CN112190567B - Preparation method and application of ivermectin sustained-release microspheres - Google Patents
Preparation method and application of ivermectin sustained-release microspheres Download PDFInfo
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Abstract
The invention discloses a preparation method of ivermectin sustained-release microspheres, which relates to the field of veterinary drugs and comprises the following steps: step 1, dissolving chitosan-polyethylene glycol block copolymer serving as a carrier material in purified water, dispersing drug ivermectin in the carrier material solution, and stirring and fully mixing to prepare a dispersed phase; step 2, taking castor oil as a continuous phase, heating the dispersed phase and the continuous phase in a water bath, and emulsifying under continuous stirring to obtain emulsion; and 3, placing the emulsion in a cold water bath, adding organic acid serving as a catalyst, adding glutaraldehyde for crosslinking, standing for a period of time, filtering, washing and drying to obtain the finished product microspheres. The invention adopts an emulsion crosslinking method, and adopts a stable, nontoxic and biodegradable synthetic polymer material chitosan-polyethylene glycol block copolymer as a carrier to encapsulate the drug ivermectin, so as to prepare the long-acting and stable ivermectin sustained-release microsphere.
Description
Technical Field
The invention relates to the field of veterinary drugs, in particular to a preparation method of ivermectin sustained-release microspheres.
Background
Ivermectin (IVM), a 22, 23-dihydro derivative of B1 fermentation product of macrolide antibiotic Avermectins (Avermectins), has the function of killing various parasites, and is a well-known multi-component antibiotic with broad spectrum, high efficiency, safety, less residue and no drug resistance. It is widely used in the field of insect repelling in animal husbandry worldwide since its introduction in 1981.
Ivermectin is produced and marketed in various preparations, such as ivermectin injection, solution, tablets, compound powder, premix, tablets and the like added with albendazole, fenbendazole and other components, and is widely applied in production, and particularly, the ivermectin injection is more commonly used clinically. However, the conventional preparation products generally have the problems of short maintenance time of blood concentration, poor stability and the like in single administration, and can achieve the effect of preventing and treating repeated infection of parasites by multiple administrations. On one hand, frequent injection and administration of an individual easily cause adverse stress reaction of an affected animal, and on the other hand, a common preparation is often administered in a large dose once to achieve an ideal treatment effect, so that the peak concentration of a blood drug is too high, and animal poisoning is caused. In order to overcome the side effects brought by the clinical medication, the development of a long-acting and stable ivermectin preparation with convenient administration is very necessary.
The new technology of microencapsulation as a medicinal preparation has been widely researched, and the new dosage form prepared by applying the microspheres to a carrier of a medicament has many incomparable advantages compared with the traditional preparation, and has obvious effects on covering bad smell and taste of the medicament, prolonging medicament effect, reducing toxicity, and improving activity and bioavailability. Currently, there are various methods and materials for preparing ivermectin microspheres, which are used as slow-release components for further preparing long-acting ivermectin preparations. The microencapsulated product prepared by different methods and materials has larger process and prescription difference, so the particle size, drug loading rate, biocompatibility, drug release characteristic and the like of the product also have great difference, thereby restricting the dosage form selection and the sustained release effect of the final preparation.
The chitosan is natural alkalescent linear polysaccharide with double effects of electrostatic repulsion and steric hindrance, and the combined action of the double effects can effectively prevent aggregation and irreversible flocculation and increase the physical stability of a microsphere system. In addition, chitosan and its derivatives are positively charged in body fluid environment, and can generate electrostatic attraction and combination with negatively charged phospholipid head group on the cell membrane surface of infection site, so as to gather the medicine at the affected site. In addition, chitosan is a polymer with good biocompatibility, biodegradability, no antigenicity, immunogenicity and toxicity. However, chitosan is only dissolved in an acidic solvent, and the solubility in other solvents is poor, thereby restricting the effective utilization of chitosan. On the premise of not changing the characteristic structure and function of chitosan, the solubility of chitosan is further improved by combining coupling effect with a compound with strong hydrophilization effect. Polyethylene glycol can cause crosslinking and form a hydrophilic shell on the surface of other graft copolymers, and is widely used as a material for graft compounds. The chitosan is rich in amino and hydroxyl, and can be modified by pegylation through acylation or carboxylation to increase the flexibility and hydrophilicity.
