CN108478536B - A kind of salinomycin prilling process - Google Patents

A kind of salinomycin prilling process Download PDF

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CN108478536B
CN108478536B CN201810287348.1A CN201810287348A CN108478536B CN 108478536 B CN108478536 B CN 108478536B CN 201810287348 A CN201810287348 A CN 201810287348A CN 108478536 B CN108478536 B CN 108478536B
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salinomycin
added
prilling process
particle
air temperature
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CN108478536A (en
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马光辉
杨爱华
周彦乐
钟迎东
杨林
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INNER MONGOLIA BIOK BIOLOGY CO Ltd
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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Abstract

The invention belongs to field of veterinary, and in particular to a kind of salinomycin prilling process, this method mainly comprise the steps that (1) demulsifier and flocculant are added into salinomycin fermentation liquid, abandon supernatant after standing；(2) salinomycin is precipitated and is sequentially added to be granulated in fluidized bed with auxiliary material；(3) whole grain is sieved to obtain finished product.Salinomycin prilling process provided by the invention is simple, has not only avoided to the active destruction of salinomycin, but also improves the water solubility and mobility of product, and then improves the bioavilability and safety of salinomycin in animal body.

Description

A kind of salinomycin prilling process
Technical field
The invention belongs to field of veterinary, and in particular to a kind of salinomycin prilling process.
Background technique
With the development of animal husbandry, more and more antibiotics are widely used in treating and preventing each of poultry Class disease, medicament residue are an important factor for influencing animal product international trade.Chinese development level falls behind, livestock and poultry scale The problems such as cultivation degree is not high, feeding and management level is lower, dosage is lack of standardization, withdrawal time is insufficient, medicament residue is difficult to reach The requirement of developed country causes poultry and livestock to be difficult to enter the market of developed country or even some come into international city The old brand key product of field, which is also forced, to be exited.This problem has become the bottleneck for restricting Chinese animal product outlet.
Salinomycin is the polyethers ionophore type animal specific antibiotic generated by streptomyces albus, blue to most of leather Family name's positive bacteria and various coccidias have stronger inhibition and killing effect, are not likely to produce drug resistance and cross-resistance, and excretion is rapid, Residual quantity is extremely low, is veterinary drug circle veterinary drug kind irreplaceable at present.Salinomycin is by changing in the large intestines such as pig, ox and cud The content of tolerant effumability fatty acid improves the content of propanoic acid molecules, reduces the content of acetic acid, butyric acid molecule, increases total Energy, to play the effect of weight gain, fattening.Crude protein in feed, crude fat, coarse-fibred digestibility can also be changed, thus Play the role of weight gain and improves feed digestibility.Meanwhile the particularly ring-shaped chemical structure of salinomycin can consumingly and carefully Cation in born of the same parents, especially K+、Na+It combines closely, to change and increase the permeability of rouge barrier on cell membrane, to gram Positive bacteria, fungi have very strong killing effect.Therefore, salinomycin can be used for pig prevention and treatment diarrhea, growth promotion, improve survival rate, main It is used for the anti-coccidia of poultry, is the anticoccidiosis medicine being approved by the FDA in the United States, is recognized extensively by countries in the world.
Salinomycin is a kind of antibiotic not soluble in water, therefore is difficult to be made into soluble powder or solution, serious to restrict The application range of salinomycin clinically.Animal is fed to after usually salinomycin is mixed with feed, still, if mixing is not It is uniform then may result in animal poisoning, the malaise symptoms such as feed intake decline, weight loss, incoordination and skelasthenia occur. So how to increase the dissolubility of salinomycin during preparing salinomycin, increase its bioavilability in animal body, Effectively avoid the problem that animal poisoning phenomenon is current urgent need to resolve.It is dry that patent CN101926776B discloses a kind of Salinomycin Sodium Suspension increases the water solubility of Salinomycin Sodium by adjusting the type and dosage of auxiliary material, is prepared as a kind of dry suspensoid agent. But the patent relies solely on the wetting agent in auxiliary material to increase the dissolubility of Salinomycin Sodium, has little effect.
Patent application CN105326797A discloses a kind of processing technology of salinomycin particle preparation, but its technical process It is middle that salinomycin fermentation liquid is adjusted to acid fermentation liquid, the activity of salinomycin can be destroyed, the yield that makes product, purity are by shadow It rings.
Patent application CN104546739A discloses a kind of extraction process of salinomycin, wherein being extracted using flocculated method Salinomycin in fermentation liquid, technical process is simple, avoids acid-base accommodation to the active influence of salinomycin.But salinomycin is sent out Remaining soybean oil will affect flocculating effect in zymotic fluid, and then reduce product yield, energy consumption needed for increasing subsequent plate-frame filtering.
