CN107773554A - A kind of ivermectin slow-releasing microcapsule and its preparation method and application - Google Patents

Abstract

The invention discloses an ivermectin sustained-release microcapsule, a preparation method and application thereof. The ivermectin sustained-release microcapsules include the following components in mass percentage: 0.1-1% of ivermectin raw material, 20-60% of water-soluble carrier, and 30-70% of enteric-soluble wrapping material; wherein the water-soluble carrier Hydroxypropyl-β-cyclodextrin, Methyl-β-cyclodextrin, HPMC, PVP, PEG, Poloxamer 188, Mannitol, D-α-Tocopheryl PEG1000 Succinate, Bile Salts/Phospholipids One or more of mixed micelles, polyethylene diamine dendrimers, phospholipids or cholesterol; enteric coating materials are hydroxypropyl methylcellulose phthalate, acrylic resin No. Ⅱ, acrylic resin No. Ⅲ One or more of cellulose acetate phthalate, polyethylene phthalate or hydroxypropyl methylcellulose acetate succinate. The ivermectin slow-release microcapsule of the present invention has outstanding advantages in acid resistance, enables the drug to disintegrate and release after reaching the intestinal tract, significantly improves bioavailability and has remarkable curative effect.

Description

A kind of ivermectin sustained-release microcapsules and its preparation method and application

technical field

The invention belongs to the technical field of preparation of animal medicines, and in particular relates to a vermectin sustained-release microcapsule and its preparation method and application.

Background technique

Animal parasitic diseases are an important part of livestock infectious diseases that cannot be ignored, and there are many types of pathogenic parasites. Common internal parasites include roundworms, flagellates, strongyloids, trichinella, nodularia, coccidia, tapeworms, trematodes Etc. External parasites include ticks, fleas, flies, ticks, lice, etc. It seriously affects the output of meat, milk and eggs, the quality of fur, seriously restricts the healthy development of animal husbandry, and some zoonotic parasitic diseases also directly endanger human health, causing huge economic losses to the animal husbandry industry and causing serious public health problem.

Ivermectin (IVM) was discovered by Berge in 1979. The foreign trade name is Ivemec, and the import trade name is Harvest. It is a macrolide antibiotic Avermectins (Avermectins) fermentation product B1 22, 23-Dihydro derivatives have repellent and killing effects on various parasites, and are recognized as multi-component antibiotics with broad-spectrum, high efficiency, safety, less residue, and no drug resistance. The insecticidal mechanism is ivermectin Binding to the specific high-affinity site on the target worm cells affects the permeability of the cell membrane to Cl-, and then causes the inhibitory neurotransmitter γ-aminobutyric acid (γ-aminobutyric acid ( GABA) release increases, and opens the Cl- channel controlled by glutamate, and enhances the permeability of the nerve membrane to Cl-. GABA acts on the presynaptic nerve endings, reduces the release of excitatory transmitters, and weakens the excitatory postsynaptic potential generated by the post-synaptic membrane. The post-synaptic neuron cannot reach the threshold because the degree of depolarization of the membrane potential does not reach the threshold. Enter the excited state, which causes inhibition, leading to paralysis and death of the insect body. The drug was produced by MerckShorp and Dohme pharmaceutical companies in the United States in 1987 and used for the treatment of human onchocerciasis.

With the rapid development of animal husbandry, a variety of dosage forms of ivermectin have been developed, which have been made into conventional dosage forms such as premixes, tablets, ointments, solutions, injections, and transdermal agents. The most widely used is Ordinary injections. The half-life of the injection is short, and although the curative effect is significant, the drug effect is not durable enough and in the process of clinical application, it consumes a lot of manpower, and it is difficult to administer drugs on a large scale at the same time. In addition, the existing common preparations of ivermectin have problems such as short half-life and poor stability. Livestock and poultry need multiple doses of administration. Common preparations greatly increase the labor intensity and supplies of veterinary staff when administering individual administration of deworming. At the same time, multiple individual administrations cause great stress to livestock and poultry, and ordinary preparations often require a large dose of anthelmintics at one time, which can easily cause the peak concentration to be too high, so that livestock and poultry are poisoned. Ordinary premixes cannot be well mixed with feed due to poor fluidity and dispersibility. At the same time, this preparation is prone to insufficient or excessive intake due to uneven premixing and different feed intake. Another result shows that the oral bioavailability of ordinary preparations for pigs is 41% or 59% lower than that of subcutaneous administration, resulting in low bioavailability, and the blood drug concentration in the animal epidermis is lower than the effective blood drug concentration, which makes the animal epiparasite treatment effect It is very poor. It has been proved by experiments that the oral bioavailability of ivermectin is greatly reduced due to the destruction of the structure of ivermectin and the first-pass effect of ivermectin after passing through the acidic environment of the stomach.