Chitosan-polyethylene glycol block copolymer microsphere drug delivery systems have many advantageous properties in vivo: can reduce the recognition and phagocytosis of reticuloendothelial phagocytosis system, change the distribution of the raw medicine in vivo, realize the aggregation and release of the medicine in target organs and target tissues, improve the medicine effect and reduce the toxicity. The nano-scale microspheres can prolong the half-life (t1/2) of the medicine in vivo, so that the medicine can exert better medicine effect. The degradation rate of the microspheres of the chitosan-polyethylene glycol block copolymer can be controlled by changing the block proportion, the relative molecular mass and the like of the chitosan-polyethylene glycol block copolymer, so that the effective control of the drug release rate is realized. The chitosan-polyethylene glycol block copolymer and the ivermectin have excellent balling performance and excellent medicament stability after being combined.
In China, the research on the long-acting formulation of ivermectin is also paid much attention, and related formulations of ivermectin microsphere components are prepared and subjected to pharmacokinetic research and clinical tests.
Disclosure of Invention
The invention adopts the following technical scheme: a preparation method of ivermectin sustained-release microspheres comprises the following steps:
step 1, dissolving chitosan-polyethylene glycol block copolymer serving as a carrier material in purified water, dispersing drug ivermectin in the carrier material solution, and stirring and fully mixing to prepare a dispersed phase;
step 2, taking refined castor oil containing glyceryl monostearate as a continuous phase, heating the dispersed phase and the continuous phase in a water bath, and emulsifying under continuous stirring to obtain an emulsion;
and 3, placing the emulsion in a cold water bath, adding organic acid serving as a catalyst, adding glutaraldehyde for crosslinking, standing for a period of time, filtering, washing and drying to obtain the finished product microspheres.
Preferably, the mass percentage of the carrier material to the drug ivermectin is 1: 1 to 10.
Preferably, the heating temperature of the water bath in the step 2 is 60 ℃.
Preferably, the standing time in the step 3 is 16-24 h.
Preferably, in each block of the chitosan-polyethylene glycol block copolymer, the molecular weight of chitosan is 5000-10000, the molecular weight of polyethylene glycol is 750-1000, and the mass ratio of polyethylene glycol to chitosan block is 1: 5 to 10.
Preferably, the concentration of glyceryl monostearate in the continuous phase is from 0.1% to 3.5% g/ml.
Preferably, the dropping speed of the dispersed phase to the continuous phase is 5-10 ml/min.
Preferably, the mass ratio of the organic acid to the chitosan-polyethylene glycol block copolymer is 1-3: 100.
preferably, the organic acid comprises one of p-toluenesulfonic acid, salicylic acid and formic acid as a catalyst.
The invention adopts an emulsion crosslinking method, and adopts a stable, nontoxic and biodegradable synthetic polymer material chitosan-polyethylene glycol block copolymer as a carrier to encapsulate the drug ivermectin, so as to prepare the long-acting and stable ivermectin sustained-release microsphere.
Detailed Description
The present invention will be further described with reference to the following examples.
The components, materials and the like referred to in the following examples are, unless otherwise specified, conventional components, materials and the like known in the art, and are commercially available in normal forms.
The first embodiment is as follows: a preparation method of ivermectin sustained-release microspheres comprises the steps of dissolving chitosan-polyethylene glycol block copolymer in purified water, dispersing drug ivermectin in a carrier material solution, fully mixing through ultrasonic stirring to prepare a dispersed phase, wherein the mass percentage of the carrier material to the drug ivermectin is 1: 5.
refined castor oil containing glyceryl monostearate is used as a continuous phase. And heating the dispersed phase and the continuous phase in a water bath to 60 ℃, emulsifying under continuous and rapid stirring to obtain stable emulsion, and dripping the dispersion phase and the continuous phase at a speed of 5-10 ml/min. And (3) placing the emulsion in a cold water bath, slowly adding glutaraldehyde for crosslinking by using p-toluenesulfonic acid as a catalyst, standing for 18h, and filtering, washing and drying after the reaction is finished to obtain the finished product microspheres.