Summary of the invention
Based on above-mentioned defect in the prior art, the present invention provides a kind of salinomycin prilling process, ferment in salinomycin Demulsifier and flocculant are added in liquid and collects bacterial sediment, not only avoids acid-base accommodation to the active destruction of salinomycin, And can effectively increase flocculated effect, shorten the flocculated time.Meanwhile the type and use of auxiliary material are adjusted in prilling The parameter of amount and fluid unit makes salinomycin particle obtained have good water-soluble, mobility and stability.This hair The salinomycin prilling process simple process of bright offer, energy consumption and cost is relatively low, is suitble to large-scale production.
The present invention provides a kind of salinomycin prilling process, is completed by following steps:
(1) fermentation liquor pretreatment: sequentially adding demulsifier and flocculant into salinomycin fermentation liquid, be stirred, and stands Liquid is discarded supernatant after layering, sediment is spare；
(2) it is granulated: by the sediment in step (1) and after cosolvent is sufficiently mixed and grinds, being added to fluidized bed charging Adhesive is added in mouthful, in mouth spray to be sprayed, bed spray speed, atomizing pressure and inlet air temperature are adjusted, control is dry The dry time, then after lubricant is added by feed inlet, then bed spray speed, atomizing pressure and inlet air temperature are adjusted, control is dry The dry time, then filler is added by feed inlet, bed spray speed, atomizing pressure and inlet air temperature are adjusted, when control is dry Between, finally obtain salinomycin particle；
(3) whole grain: by the screened machine sieving of salinomycin particle to get finished product.
Further, the volume ratio of salinomycin fermentation liquid, demulsifier and flocculant is 1000:4-10 in the step (1): 10-50。
Preferably, the volume ratio of salinomycin fermentation liquid, demulsifier and flocculant is 1000:6-8:20- in the step (1) 30。
Further, the unit concentration of salinomycin fermentation liquid is every milliliter containing 7 × 10 in the step (1)4-13×104U Salinomycin.
Further, demulsifier concentration is 4%-10% (w/v) in the step (1).
Further, the demulsifier is selected from odium stearate, hard fatty acids potassium, sodium soap, sodium alkyl benzene sulfonate, ten One of dialkyl sulfonates, polyoxyethylene fatty alcohol sodium phosphate are a variety of.
Still further, the demulsifier is selected from one of odium stearate, sodium soap, dodecyl sodium sulfate or more Kind.
Further, flocculant concentration is 1%-5% (w/v) in the step (1).
Preferably, flocculant concentration is 2%-3% (w/v) in the step (1).
Further, the flocculant is that inorganic flocculating agent, organic flocculant or both are used in mixed way.
Wherein, the inorganic flocculating agent is selected from one of ferric sulfate, iron chloride, poly-ferric chloride or bodied ferric sulfate Or it is a variety of.
The organic flocculant is selected from protein, starch, chitosan, sodium carboxymethylcellulose, polyacrylamide, poly- second One of annulated pyridine salt, polyethyleneimine are a variety of.
Preferably, flocculant is selected from non-ionic polyacrylamide, amphoteric ionic polyacrylamide, yin in step (1) One of Polyacrylamide is a variety of.
Mixing speed after demulsifier is added in the step (1) is 50-100r/min, stirs 10-40min；Wadding is added Mixing speed after solidifying agent is 40-80r/min, and mixing speed is reduced to 10-30r/min after mixing time 2-10min, stirs 20- 30min。
Time of repose in the step (1) is 1-3h.
Preferably, the time of repose in the step (1) is 2h.
Further, in the step (2), according to poidometer, wherein salinomycin coarse granule 5-40 parts, filler 25-80 Part, 2-20 parts of wetting agent, 5-20 parts of cosolvent, 3-30 parts of adhesive.
Preferably, in the step (2), according to poidometer, wherein salinomycin coarse granule 15-30 parts, filler 40-60 Part, 5-15 parts of wetting agent, 8-15 parts of cosolvent, 15-20 parts of adhesive.
Further, cosolvent described in the step (2) be selected from lecithin, cephalin, beeswax, soya bean fatty acid, Oleic acid, ethyl oleate, hydrogenated soya phosphatide, cholesterol, meglumine, cyclodextrin and its derivative, distearoylphosphatidylglycerol, Dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, VE succinic acid macrogol ester, the poly- hydrocarbon of stearic acid One of oxygen ester is a variety of.
Preferably, the cosolvent is selected from one of lecithin, cephalin, cyclodextrin and its derivative or a variety of.
The lubricant, which is selected from, magnesium stearate, superfine silica gel powder, talcum powder, polyethylene glycol, the moon hangs one of alcohol magnesium sulfate Or it is a variety of.
Filler is selected from starch, lactose, dextrin, Icing Sugar, calcium sulfate, calcium carbonate, sucrose, mannitol, microcrystalline cellulose, Portugal One of grape sugar is a variety of.
