to 8.0, at 5 DEG C, solidify, wash away formaldehyde with 165 parts of distilled water, then vacuum drying gets product.
Comparative example 4
Enrofloxacin clathrate, the medicament of being made by the raw material of following weight proportioning: enrofloxacin 10-15 part, HP-β-CD 30-45 part, 0.1mol/L sodium hydroxide 8-12 part;
The preparation method that above-mentioned each component is made to enrofloxacin clathrate of the present invention is: enrofloxacin and HP-β-CD, according to 1:1 molar ratio weighing, are first used enrofloxacin to 0.1mol/L dissolution of sodium hydroxide; In the another distilled water that remaining HP-β-CD is added to 40 DEG C, make saturated solution, under magnetic force electric stirring, enrofloxacin solution is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continues to be stirred to room temperature, obtains white suspension, putting refrigerator and cooled hides after 24h, sucking filtration, with enrofloxacin quality 6-12 chloroform washing doubly 3 times, 60 DEG C are drying to obtain.
Test example
1, drug release determination
Accurately respectively take enrofloxacin clathrate prepared by 30mg embodiment 1-5 and comparative example 1-4, render to respectively in nine stripping rotors that respectively contain 900 mL release medium, measure by dissolution method second method of 98 pages of " People's Republic of China's veterinary drug allusion quotation " version First annex in 2005,0.5 DEG C of 37 DEG C of scholar of release medium temperature, Kaplan rotating speed 50 r/min.Self-preparing agent contact release medium plays 1min, 2min, 4min, 6min and samples respectively, each time point samples 5 mL from each stripping rotor, 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 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 gathers, with crude drug release conditions in contrast, investigate the slow release effect of clathrate.The results are shown in Table 1:
The comparison of table 1 slow release effect
As seen from the above table: compared with crude drug, each experimental group all has obvious slow releasing function, wherein embodiment 1-3 is better than embodiment 4-5, embodiment 4-5 is better than comparative example 1-4, wherein embodiment 1 effect optimum, the factors such as visible formula, each supplementary material proportioning, technique and technological parameter, all can affect the slow release effect of product, only have four to complement each other, reasonable compatibility, can get a desired effect.
2, stability test
Get respectively enrofloxacin clathrate prepared by embodiment 1-5 and comparative example 1-4, press commercially available back (plastic bag sealing packaging, every bag of 100g), 2 DEG C of temperature 40 scholars, under relative humidity 75% scholar's 5% condition, place 6 months, sample respectively once the 1st, 2,3,6 the end of month, investigate test sample cosmetic variation, and carry out assay, investigate the stability of test sample.Assay: accurately respectively take enrofloxacin clathrate prepared by 25.0mg embodiment 1-5 and comparative example 1-4 and be placed in 100mL volumetric flask, add the sodium hydroxide solution 10mL of 0.1mol/L to dissolve and add tri-distilled water standardize solution, after 0.45 μ m filtering with microporous membrane, dilute 10 times, obtain need testing solution, inject high performance liquid chromatograph and measure, the results are shown in Table 2:
The comparison of table 2 stability
As seen from the above table: due to each experimental group supplementary material proportioning difference, cause its determining enrofloxacin content difference, under high humidity hot environment is preserved, the determining enrofloxacin content of each experimental group all has fluctuation in various degree, wherein embodiment 1-3 fluctuation is less, stability is obviously better than embodiment 4-5 and comparative example 1-4, and embodiment 1 effect optimum.Comparative example 1, comparative example 4 fluctuate larger, and this is to only to contain enrofloxacin and enclose adjuvant and technique in its prescription relevant, and high concentration enrofloxacin causes product stability to reduce, and difficulty of processing increases simultaneously, visible rationally composite addressing this problem.
3, animal experiment
Broiler, without pasteurellosis bacillus vaccine immunity, male and female has concurrently, raises routinely, feeds complete feed, free choice feeding and drinking-water.Before test, carry out clinical observation, healthy person is selected.When 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 use, the strong toadstool kind of preservation is first inoculated blood agar plate, is incubated at 37 DEG C, after 24h, selects colonies typical and is inoculated in meat soup, takes out again after 37 DEG C are cultivated 18h.By this broth culture inoculation chicken, also can be by lethal inoculation chicken in the hope of its pathogenicity rejuvenation, separate pasteurellosis bacillus and inoculate blood agar plate and cultivate from the liver of dead chicken, finally selecting colonies typical ordinary broth cultivates, 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: inoculate above-mentioned bacterium liquid 0.05ml by the Muscle of chicken of every 100g body weight, approximately containing 2,500,000 CFU viable bacterias.
Reaction is observed: before inoculation and after inoculation, observes the clinical symptoms of chicken, mainly comprises the mental status, appetite, feces etc., and record respectively.Dead chicken is carried out to necropsy, get liver and carry out antibacterial separation and Culture.
