CN1272017C - Method for preparing nano-microballons of Avermectins medicine and usage - Google Patents
Method for preparing nano-microballons of Avermectins medicine and usage Download PDFInfo
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- CN1272017C CN1272017C CN 02103759 CN02103759A CN1272017C CN 1272017 C CN1272017 C CN 1272017C CN 02103759 CN02103759 CN 02103759 CN 02103759 A CN02103759 A CN 02103759A CN 1272017 C CN1272017 C CN 1272017C
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Abstract
The present invention relates to a preparation method for a slow release nanometer microsphere containing abamectin and ivermectin as a derivative of the abamectin. The preparation method comprises the following technical steps that 1. a copolymer (PLGA) of different proportions of polylactic acid to polyglycolic acid is prepared, and the molecular weight of the copolymer is suitable for the condition that the final degraded products of the copolymer are CO2 and water in organisms and soil by control within a certain period of time; 2. the processes of ultrasonic emulsification, solvent volatilization, ultracentrifugation, mixing and concentration operation, distilled water leaching, ultracentrifugation for the second time, mixing and concentration for the second time and freeze-drying operation at a temperature of minus 106 to minus 108 DEG C are carried out on the prepared PLGA as auxiliary materials for abamectin medicines, and the nanometer controlled release microsphere with the spheric diameter of 50 to 150 nm is embedded. The slow release nanometer microsphere with the medicine carrying quantity of 1 to 40% is prepared according to human beings, various organisms and the requirements of agricultural medicines, and the entrapment rate reaches more than 92%. Thus, the long acting controlled release of medical medicines is realized, the controlled release of biological agricultural medicines is also realized, and the duration time of medicinal effect is prolonged; the toxicity is reduced, the cost is lowered, the problem of soil ecology is solved, and the use range is enlarged.
Description
Technical field
The present invention relates to the preparation method and the application thereof of avilamycin medicine and derivant ivermectin slow released nano microsphere thereof.
Technical background
Avermectins medicine (Avermectins) is a present the best class broad-spectrum high efficacy antiparasitic, also is with fastest developing speed in the world at present, most widely used biological medicine and pesticide.But only keep about 68 o'clock as organism innerlich anwenden effective blood drug concentration, bioavailability is low to exist toxicity, residual effect for 20%-30%0 as pesticide, big to ecological environment of soil influence, and the large tracts of land that problems such as poor stability, drug effect are low, expense height have limited this biological pesticide is promoted the use of.
Summary of the invention
The objective of the invention is drawback, provide a kind of employing Biodegradable polymer material polylactic acid one co-glycolic acid (PLGA) and avilamycin and derivant ivermectin thereof to prepare the preparation method and the application thereof of slow released nano microsphere at above-mentioned prior art.
Can take following technical scheme to realize purpose.
The preparation method of Avermectins medicine and derivant ivermectin Nano microsphere thereof, processing step is:
A, with biodegradable polylactic acid one co-glycolic acid (Poly lactic acid-co-glyclicacid, PLGA) be carrier material, with contained medicine (content 1%-40%) in corresponding ratio 10-14: 1.2 take by weighing, and the mixed solvent that adds dichloromethane and acetone makes its dissolving;
B, compound concentration are polyvinyl alcohol (PVA) aqueous solution of 1%-6% concentration, are scattered in the aqueous solution of PVA with ultraemulsifier PLGA solution, form oil-in-water emulsion;
C removes the prepared Nano microsphere in organic solvent 10 1 24 backs with emulsion evacuation under constantly stirring of oil-in-water type and solidifies;
D, solidified Nano microsphere is centrifugal on the low temperature supercentrifuge, and rotating speed is 10,000-40,000 rev/min, centrifugal 20-30 minute, collecting precipitation thing;
E, with the precipitate collected through the 2-10ml dissolved in distilled water, low temperature ultracentrifugation behind ultrasonic breast again, rotating speed 10,000-40,000r/min, centrifugal 20-30min collecting precipitation thing;
F, repeat E step 3 time after, use the 20-50ml dissolved in distilled water, freeze more than 24 hours-20--50 ℃ refrigerator and cooled in the packing drying bottle;
G, with the dry bottle lyophilization of refrigerated medicine carrying 15-30 hour, make avilamycin series slow released nano microsphere.
The purposes of made Nano microsphere, 1, by the administered intramuscular of human or animal body, the parasitic infection of treatment people and animal; 2, be used to prevent and treat diseases and pests of agronomic crop.
