CN102302457B - Preparation method of ivermectin sustained-release microspheres - Google Patents
Preparation method of ivermectin sustained-release microspheres Download PDFInfo
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Abstract
The invention relates to ivermectin sustained-release microspheres used as an animal medicine for animal injection, and a preparation method thereof. The invention belongs to an interdisciplinary field of biomedical polymer materials and controlled release preparations. The invention discloses ivermectin sustained-release microspheres, which are characterized in that: the ivermectin sustained-release microspheres have particle sizes of 0.1 to 10mum, a medicine loading capacity of 20% to 35%, and an entrapment rate of above 80%. The preparation method of the ivermectin sustained-release microspheres comprises steps that: a carrier material and the medicine ivermectin with a mass ratio of 1:1-10 are dissolved in an organic solvent; the solution is processed through supersonic wave or mechanical stirring, such that the solution is emulsified into an oil phase, wherein a volume ratio of oil phase to water phase is 1:5-10; under a temperature of -10 DEG C to 30 DEG C, the oil phase is injected into a water phase disperse medium solution step-by-step; constant-temperature magnetic stirring is carried out with a rotation speed of 400 to 10000rpm, the mixture is sufficiently emulsified, such that an S/O/W type emulsion is obtained; the emulsion is stirred under room temperature for 3 to 4 hours, such that the organic solvent is sufficiently volatilized; the obtained product is centrifuged, washed, collected, and is vacuum-dried with a pressure of 0.01 to 0.04MPa under room temperature for 10 to 12 hours or is lyophilized under a temperature of -0 DEG C to -20 DEG C. With the processes, ivermectin sustained-release microspheres with particle sizes of 0.1 to 10mum are obtained.
Description
Technical field
The present invention relates to a kind of animal medicine, animal health injection ivermectin sustained-release micro-spheres and preparation method thereof, belong to the crossing research field of biological medical polymer material and pharmaceutical controlled release formulation.The method adopts improved emulsion solvent volatility process, wrap up ivermectin (IVM) with Biodegradable polymer material polylactic acid (PLA) or Poly(D,L-lactide-co-glycolide (PLGA) for carrier, under mechanical agitation, prepare the ivermectin sustained-release micro-spheres.
Background technology
In recent years, high speed development along with livestock breeding industry, the different dosage form medicine of increasing ivermectin is developed out, such as oral liquid, capsule, paste, injection, Emulsion, spray, pre-mixing agent, dashing agent, tablet, slow release bolus, powder etc. are arranged.All shown unique curative effect at these commercially available on market medicines in clinical application, using maximum dosage forms is the normal injection agent.But because the half-life of ivermectin injection is short, this problem of poor stability, animal body needs long-term a large amount of administration, expends a large amount of man power and materials, has hindered its application clinically.Thereby, in view of the weak point of existing dosage form, be necessary that exploitation is efficient, low toxicity, targeting, slow release and controlled release preparation.
Ivermectin is the semi-synthetic Macrolide multicomponent antibiotic that is produced by Avid kyowamycin (streptomyces avermitilis) fermentation.Be novel wide spectrum, efficient, low toxicity, safe antibiotics antiparasitic, particularly nematicide and arthropod all have and well kill effect to endoparasite and ectoparasite.This product all has effect to most of nematicide (but non-all nematicides) of various life cycle; Microfilariae of ohchocerciasis to filaria volvulus is effective, but invalid to adult; Also effective to the excrement strongylid that only is in intestinal.This product has optionally inhibitory action, by being combined with the high-affinity that without spinal animals neurocyte and muscle cell Glutamic Acid is the chloride channel of valve, thereby cause cell membrane to the increase of chloride ion permeability, cause neurocyte or muscle cell hyperpolarization, make parasite paralysis or dead.This product also can interact with the chloride channel of other part valve (passing g-aminobutyric acid (GABA) such as nerve).The selectivity of this product is because do not have glutamic acid-chloride channel in some mammalian bodies, and avilamycin only has low-affinity to mammal part-chloride channel.This product can not penetrate people's blood brain barrier.Onchocerciasis and strongyloidiasis and ancylostome, ascarid, whipworm, retrofection.
