CN1444946A - 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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- CN1444946A CN1444946A CN 02103759 CN02103759A CN1444946A CN 1444946 A CN1444946 A CN 1444946A CN 02103759 CN02103759 CN 02103759 CN 02103759 A CN02103759 A CN 02103759A CN 1444946 A CN1444946 A CN 1444946A
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Abstract
A nanosphere of abamectin used as both medicine and agricultural chemical is prepared through preparing the polylactic acid-polyglycollic acid copolymer (PLGA), mixing abemectin with PLGa, ultrasonic emulsifying, volatilizing solvent, supersonic centrifugal treating, mixing, concentrating, leaching with distilled water, and supersonic centrifugal treating, mixing, concentrating again, and freeze drying at -106- -108 deg.C. Its advantages are slow release, low poison and low cost.
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 hours as organism innerlich anwenden effective blood drug concentration, bioavailability is low to be 20%-30%.There are toxicity, residual effect 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-polyglycolic acid copolymer (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 thereof and doractin Nano microsphere, processing step is:
A, usefulness biodegradable polylactic acid-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, are scattered in the aqueous solution of PVA with ultraemulsifier PLGA solution, form oil-in-water emulsion;
C, the emulsion of oil-in-water type evacuation under constantly stirring is removed the prepared Nano microspheres in organic solvent 10～24 backs solidify;
D, solidified Nano microsphere is centrifugal on the low temperature supercentrifuge, rotating speed are 10,000～40,000 rev/min, centrifugal 20～30 minutes, and the collecting precipitation thing;
E, with the precipitate collected through 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 in the refrigerator and cooled of-20～-50 in the packing drying bottle;
G, with the dry bottle lyophilization of refrigerated medicine carrying 15～30 hours, make avilamycin series slow released nano microsphere.
The purposes of made Nano microsphere, 1, the administered intramuscular by 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, performance wide spectrum nematicide and arthropodan effect; 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 hours 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 thereof and doractin Nano microsphere, processing step is:
A, usefulness biodegradable polylactic acid-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, the emulsion of oil-in-water type evacuation under constantly stirring was removed organic solvent after 10～24 hours, prepared Nano microsphere solidifies;
D, solidified Nano microsphere is centrifugal on the low temperature supercentrifuge, rotating speed are 10,000～40,000 rev/min, centrifugal 20～30 minutes, and the collecting precipitation thing;
E, with the precipitate collected through 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 hours, make avilamycin series slow released nano microsphere.
As 1, the polylactic acid-polyglycolic acid copolymer (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 be 20000 rev/mins 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 behind the physiological saline solution in vivo blood drug level can be in 96 hours～360 hours constant release, the endoparasite cure rate reaches more than 93%, kills rate about 95.8%.
As 2, the polylactic acid-polyglycolic acid copolymer (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 be 30000 rev/mins 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～385 hours constant release, the endoparasite cure rate reaches more than 94%, kills rate about 98.3%.
As 3, the polylactic acid-polyglycolic acid copolymer (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, again with rotating speed be 40000 rev/mins centrifugal 30 minutes, the collecting precipitation thing, after the repetitive operation three times in the packing drying bottle after-45 ℃ refrigerator and cooled is frozen 72 hours, lyophilization is 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 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, only for the bioavailability that 20%-30% is prepared into the Yi Wei Nano microsphere can reach more than 70%, purpose is the reduction toxic and side effects of reducing expenses to the bioavailability of the naked medicine of ivermectin, improves curative effect, reduces and pollutes.
5, survey method adopts high performance liquid chromatography, and detection range can be from more than 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, 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, microsphere supported material is polylactic acid-polyglycolic acid copolymer (PLGA).
Embodiment 3, preparation method, on embodiment 1 basis, the pharmaceutical dosage form microsphere of embedding is below 150nm.
Embodiment 4, preparation method, on embodiment 1 basis, the formulations of pesticide microsphere of microsphere supported material institute embedding is below 250nm.
The purposes of embodiment 5, 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.