Described adhesive is selected from starch slurry, pregelatinized starch, dextrin, povidone, methylcellulose, ethyl cellulose, carboxylic One of sodium carboxymethylcellulose pyce, hydroxypropyl cellulose are a variety of.
Preferably, described adhesive is one of starch slurry, povidone, sodium carboxymethylcellulose or a variety of.
Further, the concentration of described adhesive is 3%-10% (w/v).
Further, bed spray speed 10- is adjusted after salinomycin coarse granule and cosolvent are added in the step (2) 15mL/min, atomizing pressure 0.01-0.02Mpa, 50-60 DEG C of inlet air temperature, after drying 10-30min；It is added and is moistened by feed inlet again Lubrication prescription adjusts bed spray speed 20-30mL/min, atomizing pressure 0.02-0.03Mpa, 53-57 DEG C of inlet air temperature, dry 20-30min；Filler is added by feed inlet again, adjusts bed spray speed 15-20mL/min, atomizing pressure 0.015- 53-57 DEG C of 0.02Mpa, inlet air temperature obtain salinomycin particle after drying 60-80min.
Further, the particle of 15-25cm height, the setting of fluidized bed two sides are spread in the step (2) in fluidized bed in advance 15-25 mouth spray.
Preferably, the particle of 18-22cm height is spread in the step (2) in fluidized bed in advance, 16- is arranged in fluidized bed two sides 20 mouth sprays.
Further, screen-dividing machine is the double-deck screen-dividing machine in the step (3), and upper layer is 20-30 mesh, and lower layer is 50-60 mesh Screen-dividing machine.
Beneficial effects of the present invention:
(1) demulsifier is used in combination in the present invention and flocculant collects thallus, avoids acid-base accommodation active to salinomycin broken It is bad, and demulsifier and flocculant usage are less, can reduce the salt content of salinomycin, and obtaining product, with high purity, impurity is few.
(2) emulsion that soybean oil remaining in fermentation liquid and water phase are formed, the addition of demulsifier can effectively will be big Soya-bean oil is therefrom separated, the effect of flocculant is improved, avoid because soybean oil there are due to interfere the effect of flocculant, improve The efficiency of subsequent settle and separate reduces production energy consumption, and at the same time, the presence of soybean oil may cause salinomycin particle Flocculant removal soybean oil is added it is possible to prevente effectively from this problem in the problems such as agglomeration and unstable quality occur during storage.
(3) addition of cosolvent effectively increases the dissolubility of salinomycin in water in auxiliary material, so that salinomycin obtained Grain is water-soluble higher, effectively increases its bioavilability in animal body.Simultaneously as the water-soluble increase of salinomycin, it can To mix salinomycin particle dissolution with feed again, salinomycin particle is effectively avoided to mix with feed unevenly, and caused Salinomycin local concentration is excessively high, and then leads to the possibility of animal poisoning.
(4) after salinomycin being first sufficiently mixed and ground with cosolvent in salinomycin prilling, salinomycin is improved first Solubility, sequentially add wetting agent and filler, while adjusting the corresponding technical parameter of fluidized bed, be conducive to increase its stream Dynamic property and dissolubility.
(5) when the present invention uses fluidized bed prilling, multiple mouth sprays is subjected to hydrojet operation simultaneously, effectively improve granulation effect Rate, salinomycin particle mobility and homogeneity obtained are good.And it is whole to realize automation, there is no dust substantially in the process, Small to the occupational hazards of worker, labour protection degree is high.
Detailed description of the invention
Fig. 1 is salinomycin prilling flow chart
Specific embodiment
1 salinomycin prilling process of embodiment
(1) fermentation liquor pretreatment: to 10L 10 × 104The dodecyl of 40mL7% is added in U/mL salinomycin fermentation liquid After stirring 20min after benzene sulfonic acid sodium salt with the speed of 50r/min, 500mL4% anion-polyacrylamide is added, 40r/min is stirred Mix 8min, after again with 15r/min stir 24min, stand 1h after discard supernatant liquid；
(2) be granulated: the particle of the preparatory place mat 22cm height of fluidized-bed bottom precipitates 30 parts of salinomycins in step (1) It after object and 18 parts of beta-cyclodextrins are sufficiently mixed and grind, is added in fluidized bed feed inlet, is added 3 parts in 24 mouth sprays 9% starch slurry is sprayed, adjust bed spray speed 10mL/min, atomizing pressure 0.01Mpa, 60 DEG C of inlet air temperature, After dry 20min, then by feed inlet 5 parts of talcum powder of addition, adjust bed spray speed 20mL/min, atomizing pressure 55 DEG C of 0.03Mpa, inlet air temperature, dry 20min, then 70 parts of starch are added by feed inlet, adjust bed spray speed 15mL/ Min, atomizing pressure 0.02Mpa, 55 DEG C of inlet air temperature obtain salinomycin particle after drying 70min；
(3) whole grain: the screened machine of salinomycin particle is sieved, 20 mesh of upper layer, 60 mesh of lower layer is to get finished product.