The relative prior art of the technical program has following advantage and effect:
This microsphere mainly contains two aspect purposes: 1, by the administered intramuscular of human or animal body, effective ingredient slowly discharges, and through the mediation of r-aminobutyric acid, hinders the nematicide nerve conduction, the effect of performance wide spectrum Hangzhoupro nematicide and joint skin animal; The parasitic infection of treatment people and animal.By routine 68 hours of the effective blood drug concentration of Avermectins medicine are brought up to 200-400 hour and kept constant release, reach human body and animal body and treat needed active drug concentration and therapeutic purposes, this dosage form is lowered than original oral formulations toxic and side effects, improve drug bioavailability more than 70%.2, the Avermectins slow released nano microsphere is used to prevent and treat diseases and pests of agronomic crop, has and reduce contact toxicity and, prolong drug effect the toxicity of people poultry, sustained release in soil reduces and pollutes, odour masking, improve stability, reduce control number of times and pesticide dosage.Economical, safety, difficult by environmental factors and microbial destruction and loss significantly improve the bioavailability of its pesticide.
This method not only solves the long-acting controlled release of medical, and the controlled release of biological pesticide is become a reality, the slow releasing function minimizing drug dose by Nano microsphere increases duration of efficacy, reach and reduce toxicity, minimizing cost, solution soil ecology problem, enlarge the scope of application.
The specific embodiment
The nano-microballons of Avermectins medicine preparation method is described further with representative instance.
The system method of embodiment 1, Avermectins medicine and derivant ivermectin and Nano microsphere, processing step is:
A, with biodegradable polylactic acid one co-glycolic acid (Poly lactic acid-co-glyclic acid, PLGA) be carrier material, (content 1%-40%) takes by weighing in corresponding ratio with contained medicine, and the mixed solvent that adds dichloromethane and acetone makes its dissolving;
B, compound concentration are polyvinyl alcohol (PVA) aqueous solution of 1%-6% concentration, PLGA solution are scattered in the aqueous solution of PVA with ultraemulsifier, form oil-in-water emulsion;
C, after evacuation was removed organic solvent 10-24 hour under constantly stirring with the emulsion of oil-in-water type, prepared Nano microsphere solidified;
D, solidified Nano microsphere is centrifugal on the low temperature supercentrifuge, and rotating speed is 10,000-40,000 rev/min, centrifugal 20-30 minute, collecting precipitation thing;
E, with the precipitate collected through the 2-10ml dissolved in distilled water, low temperature ultracentrifugation behind ultrasonic breast again, rotating speed 10,000-40,000r/min, centrifugal 20-30min collecting precipitation thing:
F, repeat E step 3 time after, use the 20-50ml dissolved in distilled water, freeze more than 24 o'clock-20--50 ℃ refrigerator and cooled in the packing drying bottle;
G, with the dry bottle lyophilization of refrigerated medicine carrying 15-30 hour, make avilamycin series slow released nano microsphere.
Example 1, polylactic acid one co-glycolic acid (PLGA) of 10g is dissolved in 500ml methylene chloride acetone (V: V=1: 2) in the solution, that avilamycin or the ivermectin of 1.2g is miscible with PLGA solution with 10ml dichloromethane dissolving back.Joining concentration and be 1% polyvinyl alcohol (PVA) aqueous solution 3500ml is scattered in the PLGA drug solution in the aqueous solution of PVA with ultraemulsifier, evacuation is 15 hours under stirring, with rotating speed is 20,000 rev/min centrifugal 25 minutes, the collecting precipitation thing, behind the 25ml dissolved in distilled water, ultrasonic emulsification is 10 minutes once more, again with rotating speed be 20000 rev/mins centrifugal 20 minutes, the collecting precipitation thing, after the repetitive operation three times in the packing drying bottle after-25 ℃ refrigerator and cooled is frozen 24 hours, lyophilization is 28 hours on freezer dryer.Through blood drug level can be at 96 hours in vivo behind the physiological saline solution--constant release in 360 hours, the endoparasite cure rate reaches more than 93%, kills rate about 95.8%.
Example 2, polylactic acid one co-glycolic acid (PLGA) of 12g is dissolved in 500ml methylene chloride acetone (V: V=1: 2) in the solution, that avilamycin or the ivermectin of 1.2g is miscible with PLGA solution with 10ml dichloromethane dissolving back.Joining concentration and be 3% polyvinyl alcohol (PVA) aqueous solution 3500ml is scattered in the PLGA drug solution in the aqueous solution of PVA with ultraemulsifier, evacuation is 18 hours under stirring, with rotating speed is 30,000 rev/min centrifugal 25 minutes, the collecting precipitation thing, behind the 25ml dissolved in distilled water, ultrasonic emulsification is 10 minutes once more, again with rotating speed be 30000 rev/mins centrifugal 25 minutes, the collecting precipitation thing, after the repetitive operation three times in the packing drying bottle after-35 ℃ refrigerator and cooled is frozen 48 hours, lyophilization is 28 hours on freezer dryer.Through behind the physiological saline solution in vivo blood drug level can be in 72 hours one 385 hours constant release, the endoparasite cure rate reaches more than 94%, kills rate about 98.3%.