Polylactic acid and Poly(D,L-lactide-co-glycolide be a kind of good biocompatibility, can biodegradation, safety is good, have good blood dissolubility, the high molecular polymer of physicochemical property excellence, be the microsphere sustained-release carrier material of at present domestic and international most study, be used as drug carrier material by drugs approved by FDA.Utilizing the bag medicine microsphere controlled release durg delivery system of Biodegradable material preparation that widely research has been arranged, is the Novel Drug Delivery Systems that has development potentiality.This system can holder in best drug level, and time of prolong drug effect, make medicine stable.Abroad, successfully developed the agent of ivermectin long-acting controlled release, and dropped into and use.At home, the research of ivermectin long-acting dosage form is also quite paid attention to, clinical trial and the pharmacokinetic of Properties of Ivermectin Loaded Pla Microspheres nano-emulsion arranged.The present invention has had lifting with respect to the Properties of Ivermectin Loaded Pla Microspheres of domestic present research and development on particle diameter, relatively less, distribution is narrower; The present invention has very large lifting with respect to the ivermectin nanoemulsion above the existing market on the drug loading of microsphere, the drug loading of nano-emulsion is generally about ten Percent, and the drug loading of microsphere of the present invention can reach about 30 percent.
Summary of the invention
The object of the invention is to avoid the deficiencies in the prior art that a kind of ivermectin sustained-release micro-spheres is provided.
Another purpose of the present invention is a kind of preparation method of ivermectin sustained-release micro-spheres, the method with polylactic acid or Poly(D,L-lactide-co-glycolide as carrier material entrapped drug ivermectin, the particle diameter of the ivermectin sustained-release micro-spheres that makes is controlled in 0.1～10um scope, the surface rounding, good evenness, drug loading and envelop rate are high.
For achieving the above object, the technical scheme that the present invention takes is: a kind of ivermectin sustained-release micro-spheres, its main feature are that described ivermectin sustained-release micro-spheres particle diameter is 0.1～10um, and drug loading is 20%～35%, and envelop rate is more than 80%;
The preparation method of ivermectin sustained-release micro-spheres comprises the steps:
With polylactic acid or Poly(D,L-lactide-co-glycolide as carrier material, with described carrier material and medicine ivermectin take mass percent as 1:1～10 be dissolved in the organic solvent through ultrasound wave or the fully emulsified oil phase of making of mechanical agitation, the volume ratio of described oil phase and water is 1:5～10; It is-10 ℃～30 ℃ in temperature, described oil phase is expelled in the water dispersion medium solution step by step, temperature constant magnetic stirring, rotating speed 400～10000rpm is fully emulsified, obtains S/O/W type (S: represent solid drugs/O: represent oil phase/W: represent water) emulsion; Then it is complete to the organic solvent volatilization at room temperature to stir emulsion 3～4h, again through centrifugal, washing, collection, room temperature vacuum 0.01～0.04MPa drying, time is 10-12h or lyophilization, and temperature is-0 ℃～-20 ℃, and obtaining particle diameter is the ivermectin sustained-release micro-spheres of 0.1～10um.
Described ivermectin sustained-release micro-spheres, described ivermectin are the two hydroperoxide derivatives of avilamycin macrolide 22,23-; The relative molecular weight of described polylactic acid or Poly(D,L-lactide-co-glycolide is 8.0 * 10
3～1.5 * 10
5Between.
Described ivermectin sustained-release micro-spheres, described organic solvent are the mixed liquor of dichloromethane or dichloromethane and acetone, and the percent by volume of dichloromethane and acetone is 70～100:0～30.
