CN107593699A - A kind of sustained-release micro-spheres for being used to sterilize and preparation method thereof - Google Patents
A kind of sustained-release micro-spheres for being used to sterilize and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of agent sustained-release micro-spheres for being used to sterilize and preparation method thereof, and for this method using absorbability triazole type composite bactericide Difenoconazole flusilazole as core, the degradable material PLA of macromolecule is wall material, is prepared using solvent evaporation method.The preparation method of the present invention solves the features such as traditional agricultural chemicals easily drifts about, be degradable, utilization rate is low, lapping used is PLA, compared to traditional chemical synthetic material polyureas, Lauxite, polyurethane, polyamide etc., there is the features such as safe, less toxic, degradable, environmentally safe.Preventing and treating spectrum can not only be expanded, improve drug effect, reduce environmental pollution, reducing cost accounting by being prepared by composite reagent and sustained-release micro-spheres, meet pollution-less agriculture production requirement.
Description
Technical field
The present invention relates to preparation technique of pesticide field, more particularly to a kind of sustained-release micro-spheres for being used to sterilize and its preparation side
Method.
Background technology
Formulations of pesticide processing refers to add appropriate adjuvant in pesticide original medicine and it is assigned certain use
Form, to improve active ingredient decentralization, optimize bioactivity, be easy to use.The formulations of pesticide are processed as the commodity metaplasia of agricultural chemicals
Production and the popularization and application of large area provide effective way, are the key components of pesticide industry, and Pesticide Science research
Important directions.
Since modern age, formulations of pesticide processing develops rapidly all over the world.But the present stage of china formulations of pesticide still with missible oil,
Based on the old formulation such as pulvis.Cream preparation, for solvent, very big pollution is caused to environment with toluene, dimethylbenzene etc.；Pulvis and can
Although WP etc. easily produces dust in its use, may influence operator health, make without using organic solvent
Into environmental pollution, and it is also easy to produce poisoning.Meanwhile traditional formulations of pesticide lasting period it is short, it is necessary to increase formulation rate or increase apply
Medicine frequency, which not only improves production cost, and the persticide residue of agricultural product can be increased；In addition, frequently dispenser can cause
The resistance to the action of a drug enhancing of harmful organism.It is environmentally friendly with the needs of attention of the people to environmental protection and sustainable development
The formulations of pesticide be increasingly valued by people.Some efficient, environmental protection, the pesticides application prospect of low toxicity are wider, will substitute
Old formulation.
Sustained release agent is the general name of the various formulations with control release ability, is pests occurrence rule, danger according to harmful organism
Evil feature and environmental condition, make agricultural chemicals dosage as required, specific time by pesticide processing means, sustainedly and stably exist
Discharged on target, effect that is economic, safely, effectively controlling harmful organism can be reached.
And when preparing sustained release agent at present, it usually needs the form by pharmaceutical production into sustained-release micro-spheres, and conventional PLA
In method for preparing microsphere, for example：Spray drying process is to be dispersed into the polymer solution dissolved with medicine in the presence of atomizer
Minimum drop, inert thermal current being re-introduced into, the solvent in drop is evaporated rapidly, droplet retracts form micro-capsule or microballoon,
This method is not suitable for temperature sensitive medicine and the bad control of diameter of aspirin particle；For example fusion method is higher than melting point polymer again
At a temperature of by medicine and PLA emulsifying mixtures, then collect microballoon by way of being spray-dried, centrifuging or be freeze-dried, this
The temperature that method uses is higher, and medicine needs higher stability；Again or phase separation method, first by wrappage and polymer one
Play emulsification and form W/O emulsions, a kind of liquid insoluble in polymer is then added into colostric fluid, emulsion precipitates, finally
Form microballoon, then a large amount of nonsolvents added in this suspension, finally all take organic solvent away, by through sieving, washing,
Particulate can be obtained after drying, and this method needs substantial amounts of organic solvent, the particle drug-loaded amount of gained is low, granularity is larger.
The content of the invention
It is an object of the invention to solve the defects of above-mentioned prior art is present, there is provided a kind of drugloading rate and envelop rate compared with
High sustained-release micro-spheres for being used to sterilize and preparation method thereof.