Ivermectin itself is insoluble in water and easily soluble in organic solvents, but ivermectin must exist in molecular form to be absorbed by the body. Therefore, there is an urgent need for a drug that can exist in molecular form and can pass through gastric acid without degradation. The oral preparation of ivermectin can significantly improve the oral bioavailability of ivermectin, increase the blood concentration of animal epidermis, thereby effectively treating ectoparasites, and further strengthening the inhibition of nematode infection in the body. In order to further save labor costs, at the same time Achieve the effect of repelling insects inside and outside the body, and achieve an effective effect of repelling insects.

Contents of the invention

The problem to be solved by the present invention is to degrade the existing ivermectin preparations under acidic environment conditions, resulting in oral bioavailability of only 40% to 80%, resulting in animal body surface blood drug concentration lower than therapeutic blood drug concentration, for Insufficient technology for poor efficacy of ectoparasite treatment. Provides a drug that can pass through gastric acid without degrading, significantly improves the oral bioavailability of ivermectin, increases the effective blood concentration of animal body surface, effectively treats parasites on the body surface, strengthens the inhibition of parasite infection in the body, and has good palatability. An ivermectin sustained-release microcapsule.

Another technical problem to be solved by the present invention is to provide a preparation method of the above-mentioned ivermectin sustained-release microcapsules.

Another technical problem to be solved in the present invention is to provide the application of the above-mentioned ivermectin sustained-release microcapsules in the treatment of animal parasitic diseases.

Another technical problem to be solved in the present invention is to provide the application of the ivermectin sustained-release microcapsules in treating nematode infection in vivo and in vitro of animals.

The object of the invention is achieved through the following technical solutions:

Provide an ivermectin sustained-release microcapsule, including the following components in mass percentage: 0.1-1% of ivermectin raw material, 20-60% of water-soluble carrier, and 30-70% of enteric coating material;

The water-soluble carrier is hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, HPMC (hydroxypropylmethylcellulose), PVP (polyvinylpyrrolidone), PEG (polyethylene glycol), One or more of poloxamer 188, mannitol, D-α-tocopherol PEG1000 succinate, bile salt/phospholipid mixed micelles, polyethylenediamine dendrimers, phospholipids or cholesterol;

Compared with commonly used water-soluble carriers, the water-soluble carrier provided by the present invention slowly releases drugs in the intestinal tract and can fully release all drugs, and the in vitro dissolution can reach more than 98%.

The enteric wrapping material is HPMCP (hydroxypropyl methylcellulose phthalate), acrylic resin No. Ⅱ, acrylic resin No. Ⅲ, CAP (cellulose acetate phthalate), PVAP (polyethylene phthalate Acetate) or HPMCAS (hydroxypropylmethylcellulose acetate succinate) or one or more.

Compared with common enteric coating materials on the market, the enteric coating material provided by the present invention can significantly improve the protection rate of drugs under acidic environment conditions after being mixed with other components of the present invention, so that the drugs can avoid entering into the acidic environment. The intestinal tract is fully released, and the in vitro dissolution data show that the solid drug content after dissolution in an acidic environment reaches more than 95%.

Further, the ivermectin sustained-release microcapsules also include fenbendazole and/or albendazole.