Described ivermectin sustained-release micro-spheres, described water dispersion medium solution are polyvinyl alcohol or polyvinyl alcohol and Tween 80 mixed liquor, and wherein the concentration of polyvinyl alcohol is 0.1%～4% g/ml in the 100ml aqueous solution; In the mixed liquor in the 100ml aqueous solution concentration of polyvinyl alcohol be 0.1%～3.5% g/ml, the concentration of Tween 80 is 0.01～0.5% g/ml.
Described ivermectin sustained-release micro-spheres, described oil phase is expelled to the method in the water dispersion medium solution step by step, at first the volume ratio by oil phase and water is 1:5～10 water intaking phase dispersion medium solutions, with oil phase be distributed to the phase dispersion medium solution of fetching water 10%～40% in, obtain S/O/W
1Emulsion for the first time, 2 minutes 2000～10000rpm of high-speed stirred, and then for the first time emulsion dispersion to all the other water dispersion medium solutions 60%～90% in obtain S/O/W
2Emulsion at room temperature stirs 3～4h, 400～1000rmp more for the second time, obtains S/O/W type emulsion.
A kind of preparation method of ivermectin sustained-release micro-spheres, its main feature is to comprise the steps:
With polylactic acid or Poly(D,L-lactide-co-glycolide as carrier material, with described carrier material and medicine ivermectin take mass percent as 1:1～10 be dissolved in the organic solvent through ultrasound wave or the fully emulsified oil phase of making of mechanical agitation, the volume ratio of described oil phase and water is 1:5～10; It is-10 ℃～30 ℃ in temperature, described oil phase is expelled in the water dispersion medium solution step by step, temperature constant magnetic stirring, rotating speed 400～10000rpm is fully emulsified, obtains S/O/W type (S: represent solid drugs/O: represent oil phase/W: represent water) emulsion; Then it is complete to the organic solvent volatilization at room temperature to stir emulsion 3～4h, again through centrifugal, washing, collection, room temperature vacuum 0.01～0.04MPa drying, time is 10-12h or lyophilization, and temperature is-0 ℃～-20 ℃, and obtaining particle diameter is the ivermectin sustained-release micro-spheres of 0.1～10um.
The preparation method of described ivermectin sustained-release micro-spheres, described ivermectin are the two hydroperoxide derivatives of avilamycin macrolide 22,23-; The relative molecular weight of described polylactic acid or Poly(D,L-lactide-co-glycolide is 8.0 * 10
3～1.5 * 10
5Between.
The preparation method of described ivermectin sustained-release micro-spheres, described organic solvent are the mixed liquor of dichloromethane or dichloromethane and acetone, and the percent by volume of dichloromethane and acetone is 70～100:0～30.
The preparation method of described ivermectin sustained-release micro-spheres, described water dispersion medium solution are polyvinyl alcohol or polyvinyl alcohol and Tween 80 mixed liquor, and wherein the concentration of polyvinyl alcohol is 0.1%～3% g/ml in the 100ml aqueous solution; In the mixed liquor in the 100ml aqueous solution concentration of polyvinyl alcohol be 0.1%～2.5% g/ml, the concentration of Tween 80 is 0.01～0.5% g/ml.
The preparation method of described ivermectin sustained-release micro-spheres, described oil phase is expelled to the method in the water dispersion medium solution step by step, at first the volume ratio by oil phase and water is 1:5～10 water intaking phase dispersion medium solutions, with oil phase be distributed to the phase dispersion medium solution of fetching water 10%～40% in, obtain S/O/W
1Emulsion for the first time, 2 minutes 2000～10000rpm of high-speed stirred, and then for the first time emulsion dispersion to all the other water dispersion medium solutions 60%～90% in obtain S/O/W
2Emulsion at room temperature stirs 3～4h, 400～1000rmp more for the second time, obtains S/O/W type emulsion.