5h after test method: 1-8 group chicken inoculation bacterium liquid, gives respectively enrofloxacin clathrate prepared by embodiment 1-5, comparative example 1-4, and clathrate mixes in broiler fodder, (every 1kg feedstuff adds 10g clathrate) 3d continuously.Another group does not infect not administration, and as normal healthy controls group, last group, as infecting matched group, infects not administration.Observation period, for the rear 15d of inoculation, is observed the various clinical manifestations of chicken every day, and dead chicken is carried out to necropsy, makes antibacterial separation and Culture, determines the cause of the death.And weighing and body condition observation before and after every chicken is tested.The results are shown in Table 3.
The standard of curative effect evaluation:
1) death: at duration of test, occur classical symptom the death of chicks, necropsy has typical characteristics of lesion, and separation and Culture goes out chicken source pasteurella multocida from liver, is judged to be to infect dead.Calculate the mortality rate of each group according to dead chicken number.
2) cure: at duration of test, after for oral administration or intramuscular administration, the mental status, appetite recover normal, no longer occur that clinical symptoms all belongs to healing.The ratio that accounts for test group according to healing chicken calculates cure rate.
3) effective: after for oral administration or intramuscular administration, the chicken of healing and there is no death but have Symptoms person is " effectively " completely; The percentage rate that when off-test, the chicken number of every group of survival accounts for test chicken number 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, then calculate accordingly average weight gain and the standard deviation of every group of test chicken.The relative weight gain rate is to calculate by each medication treatment group and the ratio of the average weight gain of normal healthy controls group, and wherein normal healthy controls group is made as 100%.
The curative effect situation of table 3 enrofloxacin clathrate to test chicken Bacillus pasteurii disease
As seen from the above table: embodiment 1-3 group, to the effective percentage of test chicken Bacillus pasteurii disease, up to 100%, and the relative weight gain rate is also higher than other test group, wherein especially with embodiment 1 effect optimum, each component proportion science in this and embodiment 1, technique is rationally closely related.Embodiment 4-5 effect is slightly inferior to embodiment 1-3, and this is unreasonable relevant to the ratio range of two groups, and comparative example 1-4 effect is inferior to embodiment 1-5, illustrates and only has formula, technique to complement each other, and just can bring into play maximum drug effect.
Claims (4)
1. enrofloxacin clathrate, is characterized in that: it is the medicament of being made up of the raw material of following weight proportioning: enrofloxacin 10-15 part, Semen Trigonellae 8-12 part, hydroxypropyl emthylcellulose 5-8 part, mannitol 2-4 part, HP-β-CD 30-45 part, Polyethylene Glycol 3-5 part, propylene glycol 1-3 part, gelatin 8-12 part, acetone 3-5 part.
2. enrofloxacin clathrate according to claim 1, is characterized in that: it is the medicament of being made up of the raw material of following weight proportioning: 12 parts of enrofloxacins, 11 parts of Semen Trigonellaes, 6 parts of hydroxypropyl emthylcelluloses, 3 parts, mannitol, 37 parts of HP-β-CD, 4 parts of Polyethylene Glycol, 2 parts of propylene glycol, 10 parts, gelatin, 4 parts, acetone.
3. enrofloxacin clathrate according to claim 1, 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 DEG C of heating lixiviate 2-4h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add gelatin quality 40-60 distilled water doubly in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 45 DEG C-55 DEG C, regulate pH value to 3.2-3.5, add acetone, make emulsion cohesion, then add 2-4 part formaldehyde, regulate pH value to 8.0, at 4-6 DEG C, solidify, wash away formaldehyde with 100-200 part distilled water, then vacuum drying gets product.
4. enrofloxacin clathrate according to claim 2, 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 DEG C of heating lixiviate 3h, filtering and collecting filter liquid, distilling under reduced pressure filtrate is original volume 1/5, obtains Semen Trigonellae extracting solution for subsequent use;
The preparation of elementary complex: hydroxypropyl emthylcellulose, mannitol, Semen Trigonellae extracting solution are fully mixed, and it is for subsequent use that interpolation distilled water is made 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, obtains elementary complex for subsequent use;
The preparation of middle rank complex: HP-β-CD is added in the distilled water of 40 DEG C and make saturated solution, under magnetic force electric stirring, elementary complex is joined in HP-β-CD saturated solution, constant temperature stirs 30min and stops heating, continue to be stirred to room temperature, obtain white suspension, carry out freezing preservation 24 hours, sucking filtration, dry that intermediate complex is for subsequent use in 60 DEG C;
The preparation of finished product: add the distilled water of 52 times of gelatin quality in gelatin, make gelatin solution for subsequent use, intermediate complex, Polyethylene Glycol, propylene glycol and this gelatin solution are mixed into emulsion; At 50 DEG C, regulate pH value to 3.3, add acetone, make emulsion cohesion, then add 3 parts of formaldehyde, regulate pH value to 8.0, at 5 DEG C, solidify, wash away formaldehyde with 165 parts of distilled water, then vacuum drying gets product.
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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. |