A preparation method of the ivermectin sustained-release microcapsules is provided, comprising the following steps:

S1. Weigh the water-soluble carrier according to the proportion, heat and melt to obtain the mixture A;

S2. After dissolving the ivermectin raw material, add it to the mixture A described in step S1, and stir evenly to combine the ivermectin molecules with the carrier to obtain the mixture B;

S3. Add the enteric coating material to the mixture B obtained in the step S2, and stir evenly at the heat preservation temperature to obtain the mixture C;

S4. Insulating and atomizing the mixture C in step S3, and spraying and granulating through a fluidized bed;

S5. Sieving the pellets described in step S4 to collect pellets with a particle size below 40 mesh;

The method of fluidized bed spray granulation can make the particles more uniform, the drug and the carrier excipients can be more fully combined, and the preparation process is simple, the energy consumption is less, the equipment is innovatively improved, and it is easy to industrialize mass production. Traditional premix production process, this preparation process avoids dust and static electricity.

Preferably, the heating and melting temperature in step S1 is 90-140°C.

Preferably, the heat preservation temperature of the mixed material in step S3 is 35-85°C.

Preferably, the linear velocity of the fluidized bed spray droplets in step S5 is 30-130 m/s; the temperature of the fluidizing air is 15-25°C.

Preferably, the particle size of the pellets obtained in step S5 is 80-450 μm.

Further, in step S2, after adding fenbendazole and/or albendazole raw drug to dissolve, mix with the dissolved ivermectin raw material, and jointly add to the mixture A described in step S1.

The application of the ivermectin sustained-release microcapsule in treating animal parasitic diseases is provided.

The invention provides the application of the ivermectin sustained-release microcapsules in treating nematode infection and arthropod infection inside and outside animals.

Beneficial effects of the present invention:

Aiming at the technical deficiencies of existing ivermectin preparations, a new type of ivermectin sustained-release microcapsules is provided, which simultaneously achieves the outstanding effects of high efficiency, low toxicity, targeting, sustained release, and controlled release. The drug is dissolved in ethanol and exists in the form of molecules. By combining the hydrophobic carrier with the ivermectin molecule and wrapping the carrier with an acid-resistant adjuvant, the ivermectin can pass through the gastric acid without degradation, which significantly improves the ivermectin. The oral bioavailability of the drug and the stability of the preparation itself, so that the blood drug concentration on the animal body surface can reach an effective therapeutic concentration through mixed feeding, and it also enhances the treatment of internal parasites and avoids the infection of internal and external parasites.

In order to ensure the activity of the drug, the new research preparation can release the drug in a small amount or not in the acidic environment of the stomach. It can be released in the whole process of the intestinal tract and fully absorbed in the intestinal tract, so that the blood drug concentration can be stabilized and the peak-valley phenomenon can be avoided. , increase the epidermal drug concentration, achieve the effect of deworming on the body surface, thereby improving the bioavailability of ivermectin, and solve the problems of low oral bioavailability and low blood drug concentration on the body surface of common preparations. At the same time, it can reduce the number of administrations, intensively prevent or treat medications in farms, minimize the labor intensity of veterinary staff, and reduce the degree of animal stress; it is beneficial to reduce the toxic and side effects of drugs, and the deworming can achieve an effective detoxification rate; ensure that the drugs safety and efficacy.

The preparation method of the ivermectin sustained-release microcapsule preparation of the present invention has a simple process and is easy to realize industrialization; the appearance of the ivermectin sustained-release microcapsule preparation prepared by it is white or milky white, and the spherical shape of the microsphere or microcapsule is small Microcapsules, with a particle size of 80-450µm, have high fluidity and dispersion, stable performance, easy storage, and are conducive to mixing evenly with feed. Scientifically determined the compatibility ratio of dispersant, release blocker, etc., and successfully achieved ivermectin passing through the gastric environment, solubilizing and slowly releasing in the intestinal tract.

Compared with the prior art, the ivermectin sustained-release microcapsule anthelmintic of the present invention has the following beneficial effects

(1) The selected excipients are resistant to strong acidic environment in animals, easy to dissolve in weak acid or neutral environment, have little toxicity to animals, and the excipients are cheap and easy to obtain, suitable for industrial production;

(2) The particle size of the ivermectin sustained-release microcapsules of the present invention is controllable within the range of 80-450 μm, the particle size distribution is uniform, the stability is high, and it is easy to store.