Adopt ivermectin polylactic acid or the Poly(D,L-lactide-co-glycolide sustained-release micro-spheres of method preparation of the present invention, the microsphere surface rounding, good evenness, particle size distribution is controlled in 0.1～10um scope, and drug loading can reach more than 25%, and envelop rate is more than 80%.
The antibiotic medicine of ivermectin polylactic acid of the present invention or Poly(D,L-lactide-co-glycolide sustained-release micro-spheres compared with prior art has the following advantages:
1. controlled in particle diameter 0.1～10um scope of ivermectin sustained-release micro-spheres of the present invention, narrow diameter distribution.Can be according to the size of animal, required sustained drug action time that reaches and select the polylactic acid of different molecular weight to control particle diameter as carrier material.
2. ivermectin sustained-release micro-spheres of the present invention is milky solid powdery microsphere, and particle size distribution is even, and good stability is easy to preserve, and is easy to body to absorption, the utilization of medicine, reduces side effect, improves drug effect.
3. the slow-release function of the ivermectin sustained-release micro-spheres of the present invention's preparation is remarkable, and drug loading is high, can keep long administration time, need not multiple dosing, has reduced consumption and the medication number of times of medicine.It is convenient to use, and has saved a large amount of manpower and materials.
4. the method for ivermectin sustained-release micro-spheres preparation of the present invention is simple, power consumption is low, do not need special equipment just can produce in a large number.
Description of drawings
Fig. 1 is that the ivermectin polylactic acid-co-glycolic acid sustained-release micro-spheres of the embodiment of the invention 5 preparation amplifies 12000 times vacuum scanning electron microscope diagram, and visible microsphere features smooth surface is even, does not have the slit, and particle diameter is 8.23um.
Fig. 2 is that the ivermectin polylactic acid sustained-release micro-spheres of the embodiment of the invention 1 preparation amplifies 1000 times scanning electron microscope diagram, and the whole balling-up of visible microsphere, dispersibility are fine, smooth rounding, and the microspherulite diameter suitable size is all in 0.1～10um scope.
The specific embodiment
Below principle of the present invention and feature are described, institute only gives an actual example and to be used for explanation the present invention, is not be used to limiting scope of the present invention.
Embodiment 1: the preparation of ivermectin polylactic acid sustained-release micro-spheres.
Accurately take by weighing polylactic acid 0.5g and medicine ivermectin 0.25g is dissolved in the mixed solution of 20ml dichloromethane and acetone, the percent by volume of dichloromethane and acetone is 9:1, ultrasonic echography 5min fully dissolves and makes oil phase, and the relative molecular mass of polylactic acid is 10,000; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 40ml contain 2.0%(g/ml) under 2000rpm, stir 2min in polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water), form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 60ml and contains 1.0%(g/ml) in polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution, under the magnetic agitation of 400rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 12h of room temperature vacuum (0.02 MPa) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 3.32um, drug loading 28.41%, envelop rate 83.87%.
Embodiment 2:
Accurately take by weighing in the mixed solution that polylactic acid 0.5g and medicine ivermectin 0.25g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 9:1), ultrasonic echography 5min fully dissolves and makes oil phase, and the relative molecular mass of polylactic acid is 2.5 ten thousand; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 40ml contain 2.0%(g/ml) polyvinyl alcohol and 0.1%(g/ml) under 2000rpm, stir 2min in the Tween 80 aqueous solution (water), form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 60ml and contains 1.0%(g/ml) in polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution, under the magnetic agitation of 500rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 12h of room temperature vacuum (0.02 MPa) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 3.52um, drug loading 28.17%, envelop rate 84.51%.
Embodiment 3:
Accurately take by weighing in the mixed solution that polylactic acid 0.5g and medicine ivermectin 0.35g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 8:2), ultrasonic echography 5min fully dissolves and makes oil phase, and the relative molecular mass of polylactic acid is 10,000; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 20ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 80ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 500rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 12h of room temperature vacuum (0.02 MPa) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.23um, drug loading 31.24%, envelop rate 82.54 %.
