CN102600184B - Veterinary-use intestinal targeted antibacterial pellet and preparation method thereof - Google Patents
Veterinary-use intestinal targeted antibacterial pellet and preparation method thereof Download PDFInfo
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- CN102600184B CN102600184B CN 201210053048 CN201210053048A CN102600184B CN 102600184 B CN102600184 B CN 102600184B CN 201210053048 CN201210053048 CN 201210053048 CN 201210053048 A CN201210053048 A CN 201210053048A CN 102600184 B CN102600184 B CN 102600184B
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Abstract
The invention discloses a veterinary-use intestinal targeted antibacterial pellet. The veterinary-use intestinal targeted antibacterial pellet comprises a main drug and auxiliary drugs, wherein the main drug is composed of valnemulin hydrochloride and chlortetracycline hydrochloride; the mass of the valnemulin hydrochloride is 1-5% of that of the pellet; the mass of the chlortetracycline hydrochloride is 5-16 times of that of the valnemulin hydrochloride; the pellet sequentially comprises a valnemulin hydrochloride core, an intestinal targeted coating layer, a chlortetracycline hydrochloride drug layer and an outer coating layer from inside to outside. The invention further discloses a preparation method of the veterinary-use intestinal targeted antibacterial pellet. Through the combination of the method and the formula, the valnemulin hydrochloride and the chlortetracycline hydrochloride are adopted for preparing the pellet; the pellet is released in a gradient form in an animal digestion system; the chlortetracycline hydrochloride is firstly released and absorbed by the stomach and the intestine; the valnemulin hydrochloride is rapidly released and absorbed by the intestinal tract with the pH value larger than or equal to 6.8, so that an excellent intestinal tract sterilization effect is achieved, the drug absorbed by the colon can be prevented from suffering from the first-pass effect of the liver and the intestine, the haemoconcentration and bioavailability of the valnemulin hydrochloride can be improved, and an excellent treatment effect for systemic diseases is obtained.
Description
Technical field
The present invention relates to a kind of animal with antibacterials and preparation method thereof, be specifically related to antibiotic micropill of a kind of intestinal targeting for animals and preparation method thereof, belong to the veterinary drug technical field.
Background technology
Valnemulin (Valnemulin) is pleuromutilin of new generation (pleuromutilin) class semisynthetic antibiotics, belongs to two terpenes, belongs to same class medicine with taimulin, is the animal specific antibiotic.The valnemulin has a broad antifungal spectrum is to G
+, G
-With the mycoplasma bacterium effect is arranged all, be mainly used in preventing and treating the dysentery that is caused by the short spirillum of swine dysentery, the pneumonia that mycoplasma hyopneumoniae causes, the hog middle inflammation that colon pili sample weak point spirillum causes, the pig hypertrophy ileitis of thin lawsonia intracellularis initiation, the chronic respiratory tract disease that is caused by the fowl Frustrate blood and mycoplasma, the secondary pneumonia that is caused by pasteurella multocida, Actinobacillus pleuropneumoniae, haemophilus parasuis, the sheep that pasteurella haemolytica causes and the pneumonia of cattle are by mycoplasma hyosynoviae polyarthritis etc.Particularly Mycoplasma and Spirochaetes are extremely sensitive.The EMEA data shows, 425 ~ 250 mg/kg valnemulins control mycoplasma pneumoniae of swine, rate of growth have improved 6% ~ 13%, feed conversion rate improves 40%, pulmonary lesion is long-pending reduces 40%.In addition, Poulsen etc. discover, valnemulin can with the V district combination of pathogenic microorganism ribosome 23sRNA, stop transpeptidase in the accurate location of the CCA-of tRNAs end, thereby suppress the synthetic of pathogenic microorganism protein, cause its death, with act on the 30s subunit press down the germ killing drugs use in conjunction, have synergism.