Difenoconazole and Flusilazole of the present invention belong to triazole bactericidal agent, and its mechanism of action is to suppress pathogen wheat
The biosynthesis of angle sterol is destroyed somatic cells film function, thus suppresses or disturb the hair of thalline appresorium and haustorium
Educate, the formation of mycelia and spore.Triazole bactericidal agent is by destroying membrane structure, so as to reduce pathogen pathogenicity.Such
Bactericide can be absorbed by root of the crop, stem, leaf, be conducted upwards by xylem, have it is interior inhale, conduction is fast, to crop safety, in plant
The features such as stable in vivo.Traditional formulations of pesticide are easily affected by environment, and lasting effect is shorter.If medicament is prepared as sustained-release micro-spheres
Impose in soil, be absorbed to by crop root up to plant tissue position, can not only extend drug effect, long control, can be with
Reduce pollution on the environment.
A kind of preparation method for the sustained-release micro-spheres for being used to sterilize, comprises the following steps：
Step 1：A certain amount of Difenoconazole flusilazole and PLA are weighed, is dissolved in dichloromethane
In, as oil phase；
Step 2：Oil phase is added in the aqueous phase containing emulsifying agent；
Step 3：:After being stirred with high speed disperser, 1-2 drop organic silicon defoamers are added into colostrum, magnetic force is transferred to and stirs
The reaction temperature for keeping certain on device, mixing speed are mixed, lasting stirring a period of time, filtering, is dried both；
Wherein, the mass ratio of Difenoconazole flusilazole and PLA is：1:3；
PLA concentration in oil phase is：180mg/ml；
Emulsifying agent glue mass fraction:1.5%；
Profit phase volume ratio:1:20；
High speed emulsion dispersion speed:4000rpm/min；
The mass ratio of the Difenoconazole and Flusilazole is 1:1.
Further, method as described above, the emulsifying agent are 1 according to mass ratio by gelatin and Arabic gum:1 group
Into.
Further, method as described above, when being stirred using high speed disperser in step 3, mixing time 0.4-
1.2min。
Further, method as described above, the mixing time are 0.8min.
Further, method as described above, when using magnetic stirring apparatus in step 3, mixing time 1-4h；Stirring speed
Spend 500-800rpm/min.
Further, method as described above, mixing time 3h；Mixing speed 600rpm/min.
According to the sterilization sustained-release micro-spheres that as above any described method is prepared.
Beneficial effect：
(1) present invention uses emulsion-solvent evaporation method, and this method is will not by way of mechanical agitation or ultrasonic emulsification
Emulsion is made in miscible two-phase, then by heating, vacuumizing or be stirred continuously the methods of will contain the balling-up such as medicine and PLA
The organic solvent volatilization of material removes, and makes into ball material and medicine is wrapped to form into microballoon during precipitation, be prepared by this method
Microsphere encapsulation rate, drugloading rate it is higher, microsphere features smooth surface, particle size is homogeneous.
(2) lapping of the present invention is PLA, be it is a kind of have good biocompatibility, can biology drop
The aliphatic polyester series high polymer material of solution property and bioresorbable, is finally degraded to water and CO2, it is right to human height's safety
Environment-friendly, plasticity is good, easily processed into type to have extensive research and application prospect, meet advocated now it is sustainable
Development strategy.
(3) compound drug selected by the present invention is triazole type Difenoconazole and Flusilazole, can be expanded by compounding anti-
Object is controlled, Pesticide use amount is reduced, delays drug-fast generation.The bactericide can be absorbed by root of the crop, stem, leaf simultaneously, pass through
Xylem conducts upwards, have it is interior inhale, conduction is fast, to crop safety, it is stable in plant the features such as.
(4) present invention is wrapped up medicament, is processed into sustained-release micro-spheres, more traditional formulations of pesticide missible oil, pulvis etc., is subtracted
Few agricultural chemicals drift, people and animals are avoided directly to contact, it is environmentally safe.By the protection of wall material, reduce environment is influenceed on it, and medicament is held
Continuous slowly release, can reach the effect for killing pathogen for a long time, drastically increase the medicament lasting period.