Example 3, polylactic acid one co-glycolic acid (PLGA) of 14g is dissolved in 500ml methylene chloride acetone (V: V=1: 2) in the solution, that avilamycin or the ivermectin of 1.2g is miscible with PLGA solution with 10ml dichloromethane dissolving back.Joining concentration and be 5% polyvinyl alcohol (PVA) aqueous solution 3500ml is scattered in the PLGA drug solution in the aqueous solution of PVA with ultraemulsifier, evacuation is 24 hours under stirring, with rotating speed be 40000 rev/mins centrifugal 25 minutes, the collecting precipitation thing, behind the 25ml dissolved in distilled water, ultrasonic emulsification is 10 minutes once more, be 40 with rotating speed again, 000 rev/min centrifugal 30 minutes, the collecting precipitation thing, after-45 ℃ refrigerator and cooled was frozen 72 hours in the packing drying bottle after the repetitive operation three times, lyophilization was 28 hours on freezer dryer.Through behind the physiological saline solution in vivo blood drug level can be in 106 hours-397 hours constant release, the endoparasite cure rate reaches more than 95%, kills rate about 96.5%.The key technical indexes:
1, carrier material is a Biodegradable polymer material, has good biocompatibility, and is nontoxic, is CO at the end product of human or animal's vivo degradation
2And H
2O, the degradable high polymer material of being used by the FDA approval.
2, the drug loading of ivermectin Nano microsphere can be selected more than the 10%-40% according to animal drug disposition content requirement.Envelop rate can reach more than 93.5%.
3, ivermectin is become nanoparticle microsphere (sphere diameter is 100-300nm) with the Biodegradable polymer material embedding.By selecting the macromolecular material of different proportionings, can be controlled at the release time of ivermectin Nano microsphere 15-25 days, can select to prolong the sustained release natural law according to different needs.
4, the bioavailability of the naked medicine of ivermectin only can reach more than 70% for the bioavailability that 20%-30% is prepared into the Yi Wei Nano microsphere, and purpose is the reduction toxic and side effects of reducing expenses, and improves curative effect, reduces and pollutes.
5, the survey method adopts high performance liquid chromatography, and detection range can be from more than the 0.1ug/L-200ug/L, trace detection different time burst size, and its rate of release meets the first order reaction equation.
6, selecting the controlled release time with zoopery was two weeks, with drug loading is that 15% ivermectin nanoparticle is an example, 5 hours blood drug level is 0.3ug/L after the administration, after 15 hours, discharged medicine with the speed of equal perseverance to 16 days, its concentration is between 0.5-1.7ug/L, and drug level reduces gradually after 17 days, and blood drug level is 0.26ug/L after after the injection 25 days.
Embodiment 2, preparation method, on embodiment 1 basis, the pharmaceutical dosage form microsphere of embedding is below 150nm.
Embodiment 3, preparation method, on embodiment 1 basis, the formulations of pesticide microsphere of microsphere supported material institute embedding is below 250nm.
The purposes of Nano microsphere, by the administered intramuscular of human or animal body, the parasitic infection of treatment people and animal; Be used to prevent and treat diseases and pests of agronomic crop.
Polylactic acid one co-glycolic acid that is used for medicament sustained-release matrix is a kind of Biodegradable material, but and in the humans and animals body nonenzymic hydrolysis, mix fully with blood, be hydrolyzed to harmless lactic acid and glycolic in vivo lentamente, finally be decomposed into carbon dioxide and water.Adopting the nano-microballons of Avermectins medicine of the method preparation of ultrasonic emulsification solvent evaporates is that avilamycin or ivermectin package action portion are positioned at controlled release carrier particle inside, makes medicine make drug osmotic and diffuse out by the cyst wall leaching with for the corrosion of substrate.Controlled release preparation discharges by the first order reaction equation.Substantially discharge with steady constant blood drug level, be not subjected to the influence of biological and food factor, avoid in vivo prominent of medicine to release the side effect that is caused, reach 0.3-1.8ug/L to 5 hours-384 hours blood drug level behind this controlled release medicine.Parasitic infection patient's cure rate is reached more than 92%.The inside and outside multiple parasitic cure rate of animal body is reached more than 90%, in soil, be about half a year as the Nano microsphere slow-release time of pesticide uses.Be used to prevent and treat 80 various pests such as harmful end on the plants such as fruit tree, vegetable, flowers, Cotton Gossypii, Nicotiana tabacum L. and liriomyza bryoniae, diamondback moth, Pieris rapae, bollworm, pear sucker, have efficient, low toxicity, lowly pollute, the characteristics of low expense.