(3) The ivermectin sustained-release microcapsule preparation prepared by the present invention well conceals the irritation of the drug to the gastric mucosa, increases the palatability of the drug, and prevents the drug from being destroyed by gastric acid in the stomach at the same time, ensuring that the drug remains in the stomach. Intestinal release improves bioavailability and achieves the therapeutic effect of ivermectin;

(4) The microcapsules of the present invention can be mixed for feeding and administration, which is convenient for administration, reduces the frequency of administration or dosage, saves labor costs, reduces the degree of animal stress, and is suitable for intensive use in large-scale enterprises;

(5) After the animals eat, the drug increases in the intestinal tract and releases slowly, the effective blood drug concentration lasts for a long time, and the epidermal drug concentration is high, which meets the clinical treatment requirements and has high safety.

(6) At the same time, reduce the total dose of medication, and use the smallest dose to achieve the maximum drug effect, which can stabilize the blood drug concentration, avoid the peak and valley phenomenon, help reduce the toxic and side effects of the drug, and achieve an effective deworming rate; ensure that the drug safety and efficacy

(7) The preparation process of the ivermectin sustained-release microcapsules of the present invention is simple, consumes less energy, innovatively improves equipment, and is easy for industrialized mass production.

(8) Compared with the traditional premix production process, the preparation process of the present invention avoids dust and static electricity.

Detailed ways

The present invention will be further described in detail below in conjunction with specific examples, but the examples do not limit the present invention in any form, but are only illustrative illustrations. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

Example 1

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.2% ivermectin, 38.8% hydroxypropyl-β-cyclodextrin, 60% PVAP (polyethylene phthalate) according to the proportion, heat and melt hydroxypropyl-β-cyclodextrin at 90°C , mixed evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add PVAP (polyethylene phthalate) to the mixture described in step S2, and stir evenly at 40°C to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 20°C, and the linear velocity is 55 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.2% ivermectin sustained-release microcapsules with a particle size of about 400 μm.

Example 2

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. According to the proportion, weigh 0.4% ivermectin, 44.6% HPMC (hydroxypropyl methylcellulose), 55% acrylic resin No. II, heat and melt HPMC (hydroxypropylmethylcellulose) at 95°C, and mix evenly to obtain a mixture ;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 135 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.4% ivermectin sustained-release microcapsules with a particle size of about 80 μm.

Example 3

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% ivermectin, 45.4% bile salt/phospholipid mixed micelles, 54% HPMCAS (hydroxypropyl methylcellulose acetate succinate) according to the proportion, heat and melt the bile salt/phospholipid mixed micelles at 100°C , mixed evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add HPMCAS (hydroxypropylmethylcellulose acetate succinate) to the mixture described in step S2, and stir evenly at 50°C to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 25°C, and the linear velocity is 100 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 150 μm.

Example 4

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.8% ivermectin, 30% phospholipid, 20% cholesterol, and 49.2% PVAP (polyethylene phthalate) according to the proportion, heat and melt the phospholipid and cholesterol at 90°C, and mix evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add PVAP (polyethylene phthalate) to the mixture described in step S2, and stir evenly at 50°C to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, perform fluidized bed spray granulation, the temperature of the fluidized air is 15°C, and the linear velocity is 80 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.8% ivermectin sustained-release microcapsules with a particle size of about 250 μm.

Example 5

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% ivermectin, 50% polyethylenediamine dendrimer, 49.4% CAP (cellulose acetate phthalate) according to the proportion, heat and melt the polyethylenediamine dendrimer at 100°C, and mix evenly, to get a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add CAP (cellulose acetate phthalate) to the mixture described in step S2, and stir evenly at 50°C to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 15°C, and the linear velocity is 50 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 400 μm.

Example 6

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 1% ivermectin, 13.5% PVP (polyvinylpyrrolidone), 0.5% acrylic resin No. III according to the proportion, heat and melt PVP (polyvinylpyrrolidone) at 100°C, and mix well to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. Ⅲ to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and perform fluidized bed spray granulation, the temperature of fluidized air is 20°C, and the linear velocity is 30 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 1% ivermectin sustained-release microcapsules with a particle size of about 300 μm.

Example 7

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% ivermectin, 5% fenbendazole, 40.6% HPMC (hypromellose) and 44% acrylic resin No. II according to the proportion, and heat the HPMC (hypromellose) at 95°C Heat to melt, mix evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 120 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.4% ivermectin compound slow-release microcapsules with a particle size of about 380 μm.