Brief description of the drawings
Fig. 1 is Flusilazole microballoon HPLC spectrograms；
Fig. 2 is Difenoconazole microballoon HPLC spectrograms；
Fig. 3 is Difenoconazole Flusilazole microballoon HPLC spectrograms；
Fig. 4 is Difenoconazole standard curve；
Fig. 5 is Flusilazole standard curve；
Fig. 6 is influence curve figure of the PLA concentration to microballoon drugloading rate；
Fig. 7 is influence curve figure of the PLA concentration to microballoon drugloading rate；
Fig. 8 is influence curve figure of the PLA concentration to microspherulite diameter；
Fig. 9 is influence curve figure of the profit phase volume ratio to microballoon drugloading rate；
Figure 10 is influence curve figure of the profit phase volume ratio to microsphere encapsulation rate；
Figure 11 is influence curve figure of the profit phase volume ratio to microspherulite diameter；
Figure 12 is influence curve figure of the emulsion dispersion speed to microballoon drugloading rate；
Figure 13 is influence curve figure of the emulsion dispersion speed to microsphere encapsulation rate；
Figure 14 is influence curve figure of the emulsion dispersion speed to microspherulite diameter；
Figure 15 is influence curve figure of the core wall material mass ratio to microballoon drugloading rate；
Figure 16 is influence curve figure of the core wall material mass ratio to microsphere encapsulation rate；
Figure 17 is influence curve figure of the core wall material mass ratio to microspherulite diameter；
Figure 18 is influence curve figure of the emulsifying agent mass fraction to microballoon drugloading rate；
Figure 19 is influence curve figure of the emulsifying agent mass fraction to microsphere encapsulation rate；
Figure 20 is influence curve figure of the emulsifying agent mass fraction to microspherulite diameter；
Figure 21 is influence curve figure of the high speed jitter time to microballoon drugloading rate；
Figure 22 is influence curve figure of the high speed jitter time to microsphere encapsulation rate；
Figure 23 is influence curve figure of the high speed jitter time to microspherulite diameter；
Figure 24 is influence curve figure of the magnetic agitation time to microballoon drugloading rate；
Figure 25 is influence curve figure of the magnetic agitation time to microsphere encapsulation rate；
Figure 26 is influence curve figure of the magnetic agitation time to microspherulite diameter；
Figure 27 is influence curve figure of the magnetic stirring speed to microballoon drugloading rate；
Figure 28 is influence curve figure of the magnetic stirring speed to microsphere encapsulation rate；
Figure 29 is influence curve figure of the magnetic stirring speed to microspherulite diameter；
Figure 30 is 1000 times of scanning electron microscope (SEM) photographs of Difenoconazole Flusilazole sustained-release micro-spheres；
Figure 31 is Difenoconazole Flusilazole sustained-release micro-spheres and degraded figure of the active compound in water body.
Embodiment
To make the object, technical solutions and advantages of the present invention clearer, below technical scheme in the present invention carry out it is clear
Chu, it is fully described by, it is clear that described embodiment is part of the embodiment of the present invention, rather than whole embodiments.It is based on
Embodiment in the present invention, those of ordinary skill in the art are obtained every other under the premise of creative work is not made
Embodiment, belong to the scope of protection of the invention.
Using Difenoconazole and Flusilazole as core, PLA is wall material for invention, using solvent evaporation method, passes through single factor test
Experiment investigation emulsifying rate and time, emulsifier concentration, mixing speed and time, profit phase volume ratio, PLA concentration and
The influence that core wall material mass ratio is prepared to microballoon, choose and prepared by five factors having a great influence to microballoon, with the drugloading rate of microballoon,
Envelop rate is inspection target, and preparation technology is optimized using the horizontal quadrature design experiment of five factor four.
Instrument and equipment
Cut disperser, electronic analytical balance, magnetic force heating stirrer, efficient liquid phase in laser particle size analyzer, high speed
Chromatograph (Hitachi's electronics).
Main agents and medicine
PLA (PLA, molecular weight be about 8 ten thousand), gelatin, Arabic gum, dichloromethane, organic silicon defoamer, 96.4%
Difenoconazole technical material (Hainan Zhengye Zhongnong Hi-Tech Industry Co., Ltd), 95% flusilazole (Hainan decent job middle peasant's high-tech
Limited company).
