CN108309953B - A kind of production method of salinomycin microcapsule granule - Google Patents
A kind of production method of salinomycin microcapsule granule Download PDFInfo
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The invention discloses a kind of production methods of salinomycin microcapsule granule: being separated by solid-liquid separation after the fermentation liquid sterilizing completed to fermentation; isolated solid is dried; obtain salinomycin powder; salinomycin powder is first set to carry out reuniting with growing up preparing salinomycin particle in fluid bed granulator using aqueous sucrose solution as adhesive; again using the mixed aqueous solution of starch and gelatin as capsule material liquid; using salinomycin particle as core-clad material; it is coated salinomycin particle in fluid bed granulator to grow up, salinomycin microcapsule granule is prepared.It is a discovery of the invention that sucrose solution used in salinomycin particle preparation process can be improved the encapsulation rate and drugloading rate in salinomycin micro-capsule preparation process；And the type of starch used in capsule material liquid has a significant effect to the encapsulation rate and drugloading rate of salinomycin micro-capsule.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly to a kind of production method of animal particles containing antibotics, more
Body it is related to a kind of production method of salinomycin microcapsule granule.
Background technique
Salinomycin belongs to polyethers monocarboxylic acid antibiotic, is fermented and is generated by streptomyces albus, has particularly ring-shaped knot
Structure is typical ion carrier antibiotic, it in cell cation affinity it is especially strong, make sun necessary to biology from
Son interferes the transmitting of intraor extracellular cation, changes intraor extracellular ion concentration by the impregnability enhancing of lipid barrier on film,
Osmotic pressure is influenced, finally makes cell disruption, plays bactericidal effect.
Salinomycin is a kind of novel anti-coccidia agent of chicken and the growth promoter of piglet, growing and fattening pigs, in the breeding process
Feed in add.Belong to ionic growth accelerator of new generation, main function is effectively controlled by interference harmful microorganism growth
The morbidity and mortality of diarrhea processed improve the digestion and absorption of nutriment, guarantee and promote the healthy growth of livestock and poultry, improve
Feed conversion rate is increased economic efficiency.
Chinese patent announces CN 105326800A and discloses a kind of preparation method of salinomycin particle preparation: by preparation
Acid fermentation liquid and acid fermentation liquid pretreatment is prepared for salinomycin feed liquid, into the salinomycin feed liquid of preparation add corn flour,
Salinomycin particle preparation has been made in bentonite and calcium carbonate, spray-dried method.But in the salinomycin of this method preparation
There is the salinomycin of special odor to be an exposure to outside in grain preparation, easily causing animal anorexia influences the normal feeding of animal,
Moreover, rate of release is fast in animal body for the salinomycin of exposure, drug effect is not lasting.At the same time, exposed salinomycin is easy
Toxic side effect is generated to operator.
Microcapsule technology is with certain method and instrument, using natural or synthesis high molecular material by solid, liquid
The molecule of body or gas is wrapped in the technology in the microencapsulation of the semi permeability that diameter is 1-500 μm or sealing cyst membrane.It will
Salinomycin is wrapped in micro-capsule the smell guarantee animal feed that can effectively completely cut off salinomycin, and can be reduced the poison to operator
Side effect.
Chinese patent announces CN 107137376A and discloses a kind of black fruit fructus lycii extract microcapsule and fructus lycii prepared therefrom
Wolfberry fruit extract is dispersed in capsule material and forms spray liquid by preparation, is then made of spray drying process or spray condensation method
Wolfberry fruit extract micro-capsule then combines suitable granulation technique that the wolfberry fruit extract of microencapsulation is made to the graininess of a variety of dosage forms
Solid pharmaceutical preparation.The invention improves the bitter taste of fructus lycii, especially by carrying out microencapsulation processing to the black fruit fructus lycii extract of preparation
It is the hygroscopicity problems for improving the wolfberry fruit extract as caused by polysaccharide component.Lack simple be applicable in microencapsulation
In the packaging method of all capsule core materials, many factors such as selection of capsule material and capsule-core ratio all can generate shadow to the quality of micro-capsule product
It rings.The patent application merely discloses the microcapsule preparation method of black fruit fructus lycii extract, and there is no the systems of open salinomycin micro-capsule
Preparation Method.