Example 8

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% of ivermectin, 6% of albendazole, 42% of HPMC (hydroxypropyl methylcellulose) and 51.4% of acrylic resin No. II according to the proportion, and heat the HPMC (hydroxypropylmethylcellulose) at 95°C Heat and melt, and mix evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 120 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.4% ivermectin compound slow-release microcapsules with a particle size of about 250 μm.

Example 9

Prepare ivermectin compound sustained-release microcapsules according to the following steps:

S1. Weigh 0.4% ivermectin, 10% albendazole, 44.6% HPMC (hypromellose) and 55% acrylic resin No. Ⅱ according to the proportion, and heat the HPMC (hypromellose) at 95°C Heat to melt, mix evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, perform fluidized bed spray granulation, the temperature of the fluidized air is 18°C, and the linear velocity is 100 m/s;

S5. Cool the powder described in step S4, sieve through a 40 mesh, and collect to obtain 0.4% ivermectin compound slow-release microcapsules, with a particle size of about 80 μm.

Comparative Example 1

Follow the steps below to prepare the ivermectin premix:

S1. Accurately weigh 0.6% ivermectin, 2% oregano oil, 45% calcium carbonate, and 52.75% defatted cornstarch according to the mass percentage;

S2 takes ivermectin pretreatment agent, heats and melts; heating temperature is 95°C, stirs calcium carbonate and defatted cornstarch evenly; passes through No. 4 sieve, adds ivermectin and oregano oil, and mixes evenly, the prepared The particle size of the powder was 90 μm, and the ivermectin premix was prepared by sieving.

Comparative Example 2

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% ivermectin, 45.4% glyceryl monostearate, and 54% HPMCAS (hydroxypropyl methylcellulose acetate succinate) according to the proportion, heat and melt glyceryl monostearate at 100°C, Mix evenly to obtain a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 25°C, and the linear velocity is 100 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 320 μm. In the neutral environment of pH 6.8, the release rate reached 54% in 30 minutes, and reached 84% after 60 minutes. Compared with the examples provided by the present invention, the release rate was too fast and could not achieve a better sustained release effect.

Comparative Example 3

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% ivermectin, 44.4% HPMC (hydroxypropylmethylcellulose) and 55% cellulose acetate phthalate according to the proportion, heat and melt HPMC (hydroxypropylmethylcellulose) at 95°C, and mix evenly, to get a mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 135 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 280 μm. The 6h release rate is about 7% in a strongly acidic environment, and the 30 min release rate exceeds 60% in a neutral pH6.8 environment. Compared with the examples provided by the present invention, the release rate is too fast, and the effect of sustained release cannot be achieved. .

Comparative Example 4

Follow the steps below to prepare ivermectin sustained-release microcapsules:

S1. Weigh 0.6% ivermectin, 44.6% HPMC (hydroxypropyl methylcellulose) and 55% acrylic resin No. Ⅱ according to the proportion, heat and melt HPMC (hydroxypropylmethylcellulose) at 95°C, and mix evenly to obtain mixture;

S2. Dissolving the ivermectin raw material with carboxymethyl cellulose and adding it to the mixture described in step S1, stirring evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 135 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 350 μm. The 6h release rate in a strongly acidic environment exceeds 12%, that is, in the gastric acid environment of animals, a certain amount of drug loss will be caused, which will cause a certain amount of waste compared with the examples provided by the present invention.

Comparative Example 5

Prepare ivermectin compound sustained-release microcapsules according to the following steps:

S1. Weigh 0.6% ivermectin, 44.6% HPMC (hydroxypropylmethylcellulose) and 50% acrylic resin No. Ⅱ according to the proportion, heat and melt HPMC (hydroxypropylmethylcellulose) at 95°C, and mix evenly to obtain mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 250 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 50-500 μm. The large difference in particle size affects palatability, and the proportion of self-feeding pigs in clinical application is only about 70%.