Preparation method：
A certain amount of Difenoconazole flusilazole and PLA are accurately weighed, is dissolved in dichloromethane,
As oil phase.Oil phase is added in the aqueous phase containing emulsifying agent to (emulsifying agent is gelatin and Arabic gum, mass ratio 1:1),
After being stirred with high speed disperser, 1-2 drop organic silicon defoamers are added into colostric fluid, is transferred on magnetic stirring apparatus and keeps certain
Reaction temperature, mixing speed, lasting stirring a period of time.It is micro- that filtering, drying had both obtained Difenoconazole Flusilazole PLA
Ball, it is standby that dry microballoon is loaded into sealed bag.
On the basis of experiment of single factor, 5 factors being had a great influence to microballoon property are filtered out as object is investigated, i.e.,
Difenoconazole Flusilazole/PLA mass ratio (A), PLA concentration (B), gelatin-gum arabic quality point in oil phase
5 number (C), profit phase volume ratio (D), high speed emulsion dispersion speed (E) factors, it is orthogonal that each factor chooses 4 horizontal progress
Analysis of experiments, by L16 (45) orthogonal trial experiment, using the envelop rate of microballoon and drugloading rate as evaluation index, screen optimal work
Skill condition.
Microspherulite diameter size
Particle size measures：Take a certain amount of microsphere powder to add appropriate dispersant, add 20ml distilled water in beaker,
After ultrasonication 5 minutes, using circulation sampling system, microspherulite diameter is determined with laser particle analyzer, records its meso-position radius D50。
Microspheres quality determines
1st, HPLC condition determinations
Chromatographic column：Amethyst C18- H (4.6 ㎜ × 250 ㎜, 5 μm)；Detector：UV-detector.By searching document
Mobile phase is determined with preliminary experiment：Methanol-water (volume ratio 85:15)；Detection wavelength：260nm；30 DEG C of column temperature；Flow velocity：1.0ml/
min；The μ l of sample size 10；Retention time：Difenoconazole is about 6.4min, and Flusilazole is about 4.7min (Fig. 1, Fig. 2).
2nd, the drafting of standard curve
Accurately weigh 95% flusilazole 0.0105g (being accurate to 0.0001g), 96.4% difenoconazole technical material
0.0103g (is accurate to 0.0001g), is placed in 10ml brown volumetric flask, and first plus the dissolving of a small amount of dichloromethane, again with methanol are fixed
Hold to 10ml, ultrasound degassing 10min, producing Difenoconazole Flusilazole standard liquid, (Difenoconazole concentration is 1g/L, fluorine
Silicon azoles concentration is 1g/L).By two kinds of standard liquids be diluted to respectively 0.2g/L, 0.4g/L, 0.6g/L, 0.8g/L, 1.0g/L in
In 10ml brown volumetric flasks, ultrasonic 10min, with standby after 0.22 μm of filtering membrane filtration.According to above-mentioned chromatographic test strip part,
After instrumental baseline stabilization, several pin standard liquids are continuously injected into, calculate the repeatability of each pin peak area, treat that the peak area of two pins is steady
After fixed, each concentration METHOD FOR CONTINUOUS DETERMINATION 3 times, using sample introduction concentration as abscissa, peak area average value be ordinate, draws standard song
Line.