Chlortetracycline (Chlortetracycline) claims duomycin again, belongs to a kind of of derivant in the Tetracyclines, is yellow or golden yellow crystallization, bitter in the mouth, and it is dark to meet photochromic gradual change, and slightly soluble in water or ethanol is almost insoluble in acetone, ether or chloroform.The chlortetracycline has a broad antifungal spectrum all can produce inhibitory action to positive bacteria, negative bacterium, spirillum, rickettsia, mycoplasma, chlamydia, some protozoon etc.Chlortetracycline mainly is combined with the 30S of microorganism small subunit A position, and then disturbs aminoacyl tRNA to be combined with the 30S small subunit, makes aminoacyl tRNA can not enter the position that is subjected on the mRNA, the prolongation of peptide chain when having suppressed protein synthesis; Chlortetracycline can also stop synthetic protein peptide chain to discharge, and chlortetracycline is more responsive to the ribosomal effect of 70S, and therefore, chlortetracycline can suppress sensitive microbial by selectivity, has good security performance.Chlortetracycline has synergism with the drug combination that acts on the 50s subunit.Proof valnemulins such as L á szl ó Stipkovits and chlortetracycline drug combination obviously are better than other application method, and the prescription of valnemulin+chlortetracycline is with 75mg/kg+400mg/kg resultant effect optimum.
Non-targeting valnemulin is absorbed substantially at harmonization of the stomach duodenum place, and the liver sausage first pass effect is obvious, and bioavailability is lower; Lawsonia intracellularis, treponema, the short spirillum of colon pili sample and mycoplasma hyopneumoniae main parasitic are at ileum, ileocecum junction, colon and lungs, and valnemulin is lower at the drug level at this place; In addition, valnemulin antimicrobial spectrum relative narrower.
Summary of the invention
At above deficiency, the invention provides the antibiotic micropill of a kind of intestinal targeting for animals, this micropill has carried out the targeting compound recipe design of valnemulin hydrochloride and chlortetracycline hydrochloride, evidence, targeting design effectively reduce valnemulin hydrochloride the liver sausage first pass effect, improved bioavailability, improved its drug level in the pathogenic microorganism parasitic site; Compositely not only increase scope of restraining fungi, and strengthened therapeutic effect, be significantly higher than independent use valnemulin hydrochloride or chlortetracycline hydrochloride and both is simply composite.
The present invention also provides the preparation method of this micropill, and this method designs according to the structure of micropill, has farthest guaranteed the therapeutic effect of medicine.
Micropill of the present invention (is called for short the ball core by valnemulin hydrochloride ball core, down together), intestinal targeting coatings, chlortetracycline hydrochloride medicine layer and outer coatings layer are formed, described intestinal targeting coatings is made up of acrylic resin intestinal-specific coating material and other coating materials, the chlortetracycline hydrochloride medicine layer is made up of chlortetracycline hydrochloride principal agent and adjuvant, and the outer coatings layer is made up of coating material.Concrete technical scheme is as follows:
The antibiotic micropill of a kind of intestinal targeting for animals, comprise principal agent and adjuvant, it is characterized in that: described principal agent is valnemulin hydrochloride and chlortetracycline hydrochloride, valnemulin hydrochloride is 1～5% of micropill quality, chlortetracycline hydrochloride is 5～16 times of valnemulin hydrochloride quality, and micropill is respectively valnemulin hydrochloride ball core, intestinal targeting coatings, chlortetracycline hydrochloride medicine layer and outer coatings layer from inside to outside.
Concrete, described valnemulin hydrochloride ball core comprises following composition: valnemulin hydrochloride 30-45%, adhesive 5-10wt%, disintegrating agent 2-4wt%, filler 50-65wt%, with mentioned component with alcoholic solution soft material processed, make the ball core, concentration of ethanol is 75-95vol%.Described adhesive is starch slurry, and disintegrating agent is carboxymethylstach sodium, and filler is the mixture of starch and sucrose, and acrylic resin is acrylic resin II and III, and antistatic additive is dodecyl sodium sulfate, and plasticizer is diethyl phthalate.Preferably, the mass ratio of starch and sucrose is 1:0.5-2, and the mass ratio of acrylic resin II and acrylic resin III is 1-2:1.
In the preparation of valnemulin hydrochloride ball core, concentration of ethanol is 75-95vol%, and the mass ratio of filler and alcoholic solution is 0.5-2:1.