Comparative Example 6

Prepare ivermectin compound sustained-release microcapsules according to the following steps:

S1. Weigh 0.6% ivermectin, 44.6% HPMC (hydroxypropyl methylcellulose) and 55% acrylic resin No. Ⅱ according to the proportion, heat and melt HPMC (hydroxypropylmethylcellulose) at 95°C, and mix evenly to obtain mixture;

S2. The ivermectin raw material is dissolved in ethanol and added to the mixture described in step S1, and stirred evenly to obtain the mixture;

S3. Add acrylic resin No. II to the mixture described in step S2, and stir evenly at 50° C. to obtain a mixture;

S4. Cool the mixture described in step S3 to 65-80°C, and carry out fluidized bed spray granulation, the temperature of fluidized air is 18°C, and the linear velocity is 10 m/s;

S5. Cool the powder described in step S4, sieve through a 40-mesh sieve, and collect to obtain 0.6% ivermectin sustained-release microcapsules with a particle size of about 400-700 μm. The particle size is large, and the protection rate of ivermectin is high in acidic environment, but the release rate of ivermectin is only 57% in 3 hours at pH 6.8 and neutral environment.

Example 10 In vitro release test of ivermectin sustained-release microcapsules

1. Drugs for testing: 0.6% ivermectin sustained-release microcapsules (illustrated with the test results obtained in Example 3); common 0.6% ivermectin premix (based on the test results obtained in Comparative Example 1) result will be explained).

2. Test method: Accurately weigh 0.6% ivermectin sustained-release microcapsules and 0.6% ivermectin pre-treated Mix 1.5g each, put the drug into the blue of the dissolution apparatus, refer to "The Veterinary Pharmacopoeia of the People's Republic of China", "US Pharmacopoeia" and "Japanese Pharmacopoeia" in 900ml of different pH release buffer media (pH=1.2 hydrochloric acid, pH=4.1 Acetate buffered saline, pH = 6.8 phosphate buffered saline, water), constant temperature 37°C ± 0.5°C, turn blue at 100r/min. 0.6% ivermectin sustained-release microcapsules were sampled 5ml at 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, and 8h, and 5ml of fresh release medium was added to the dissolution vessel at the same time; 20% ivermectin Sample 1ml of the premix at 5min, 10min, 15min, 30min, 45min, and 60min respectively, and add 1ml of fresh release medium at the same temperature to the dissolution vessel at the same time. The sample taken out is passed through a 0.22um filter membrane and put on the machine. The HPLC method was used for detection under the chromatographic conditions (C18 column, mobile phase: acetonitrile:methanol:water (53:32:15), column temperature 30°C, flow rate 1mL/min, detection wavelength 245nm). The content of ivermectin was determined by HPLC and the cumulative release percentage was calculated according to the following formula, and the cumulative release percentage-time curve was drawn.

In the formula: Cn is the mass concentration of solids in the sample taken at the nth time point, V is the total volume of the release medium, Vi is the sampling volume at the i-th time point, and Ci is the mass concentration of the sample taken at the i-th time point , W is the total mass of microspheres, DL is the mass fraction of drug loading in microspheres.

The cumulative release of 0.6% ivermectin sustained-release microcapsules at different time points in different release media is shown in Table 1, and the cumulative release of 0.6% ivermectin premix at different time points in different release media is shown in Table 2 As shown, the protection rate of the main component of ivermectin in an acidic environment is shown in Table 3, and the content of ivermectin after being destroyed with time under different pH environments is shown in Table 4.

The above in vitro dissolution test data and the stability of ivermectin in acidic environment show that ivermectin has poor stability in acidic environment and is easily degraded. Conventional 0.6% ivermectin premix dissolves more than 90% in vitro within 45 minutes under pH 6.8 and aqueous medium conditions, and the protection rate of the main component ivermectin within 2 hours under acidic conditions is less than 70%; while 0.6% ivermectin sustained-release microcapsules can maintain a release rate of almost zero for 6 hours in a strongly acidic environment, and the protection rate of the main component ivermectin within 2 hours in an acidic environment is above 90%. At pH 6.8 and neutral environment, the release rate is higher than 90% within 3 hours. It shows that 0.6% ivermectin sustained-release microcapsules can pass through the gastric acid environment of animals smoothly and be protected from degradation, release and absorb after reaching the intestinal tract of animals, improve bioavailability, delay the release of ivermectin drugs, and prolong the lifespan of animals in vivo. Effective blood concentration time, and ensure full release before defecation, to avoid drug loss and waste.