The chitosan-polyethylene glycol block copolymer is composed of blocks, wherein the molecular weight of chitosan is 5000-7000, the molecular weight of polyethylene glycol is 750-850, and the mass ratio of the polyethylene glycol to the chitosan blocks is 1: 5 to 10.
The continuous phase is glyceryl monostearate castor oil solution, and the concentration of the glyceryl monostearate in the continuous phase is 0.1-3.5% g/ml.
The mass ratio of the p-toluenesulfonic acid to the chitosan-polyethylene glycol block copolymer is 1: 100.
the indexes of the ivermectin sustained release microspheres prepared by the method are measured: the average particle size of the microspheres is 13.55 microns, and the particle size of more than 90% of the microspheres is 10-19 microns. The electron microscope shows that the medicine is a regular spherical structure, the medicine-loading rate reaches 81.3%, the encapsulation rate reaches 24.8%, and the medicine can be slowly released for 15 days in vitro by in vitro medicine release rate measurement.
Example two: a preparation method of ivermectin sustained-release microspheres comprises the steps of dissolving chitosan-polyethylene glycol block copolymer in purified water, dispersing drug ivermectin in a carrier material solution, fully mixing through ultrasonic stirring to prepare a dispersed phase, wherein the mass percentage of the carrier material to the drug ivermectin is 1: 5.
refined castor oil containing glyceryl monostearate is used as a continuous phase. And heating the dispersed phase and the continuous phase in a water bath to 60 ℃, emulsifying under continuous and rapid stirring to obtain stable emulsion, and dripping the dispersion phase and the continuous phase at a speed of 5-10 ml/min. And (3) placing the emulsion in a cold water bath, slowly adding glutaraldehyde for crosslinking by using p-toluenesulfonic acid as a catalyst, standing for 18h, and filtering, washing and drying after the reaction is finished to obtain the finished product microspheres.
The chitosan-polyethylene glycol block copolymer is composed of blocks, wherein the molecular weight of chitosan is 7000-10000, the molecular weight of polyethylene glycol is 850-1000, and the mass ratio of the polyethylene glycol to the chitosan blocks is 1: 5 to 10.
The continuous phase is glyceryl monostearate castor oil solution, and the concentration of the glyceryl monostearate in the continuous phase is 0.1-3.5% g/ml.
The mass ratio of the p-toluenesulfonic acid to the chitosan-polyethylene glycol block copolymer is 1: 100.
the indexes of the ivermectin sustained release microspheres prepared by the method are measured: the average particle size of the microspheres is 13.1 microns, and the particle size of more than 90% of the microspheres is 10-18 microns. The electron microscope shows that the medicine is a regular spherical structure, the medicine-loading rate reaches 81.5%, the encapsulation rate reaches 24.2%, and the medicine can be slowly released for 15 days in vitro by in vitro medicine release rate measurement.
Example three: a preparation method of ivermectin sustained-release microspheres comprises the steps of dissolving chitosan-polyethylene glycol block copolymer in purified water, dispersing drug ivermectin in a carrier material solution, fully mixing through ultrasonic stirring to prepare a dispersed phase, wherein the mass percentage of the carrier material to the drug ivermectin is 1: 5.
refined castor oil containing glyceryl monostearate is used as a continuous phase. And heating the dispersed phase and the continuous phase in a water bath to 60 ℃, emulsifying under continuous and rapid stirring to obtain stable emulsion, and dripping the dispersion phase and the continuous phase at a speed of 5-10 ml/min. And (3) placing the emulsion in a cold water bath, slowly adding glutaraldehyde for crosslinking without adopting a catalyst, placing for 18h, filtering after the reaction is finished, washing and drying to obtain the finished product microspheres.