The polylactic acid-polyglycolic acid copolymer 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 demodicid mite 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 (5)
1, the preparation method of a kind of Avermectins medicine and derivant ivermectin thereof and doractin Nano microsphere is characterized in that processing step is:
A, usefulness biodegradable polylactic acid-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, the emulsion of oil-in-water type evacuation under constantly stirring was removed organic solvent after 10～24 hours, prepared Nano microsphere solidifies;
D, solidified Nano microsphere is centrifugal on the low temperature supercentrifuge, rotating speed are 10,000～40,000 rev/min, centrifugal 20～30 minutes, and the collecting precipitation thing;
E, with the precipitate collected through 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 in the refrigerator and cooled of-20～-50 in the packing drying bottle;
G, with the dry bottle lyophilization of refrigerated medicine carrying 15～30 hours, make avilamycin series slow released nano microsphere.
2, preparation method according to claim 1 is characterized in that microsphere supported material is polylactic acid-polyglycolic acid copolymer (PLGA).
3, preparation method according to claim 1, the pharmaceutical dosage form microsphere that it is characterized in that embedding is below 150nm.
4, preparation method according to claim 1 is characterized in that: the formulations of pesticide microsphere of microsphere supported material institute embedding is below 300nm.
5, the purposes of Nano microsphere according to claim 1 is characterized in that: by the administered intramuscular of human or animal body, and the parasitic infection of treatment people and animal; Be used to prevent and treat diseases and pests of agronomic crop.
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| CN 02103759 CN1272017C (en) | 2002-03-20 | 2002-03-20 | Method for preparing nano-microballons of Avermectins medicine and usage |
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100388970C (en) * | 2004-07-15 | 2008-05-21 | 浙江大学 | Method for preparing polylactic porous microball |
| CN101773478A (en) * | 2010-03-22 | 2010-07-14 | 青岛康地恩药业有限公司 | Pulmonary targeting microsphere of veterinary ceftiofur hydrochloride and preparation method thereof |
| CN101406458B (en) * | 2008-11-21 | 2011-08-17 | 吉林大学 | Biodegradable polyester medicine-carrying microsphere of mimetic peroxidase |
| CN102302457A (en) * | 2011-09-14 | 2012-01-04 | 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 |
| CN102919221A (en) * | 2012-11-09 | 2013-02-13 | 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 |
| 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 |
| CN103548823A (en) * | 2013-11-09 | 2014-02-05 | 福建农林大学 | Method for preparing thiophanate-methyl nano-pesticide |
| 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 |
| JP2019069906A (en) * | 2017-10-06 | 2019-05-09 | 学校法人北里研究所 | Pharmaceutical composition |
| CN110381924A (en) * | 2017-09-06 | 2019-10-25 | 创技公司株式会社 | Particle and preparation method thereof comprising moxidectin |
| CN112190567A (en) * | 2020-11-09 | 2021-01-08 | 山东华辰制药有限公司 | Preparation method and application of ivermectin sustained-release microspheres |
| CN115644175A (en) * | 2022-11-14 | 2023-01-31 | 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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2002
- 2002-03-20 CN CN 02103759 patent/CN1272017C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN101773478A (en) * | 2010-03-22 | 2010-07-14 | 青岛康地恩药业有限公司 | Pulmonary targeting microsphere of veterinary ceftiofur hydrochloride and preparation method 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 |
| CN102302457A (en) * | 2011-09-14 | 2012-01-04 | 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 |
| CN102919221A (en) * | 2012-11-09 | 2013-02-13 | 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 |
| CN103548823A (en) * | 2013-11-09 | 2014-02-05 | 福建农林大学 | Method for preparing thiophanate-methyl nano-pesticide |
| CN110381924A (en) * | 2017-09-06 | 2019-10-25 | 创技公司株式会社 | Particle and preparation method thereof comprising moxidectin |
| US11931461B2 (en) | 2017-09-06 | 2024-03-19 | Inventage Lab Inc. | Microparticles containing moxidectin, and preparation method therefor |
| 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 |
| CN112190567A (en) * | 2020-11-09 | 2021-01-08 | 山东华辰制药有限公司 | Preparation method and application of ivermectin sustained-release microspheres |
| CN115644175A (en) * | 2022-11-14 | 2023-01-31 | 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 |
| 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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