3rd, microballoon drugloading rate, entrapment efficiency determination
The accurate Difenoconazole Flusilazole compounding microballoon 0.0100g (being accurate to 0.0001g) that weighs is in 10ml brown
In volumetric flask, add q. s. methylene chloride and be placed in refrigerator and dissolve 1h, take out volumetric flask after microballoon dissolving, add proper amount of methanol
Sonic oscillation twice, finally with methanol constant volume to scale, it is standby to cross 0.22 μm of filter membrane.It is measured by above-mentioned chromatographic condition,
Each sample is continuously surveyed three times, and peak area average value is substituted into standard curve, calculates Difenoconazole Flusilazole concentration and matter
Amount.Drugloading rate, envelop rate are calculated according to below equation：
The quality * of actual drugloading rate (%)=(quality of quality+Flusilazole of Difenoconazole in microballoon)/microballoon
100%
Quality/(quality of actual input active compound+poly- breast actually put into of theoretical drugloading rate (%)=reality input active compound
The quality of acid) * 100%
Envelop rate (%)=actual drugloading rate/theoretical drugloading rate * 100%
4th, the veracity and precision of method
Difenoconazole Flusilazole microballoon core wall material mass ratio prepared by the present invention is from 1:2 to 1:5, theoretical drugloading rate is situated between
Between 16.7% to 33.3%, for the accuracy of checking drug bearing microsphere detection, it is prepared for being free of phenylate first according to same process
The blank microballoon of ring azoles Flusilazole, add the Difenoconazole flusilazole of different quality respectively in blank microballoon
(being mixed by optimum proportioning), handled according to aforesaid operations method, detection, each concentration repeats 3 times, and the measure rate of recovery is
97.86%, choose a concentration, METHOD FOR CONTINUOUS DETERMINATION 5 times, calculate standard deviation as 0.0168, the results showed that this method it is accurate
Degree is preferable with precision.
HPLC determines microspheres amount
1st, Difenoconazole Flusilazole microballoon chromatogram
Analyzed according to as above chromatographic test strip part, Difenoconazole and Flusilazole are kept completely separate, and peak shape is preferable, and chromatogram is shown in
Fig. 3.
2nd, the linear dependence of assay method
According to above-mentioned chromatographic test strip part, a series of Difenoconazole Flusilazole standard for determining concentration gradients respectively is molten
Liquid, to detect liquid concentration as abscissa, the peak area average value of detection is ordinate, draws standard curve, obtains linear equation：
Difenoconazole y=1251x+13248, coefficient correlation 0.9993；Flusilazole y=408.74x-4616.2, coefficient correlation are
0.9999, understand that Difenoconazole and Flusilazole linear relationship in the range of 200~1000mg/ml are good by Fig. 4,5.
Experiment of single factor result and analysis
1st, influence of the PLA concentration to microspherulite diameter, envelop rate and drugloading rate
PLA is to determine microspherulite diameter size and the principal element of envelop rate height.It is to study PLA concentration to microballoon
The influence of preparation technology, other microballoon preparation conditions are fixed, it is 90,120,150,180 (mg/ml) to choose PLA concentration respectively
Polylactic acid microsphere is prepared, as a result sees Fig. 6, Fig. 7, Fig. 8.
As a result show：Concentration of the PLA in dichloromethane is bigger, and microspherulite diameter, drugloading rate, the envelop rate of preparation are got over
Greatly.PLA concentration is bigger in oil phase, is less susceptible to disperse in aqueous phase, and the active force suffered by emulsion droplet is also different.Due to
The increase of viscosity, the probability increase that microballoon is reunited, so as to cause particle diameter gradually to increase.PLA concentration increases, that is, wraps up
The wall material of medicine is more, and with the volatilization of dichloromethane, leakage can does not occur also and wraps up medicine for medicine, therefore drugloading rate,
Envelop rate is higher.Comprehensive particle size, envelop rate and drugloading rate consider that the concentration that should choose PLA is 150mg/ml.
2nd, influence of the profit phase volume ratio to microspherulite diameter, envelop rate and drugloading rate
Profit phase volume ratio has a very big impact to the emulsion stability originally formed.Fix other microballoons and prepare bar
Part, it is 1 to choose profit phase volume ratio respectively:5、1:10、1:15、1:20、1:25 prepare polylactic acid microsphere, and it is big to determine its particle diameter
Small, envelop rate, drugloading rate.As a result Fig. 9, Figure 10, Figure 11 are seen.
As a result show：As watr-proportion increases in system, the meso-position radius of microballoon gradually increase, and drugloading rate, encapsulating take the lead in
Increase and then the trend for having reduction again.But generally envelop rate and drugloading rate is all higher.The timing of mixing speed one, watr-proportion are got over
Big cumulative volume is bigger, and suffered shearing force is smaller, and prepared microspherulite diameter is bigger.With the increase of watr-proportion, encapsulating
Rate is gradually reduced but declines simultaneously unobvious, because when watr-proportion is larger, medicine is easier to spread into aqueous phase in drop, makes bag
Envelope rate and drugloading rate decline.Therefore, profit phase 1 is selected:20 than convenient.