The chitosan-polyethylene glycol block copolymer is composed of blocks, wherein the molecular weight of chitosan is 7000-10000, the molecular weight of polyethylene glycol is 850-1000, and the mass ratio of the polyethylene glycol to the chitosan blocks is 1: 5 to 10.
The continuous phase is glyceryl monostearate castor oil solution, and the concentration of the glyceryl monostearate in the continuous phase is 0.1-3.5% g/ml.
The indexes of the ivermectin sustained release microspheres prepared by the method are measured: the average particle size of the microspheres is 14.5 microns, and the particle size of more than 80% of the microspheres is 10-18 microns. The electron microscope shows that the drug carrier is a more regular spherical structure, the drug loading rate reaches 78.7%, the encapsulation rate reaches 21.5%, and the drug can be slowly released in vitro for 13 days by in vitro drug release rate measurement.
Comparative example: a preparation method of ivermectin sustained-release microspheres comprises the steps of dissolving chitosan-polyethylene glycol block copolymer in purified water, dispersing drug ivermectin in a carrier material solution, fully mixing through ultrasonic stirring to prepare a dispersed phase, wherein the mass percentage of the carrier material to the drug ivermectin is 1: 5.
common refined castor oil without glyceryl monostearate is used as a continuous phase. And heating the dispersed phase and the continuous phase in a water bath to 60 ℃, emulsifying under continuous and rapid stirring to obtain stable emulsion, and dripping the dispersion phase and the continuous phase at a speed of 5-10 ml/min. And (3) placing the emulsion in a cold water bath, slowly adding glutaraldehyde for crosslinking by using p-toluenesulfonic acid as a catalyst, standing for 18h, and filtering, washing and drying after the reaction is finished to obtain the finished product microspheres.
The chitosan-polyethylene glycol block copolymer is composed of blocks, wherein the molecular weight of chitosan is 5000-10000, the molecular weight of polyethylene glycol is 750-1000, and the mass ratio of the polyethylene glycol to the chitosan blocks is 1: 5 to 10.
The mass ratio of the p-toluenesulfonic acid to the chitosan-polyethylene glycol block copolymer is 1: 100.
the indexes of the ivermectin sustained release microspheres prepared by the method are measured: the average particle size of the microspheres is 15.78 micrometers, and the particle size of more than 90% of the microspheres is 10-23 micrometers. The electron microscope shows that the medicine is a regular spherical structure, the medicine loading rate reaches 76.3%, the encapsulation rate reaches 21.8%, and the medicine can be slowly released in vitro for 12 days by in vitro medicine release rate measurement.
From the detection results of the above examples and comparative examples, it can be seen that the drug loading and encapsulation efficiency of the prepared ivermectin sustained release microspheres are significantly improved by using the chitosan-polyethylene glycol block copolymer as a carrier material and using the common refined castor oil containing glyceryl monostearate as a continuous phase. Meanwhile, the p-toluenesulfonic acid is used as a catalyst to form better balls through crosslinking, and the drug loading is larger.
Insect repelling effect test:
in a Weifang shouguang pig farm, 50 parasitic infection pigs are selected, and every 10 parasitic infection pigs are compiled into a group, namely a group A, a group B, a group C, a group D and a group E. The first group was orally administered with 0.2mg/kg of the first preparation of example, the second group was orally administered with 0.2mg/kg of the second preparation of example, the third group was orally administered with 0.2mg/kg of the third preparation of example, the third group was orally administered with 0.2mg/kg of the comparative preparation, and the fifth group was not administered as a control group. The group is raised in a pen to avoid cross infection. Feces samples of each group were collected for microscopic examination 15 days after administration. The test results are given in the following table:
egg reduction rate (%) { [ number of eggs before administration-number of eggs after administration ]/number of eggs before administration }. 100%
Relative reduction rate (%) of eggs { [ number of eggs of nematodes in drug group-administration ]/number of eggs of nematodes in drug group-absence }. 100%
Nematode egg negative conversion rate (%) ([ nematode egg inspection negative animal number/test animal number ]. about.100%)
From the above test results, it can be seen that the preparations of examples one and two have very good therapeutic effects on the parasites common to swine, while the therapeutic effects of comparative example and example three are somewhat inferior.