The production method for needing to develop a kind of salinomycin microcapsule granule at present, is made micro-capsule for salinomycin, covers drug
Poor taste improves the stability of drug, reduces contact sensitization situation of the staff in feeding animals with salinomycin.
Summary of the invention
The present invention provides a kind of methods for preparing salinomycin microcapsule granule, and salinomycin is wrapped in natural macromolecular material
Salinomycin microcapsule granule is made inside the cyst membrane of formation, method of the invention obtains higher encapsulation rate, effectively completely cut off salt
The smell of mycin reduces the toxic side effect to operator, keeps the rate of release of salinomycin more uniform gentle.
The invention discloses a kind of production methods of salinomycin microcapsule granule, the described method comprises the following steps:
(1) fermentation liquor pretreatment: the salinomycin fermentation liquid for taking fermentation to finish is heated to 70-95 DEG C to sterilizing, to going out
Salinomycin fermentation liquid after bacterium is separated by solid-liquid separation, and the liquid after separation carries out biochemical treatment into sewage plant, leaves and takes separation of solid and liquid
Obtained solid；
(2) it is dried: will be dried in step (1) through being separated by solid-liquid separation obtained solid, obtain salinomycin powder；
(3) boiling granulating: salinomycin powder obtained in step (2) is put into and uses syrup as bonding in fluid bed granulator
Agent carries out boiling granulating and obtains salinomycin particle；
(4) prepare capsule material liquid: capsule material is the mixture of starch and gelatin, the preparation method of capsule material liquid are as follows: prepares starch weight
The amidin that percentage composition is 8-15% is measured, then the weight percent with amidin is added in the amidin
It for the gelatin of 0.5-5%, stirs evenly, obtains capsule material liquid；
(5) microencapsulation: it is added in fluid bed granulator using salinomycin particle obtained in step (3) as capsule-core, with step
Suddenly salinomycin microcapsule granule is prepared as spraying liquid in capsule material liquid obtained in (4) in the form of boiling granulating.
Further, the separation of solid and liquid in step (1) can be in gravity filter, vacuum filter, deckle board filter press, three
It is carried out in the solid-liquid separating equipments such as sufficient formula centrifuge；Preferably, the separation of solid and liquid in step (1) is in vacuum filter or deckle board pressure
It is carried out in filter.
Further, in step (1), the salinomycin fermentation liquid that fermentation is completed is preferably heated to 75-85 DEG C, is gone out
Bacterium.
Further, drying described in step (2) is expansion drying, is obtained using flash dryer to separation of solid and liquid
Solid carries out expansion drying.
Further, the inlet air temperature of above-mentioned flash dryer is 110-150 DEG C, and temperature of outgoing air is 70-90 DEG C, and flash distillation is dry
Water content is less than 5% in dry rear salinomycin powder；Preferably, the inlet air temperature of flash dryer is 120-140 in step (2)
DEG C, temperature of outgoing air is 75-85 DEG C.
Further, boiling granulating built-in temperature is 80-120 DEG C in step (3), atomizing pressure 0.18-2.0MPa；It is excellent
Selection of land, boiling granulating built-in temperature is 80-100 DEG C in step (3).
Further, the syrup in step (3) selects aqueous sucrose solution, and the content of sucrose is in every 100g aqueous sucrose solution
50-70g；Preferably, the content of sucrose is 55-65g in every 100g aqueous sucrose solution.
Further, the preparation method of the amidin of step (4) are as follows: starch is dissolved in 20-50 DEG C of warm water, and
It is stirred continuously, is prepared into amidin；Preferably, the preparation method of amidin are as follows: starch is dissolved in 40-50 DEG C of temperature
It in water, and is stirred continuously, is prepared into amidin.