Embodiment 4:
Accurately take by weighing in the mixed solution that polylactic acid 0.5g and medicine ivermectin 0.35g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 7:3), ultrasonic echography 5min fully dissolves and makes oil phase, and the relative molecular mass of polylactic acid is 2.5 ten thousand; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 20ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 80ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 600rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 12h of room temperature vacuum (0.02 MPa) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.36um, drug loading 31.68%, envelop rate 82.79 %.
Embodiment 5:
Accurately take by weighing in the mixed solution that Poly(D,L-lactide-co-glycolide 0.5g and medicine ivermectin 0.25g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 9:1), the constant temperature blender with magnetic force mechanical agitation, speed 2000rpm, 4min fully dissolves and makes oil phase, and the relative molecular mass of Poly(D,L-lactide-co-glycolide is 1.5 ten thousand; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 40ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 60ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 600rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 10h of lyophilization (10 ℃) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.57um, drug loading 29.39%, envelop rate 84.59%.
Embodiment 6:
Accurately take by weighing in the mixed solution that Poly(D,L-lactide-co-glycolide 0.5g and medicine ivermectin 0.25g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 9:1), the constant temperature blender with magnetic force mechanical agitation, speed 2000rpm, 4min fully dissolves and makes oil phase, and the relative molecular mass of Poly(D,L-lactide-co-glycolide is 1.5 ten thousand; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 40ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 60ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 600rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 10h of lyophilization (10 ℃) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.83um, drug loading 30.07%, envelop rate 83.41%.
Embodiment 7:
Accurately take by weighing in the mixed solution that Poly(D,L-lactide-co-glycolide 0.5g and medicine ivermectin 0.35g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 8:2), the constant temperature blender with magnetic force mechanical agitation, speed 2000rpm, 4min fully dissolves and makes oil phase, and the relative molecular mass of Poly(D,L-lactide-co-glycolide is 2.5 ten thousand; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 10ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 90ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 600rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 10h of lyophilization (10 ℃) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.85um, drug loading 31.22%, envelop rate 82.52%.
Embodiment 8:
Accurately take by weighing in the mixed solution that Poly(D,L-lactide-co-glycolide 0.5g and medicine ivermectin 0.35g be dissolved in 20ml dichloromethane and acetone (percent by volume of dichloromethane and acetone is 8:2), the constant temperature blender with magnetic force mechanical agitation, speed 2000rpm, 4min fully dissolves and makes oil phase, and the relative molecular mass of Poly(D,L-lactide-co-glycolide is 2.5 ten thousand; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 10ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 90ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 600rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 10h of lyophilization (10 ℃) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.92um, drug loading 32.03%, envelop rate 81.39%.
Embodiment 9:
Accurately take by weighing polylactic acid 0.5g and medicine ivermectin 0.25g is dissolved in the 20ml dichloromethane solution, ultrasonic echography 5min fully dissolves and makes oil phase, and the relative molecular mass of polylactic acid is 10,000; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 40ml contain in 2.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) the Tween 80 aqueous solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 60ml and contains in 1.0% (g/ml) polyvinyl alcohol and 0.1% (g/ml) Tween 80 aqueous solution, under the magnetic agitation of 400rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 12h of room temperature vacuum (0.01MPa) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 3.98um, drug loading 27.56%, envelop rate 80.23%.