Claims (3)
1, the preparation method of a kind of Avermectins medicine and derivant ivermectin Nano microsphere thereof is characterized in that processing step is:
A, be carrier material with biodegradable polylactic acid-co-glycolic acid, with content be that the contained medicine of 1%-40% took by weighing in proportion in 10: 1.2 or 12: 1.2 or 14: 1.2, the mixed solvent that adds dichloromethane and acetone makes its dissolving;
B, compound concentration are the polyvinyl alcohol water solution of 1%-6%, the polylactic acid-polyglycolic acid copolymer solution are scattered in the aqueous solution of polyvinyl alcohol with the excusing from death emulsator, form oil-in-water emulsion;
C, after evacuation is removed organic solvent 10-24 hour under constantly stirring with the emulsion of oil-in-water type, prepared Nano microsphere solidifies;
D, solidified Nano microsphere is centrifugal on the low temperature supercentrifuge, rotating speed are 10000-40000 rev/min, centrifugal 20-30 minute, and the collecting precipitation thing;
The precipitate of E, collection is through the 2-10ml dissolved in distilled water, low temperature ultracentrifugation after having children outside the state plan breast again, rotating speed 10000-40000 rev/min, centrifugal 20-30 minute, collecting precipitation thing;
F, repeat E step 3 time after, use the 20-50ml dissolved in distilled water, freeze more than 24 hours-20--50 ℃ refrigerator and cooled in the packing drying bottle;
G, with the dry bottle lyophilization of refrigerated medicine carrying 15-30 hour, make Avermectins series slow released nano microsphere.
2, preparation method according to claim 1 is characterized in that: the pharmaceutical dosage form microsphere of embedding is below 150nm.
3, preparation method according to claim 1 is characterized in that: the formulations of pesticide microsphere of microsphere supported material institute embedding is below 300nm.
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| CN100388970C (en) * | 2004-07-15 | 2008-05-21 | 浙江大学 | Method for preparing polylactic porous microball |
| CN101406458B (en) * | 2008-11-21 | 2011-08-17 | 吉林大学 | Biodegradable polyester medicine-carrying microsphere of mimetic peroxidase |
| CN101700008B (en) * | 2009-11-11 | 2013-08-21 | 深圳诺普信农化股份有限公司 | Solid lipid nano-avermectin and preparation method and application thereof |
| CN101755738B (en) * | 2009-11-11 | 2013-11-06 | 深圳诺普信农化股份有限公司 | Solid lipid nano spinosad and preparation method and application thereof |
| CN101773478B (en) * | 2010-03-22 | 2012-09-05 | 青岛康地恩药业股份有限公司 | Pulmonary targeting microsphere of veterinary ceftiofur hydrochloride and preparation method thereof |
| CN102302457B (en) * | 2011-09-14 | 2013-04-17 | 中国科学院近代物理研究所 | Preparation method of ivermectin sustained-release microspheres |
| CN102423300A (en) * | 2011-11-24 | 2012-04-25 | 河北科技大学 | Acetyl amino abamectin sustained-release microsphere and preparation method as well as sustained-release microsphere injection |
| CN102919221B (en) * | 2012-11-09 | 2014-07-02 | 中国农业科学院农业环境与可持续发展研究所 | Application of nanometer silicon dioxide to pesticide controlled release |
| CN102919226A (en) * | 2012-12-03 | 2013-02-13 | 贵州省烟草科学研究院 | Abscisic acid nano-emulsion and preparation method thereof |
| CN103548823B (en) * | 2013-11-09 | 2014-12-31 | 福建农林大学 | Method for preparing thiophanate-methyl nano-pesticide |
| KR102101969B1 (en) * | 2017-09-06 | 2020-04-22 | (주)인벤티지랩 | Microparticles containing moxidectin and method for manufacturing same |
| JP2019069906A (en) * | 2017-10-06 | 2019-05-09 | 学校法人北里研究所 | Pharmaceutical composition |
| 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 |
| CN109005748A (en) * | 2018-08-16 | 2018-12-18 | 内蒙古蒙草生态环境（集团）股份有限公司 | A kind of greening rope, preparation method and application with grass seeds |
| 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 |
| CN115644175B (en) * | 2022-11-14 | 2023-11-10 | 中国农业科学院农产品加工研究所 | Preparation method of nano-embedded pesticide and nano-embedded pesticide |
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