Described intestinal targeting coatings is made by intestinal targeting coating solution, and intestinal targeting coating solution is solvent with the alcoholic solution, and concentration is 4-8%, solute comprises following composition: acrylic resin 65-70%, antistatic additive 0.2-0.5%, plasticizer 30-35%, concentration of ethanol is 60-85vol%.
Described chlortetracycline hydrochloride medicine layer is made by the chlortetracycline hydrochloride medicinal liquid, the chlortetracycline hydrochloride medicinal liquid is that concentration is 20% ~ 40% suspension, solvent is water, the solute composition is as follows, each composition sum is 100wt%: chlortetracycline hydrochloride 53-66wt%, adhesive 5-10wt%, disintegrating agent 2-4wt%, filler 20-40wt%.
The outer coatings layer is made by overcoat solution, the overcoat solution composition comprises: Pulvis Talci 4-6 weight portion, Eudragit(is You Teqi) the 8-12 weight portion, the PEG6000(polyethylene glycol 6000) 0.5-1.5 weight portion, the 0.08-0.12% of polyoxyethylene sorbitan monoleate chlortetracycline hydrochloride quality, deionized water 2 weight portions, alcoholic solution 140 weight portions, concentration of ethanol is more than 50vol%.
In the antibiotic micropill of above-mentioned intestinal targeting for animals, micropill weightening finish 5-20wt% after the coating intestinal targeting coatings, coat behind the chlortetracycline hydrochloride medicine layer wherein contained chlortetracycline hydrochloride and be 5～16 times of valnemulin hydrochloride quality, coat micropill weightening finish 3-13wt% behind the outer coatings layer.
The invention provides the preparation method of the antibiotic micropill of above-mentioned intestinal targeting for animals, it is characterized in that may further comprise the steps:
(1) principal agent and adjuvant are pulverized respectively, standby;
(2) preparation of ball core: with valnemulin hydrochloride, filler, disintegrating agent and adhesive mix homogeneously, with alcoholic solution soft material processed, make the ball core by extruding spheronization;
(3) preparation of intestinal targeting coatings: be made into intestinal targeting coating solution by proportioning, the ball core is carried out coating, the ball core stops when increasing weight to 5-20wt% coating;
(4) preparation of chlortetracycline hydrochloride medicine layer: be made into the chlortetracycline hydrochloride medicinal liquid by proportioning, further coat and go up the chlortetracycline hydrochloride medicine layer, the chlortetracycline hydrochloride in the medicine layer stops to coat when satisfying proportioning with valnemulin hydrochloride;
(5) preparation of outer coatings layer: be made into overcoat solution by proportioning, further coat and go up the outer coatings layer, micropill stops when increasing weight to 3-13wt% coating, and gets the antibiotic micropill of intestinal targeting that gradient for animals discharges.
In the said method, during preparation ball core, the process conditions of extruding spheronization are: extruded velocity 35 ~ 45 r/min, round as a ball speed 40 ~ 50 r/min, round as a ball times 2 ~ 6 min.
In the said method, be equipped with intestinal targeting coatings by the fluidized coating legal system, process conditions are: the hydrojet mode is end spray, intestinal targeting coating solution flow velocity 3 ~ 5ml/min, air intake pressure 0.22 ~ 0.25 bar, inlet temperature 40-55 ℃, 55 ~ 60 ℃ of baking temperatures, drying time 2-4h.
In the said method, chlortetracycline hydrochloride medicine layer and outer coatings layer are undertaken by the fluidized coating method, and process conditions are: the hydrojet mode is end spray, and chlortetracycline hydrochloride medicinal liquid or overcoat solution flow velocity are 3 ~ 5mL/min, inlet temperature is 40-55 ℃, and atomizing pressure is 1.3 ~ 1.45bar.
The present invention is by (core that refers to micropill is valnemulin hydrochloride ball core to the micropill structure, coat intestinal targeting coatings on it, be coated with one deck chlortetracycline hydrochloride medicine layer again, outermost is one deck outer coatings layer) design realized the purpose that drug targeting discharges, effectively reduce valnemulin the liver sausage first pass effect, improved bioavailability, improved its drug level in the pathogenic microorganism parasitic site.