Claims (9)
1. A preparation method of ivermectin sustained-release microspheres is characterized by comprising the following steps:
step 1, dissolving chitosan-polyethylene glycol block copolymer serving as a carrier material in purified water, dispersing drug ivermectin in the carrier material solution, and stirring and fully mixing to prepare a dispersed phase;
step 2, taking castor oil as a continuous phase, heating the dispersed phase and the continuous phase in a water bath, and emulsifying under continuous stirring to obtain emulsion; the continuous phase is castor oil containing glyceryl monostearate;
and 3, placing the emulsion in a cold water bath, adding organic acid serving as a catalyst, adding glutaraldehyde for crosslinking, standing for a period of time, filtering, washing and drying to obtain the finished product microspheres.
2. The method for preparing the ivermectin sustained-release microspheres according to claim 1, wherein the mass percentage of the carrier material to the drug ivermectin is 1: 1 to 10.
3. The method for preparing ivermectin sustained-release microspheres according to claim 1, wherein the water bath heating temperature in the step 2 is 60 ℃.
4. The method for preparing ivermectin sustained-release microspheres according to claim 1, wherein the standing time in the step 3 is 16-24 hours.
5. The method for preparing ivermectin sustained-release microspheres according to claim 1, wherein in the block composition of the chitosan-polyethylene glycol block copolymer, the molecular weight of chitosan is 5000-10000, the molecular weight of polyethylene glycol is 750-1000, and the mass ratio of the polyethylene glycol to the chitosan block is 1: 5 to 10.
6. The method for preparing the ivermectin slow-release microspheres according to claim 1, wherein the dripping speed in the disperse phase and the continuous phase is 5-10 ml/min.
7. The method for preparing the ivermectin sustained-release microspheres according to claim 1, wherein the mass ratio of the organic acid to the chitosan-polyethylene glycol block copolymer is 1-3: 100.
8. the method for preparing ivermectin sustained-release microspheres according to claim 1, wherein the organic acid comprises one of p-toluenesulfonic acid, salicylic acid and formic acid as a catalyst.
9. Use of the ivermectin sustained release microspheres prepared by the method for preparing the ivermectin sustained release microspheres of any one of claims 1 to 8 in preparation of veterinary drugs.
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| US5788978A (en) * | 1996-12-17 | 1998-08-04 | Passeron; Eduardo Julio | Injectable pulsatile ivermectin composition |
| CN1272017C (en) * | 2002-03-20 | 2006-08-30 | 方淑昌 | Method for preparing nano-microballons of Avermectins medicine and usage |
| CN1275589C (en) * | 2002-05-31 | 2006-09-20 | 王玉万 | Slow releasing injection contg. antiparasitic medicine |
| HUE043897T2 (en) * | 2007-09-25 | 2019-09-30 | Solubest Ltd | Compositions comprising lipophilic active compounds and method for their preparation |
| US20090181068A1 (en) * | 2008-01-14 | 2009-07-16 | Dunn Richard L | Low Viscosity Liquid Polymeric Delivery System |
| CN102138904B (en) * | 2010-02-03 | 2013-01-09 | 中国科学院过程工程研究所 | Self-solidified microspheres and preparation method and application 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 |
| CN102731792B (en) * | 2012-07-19 | 2013-10-30 | 浙江大学 | Preparation method of chitosan grafted polymer with thermosensitivity |
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| CN106074447B (en) * | 2016-07-13 | 2018-11-02 | 广西师范学院 | The preparation method of chitosan-based derivative polymer point drug bearing microsphere |
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