Example 11 Observational Test of Ivermectin Sustained-release Microcapsules on the Deworming Effect of Pigs

1 test drug

Drug under test: ivermectin sustained-release microcapsules, content: 0.6%, (illustrated with the test results obtained in Example 3)

Reference preparation: commercially available common ivermectin premix (Foshan Zhengdian Biotechnology Co., Ltd.).

2. Experimental animals: 60 10-week-old Yorkshire x Landrace binary crossbreed pigs from Animal Center of South China Agricultural University, purchased from Guangzhou Fine Breed Pig Farm. Fecal examination results: natural roundworm infection, but no obvious clinical symptoms; no other nematodes, trematodes and tapeworm infections, no ectoparasite infection on the body surface.

3 Method: Dosing in groups

Divide 100 groups into 5 groups, 20 in each group. Groups A and B are test drug groups. Add ivermectin slow-release microcapsules to the feed, and add 330g ivermectin slow-release microcapsules per 1000kg feed. Microcapsules, administered once every 3 days for one week; Groups C and D are the reference preparation groups, with ivermectin premix added to the feed, and 330g of ivermectin premix added to every 1000kg of feed once a day 7 days. Group E did not use any anthelmintics. The test group, reference group and blank group were fed and managed under exactly the same conditions.

4 Effect Observation:

During the experiment, the food appetite, mental state and feces of the pigs were observed. 1 day before medication, 3, 7, 10, 15, 30, and 40 days after medication, fresh feces were collected one by one, mixed well, and the excretion of parasites in the body was checked by sedimentation method; each pig in each group was checked by McMaster method Calculate the number of eggs in the feces, calculate the number of eggs per gram of feces (EPG) and the reduction rate of eggs; use the saturated salt water flotation method to check the presence or absence of eggs in the feces of each pig in each group, and calculate the conversion rate of eggs .

The formula is as follows:

Negative rate of worm eggs (%)=(Number of pigs with worm eggs turned negative after deworming/Number of pigs with positive worm eggs before deworming)×100%

Egg reduction rate (%)=(EPG before deworming-EPG after deworming)/EPG before deworming×100%

Before administration, the feces of each pig were tested for eggs by McMaster method, and the average EPG value was about 600-700. Three days after a single administration, the worms in the feces of pigs in the ivermectin sustained-release microcapsules group The number of eggs decreased significantly, and the reduction rate was 60% to 75%. The reduction rate of the number of eggs in the feces of pigs in the ivermectin premix group was about 30% to 45%. No eggs were detected in the feces of pigs in the experimental group by the saturated salt water flotation method, and the reduction rate of eggs and the rate of negative conversion of eggs were both 100%. Until 40 days after treatment, no worm eggs were detected in the feces of 80 pigs, and the deworming effect was significantly different between ivermectin sustained-release microcapsules and ivermectin premix. In the control group, the number of worm eggs in each pig feces remained basically unchanged during the test, and there was a tendency to increase over time. It can be seen that ivermectin slow-release microcapsules can effectively drive away parasites in pigs. worms, and keep the pig body no longer infected with parasitic diseases in a longer period of time.

As can be seen from the results, the palatability of ivermectin sustained-release microcapsules of the present invention is significantly better than commercially available common ivermectin premix; the therapeutic effect on parasitic diseases is also significantly better than commercially available common ivermectin The ivermectin premix and the absence of repeated infections indicate that the ivermectin sustained-release microcapsules of the present invention also have significant effects in preventing parasitic diseases.

Example 12 Observational experiment on the deworming effect of ivermectin sustained-release microcapsules on pig body surface

1 test drug

Drug under test: ivermectin sustained-release microcapsules, content: 0.6%, (illustrated with the test results obtained in Example 3)

Reference preparation: commercially available common ivermectin premix (Foshan Zhengdian Biotechnology Co., Ltd.).

2 Experimental animals:

10-week-old sheep from the Animal Center of South China Agricultural University were purchased from Guangzhou Fine Breed Sheep Farm. The body surface of the sheep was checked one by one before the test. According to the number of lice, flies, fleas and ticks parasitized within 30 cm ² of the sheep body surface, 15 sheep with more than 10 parasitized within 30 cm ² were selected as the test sheep. The selected 15 sheep were randomly divided into two test groups and one control group, with 10 sheep in each test group and 5 sheep in the control group.