2 salinomycin prilling process of embodiment
(1) fermentation liquor pretreatment: to 10L 7 × 104After the sodium soap of 70mL4% is added in U/mL salinomycin fermentation liquid After stirring 20min with the speed of 60r/min, 300mL2% amphoteric ionic polyacrylamide is added, 80r/min stirs 2min, 30min is stirred with 20r/min again afterwards, discards supernatant liquid after standing 1h；
(2) it is granulated: the particle of the preparatory place mat 18cm height of fluidized-bed bottom, by 5 parts of salinomycin sediments in step (1) It after being sufficiently mixed and grind with 8 parts of lecithin, is added in fluidized bed feed inlet, is added 80 part 10% in 25 mouth sprays Starch slurry is sprayed, and bed spray speed 13mL/min, atomizing pressure 0.02Mpa, 52 DEG C of inlet air temperature are adjusted, dry After 30min, then by feed inlet be added 2 parts of magnesium stearates, adjust bed spray speed 15mL/min, atomizing pressure 0.03Mpa, 57 DEG C of inlet air temperature, dry 20min, then 80 parts of calcium carbonate are added by feed inlet, adjust bed spray speed 20mL/min, mist Change pressure 0.015Mpa, 57 DEG C of inlet air temperature, obtains salinomycin particle after dry 80min；
(3) whole grain: the screened machine of salinomycin particle is sieved, 20 mesh of upper layer, 50 mesh of lower layer is to get finished product.
3 salinomycin prilling process of embodiment
(1) fermentation liquor pretreatment: to 10L 13 × 104The sodium soap of 100mL5% is added in U/mL salinomycin fermentation liquid After stirring 10min afterwards with the speed of 80r/min, 200mL5% ferric sulfate is added, 50r/min stirs 10min, after again with 30r/ Min stirs 25min, discards supernatant liquid after standing 1h；
(2) be granulated: the particle of the preparatory place mat 25cm height of fluidized-bed bottom precipitates 15 parts of salinomycins in step (1) It after object and 5 parts of cholesterol are sufficiently mixed and grind, is added in fluidized bed feed inlet, is added 25 part 3% in 15 mouth sprays Sodium carboxymethylcellulose be sprayed, adjust bed spray speed 15mL/min, atomizing pressure 0.01Mpa, inlet air temperature 50 DEG C, after dry 25min, then 15 parts of polyethylene glycol is added by feed inlet, adjusts bed spray speed 30mL/min, atomization pressure 54 DEG C of power 0.02Mpa, inlet air temperature, dry 30min, then 25 parts of lactose are added by feed inlet, adjust bed spray speed 18mL/min, atomizing pressure 0.02Mpa, 53 DEG C of inlet air temperature obtain salinomycin particle after drying 70min；
(3) whole grain: the screened machine of salinomycin particle is sieved, 30 mesh of upper layer, 60 mesh of lower layer is to get finished product.
4 salinomycin prilling process of embodiment
(1) fermentation liquor pretreatment: to 10L 10 × 104After the sodium sulfonate of 80mL10% is added in U/mL salinomycin fermentation liquid After stirring 20min with the speed of 80r/min, 100mL3% non-ionic polyacrylamide is added, 60r/min stirs 10min, after 30min is stirred with 10r/min again, discards supernatant liquid after standing 3h；
(2) be granulated: the particle of the preparatory place mat 20cm height of fluidized-bed bottom precipitates 40 parts of salinomycins in step (1) It after object and 15 parts of beta-cyclodextrins are sufficiently mixed and grind, is added in fluidized bed feed inlet, is added 30 parts in 16 mouth sprays 7% povidone is sprayed, and bed spray speed 13mL/min, atomizing pressure 0.02Mpa, 50 DEG C of inlet air temperature are adjusted, After dry 15min, then by feed inlet 20 parts of polyethylene glycol of addition, adjust bed spray speed 25mL/min, atomizing pressure 53 DEG C of 0.02Mpa, inlet air temperature, dry 30min, then 40 parts of calcium carbonate are added by feed inlet, adjust bed spray speed 20mL/min, atomizing pressure 0.015Mpa, 57 DEG C of inlet air temperature obtain salinomycin particle after drying 60min；
(3) whole grain: the screened machine of salinomycin particle is sieved, 20 mesh of upper layer, 60 mesh of lower layer is to get finished product.