Embodiment 10:
Accurately take by weighing polylactic acid 0.5g and medicine ivermectin 0.25g is dissolved in the mixed solution of 20ml dichloromethane and acetone, the percent by volume of dichloromethane and acetone is 9:1, ultrasonic echography 5min fully dissolves and makes oil phase, and the relative molecular mass of polylactic acid is 10,000; Be-10 ℃～30 ℃ in temperature, oil phase dropwise be expelled to 40ml contain in 2.5% (g/ml) polyvinyl alcohol water solution (water) and under 2000rpm, stir 2min, form S/O/W
1Emulsion for the first time; Again with the S/O/W that obtains
1For the first time emulsion is expelled to 60ml and contains in 1.0% (g/ml) polyvinyl alcohol water solution, under the magnetic agitation of 400rpm 4h to the organic solvent volatilization fully, form S/O/W
2Emulsion for the second time; Again with S/O/W
2The centrifugal 20min of emulsion 4000rpm uses deionized water wash 2 times for the second time, collects microsphere, and the dry 12h of room temperature vacuum (0.01 MPa) namely gets white ivermectin polylactic acid sustained-release micro-spheres.The mean diameter of microsphere is 4.49um, drug loading 28.52%, envelop rate 80.75%.
Experimental example:
Injection ivermectin polylactic acid slow releasing preparation among the present invention and common ivermectin injection (mercaptodimethur) are done blood medicine kinetics aspect relatively.
Laboratory animal is sheep in this experiment, 10 every group, is divided into two groups of A, B; The slow-release injection that wherein the ivermectin polylactic acid sustained-release micro-spheres of preparation is prepared among the A group injection embodiment 2, microsphere drug loading are the commercially available common ivermectin injection (mercaptodimethur) of 28.17%, B group injection.Each group is all taked respectively blood sample in 0.5,1,2,4,6,10,15,20,30,40,50,80,100,120,130 day after administration, measures the concentration of ivermectin in its blood plasma, and method for measuring is: high performance liquid chromatography.According to blood drug level, provide drug level-time graph, and calculate the parameter of relevant pharmacokinetics.
The result shows that it is close that the preparation among the embodiment 2 and common ivermectin injection reach the time on blood drug level peak, and the blood drug level on the peak is: the maximum plasma concentration of the ivermectin polylactic acid slow releasing preparation injection of A group on average is about 20 ng/ml; The ivermectin injection maximum plasma concentration average out to 32ng/ml that the B group is common.The time that the ivermectin polylactic acid slow releasing preparation injection drug effect of A group continues is 100～130 days (100 days blood drug level is 5ng/ml); The common ivermectin injection of B group has been down to 3ng/ml in the time of the 30th day, to be lower than examination criteria, can't detect ivermectin in the time of 100 days.As seen the duration of efficacy of the slow-release injection developed of embodiment 2 is significantly higher than common ivermectin injection.In sum, ivermectin polylactic acid of the present invention or Poly(D,L-lactide-co-glycolide sustained-release micro-spheres are consistent with the anthelminthic effect of common ivermectin injection, but the duration of efficacy of sustained-release micro-spheres is significantly higher than common ivermectin injection.And the probability (having no side effect after polylactic acid or the Poly(D,L-lactide-co-glycolide sustained-release micro-spheres degraded itself) of generation toxic and side effects is got rid of or has been reduced in the use of sustained release microsphere agents, compare with other common ivermectin injection, although later stage blood drug level is not high, but using dosage is lower, reduce a large amount of labour's material resources, so the ivermectin sustained release microsphere agents have developmental research and wide market application foreground.
The above only is preferred embodiment of the present invention, not in order to limiting the present invention, all any modifications of doing within the spirit and principles in the present invention, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. an ivermectin sustained-release micro-spheres is characterized in that described ivermectin sustained-release micro-spheres particle diameter is 0.1～10 μ m, and drug loading is 20%～35%, and envelop rate is more than 80%;
The preparation method of ivermectin sustained-release micro-spheres comprises the steps:
With polylactic acid or Poly(D,L-lactide-co-glycolide as carrier material, with described carrier material and medicine ivermectin take mass percent as 1:0.5 or 1:0.7 be dissolved in the organic solvent through ultrasound wave or the fully emulsified oil phase of making of mechanical agitation, the volume ratio of described oil phase and water is 1:5～10; Be-10 ℃～30 ℃ in temperature, described oil phase is expelled in the water dispersion medium solution step by step, temperature constant magnetic stirring, rotating speed 400～10000rpm is fully emulsified, obtains S/O/W type emulsion; Then it is complete to the organic solvent volatilization at room temperature to stir emulsion 3～4h, again through centrifugal, washing, collection, room temperature vacuum 0.01～0.04MPa drying, time is 10-12h or lyophilization, and temperature is-0 ℃～-20 ℃, and obtaining particle diameter is the ivermectin sustained-release micro-spheres of 0.1～10 μ m.