Influence of the rotating speed to microspherulite diameter, envelop rate and drugloading rate when the 3, emulsifying
Emulsification shearing is that microballoon prepares a very crucial step during colostric fluid at a high speed, and it prepares the shadow of particle diameter to microballoon
Sound is larger.Other microballoon preparation conditions are fixed, choose emulsion dispersion speed 3000,3500,4000,4500 (rpm/min) respectively
Polylactic acid microsphere is prepared, determines its particle size, envelop rate, drugloading rate.As a result Figure 12, Figure 13, Figure 14 are seen.
As a result show：With the quickening of emulsion dispersion speed, the microspherulite diameter of preparation is gradually reduced rear and has becoming for increase
Gesture.Due to the increase of mixing speed, the shearing force that emulsion droplet is subject to also increases, and the volume of emulsion droplet diminishes, so as to cause particle diameter to diminish,
But speed is excessive, less microballoon can reunite again, cause microspherulite diameter slightly to increase.When emulsion dispersion speed is relatively low,
Oil phase is not easy to be disperseed in aqueous phase, and PLA viscosity is reunited compared with conference, causes medicine to be spread into water, drugloading rate, bag
Envelope rate is relatively low.Emulsion dispersion speed is accelerated, and oil phase obtains fully dispersed in aqueous phase, and PLA can be tied well with medicine
Close, cause drugloading rate, envelop rate higher.But speed is too fast, microballoon is easily demulsified, and leaks medicine, causes to carry
Dose, envelop rate reduce.
4th, influence of the core wall material mass ratio to microspherulite diameter, envelop rate and drugloading rate
Core wall material mass ratio is to influence the most important factor of microballoon drugloading rate.Other microballoon preparation conditions are fixed, point
Xuan Qu not core wall material mass ratio 1:2、1:3、1:4、1:5 prepare polylactic acid microsphere, determine its particle size, envelop rate, drugloading rate.
As a result Figure 15, Figure 16, Figure 17 are seen.
As a result show：With the increase of core wall material mass ratio, prepared microspherulite diameter, drugloading rate are with increase.Core wall
The increase of material mass ratio, viscosity gradually increase, and add the difficulty of shearing, shearing force can not fully dispersed emulsion, can not be formed
The microballoon of rule.Within the specific limits, the mass ratio of medicine and PLA is bigger, and the medicine of PLA parcel is more, drugloading rate
Also it is higher.When core wall material mass ratio is excessive, the ability of PLA packaging medicine reaches saturation, and excessive medicine will be distributed to
In outer aqueous phase, the loss of medicine is increased so that envelop rate has declined.Therefore, prepare microballoon and should be noted that core wall material ratio.
5th, influence of the emulsifying agent mass fraction to microspherulite diameter, envelop rate and drugloading rate
Emulsifying agent can reduce liquid-liquid interface tension force, reduce the thermodynamic instability factor of system, by adding emulsifying agent,
It is adsorbed on drop, can be effectively formed space or electrical obstacle, reduce and coalesce caused by the collision between drop.With
Gelatin and Arabic gum (mass ratio 1:1) emulsifying agent is used as, other microballoon preparation conditions is fixed, chooses mass fraction respectively
0.75%th, 1.00%, 1.25%, 1.50%, 1.75%, 2.00% emulsifying agent prepares polylactic acid microsphere, and it is big to determine its particle diameter
Small, envelop rate, drugloading rate.As a result Figure 18, Figure 19, Figure 20 are seen.
As a result show：With the increase of emulsifier concentration, microballoon drugloading rate, envelop rate are with rise, when concentration is
Reach highest when 1.50%, afterwards as concentration raises, microballoon drugloading rate and envelop rate are gradually reduced again.When emulsifier concentration compared with
When low, the emulsion stability of formation is poor, is easily demulsified in the presence of mechanical agitation, drugloading rate and envelop rate compared with
It is low.When concentration increase to a certain extent when, the absorption of more emulsifying agent adds interface film strength on emulsion droplet surface,
Core is protected well, emulsion intercalation method increase, is advantageous to PLA packaging medicine.When concentration increases, emulsifying agent
Emulsion dispersion ability strengthens, and emulsion can be made to disperse well, therefore microspherulite diameter reduces, but exceedes certain limit, and emulsifying agent glues
Degree increase, fine particle are easily reunited, and particle diameter slightly increases.