5 salinomycin prilling process of embodiment
(1) fermentation liquor pretreatment: to 10L 8 × 104The polyoxyethylene rouge of 60mL7% is added in U/mL salinomycin fermentation liquid After stirring 10min after fat alcohol sodium phosphate with the speed of 100r/min, 250mL1% anion-polyacrylamide, 60r/ is added Min stir 5min, after again with 25r/min stir 20min, stand 1h after discard supernatant liquid；
(2) be granulated: the particle of the preparatory place mat 15cm height of fluidized-bed bottom precipitates 35 parts of salinomycins in step (1) It after object and 20 parts of cephalins are sufficiently mixed and grind, is added in fluidized bed feed inlet, is added 15 part 5% in 20 mouth sprays Sodium carboxymethylcellulose be sprayed, adjust bed spray speed 10mL/min, atomizing pressure 0.02Mpa, inlet air temperature 60 DEG C, after dry 10min, then 18 parts of superfine silica gel powders is added by feed inlet, adjusts bed spray speed 28mL/min, atomization pressure 53 DEG C of power 0.02Mpa, inlet air temperature, dry 25min, then 60 parts of glucose are added by feed inlet, adjust bed spray speed 20mL/min, atomizing pressure 0.02Mpa, 57 DEG C of inlet air temperature obtain salinomycin particle after drying 60min；
(3) whole grain: the screened machine of salinomycin particle is sieved, 20 mesh of upper layer, 60 mesh of lower layer is to get finished product.
Comparative example 1: salinomycin particle is prepared by acid fermentation liquid
(1) acid fermentation liquid is prepared: by salinomycin fermentation liquid sulphur acid for adjusting pH that potency is 100000u/ml to 5.0, And in 65 DEG C of heat preservation 4h；
(2) plate-frame filtering: sodium hydroxide is added into the acid fermentation liquid obtained through step (1) as saponification agent, adjusts PH is 9.5, is sufficiently filtered after saponification；
(3) particle of the preparatory place mat 22cm height of fluidized-bed bottom, by step (2) 30 parts of salinomycin feed liquids and 18 parts It after beta-cyclodextrin is sufficiently mixed and grinds, is added in fluidized bed feed inlet, 3 part 9% of starch slurry is added in mouth spray and carries out It is spraying, adjust bed spray speed 10mL/min, atomizing pressure 0.01Mpa, 60 DEG C of inlet air temperature, after dry 20min, then 5 parts of talcum powder are added by feed inlet, adjust bed spray speed 20mL/min, atomizing pressure 0.03Mpa, inlet air temperature 55 DEG C, dry 20min, then 70 parts of starch are added by feed inlet, adjust bed spray speed 15mL/min, atomizing pressure 55 DEG C of 0.02Mpa, inlet air temperature obtain salinomycin particle after drying 70min；
(4) whole grain: the screened machine of salinomycin particle is sieved, 20 mesh of upper layer, 60 mesh of lower layer is to get finished product.
Comparative example 2: auxiliary material order of addition is not distinguished and prepares salinomycin particle
(1) fermentation liquor pretreatment: to 10L 10 × 104The dodecyl of 40mL7% is added in U/mL salinomycin fermentation liquid After stirring 20min after benzene sulfonic acid sodium salt with the speed of 50r/min, 500mL4% anion-polyacrylamide is added, 40r/min is stirred Mix 8min, after again with 15r/min stir 24min, stand 1h after discard supernatant liquid；
(2) be granulated: the particle of the preparatory place mat 22cm height of fluidized-bed bottom precipitates 30 parts of salinomycins in step (1) It after object, 18 parts of beta-cyclodextrins, 5 parts of talcum powder and 70 parts of starch are sufficiently mixed, is added in fluidized bed feed inlet, 24 mouth sprays In 3 part 9% of starch slurry be added be sprayed, adjust bed spray speed 10mL/min, atomizing pressure 0.01Mpa, into 60 DEG C of air temperature, after drying 20min, adjust bed spray speed 20mL/min, atomizing pressure 0.03Mpa, inlet air temperature 55 DEG C, dry 20min adjusts bed spray speed 15mL/min, atomizing pressure 0.02Mpa, 55 DEG C of inlet air temperature, dry Salinomycin particle is obtained after 70min；
(3) whole grain: the screened machine of salinomycin particle is sieved, 20 mesh of upper layer, 60 mesh of lower layer is to get finished product.
Comparative example 3 only uses the method that flocculant carries out salinomycin granulation
(1) fermentation liquor pretreatment: to 10L 10 × 104It is poly- that 500mL4% anionic is added in U/mL salinomycin fermentation liquid Acrylamide, 40r/min stir 8min, after again with 15r/min stir 24min, stand 1h after discard supernatant liquid；
Step (2)-(3) are the same as embodiment 5.
Content, dissolution rate and the fluidity determining of 6 salinomycin particle of embodiment
The salinomycin particle of embodiment 1, embodiment 5, comparative example 1-3 preparation is subjected to potency, dissolution rate, granulating rate and stream The measurement of dynamic property, as a result referring to table 1.