2. ivermectin sustained-release micro-spheres as claimed in claim 1 is characterized in that, the relative molecular weight of described polylactic acid or Poly(D,L-lactide-co-glycolide is 8.0 * 10
3～1.5 * 10
5Between.
3. ivermectin sustained-release micro-spheres as claimed in claim 1 is characterized in that, described organic solvent is the mixed liquor of dichloromethane or dichloromethane and acetone, and the percent by volume of dichloromethane and acetone is 70～100:0～30.
4. ivermectin sustained-release micro-spheres as claimed in claim 1 is characterized in that, described water dispersion medium solution is polyvinyl alcohol or polyvinyl alcohol and Tween 80 mixed liquor, and wherein the concentration of polyvinyl alcohol is 0.1%～4% g/ml in the 100ml aqueous solution; In the mixed liquor in the 100ml aqueous solution concentration of polyvinyl alcohol be 0.1%～3.5% g/ml, the concentration of Tween 80 is 0.01～0.5% g/ml.
5. ivermectin sustained-release micro-spheres as claimed in claim 1, it is characterized in that, described oil phase is expelled to the method in the water dispersion medium solution step by step, at first the volume ratio by oil phase and water is 1:5～10 water intaking phase dispersion medium solutions, with oil phase be distributed to the phase dispersion medium solution of fetching water 10%～40% in, obtain S/O/W
1Emulsion for the first time, 2 minutes 2000～10000rpm of high-speed stirred, and then for the first time emulsion dispersion to all the other water dispersion medium solutions 60%～90% in obtain S/O/W
2Emulsion at room temperature stirs 3～4h, 400～1000rpm more for the second time, obtains S/O/W type emulsion.
6. the preparation method of an ivermectin sustained-release micro-spheres is characterized in that comprising the steps:
With polylactic acid or Poly(D,L-lactide-co-glycolide as carrier material, with described carrier material and medicine ivermectin take mass percent as 1:0.5 or 1:0.7 be dissolved in the organic solvent through ultrasound wave or the fully emulsified oil phase of making of mechanical agitation, the volume ratio of described oil phase and water is 1:5～10; Be-10 ℃～30 ℃ in temperature, described oil phase is expelled in the water dispersion medium solution step by step, temperature constant magnetic stirring, rotating speed 400～10000rpm is fully emulsified, obtains S/O/W type emulsion; Then it is complete to the organic solvent volatilization at room temperature to stir emulsion 3～4h, again through centrifugal, washing, collection, room temperature vacuum 0.01～0.04MPa drying, time is 10-12h or lyophilization, and temperature is-0 ℃～-20 ℃, and obtaining particle diameter is the ivermectin sustained-release micro-spheres of 0.1～10 μ m.
7. the preparation method of ivermectin sustained-release micro-spheres as claimed in claim 6 is characterized in that, the relative molecular weight of described polylactic acid or Poly(D,L-lactide-co-glycolide is 8.0 * 10
3～1.5 * 10
5Between.
8. the preparation method of ivermectin sustained-release micro-spheres as claimed in claim 6 is characterized in that, described organic solvent is the mixed liquor of dichloromethane or dichloromethane and acetone, and the percent by volume of dichloromethane and acetone is 70～100:0～30.