3 Test method:

3.1 Examination of ectoparasites Examination of ectoparasites was performed on all sheep before and 20 days after administration of mixed feeding.

3.2 Administration of microcapsules and animal feeding Group A: add ivermectin sustained-release microcapsules premix to feed, add 330g ivermectin sustained-release microcapsules per 1000kg feed, and administer single dose. Group B: add ivermectin premix to feed, add 330g ivermectin premix to every 1000kg feed and give single dose. Group C: a blank group. The three groups were raised according to conventional methods.

3.3 Safety observation: observe and record the sheep's appetite, energy, breathing, gait, and toxic reactions every day.

4 results

4.1 Group A: The killing rate of lice, flies and mox is 78.5%, and the killing rate of ticks is 65%.

4.2 Group B: The killing rate of lice, flies and mox is 40%, and the killing rate of ticks is 35%.

4.3 Group C: The types and quantities of lice, flies, and moths were basically the same as before the experiment.

4.4 Safety observation: All the experimental sheep showed no abnormal behavior.

5 Conclusion

Tests have shown that ivermectin sustained-release microcapsules have a better killing effect on sheep body surface deworming than ivermectin premix, especially in areas where parasites are seriously endangered. Very good control of various parasites inside and outside the body.

Claims (10)

1. An ivermectin sustained-release microcapsule, characterized in that it comprises the following components in mass percent: 0.1-1% of ivermectin raw material, 20-60% of water-soluble carrier, 30-60% of enteric coating material 70%; The water-soluble carrier is hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, HPMC (hydroxypropylmethylcellulose), PVP (polyvinylpyrrolidone), PEG (polyethylene glycol), One or more of poloxamer 188, mannitol, D-α-tocopherol PEG1000 succinate, bile salt/phospholipid mixed micelles, polyethylenediamine dendrimers, phospholipids or cholesterol; The enteric wrapping material is HPMCP (hydroxypropyl methylcellulose phthalate), acrylic resin No. Ⅱ, acrylic resin No. Ⅲ, CAP (cellulose acetate phthalate), PVAP (polyethylene phthalate Acetate) or HPMCAS (hydroxypropylmethylcellulose acetate succinate) or one or more. 2. The ivermectin sustained-release microcapsule according to claim 1, characterized in that, the ivermectin sustained-release microcapsule further comprises fenbendazole and/or albendazole. 3. the preparation method of the described ivermectin sustained-release microcapsules of claim 1, is characterized in that, comprises the following steps: S1. Weigh the water-soluble carrier according to the proportion, heat and melt to obtain the mixture A; S2. Dissolve the ivermectin raw material in ethanol and add it to the mixture A described in step S1, and stir evenly to combine the ivermectin molecules with the carrier to obtain the mixture B; S3. Add the enteric coating material to the mixture B obtained in the step S2, and stir evenly at the heat preservation temperature to obtain the mixture C; S4. Insulating and atomizing the mixture C in step S3, and spraying and granulating through a fluidized bed; S5. Sieve the pellets described in step S4 to collect pellets with a particle size below 40 mesh. 4. The method according to claim 3, characterized in that the heating and melting temperature in step S1 is 90-140°C. 5. The method according to claim 3, characterized in that the heat preservation temperature of the mixed material in step S3 is 35-85°C. 6. The method according to claim 3, characterized in that the linear velocity of the fluidized bed spray droplets in step S5 is 30-130 m/s; the temperature of the fluidizing air is 15-25°C. 7. The method according to any one of claims 3-6, characterized in that the particle size of the pellets obtained in step S5 is 80-450 μm. 8. The method according to claim 3, characterized in that, after adding fenbendazole and/or albendazole raw material drug in step S2 to dissolve, mix with the dissolved ivermectin raw material, and join together in step S2. S1 in the mixture A. 9. The application of the ivermectin sustained-release microcapsules described in any one of claims 1 and 2 in the treatment of parasitic diseases in animals. 10. The application of any one of the ivermectin sustained-release microcapsules of claim 1 or 2 in the treatment of nematode infection and arthropod infection in vivo and in vitro of animals.