Further, by making scheme more complete to thickness, adjuvant and the consumption thereof of each layer, the selection of content of medicines.In micropill, the content of valnemulin hydrochloride is beneficial to industrial applications most when 1-5%, and selected adjuvant is to meet the coating material that pharmacopeia requires, but by the selection optimization of adjuvant and consumption thereof being made the targeting of micropill, releasing effect better.The weightening finish of each layer has considerable influence to the releasing degree of medicine in the micropill, for the release of balance medicine and the situation of targeting, has determined the weightening finish of each layer in the micropill by a large amount of experiments.
The selected adjuvant of medicine of the present invention is inertia, can not influence the effect of principal agent, also can not measure drug content, medicine stability exerts an influence.
The present invention is effective ingredient with valnemulin hydrochloride and chlortetracycline hydrochloride, selected proper supplementary material, medicine is made micropill, micropill is nuclear with the valnemulin hydrochloride, chlortetracycline hydrochloride is coated on outside it, and micropill discharges in animal digestive system in gradient, and chlortetracycline hydrochloride obtains earlier discharging, absorbed performance therapeutic effect and cytochrome P by gastrointestinal
450The non-specific inhibitory action of enzyme, valnemulin hydrochloride (also being the main parasitic position of pathogenic microorganisms such as dysentery treponema and lawsonia intracellularis) in the intestinal of pH 〉=6.8 promptly discharges, absorbs, both obtained good intestinal bactericidal action, the medicine that colon absorbs can be avoided the liver sausage first pass effect, improve haemoconcentration and the bioavailability of valnemulin hydrochloride, obtain good systemic treatment of diseases effect again.
Preparation method of the present invention, reasonable in design, easy operating has farthest guaranteed the therapeutic effect of medicine.
The specific embodiment
Below, the present invention will be further elaborated by specific embodiment, should be understood that, and following explanation only is in order to explain the present invention, its content not to be limited.
Embodiment 1
According to technical scheme of the present invention, the preparation micropill, the content of valnemulin hydrochloride is 5wt% in the micropill, seeing the following form with magnitude relation of principal agent and adjuvant, described adjuvant refer to the composition (for example filler, disintegrating agent, adhesive etc.) that contains in demineralizing acid valnemulin and the outer micropill of chlortetracycline hydrochloride:
Micropill of the present invention (is called for short the ball core by valnemulin hydrochloride ball core, down together), intestinal targeting coatings, chlortetracycline hydrochloride medicine layer and outer coatings layer are formed, contain the principal agent valnemulin hydrochloride in the ball core, it is coated with intestinal targeting coatings, contain acrylic resin intestinal-specific coating material (also can be called intestinal targeting coating material) in the intestinal targeting coatings, can make the principal agent valnemulin hydrochloride carry out targeting in intestinal discharges, significantly reduced the early stage under one's belt with duodenal release, improved drug bioavailability.According to the magnitude relation of using of micropill principal agent and adjuvant in the last table, design 3 kinds of prescription micropills, each composition specifically with magnitude relation Lie Gebiao as follows in the micropill.
Ball core prescription is:
Intestinal targeting coatings is made by intestinal targeting coating solution, and coating solution consists of:
The chlortetracycline hydrochloride medicine layer is made by the chlortetracycline hydrochloride medicinal liquid, contains chlortetracycline hydrochloride in the chlortetracycline hydrochloride medicinal liquid, is solvent with water, consists of:
The outer coatings layer is made by overcoat solution, and the overcoat solution composition consists of:
After determining the consumption of each composition in the micropill, the preparation micropill, method is as follows:
1, principal agent and adjuvant are pulverized respectively, standby.
2, with valnemulin hydrochloride, starch slurry, carboxymethylstach sodium, starch and sucrose mix homogeneously, with the alcoholic solution of 75～95vol% soft material processed, the mass ratio of alcoholic solution and filler is 1:2～2:1, and the gained soft material is held agglomerating, and light the pressure namely loose.The soft material employing of gained is extruded-round as a ball prepared ball core, and process conditions are: extruded velocity 35～45 Hz, round as a ball speed 40～50 Hz, round as a ball times 2～6 min.