Further, the starch selected in step (4) can be green starch, potato starch, wheaten starch, sweet potato and form sediment
One of common starch such as powder is a variety of.
Further, the weight percentage of starch is preferably 9-12% in amidin in step (4)；More preferably
Ground, the weight percentage of starch is 10-11% in amidin in step (4).
Further, the weight ratio of the capsule-core and capsule material liquid that are added in fluid bed granulator in step (5) are as follows: with capsule-core and capsule
The weight ratio meter of material is 2:1.3-5；Preferably, the weight ratio of the capsule-core and capsule material liquid that are added in fluid bed granulator in step (5)
Are as follows: the weight ratio meter with capsule-core and capsule material is 2:1.5-4.
Further, the atomizing pressure of fluid bed granulator is 1-3MPa in step (5)；Preferably, boiling system in step (5)
The atomizing pressure of grain machine is 1-2MPa.
Further, the temperature in step (5) in fluid bed granulator is 45-60 DEG C；Preferably, boiling system in step (5)
Temperature in grain machine is 55-60 DEG C.
Compared with prior art, the invention has the benefit that
(1) present invention effectively realizes salinomycin by selecting suitable encapsulating material and encapsulating material proportion
Efficiently encapsulating has completely cut off the smell of salinomycin, guarantees that animal normally feeds, and reduces the release speed of salinomycin in animal body
Rate reduces contact of the operator in feeding animals with salinomycin, protects operator.
(2) present invention introduces microencapsulation on the basis of boiling granulating reunion is grown up, and is reunited by boiling granulating and is grown
The synergistic effect of the capsule material in adhesive and microencapsulation during big, effectively increases salinomycin in salinomycin micro-capsule
Drugloading rate and encapsulation rate.
(3) present invention further studies different types of starch to salt while selecting starch to make encapsulating material
The influence of mycin microcapsule granule quality, wherein when discovery uses green starch as encystation starch, the quality of salinomycin micro-capsule is most
It is good.
(4) there are two types of specific modes for boiling granulating: coating is grown up and reunion is grown up.Wherein, the characteristics of coating is grown up is:
Coating solution is sprayed directly on the particle surface of the ordered movement in " boiling " state and volatile dry forms cause in a short time
Close coating membrane, this process constantly repeats, so that particle is increasing；The characteristics of reunion is grown up are as follows: in the effect of spray droplet
Under, wetted adjacent powder mutually collides in fluidized bed, forms liquid commissure between powder and builds bridge, and due to surface tension and bears
The effect of pressure suction, which makes to soak adjacent powder, to be combined together, with the progress of drying process, solvent from slurry gradually by
Evaporation forms bigger particle.It is coated the obtained particle of mechanism, the speed of growth is slower, stable uniform of growing up, rate of dissolution
But good mechanical property slowly,；The obtained particle of Agglomeration Mechanism, the speed of growth is fast, large specific surface area, and dissolubility is good, but granularity is not
Uniformly, in irregular shape, mechanical properties.The reunion that step (3) of the invention belongs in boiling granulating is grown up, in step (5)
The coating that belongs in boiling granulating of microencapsulation grow up, this law is bright by two kinds of boiling granulating methods of integrated use, has obtained product
Good salinomycin microcapsule granule of fine quality.
Detailed description of the invention
In order to keep the purpose of the present invention, technical scheme and beneficial effects clearer, the present invention provides following Detailed description of the invention:
Fig. 1 is process flow chart of the invention.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Illustrate: 1, drugloading rate refers to the weight percent of coating medicine in micro-capsule or microballoon；
2, encapsulation rate refers to the drug weight of microencapsulation and the percentage of total addition drug weight.