9. the preparation method of ivermectin sustained-release micro-spheres as claimed in claim 6, it is characterized in that, described water dispersion medium solution is polyvinyl alcohol or polyvinyl alcohol and Tween 80 mixed liquor, and wherein the concentration of polyvinyl alcohol is 0.1%～4% g/ml in the 100ml aqueous solution; In the mixed liquor in the 100ml aqueous solution concentration of polyvinyl alcohol be 0.1%～3.5% g/ml, the concentration of Tween 80 is 0.01～0.5% g/ml.
10. the preparation method of ivermectin sustained-release micro-spheres as claimed in claim 6, it is characterized in that, described oil phase is expelled to the method in the water dispersion medium solution step by step, at first the volume ratio by oil phase and water is 1:5～10 water intaking phase dispersion medium solutions, with oil phase be distributed to the phase dispersion medium solution of fetching water 10%～40% in, obtain S/O/W
1Emulsion for the first time, 2 minutes 2000～10000rpm of high-speed stirred, and then for the first time emulsion dispersion to all the other water dispersion medium solutions 60%～90% in obtain S/O/W
2Emulsion at room temperature stirs 3～4h, 400～1000rpm more for the second time, obtains S/O/W type emulsion.
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| CN103800355A (en) * | 2014-02-26 | 2014-05-21 | 江苏斯威森生物医药工程研究中心有限公司 | Compound long-acting microsphere anthelmintic containing ivermectin, albendazol sulfoxide and praziquantel |
| WO2018189314A1 (en) | 2017-04-13 | 2018-10-18 | Ceva Sante Animale | Composition for treating worms infestations |
| CN107668040A (en) * | 2017-09-01 | 2018-02-09 | 中国热带农业科学院环境与植物保护研究所 | One kind sterilization sustained-release micro-spheres and preparation method thereof |
| CN107593699A (en) * | 2017-09-01 | 2018-01-19 | 中国热带农业科学院环境与植物保护研究所 | A kind of sustained-release micro-spheres for being used to sterilize and preparation method thereof |
| JP2019069906A (en) * | 2017-10-06 | 2019-05-09 | 学校法人北里研究所 | Pharmaceutical composition |
| CN107510057A (en) * | 2017-10-09 | 2017-12-26 | 无锡盛雅生物科技有限公司佛山分公司 | A kind of preparation method of mackerel fish oil and fat-soluble tea polyphenol complex microsphere |
| CN109464701B (en) * | 2019-01-08 | 2020-08-18 | 乐国平 | Preparation method of VA @ PLGA-CS-HA composite antibacterial slow-release microspheres and application of VA @ PLGA-CS-HA composite antibacterial slow-release microspheres in bone repair scaffold material |
| CN110496105B (en) * | 2019-08-07 | 2021-09-14 | 澳门科技大学 | S-propargyl cysteine-loaded microsphere preparation and preparation method thereof |
| CN112190567B (en) * | 2020-11-09 | 2022-03-11 | 山东华辰制药有限公司 | Preparation method and application of ivermectin sustained-release microspheres |
| CN113318265A (en) * | 2021-04-30 | 2021-08-31 | 南京师范大学 | Synthetic polymer antibacterial tissue adhesive and preparation method thereof |
| CN113304125A (en) * | 2021-05-06 | 2021-08-27 | 浙江美华鼎昌医药科技有限公司 | Amphotericin B slow-release microsphere and preparation method thereof |
| CN114099448A (en) * | 2021-12-08 | 2022-03-01 | 北京林业大学 | Preparation method of uniform polymer microspheres |
| CN114848598B (en) * | 2022-05-27 | 2023-03-21 | 河北美荷药业有限公司 | Moxidectin microsphere and preparation method and application thereof |
| CN116602926B (en) * | 2023-07-04 | 2024-02-23 | 深圳聚生生物科技有限公司 | Polylactic acid microsphere preparation process for drug controlled release |
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| CN100488514C (en) * | 2005-09-01 | 2009-05-20 | 上海交通大学 | Slowly released solid ivermectin microballoon preparation |
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