3, make intestinal targeting coating solution according to above-mentioned composition, coating solution concentration 4～8%, adopt fluid bed that the ball core is carried out coating then, condition is: the hydrojet mode: end spray, intestinal targeting coating solution flow velocity 3～5mL/min, air intake pressure 0.22～0.25 bar, 40～55 ℃ of inlet temperature, 55～60 ℃ of baking temperatures, drying time 2～4h, ball core weightening finish 5-20% stops to coat.
4, make the chlortetracycline hydrochloride medicinal liquid according to above-mentioned composition, medicinal liquid is 20～40% suspension, adopt fluid bed to carry out coating, condition is: adopt end spray, medicinal liquid flow velocity 3～5mL/min, 40～55 ℃ of inlet temperature, atomizing pressure 1.3～1.45bar, fluidisation pressure 0.29～0.5bar, temperature of charge 28-35 ℃, about supply gas pressure 0.68mpa, micropill superscribes behind the medicine each other glutinous the company, micropill increases weight to the drug loading of chlortetracycline hydrochloride and reaches proportion requirement, stops to coat.
5, make overcoat solution according to above-mentioned composition, adopt fluid bed to carry out coating, condition is: adopt end spray, medicinal liquid flow velocity 3 ~ 5mL/min, 40 ~ 55 ℃ of inlet temperature, atomizing pressure 1.3 ~ 1.45bar, fluidisation pressure 0.29 ~ 0.5bar, temperature of charge 28-35 ℃, about supply gas pressure 0.68mpa, micropill increases weight and stops to coat to 3-13%, finally obtains micropill required for the present invention.
Three groups of micropills of different component in above-described embodiment 1 are carried out drug release rate mensuration by the method for regulation in the veterinary drug allusion quotation (2010) respectively, the every batch of micropill is parallel makees 6 samples, in the hydrochloric acid solution of pH=1, the average release of chlortetracycline hydrochloride is between 83.3 ~ 88.7%, and the average release of valnemulin hydrochloride is between 4.1 ~ 6.9%; In the phosphate buffer of pH=6.8, the average release of valnemulin hydrochloride is between 81.4 ~ 86.2%.
Embodiment 2
According to technical scheme of the present invention, the preparation micropill, the content of valnemulin hydrochloride is 5wt% in the micropill, seeing the following form with magnitude relation of principal agent and adjuvant, described adjuvant refer to the composition (for example filler, disintegrating agent, adhesive etc.) that contains in demineralizing acid valnemulin and the outer micropill of chlortetracycline hydrochloride:
In the micropill, ball core, intestinal targeting coatings, chlortetracycline hydrochloride medicine layer are identical with embodiment 1 with component content percentage ratio in the outer coatings layer, and preparation method is also identical with embodiment 1.
Three batches of micropills of different component in above-described embodiment 2 are carried out drug release rate mensuration by the method for regulation in the veterinary drug allusion quotation (2010) respectively, the every batch of micropill is parallel makees 6 samples, in the hydrochloric acid solution of pH=1, the average release of chlortetracycline hydrochloride is between 85.3 ~ 93.1%, and the average release of valnemulin hydrochloride is between 5.6 ~ 9.2%; In the phosphate buffer of pH=6.8, the average release of valnemulin hydrochloride is between 79.3 ~ 87.1%.
Embodiment 3
According to technical scheme of the present invention, the preparation micropill, the content of valnemulin hydrochloride is 1wt% in the micropill, seeing the following form with magnitude relation of principal agent and adjuvant, described adjuvant refer to the composition (for example filler, disintegrating agent, adhesive etc.) that contains in demineralizing acid valnemulin and the outer micropill of chlortetracycline hydrochloride:
In the micropill, ball core, intestinal targeting coatings, chlortetracycline hydrochloride medicine layer are identical with embodiment 1 with component content percentage ratio in the outer coatings layer, and preparation method is also identical with embodiment 1.