A kind of basic embodiment: production method of salinomycin microcapsule granule
(1) fermentation liquor pretreatment: the salinomycin fermentation liquid for taking fermentation to finish is heated to 80 DEG C to sterilizing, using frame
Plate filter press is separated by solid-liquid separation the salinomycin fermentation liquid of sterilized processing, and the liquid after separation carries out at biochemistry into sewage plant
Reason leaves and takes the solid for being separated by solid-liquid separation and obtaining；
(2) it is dried: being dried, obtain through being separated by solid-liquid separation obtained solid in step (1) in flash dryer
To salinomycin powder, wherein flash dryer inlet air temperature is 130 DEG C, and temperature of outgoing air is 80 DEG C, the water content of salinomycin powder
It is 3%；
(3) boiling granulating: being made the aqueous sucrose solution containing 50-70g sucrose in every 100g solution for sucrose is soluble in water,
And as adhesive；It puts salinomycin powder obtained in step (2) into hopper in fluid bed granulator, makes it in heat
It is circulated under the action of air-flow in fluidisation shape；Aqueous sucrose solution is sprayed onto circulation with mist form with the atomizing pressure of 1.0MPa
On the salinomycin powder of flowing, it is finally made salinomycin particle, during entire boiling granulating, by the temperature in fluid bed granulator
It is maintained at 90 DEG C or so；
(4) prepare capsule material liquid: capsule material is the mixture of starch and gelatin, the preparation method of capsule material liquid are as follows: be dissolved in starch
It in 45 DEG C of warm water, and is stirred continuously, is made into the amidin that starch weight percentage composition is 8-15%, then water-soluble in starch
The gelatin for being 0.5-5% with the weight percent of amidin is added in liquid, stirs evenly, obtains capsule material liquid, wherein used
Starch is selected from one of green starch, potato starch, wheaten starch, sweet potato starch or a variety of；
(5) microencapsulation: it is added in fluid bed granulator using salinomycin particle obtained in step (3) as capsule-core, with step
Suddenly salinomycin microcapsule granule is prepared as spraying liquid in capsule material liquid obtained in (4) in the form of boiling granulating, wherein
The weight ratio of the capsule-core and capsule material liquid that are added in fluid bed granulator are as follows: the weight ratio meter with capsule-core and capsule material is 2:4, boiling granulating
The atomizing pressure of machine is 1.5MPa, and temperature when granulation in fluid bed granulator is controlled at 60 DEG C.
By adjusting the specific experiment parameter in basic embodiment, the specific embodiment 1-13 as shown in table 1-4 has been obtained.
In order to which the sucrose solution in further verification step (3) salinomycin particle preparation process as adhesive is to salinomycin microcapsule granule
The influence of drugloading rate and encapsulation rate, the present invention are provided with comparative example 1.
The experimental data of embodiment 1-4 is shown in table 1, and the experiment condition recorded according to the present invention prepares salinomycin micro-capsule
93% or more entrapment efficiency may be implemented in grain, and the drugloading rate of drug can achieve 31% or more: both ensure that higher
Entrapment efficiency, improve utilization efficiency of the drug in microencapsulation production process, higher drug delivery amount of having got back.
Wherein, under the experiment condition of embodiment 4, highest drugloading rate (34.2%) and highest entrapment efficiency are obtained
(98.3%).