6th, influence of the emulsion dispersion time to microspherulite diameter, envelop rate and drugloading rate
The emulsion dispersion time includes high speed emulsion dispersion time and magnetic agitation time, fixed other conditions, setting respectively
The high speed emulsion dispersion time is 0.4min, 0.6min, 0.8min, 1.0min, 1.2min, the magnetic agitation time is 1h, 2h, 3h,
4h, other microballoon preparation conditions are fixed, determine its particle size, envelop rate, drugloading rate.As a result Figure 21, Figure 22, Figure 23, figure are seen
24th, Figure 25, Figure 26.
As a result show：High speed emulsion dispersion time microspherulite diameter in 0.4,0.6min is larger, and adhesion is more,
When 0.8min, 1.0min, 1.2min, microspherulite diameter is smaller, but the time it is longer can be destroyed microballoon, cause envelop rate and carry medicine
Amount reduces.When disperseing on magnetic stirring apparatus, with the extension of jitter time, microspherulite diameter is gradually reduced, microballoon form after 3h
Change is little, and envelop rate and drugloading rate can reach higher level during 3h.Therefore selection high speed jitter time is 0.8min, magnetic force
Mixing time is 3h.
7th, influence of the magnetic stirring speed to microspherulite diameter, envelop rate and drugloading rate
Magnetic stirring speed has a great influence to microspherulite diameter, and suitable mixing speed optimizes very to microspheres
It is important.Other microballoon preparation conditions are fixed, control magnetic stirring speed is respectively 500,600,700,800 (rpm/min) measure
Its particle size, envelop rate, drugloading rate.As a result Figure 27, Figure 28, Figure 29 are seen.
As a result show：Suitable mixing speed is the key for preparing high drug load and envelop rate under the conditions of 600rpm/min
The microballoon drugloading rate and envelop rate of preparation are higher.Microspherulite diameter is as the increase of mixing speed is first gradually reduced then and is had slightly
Rise.The reason for possible is in emulsion process, and with the raising of mixing speed, emulsion droplet is sufficiently separated, so as to the particle diameter formed
It is smaller.But if mixing speed is too high, the collision increase of drop, caused adhesion degree also increases, and microballoon is easily broken
It is bad, so that drugloading rate and envelop rate reduce.
Quadrature factor experimental result and analysis
The orthogonal design factor level table of table 1
The orthogonal experiments table of table 2
It is A ﹥ C ﹥ by the factor primary and secondary order of extreme difference discharge from table 2 it can be seen that during using microballoon drugloading rate as evaluation index
D ﹥ E ﹥ B, optimum proportioning A1B4C2D4E3, i.e. core wall material is than 1:2nd, PLA concentration 180mg/ml, emulsifier concentration are
1.5%th, profit phase volume ratio is 1:25th, high speed emulsion dispersion speed is 4000rpm/min.Using microsphere encapsulation rate as evaluation index
When, it is A ﹥ D ﹥ E ﹥ C ﹥ B by the factor primary and secondary order of extreme difference discharge, optimum proportioning A2B4C2D3E3, i.e. core wall material is than 1:3rd, gather
Lactic acid concn 180mg/ml, emulsifier concentration 1.5%, profit phase volume ratio are 1:20th, high speed emulsion dispersion speed is
4000rpm/min.Microballoon is 1 in core wall material mass ratio:Large percentage when 2 due to medicine in itself, drugloading rate is higher, but encapsulates
Rate is without 1:The high result for combining single-factor and investigating when 3, it is 1 to determine core wall material mass ratio:3.The optimised process that i.e. prepared by microballoon
For：Core wall material mass ratio is 1:3rd, PLA concentration 180mg/ml, emulsifier concentration 1.5%, profit phase volume ratio are 1:
20th, high speed emulsion dispersion speed is 4000rpm/min, the high speed emulsion dispersion time is 0.8min, magnetic agitation 600rpm/min,
Persistently stir 3h.