1 salinomycin particle potency of table, dissolution rate, granulating rate and mobility result
Embodiment 1 Embodiment 5 Comparative example 1 Comparative example 2 Comparative example 3
Potency (u/mg) 125 138 103 118 115
Dissolution rate (%) 96 98 93 82 90
Solubility (g/100g) 12 15 11 8 10
Granulating rate (%) 88 91 80 68 71
Mobility (angle of repose) 29° 27° 30° 35° 30°
As shown in Table 1, salinomycin particle made from salinomycin prilling process provided by the invention, simple process, to salt The destruction of mycin activity is small, and compared with salinomycin particle prepared by soda acid method in comparative example 1, potency is significantly raised, has aobvious Write sex differernce.And it is prepared in the present invention in the technique of salinomycin particle in such a way that substep adds auxiliary material, in comparative example 2 One step mixing method, which is compared, has better dissolution rate, solubility, granulating rate and mobility, illustrate in the present invention first by salinomycin with Cosolvent sequentially adds wetting agent and filler after being sufficiently mixed, while adjusting corresponding process parameters can to effectively increase salt mould Solubility, dissolution rate, granulating rate and the mobility of crude granule effectively increase bioavilability, the product homogeneity of salinomycin And quality.Compared with comparative example 3, the present invention uses demulsifier and flocculant when handling fermentation liquid, significantly improves salt The potency of mycin particle, is conducive to subsequent granulation technique, and dissolution rate, solubility, granulating rate and the mobility of finished product also have one It is fixed to improve.
7 salinomycin particle of embodiment treatment ablactation porkling diarrhea
Piglet 40 that diarrhea occurs are selected from 5 animal farms or pig farm, are randomly divided into 5 groups, in its feed respectively It gives
Salinomycin particle 15g prepared by embodiment 1, embodiment 5, comparative example 1-3, daily each 1 time of morning and evening.Treatment results ginseng It is shown in Table 2.
2 salinomycin particle of table treatment ablactation porkling diarrhea result
As shown in Table 2, the present invention provides salinomycin particle made from prilling process to treatment diarrhea piglet with good Curative effect first day, that is, has 60% and 80% piglet to cure, and 1 first day cure rate of comparative example is only 30%, comparative example 2 It is 60%, comparative example 3 is 50%, illustrates that soda acid processing destroys the activity of salinomycin, seriously affects the performance of its drug effect, and originally Demulsifier and flocculant is used in combination in the preparation method of invention, has not only increased the purity of salinomycin, but also reduces to salinomycin activity Destruction, while substep granulation process substantially increases the bioavilability of salinomycin, considerably increases the curative effect of salinomycin.
8 salinomycin particle anticoccidial effect of embodiment
(1) trial drug: embodiment 1, embodiment 2, comparative example 1-2
(2) experimental animal: going out shell broiler chicks 250, raises in the wire mesh cage through high-temperature sterilization, gives continuous artificial Illumination, feeding are free of the full price meat chicken particulate material of coccidia ovum, drink clean tap water.Raising is to 12 ages in days, excrement inspection before testing Natural infection, which does not occur, for the confirmation of non-ball worm egg capsule to use.
(3) test worm strain: Sporulated E. pubescens Msxim is used in test (for clinical strain).Testing forefathers is infection nothing Coccidia chicken is passed on 1 time, acquisition test egg capsule, under the conditions of 28 DEG C, after the processing of 2.5% potassium bichromate solution miosporeization.It protects It is stored in spare in 4 DEG C of refrigerators.
(4) test method and grouping: when 12 age in days in addition to healthy control group, the oral artificial infection of total Test group chick Eimeria Tenella Sporulated Oocysts, dosage of inoculation be 50,000/only.Before attacking worm and cut open kill before respectively weigh an to weight It is noted down in detail.Spreading newspaper when 15 age in days below every cage, when every group of start recording of bloody stool 19 age in days of situation, terminates to test, It weighs, cut open and kill, carry out enteron aisle lesion score.Every gram of excrement egg sac number (OPG) is measured, enteron aisle egg capsule counts, statistics each group weight gain And body weight increase rate.Free water, feeding during test.Such as there is death, answer dissect ascertain whether because the lethal of coccidia and by because The caecum of the chicken of coccidia death collects, and sets in 4 DEG C of refrigerator and saves, and non-coccidia is lethal not to be included in statistics.