Three batches of micropills of different component in above-described embodiment 3 are carried out drug release rate mensuration by the method for regulation in the veterinary drug allusion quotation (2010) respectively, the every batch of micropill is parallel makees 6 samples, in the hydrochloric acid solution of pH=1, the average release of chlortetracycline hydrochloride is between 80.2 ~ 89.4%, and the average release of valnemulin hydrochloride is between 2.1 ~ 6.3%; In the phosphate buffer of pH=6.8, the average release of valnemulin hydrochloride is between 87.1 ~ 92.3%.
Embodiment 4
According to technical scheme of the present invention, the preparation micropill, the content of valnemulin hydrochloride is 1wt% in the micropill, seeing the following form with magnitude relation of principal agent and adjuvant, described adjuvant refer to the composition (for example filler, disintegrating agent, adhesive etc.) that contains in demineralizing acid valnemulin and the outer micropill of chlortetracycline hydrochloride:
In the micropill, ball core, intestinal targeting coatings, chlortetracycline hydrochloride medicine layer are identical with embodiment 1 with component content percentage ratio in the outer coatings layer, and preparation method is also identical with embodiment 1.
Three batches of micropills of different component in above-described embodiment 4 are carried out drug release rate mensuration by the method for regulation in the veterinary drug allusion quotation (2010) respectively, the every batch of micropill is parallel makees 6 samples, in the hydrochloric acid solution of pH=1, the average release of chlortetracycline hydrochloride is between 82.0 ~ 91.6%, and the average release of valnemulin hydrochloride is between 3.6 ~ 7.0%; In the phosphate buffer of pH=6.8, the average release of valnemulin hydrochloride is between 84.4 ~ 89.0%.
Claims (9)
1. antibiotic micropill of intestinal targeting for animals, comprise principal agent and adjuvant, it is characterized in that: described principal agent is valnemulin hydrochloride and chlortetracycline hydrochloride, valnemulin hydrochloride is 1～5% of micropill quality, chlortetracycline hydrochloride is 5～16 times of valnemulin hydrochloride quality, and micropill is respectively valnemulin hydrochloride ball core, intestinal targeting coatings, chlortetracycline hydrochloride medicine layer and outer coatings layer from inside to outside;
Described valnemulin hydrochloride ball core comprises following composition, each composition sum is 100%: valnemulin hydrochloride 30-45%, starch slurry 5-10wt%, carboxymethylstach sodium 2-4wt%, filler 50-65wt%, mentioned component with alcoholic solution soft material processed, is made the ball core, and filler is the mixture of starch and sucrose;
Described intestinal targeting coatings is made by intestinal targeting coating solution, and intestinal targeting coating solution is solvent with the alcoholic solution, and concentration is 4-8%, solute comprises following composition, each composition sum is 100%: acrylic resin 65-70%, dodecyl sodium sulfate 0.2-0.5%, diethyl phthalate 30-35%;
Described chlortetracycline hydrochloride medicine layer is made by the chlortetracycline hydrochloride medicinal liquid, the chlortetracycline hydrochloride medicinal liquid is that concentration is 20% ~ 40% suspension, solvent is water, the solute composition is as follows, each composition sum is 100wt%: chlortetracycline hydrochloride 53-66wt%, adhesive 5-10wt%, disintegrating agent 2-4wt%, filler 20-40wt%;
The outer coatings layer is made by overcoat solution, the overcoat solution composition comprises: Pulvis Talci 4-6 weight portion, You Teqi 8-12 weight portion, polyethylene glycol 6000 0.5-1.5 weight portion, polyoxyethylene sorbitan monoleate, the amount of described polyoxyethylene sorbitan monoleate is the 0.08-0.12% of chlortetracycline hydrochloride quality, deionized water 2 weight portions, alcoholic solution 140 weight portions.
2. the antibiotic micropill of intestinal targeting for animals according to claim 1, it is characterized in that: micropill weightening finish 5-20wt% after the coating intestinal targeting coatings, coat behind the chlortetracycline hydrochloride medicine layer wherein contained chlortetracycline hydrochloride and be 5～16 times of valnemulin hydrochloride quality, coat micropill weightening finish 3-13wt% behind the outer coatings layer.