It is more to influence factor prepared by microballoon, on the basis of single factor exploration, choose to prepare microballoon influences the present invention
Five larger factors, four levels are set, it optimized using orthogonal design, obtained optimum proportioning is：Core wall material matter
Amount is than being 1:3, PLA concentration 180mg/ml, emulsifier concentration 1.5%, profit phase volume ratio be 1:20th, emulsify at a high speed
Rate of dispersion is 4000rpm/min, the high speed emulsion dispersion time is 0.8min, magnetic agitation 600rpm/min, persistently stirs 3h.
The preparation of polylactic acid microsphere, organic solvent should have good dissolubility to PLA and medicine, in water
Solubility is low, and boiling point is less than 100 degree, and during ensureing organic solvent volatilization, PLA can be good at solidifying, by medicine bag
Wrap up in, as shown in figure 30, the microballoon size rounding that is prepared using dichloromethane as organic solvent, surface are smooth.
When preparing microballoon, the selection of wall material should have nontoxic, non-stimulated, good biocompatibility.PLA conduct
A kind of Biodegradable material, in the environment by after a series of effects such as illumination, temperature, air, microorganism, finally it is metabolized as
Carbon dioxide and water, it is environmentally safe.Figure 31 is Difenoconazole Flusilazole sustained-release micro-spheres and degraded of the active compound in water body
Figure, as shown in figure 31, it can be seen that sustained-release micro-spheres protect active compound well, greatly reduce the degradation rate of active compound.
Finally it should be noted that：The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although
The present invention is described in detail with reference to the foregoing embodiments, it will be understood by those within the art that：It still may be used
To be modified to the technical scheme described in foregoing embodiments, or equivalent substitution is carried out to which part technical characteristic；
And these modification or replace, do not make appropriate technical solution essence depart from various embodiments of the present invention technical scheme spirit and
Scope.
Claims (7)
1. a kind of preparation method for the sustained-release micro-spheres for being used to sterilize, it is characterised in that comprise the following steps：
Step 1：A certain amount of Difenoconazole flusilazole and PLA are weighed, is dissolved in dichloromethane, is made
For oil phase；
Step 2：Oil phase is added in the aqueous phase containing emulsifying agent；
Step 3：:After being stirred with high speed disperser, 1-2 drop organic silicon defoamers are added into colostrum, are transferred to magnetic stirring apparatus
It is upper keep certain reaction temperature, mixing speed, lasting stirring a period of time, filtering, dry both；
Wherein, the mass ratio of Difenoconazole flusilazole and PLA is：1:3；
PLA concentration in oil phase is：180mg/ml；
Emulsifying agent glue mass fraction:1.5%；
Profit phase volume ratio:1:20；
High speed emulsion dispersion speed:4000rpm/min；
The mass ratio of the Difenoconazole and Flusilazole is 1:1.
2. according to the method for claim 1, it is characterised in that the emulsifying agent is by gelatin and Arabic gum according to mass ratio
For 1:1 composition.
3. according to the method for claim 1, it is characterised in that when being stirred in step 3 using high speed disperser, mixing time
For 0.4-1.2min.
4. according to the method for claim 3, it is characterised in that the mixing time is 0.8min.
5. according to the method for claim 1, it is characterised in that when magnetic stirring apparatus is used in step 3, mixing time 1-
4h；Mixing speed 500-800rpm/min.
6. according to the method for claim 5, it is characterised in that mixing time 3h；Mixing speed 600rpm/min.
7. the sustained-release micro-spheres being prepared according to any described methods of claim 1-6.
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| CN108684688A (en) * | 2018-06-14 | 2018-10-23 | 国家纳米科学中心 | A kind of nano pesticide composition and preparation method thereof |
| CN109197876A (en) * | 2018-08-31 | 2019-01-15 | 中国热带农业科学院环境与植物保护研究所 | Triazolone difenoconazole polylactic acid microsphere and preparation method thereof |
| CN112120021A (en) * | 2020-09-30 | 2020-12-25 | 浙江农林大学 | Compound type slow-release algae removal microcapsule and preparation method thereof |
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