Processing after animal packet and grouping is shown in Table 3
3 animal packet of table and processing
Group Processing Chicken number (only) Dosage Administration route Medication age in days The course for the treatment of (d)
1 Healthy control group 30 - - - -
2 Infect control group 30 - - - -
3 Example 1 group 30 60mg/kg Mixed feeding Whole medication 18
4 5 groups of embodiment 30 60mg/kg Mixed feeding Whole medication 18
5 1 group of comparative example 30 60mg/kg Mixed feeding Whole medication 18
6 2 groups of comparative example 30 60mg/kg Mixed feeding Whole medication 18
7 3 groups of comparative example 30 60mg/kg Mixed feeding Whole medication 18
(5) index of assessment of curative effect
A) average weight gain × 100% of body weight increase rate (%)=infection each group chicken draw weight gain ÷ healthy control group chicken
B) survival rate (%)=group in survive number of elements ÷ group in participate in the experiment chicken sum × 100%
C) lesion is scored: referring to the standard (Johnsan.J.and of Johnson and Reid (1970) ReidW.H..Experment Parasitology [J] .1970,28:30-36.) determined, each group chicken pathological changes value is added Obtain pathological changes value total score.
Lesion score evaluation criterion:
0 point: without naked eyes lesion；
1 point: caecum wall has the blutpunkte being dispersed on a small quantity, and intestinal wall and content are normal；
2 points: lesion quantity is more, and obviously band blood, caecum wall thickening, content are normal for cecal content；
3 points: cecal content has volume blood or has caecum core (the Banana Type block of blood clot or canescence junket sample), Caecum wall is plump obvious, and manure content is few in caecum；
4 points: because being full of a large amount of blood or intestines core due to caecum enlargement, containing excrement slag or without excrement slag in intestines core.Dead chicken 4 points of meter.
D) oocyst value: by the method progress of clear O, P, G value in angle field, (angle Tian Qing edits Chen Yi, and Ming Rujing translates chicken coccidiasis The Shanghai [M], Shanghai Scientific & Technical Publishers, 1986.).
E) bloody stool is scored: referring to Morehouse and Barom standard (Morehouse, N.F.and Baron R.R..Coccidiosis evaluation of coccidiostats by mortality, weight gains, and Fecal scores.Exp Parasitol [J] .1970,28:25-29.).
Bloody stool score evaluation criterion:
Efficient: every group of bloody stool score is at 5 points or less；
Middle effect: every group of bloody stool score is at 6-10 points；
Inefficient: every group of bloody stool score is at 11-15 points；
Invalid: every group of bloody stool score is at 16 points or more.
F) anticoccidial index (ACI)=(body weight increase rate+survival rate)-(pathological changes value+oocyst value).
Anticoccidial drug effect evaluation standard:
Anticoccidial is highly effective: ACI:180 or more
Medium anticoccidial effect: ACI:160-180
Anticoccidial effect is low: ACI:120-160
It should not make anticoccidial drug: ACI < 120
(6) experimental result
Each group anticoccidial result is referring to table 4
4 each group anticoccidial result of table
As shown in Table 4, each index of salinomycin particle of salinomycin prilling process preparation provided by the invention is superior to other Each group, anticoccidial index are an indexs of overall merit coccidiostat curative effect, according to its evaluation criterion, embodiment 1 and reality A 5ACI > 180 is applied, efficient coccidiostat is belonged to, 1 group of 120 < ACI < 160 of comparative example belongs to inefficient coccidiostat, right 3 group of 160 < ACI < 180 of 2 groups of ratio and comparative example, belongs to middle equivalent force coccidiostat, significant difference.Illustrate that the present invention mentions Using method associated with demulsifier and flocculant in the salinomycin prilling process of confession, guarantee the efficiency extracted, while avoiding tradition Acid-base conditioning process guarantees the curative effect of salinomycin to the active destruction of salinomycin.On the other hand, the addition of auxiliary material is suitable in preparation Sequence also increases the solubility of salinomycin, and then increases it in the intracorporal bioavilability of chicken, realizes that better anticoccidial is treated Effect.
The research of the flocculating effect of 9 demulsifier of embodiment and flocculant
According to the grouping of table 5, to 1L 10 × 104Corresponding demulsifier and flocculant is added in U/mL salinomycin fermentation liquid, Middle demulsifier selects sodium soap, selection of polymeric flocculants anion-polyacrylamide, when observing the effect being layered after flocculation, sedimentation Between and measure the content of salinomycin in sediment, as a result referring to table 6.
The dosage grouping of 5 demulsifier of table, flocculant concentration
Influence of the dosage to flocculating effect of 6 demulsifier of table, flocculant concentration
As shown in Table 6, the concentration of demulsifier influences highly significant to flocculating effect, when not using demulsifier, salinomycin Fermentation liquid layering is unintelligible, and the sedimentation time is long, and salinomycin content is lower in obtained sediment, when illustrating without demulsifier, Soybean oil in fermentation liquid is affected to flocculant, seriously affects flocculated effect and efficiency.With demulsifier concentration Increase, flocculating effect component improves, and the sedimentation time, which first shortens, to be further added by, and salinomycin content first increases in sediment is reduced again, 4- 10% demulsifier concentration is preferable to flocculated synergy.With the increase of flocculant concentration, flocculation time presentation is first reduced It is further added by, salinomycin concentration first increases to be reduced afterwards, and the flocculant of 1-5% can play good flocculating effect, but 3-3% is more It is good.In the volume ratio of demulsifier and flocculant, with the increase of flocculant relative quantity, flocculation time is presented first to reduce and is further added by, Salinomycin concentration first increases to be reduced afterwards, and effect is best when the two volume ratio is 1:2.5.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, the embodiment not to The scope of the patents of the invention is limited, all equivalence enforcements or change without departing from carried out by the present invention are intended to be limited solely by the technology of the present invention In the range of scheme.