Table 1
Comparative example 1
In order to which sucrose solution can act synergistically as adhesive with capsule material in verification step (3), micro-capsule is improved
The drugloading rate and encapsulation rate of grain, the present invention devise the comparative example 1 for using starch solution as adhesive therefor in step (3), and
Embodiment 4 compares, and the specific experiment process of comparative example 1 is as follows:
(1) fermentation liquor pretreatment: the salinomycin fermentation liquid for taking fermentation to finish is heated to 80 DEG C and sterilizes, using deckle board
Filter press is separated by solid-liquid separation the salinomycin fermentation liquid of sterilized processing, and the liquid after separation carries out at biochemistry into sewage plant
Reason leaves and takes the solid for being separated by solid-liquid separation and obtaining；
(2) it is dried: being dried, obtain through being separated by solid-liquid separation obtained solid in step (1) in flash dryer
To salinomycin powder, wherein flash dryer inlet air temperature is 130 DEG C, and temperature of outgoing air is 80 DEG C, the water content of salinomycin powder
It is 3%；
(3) boiling granulating: green starch being dissolved in 45 DEG C of warm water, is made in every 100g solution containing 10g starch
Amidin, and as adhesive；Put salinomycin powder obtained in step (2) into hopper in fluid bed granulator
In, circulate it under the action of thermal current in fluidisation shape；With the atomizing pressure of 1.0MPa by amidin with mist
Form is sprayed on the salinomycin powder circulated, is finally made salinomycin particle, and during entire boiling granulating, boiling is made
Temperature in grain machine is maintained at 90 DEG C or so；
(4) prepare capsule material liquid: capsule material is the mixture of starch and gelatin, the preparation method of capsule material liquid are as follows: be dissolved in starch
It in 45 DEG C of warm water, and is stirred continuously, is made into the amidin that starch weight percentage composition is 10%, then in amidin
The gelatin that middle addition is 3% with the weight percent of amidin, stirs evenly, obtains capsule material liquid, wherein starch used is
Green starch；
(5) microencapsulation: it is added in fluid bed granulator using salinomycin particle obtained in step (3) as capsule-core, with step
Suddenly capsule material liquid obtained in (4) prepares salinomycin microcapsule granule as spraying liquid in the form of boiling granulating, wherein boiling
The weight ratio of the capsule-core and capsule material liquid that are added in granulator are as follows: the weight ratio meter with capsule-core and capsule material is 2:4, fluid bed granulator
Atomizing pressure is 1.5MPa, and temperature when granulation in fluid bed granulator is controlled at 60 DEG C.
It is determined by experiment, the entrapment efficiency of microcapsule granule is 85% in comparative example 1, drugloading rate 25%, hence it is evident that point
Not Di Yu encapsulation rate and drugloading rate in the embodiment 4 in table 1 under same experimental conditions, and it is respectively lower than minimum in table 1
Encapsulation rate (93.1%) and drugloading rate (31.2%): further illustrate step (3) in uses aqueous sucrose solution as adhesive
The drugloading rate and encapsulation rate in salinomycin micro-capsule preparation process can be significantly improved.
By adjusting the content of sucrose in sucrose solution in step (3), the embodiment 4-7 in table 2 has been obtained.In table 2
Experimental data shows, the encapsulation rate and drugloading rate of salinomycin microcapsule granule with the increase of sucrose concentration in aqueous sucrose solution and
First increase and reduces afterwards, when containing 60g sucrose in every 100g aqueous sucrose solution, the encapsulation rate and drugloading rate of salinomycin microcapsule granule
Highest.
Table 2
By adjusting the type of starch used in step (4), the embodiment 4 and embodiment 8-10 in table 3 are devised.Implement
Example 4 and the experimental data of embodiment 8-10 show, selects different types of starch and gelatin to mix and is used as capsule material, it is available not
With encapsulation rate and drugloading rate, wherein other conditions under the same conditions, select green starch and gelatin mixing be used as capsule
Material, available highest drugloading rate and encapsulation rate.
Table 3
Weight percent by adjusting the gelatin and starch aqueous solution added in step (4) has obtained the implementation in table 4
Example 4 and embodiment 11-13.Experimental data in table 4 shows that the weight percent of the gelatin and starch aqueous solution of addition can be bright
Develop the drugloading rate and encapsulation rate rung in salinomycin microcapsule granule preparation process, if other conditions are the same, drugloading rate
With encapsulation rate increasing and first increase and reduce afterwards with gelatin additive amount, wherein when the weight percent of gelatin and starch aqueous solution
When than being 3%, the drugloading rate and encapsulation rate highest of the microcapsule granule of preparation.