3. the antibiotic micropill of intestinal targeting for animals according to claim 2, it is characterized in that: acrylic resin is acrylic resin II and III.
4. the antibiotic micropill of intestinal targeting for animals according to claim 3, it is characterized in that: the mass ratio of starch and sucrose is 1:0.5-2, the mass ratio of acrylic resin II and acrylic resin III is 1-2:1.
5. the antibiotic micropill of intestinal targeting for animals according to claim 1 is characterized in that: in the preparation of valnemulin hydrochloride ball core, concentration of ethanol is 75-95vol%, and the mass ratio of filler and alcoholic solution is 0.5-2:1; In the intestinal targeting coating solution, concentration of ethanol is 60-85vol%; In the overcoat solution, concentration of ethanol is more than 50vol%.
6. the preparation method of the antibiotic micropill of the described intestinal targeting for animals of claim 1 is characterized in that may further comprise the steps:
(1) principal agent and adjuvant are pulverized respectively, standby;
(2) preparation of ball core: with valnemulin hydrochloride, filler, disintegrating agent and adhesive mix homogeneously, with alcoholic solution soft material processed, make the ball core by extruding spheronization;
(3) preparation of intestinal targeting coatings: be made into intestinal targeting coating solution by proportioning, the ball core is carried out coating, the ball core stops when increasing weight to 5-20wt% coating;
(4) preparation of chlortetracycline hydrochloride medicine layer: be made into the chlortetracycline hydrochloride medicinal liquid by proportioning, further coat and go up the chlortetracycline hydrochloride medicine layer, the chlortetracycline hydrochloride in the medicine layer stops to coat when satisfying proportioning with valnemulin hydrochloride;
(5) preparation of outer coatings layer: be made into overcoat solution by proportioning, further coat and go up the outer coatings layer, micropill stops when increasing weight to 3-13wt% coating, and gets the antibiotic micropill of intestinal targeting that gradient for animals discharges.
7. preparation method according to claim 6 is characterized in that: during preparation ball core, the process conditions of extruding spheronization are: extruded velocity 35 ~ 45 r/min, round as a ball speed 40 ~ 50 r/min, round as a ball times 2 ~ 6 min.
8. preparation method according to claim 6, it is characterized in that: be equipped with intestinal targeting coatings by the fluidized coating legal system, process conditions are: the hydrojet mode is end spray, intestinal targeting coating solution flow velocity 3 ~ 5mL/min, air intake pressure 0.22 ~ 0.25 bar, inlet temperature 40-55 ℃, 55 ~ 60 ℃ of baking temperatures, drying time 2-4h.
9. preparation method according to claim 6, it is characterized in that: chlortetracycline hydrochloride medicine layer and outer coatings layer are undertaken by the fluidized coating method, process conditions are: the hydrojet mode is end spray, chlortetracycline hydrochloride medicinal liquid or overcoat solution flow velocity are 3 ~ 5mL/min, inlet temperature is 40-55 ℃, and atomizing pressure is 1.3 ~ 1.45bar.
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| CN102813629A (en) * | 2012-08-29 | 2012-12-12 | 湖北龙翔药业有限公司 | Preparation method of tartaric acid valnemulin premixing agent |
| CN105997924A (en) * | 2016-07-07 | 2016-10-12 | 驻马店华中正大有限公司 | Chlortetracycline hydrochloride effervescent tablets and preparation method thereof |
| CN107519245A (en) * | 2017-09-25 | 2017-12-29 | 广东省农业科学院蚕业与农产品加工研究所 | A kind of preparation method with the mulberry fruit fine powder for improving gastrointestinal function |
| CN109528681B (en) * | 2018-12-12 | 2021-05-25 | 华南农业大学 | A chlortetracycline microcapsule granule for ruminant oral administration and its preparation method |
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| CN101450067A (en) * | 2007-11-29 | 2009-06-10 | 天津瑞普生物技术集团有限公司 | Premixing agent for treating and preventing livestock and poultry respiratory disease |
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