Claims (10)

1. a kind of salinomycin prilling process, which is characterized in that steps are as follows for the salinomycin prilling process:
(1) fermentation liquor pretreatment: demulsifier is added into salinomycin fermentation liquid and is stirred, is slowly added to after standing a period of time Flocculant is stirred, and liquid is discarded supernatant after stratification, and sediment is spare；
(2) it is granulated: by the sediment in step (1) and after cosolvent is sufficiently mixed and grinds, being added in fluidized bed feed inlet, Adhesive is added in mouth spray to be sprayed, bed spray speed, atomizing pressure and inlet air temperature are adjusted, when control is dry Between；After lubricant is added by feed inlet again, bed spray speed, atomizing pressure and inlet air temperature are adjusted, controls drying time； Filler is added by feed inlet again, adjusts bed spray speed, atomizing pressure and inlet air temperature, controls drying time, finally Obtain salinomycin particle；
(3) whole grain: by the screened machine sieving of salinomycin particle to get finished product；
Wherein, the demulsifier is polyoxyethylene fatty alcohol sodium phosphate, concentration 4%-10%(w/v)；
Flocculant is anion-polyacrylamide, concentration 0.1%-0.5%(w/v).
2. salinomycin prilling process according to claim 1, which is characterized in that salinomycin fermentation liquid in the step (1), The volume ratio of demulsifier and flocculant is 1000:4-10:10-50.
3. salinomycin prilling process according to claim 1, which is characterized in that salinomycin fermentation liquid in the step (1) Unit concentration be every milliliter contain 7 × 104-13×104The salinomycin of U.
4. salinomycin prilling process according to claim 1, which is characterized in that according to poidometer in the step (2), 5-40 parts of middle salinomycin sediment, 25-50 parts of filler, 2-10 parts of wetting agent, 5-20 parts of cosolvent, 3-30 parts of adhesive.
5. salinomycin prilling process according to claim 4, which is characterized in that the cosolvent is selected from lecithin, brain phosphorus Rouge, beeswax, soya bean fatty acid, oleic acid, ethyl oleate, hydrogenated soya phosphatide, cholesterol, meglumine, cyclodextrin and its derivative, Distearoylphosphatidylglycerol, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, VE succinic acid are poly- One of glycol ester, polyoxyl stearate are a variety of；
The lubricant is selected from one of magnesium stearate, superfine silica gel powder, talcum powder, polyethylene glycol, magnesium laurylsulfate or more Kind；
The filler is selected from starch, lactose, dextrin, Icing Sugar, calcium sulfate, calcium carbonate, sucrose, mannitol, microcrystalline cellulose, Portugal One of grape sugar is a variety of；
Described adhesive is selected from starch slurry, pregelatinized starch, dextrin, povidone, methylcellulose, ethyl cellulose, carboxymethyl One of sodium cellulosate, hydroxypropyl cellulose are a variety of.
6. salinomycin prilling process according to claim 5, which is characterized in that the cosolvent is selected from lecithin, brain phosphorus One of rouge, cyclodextrin and its derivative are a variety of.
7. salinomycin prilling process according to claim 5, which is characterized in that described adhesive is starch slurry, adhesive Concentration be 3%-10%(w/v).
8. salinomycin prilling process according to claim 1, which is characterized in that it is heavy that salinomycin is added in the step (2) Bed spray speed 10-15mL/min, atomizing pressure 0.01-0.02Mpa, inlet air temperature 50- are adjusted after starch and cosolvent 60 DEG C, after drying 10-30min；Lubricant is added by feed inlet again, adjusts bed spray speed 20-30mL/min, atomization pressure 53-57 DEG C of power 0.02-0.03Mpa, inlet air temperature, dry 20-30min；Filler is added by feed inlet again, adjusts fluidized bed spray Mist speed 15-20mL/min, atomizing pressure 0.015-0.02Mpa, 53-57 DEG C of inlet air temperature obtain salt after drying 60-80min Mycin particle.
9. salinomycin prilling process according to claim 1, which is characterized in that in the step (2) in fluidized bed in advance The particle of 15-25cm height is spread, 15-25 mouth spray is arranged in fluidized bed two sides.
10. salinomycin prilling process according to claim 1, which is characterized in that the screening machine in the step (3) is double Layer screening machine, upper layer are 20-30 mesh, and lower layer is 50-60 mesh extension set.
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