Table 4
Claims (10)
1. a kind of production method of salinomycin microcapsule granule, it is characterised in that the following steps are included:
(1) fermentation liquor pretreatment: the salinomycin fermentation liquid for taking fermentation to finish is heated to 70-95 DEG C and sterilizes, after sterilizing
Salinomycin fermentation liquid is separated by solid-liquid separation, and the liquid after separation carries out biochemical treatment into sewage plant, leaves and takes what separation of solid and liquid obtained
Solid；
(2) it is dried: will be dried in step (1) through being separated by solid-liquid separation obtained solid, obtain salinomycin powder；
(3) boiling granulating: salinomycin powder obtained in step (2) is put into used in fluid bed granulator syrup as adhesive into
Row boiling granulating obtains salinomycin particle；
(4) prepare capsule material liquid: capsule material is the mixture of starch and gelatin, the preparation method of capsule material liquid are as follows: prepares starch weight hundred
Dividing content is the amidin of 8-15%, then the weight percent of addition and amidin is in the amidin
The gelatin of 0.5-5%, stirs evenly, and obtains capsule material liquid；
(5) microencapsulation: being added in fluid bed granulator using salinomycin particle obtained in step (3) as capsule-core, with step (4)
Obtained in capsule material liquid as spraying liquid, salinomycin microcapsule granule is prepared in the form of boiling granulating.
2. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (1)
In separation of solid and liquid can be carried out in gravity filter, vacuum filter, deckle board filter press, link-suspended basket centrifuge.
3. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (1)
In, the salinomycin fermentation liquid that fermentation is completed is heated to 75-85 DEG C, is sterilized.
4. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (2)
In drying be expansion drying, expansion drying is carried out to the obtained solid of separation of solid and liquid using flash dryer.
5. a kind of production method of salinomycin microcapsule granule according to claim 4, it is characterised in that: the expansion drying
The inlet air temperature of machine is 110-150 DEG C, and temperature of outgoing air is 70-90 DEG C, and moisture content is less than in salinomycin powder after expansion drying
5%。
6. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (3)
Middle boiling granulating built-in temperature is 80-120 DEG C, atomizing pressure 0.18-2.0MPa.
7. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (3)
In syrup select aqueous sucrose solution, the content of sucrose is 50-70g in every 100g aqueous sucrose solution.
8. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (4)
The starch of middle selection can be one of green starch, potato starch, wheaten starch, sweet potato starch or a variety of.
9. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (5)
The weight ratio of the capsule-core and capsule material liquid that are added in middle fluid bed granulator are as follows: the weight ratio meter with capsule-core and capsule material is 2:1.3-5.
10. a kind of production method of salinomycin microcapsule granule according to claim 1, it is characterised in that: the step (5)
The atomizing pressure of middle fluid bed granulator is 1-3MPa, and the temperature in fluid bed granulator is 45-65 DEG C.
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| US4066781A (en) * | 1977-01-27 | 1978-01-03 | Kaken Chemical Co., Ltd. | Miticidal method |
| CN1631365A (en) * | 2004-04-14 | 2005-06-29 | 山东鲁抗舍里乐药业有限公司 | Sodium salinomycin powder and its preparation |
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| CN105326797A (en) * | 2015-11-10 | 2016-02-17 | 成都中牧生物药业有限公司 | Processing process for salinomycin granular preparation |
| CN107496368A (en) * | 2016-06-14 | 2017-12-22 | 游锡火 | A kind of dog containing anti-parasite medicine and phagostimulant, cat pill |
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| CN101884621A (en) * | 2010-06-29 | 2010-11-17 | 金河生物科技股份有限公司 | Method for preparing salinomycin particle premix |
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| CN108309953A (en) | 2018-07-24 |
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Denomination of invention: A production method of salinomycin microcapsule granules Effective date of registration: 20210408 Granted publication date: 20190226 Pledgee: Bank of China Limited by Share Ltd. Hohhot Xinhua Branch Pledgor: INNER MONGOLIA BIOK BIOLOGY Co.,Ltd. Registration number: Y2021150000031 |