WO2003101419A1 - Anti-parasite containing sustained release injection - Google Patents

Abstract

The invention relates to a sustained release injection comprising anti- parasites. The active component carried in formulation exists as a particle of solid dispersion; preferably, the injection is solid dispersion particles consisted of macrolide insect repellents and hydrogenated castor oil (HCO); the preferred preparation process is solvent-nonsolvent method, comprising the following steps: dissolving envimycin in 1∼2-fold amount of dimethyl acetamide, mixing uniformly with melted HCO, then blending with water and glycerin, followed by grind to obtain a solid dispersion having a particle size <100 µ m, and adding injectable water and excipient to a final volume. Alternatively, a suspension injection is formulated by dispersing a prepared solid dispersion of HCO and envimycim into liquid vehicle. The present injection is biocompatible and provides an excellent sustained release effect.

Description

 TECHNICAL FIELD

 The invention relates to a veterinary preparation, specifically, a sustained-release injection containing an antiparasitic drug. The preparation is a solid dispersion composed of an antiparasitic drug and a hydrogenated castor oil (HCO). This is a salient feature of the present invention. Solid dispersions containing HCO and antiparasite drugs can be prepared by solvent evaporation or melt dispersion condensation or solvent-non-solvent methods.

Background technique

 In the previous preparation of pharmaceutical preparations, solid dispersions prepared with HCO were mainly used to prepare preparations for oral use, such as tablets, granules, or capsules. Patent WO99 / 27906 and patent EP0535734 disclose the use of HCO in the preparation of sustained-release injections. The optimized formulation composition is: ivermectin 3.15%, HCO 1.5%, a hydrophobic liquid medium such as glycerol triacetate 40%, acetyl 60% of monoglycerides. Because glycerol triacetate has a certain ability to dissolve ivermectin (about 3%) and acetylated monoglyceride (non-ionic lipophilic surfactant) has a strong ability to disperse HCO. Therefore, the The active ingredient and HCO are uniformly dispersed in triglyceride and acetylated monoglyceride, and the appearance of the preparation is in a colloidal state.

 The composition and preparation of the preparation of the present invention are different from those described in patents WO99 / 27906 and EP0535734.

The present invention combines HCO with macrolide insect repellent or N-phenylpyrazole insect repellent or other insect repellent to form solid dispersion particles (hereinafter referred to as HCO drug-loaded particles), and The HCO drug-loaded microparticles are dispersed in a dispersion medium mainly composed of water or other hydrophilic liquid to prepare an injection. The preparation is essentially a suspension injection containing drug-loaded microparticles. The therapeutic drug is dispersed in HCO, and the two constitute drug-loaded microparticles. Due to the strong hydrophobicity and slow biodegradability of HCO, the injection prepared with the HCO drug-loaded microparticles has a good sustained-release effect and does not have Permanent residue, the drug-loaded microparticles have good biocompatibility and little irritation to the injection site.

 In order to achieve a certain sustained-release effect and better stability and better biocompatibility, in addition to requiring strict control of the composition and particle size of the drug-loaded microparticles, the liquid dispersion medium used as a component of the formulation also affects the formulation. The sustained-release effect, stability, and biocompatibility have a great impact. If the liquid dispersion medium is not selected properly, the drug in the drug-loaded microparticles may be dissolved or partially dissolved. This has a great impact on the sustained-release effect and may also It can lead to drug delamination and even disintegration of drug-loaded particles. Therefore, when using HCO drug-loaded microparticles to prepare sustained-release injections, the selection of a suitable liquid dispersion medium is also important to ensure the stability, clinical effect, and biocompatibility of the formulation. The present invention particularly preferably uses water or 1,2-propanediol as the main dispersion medium of the preparation. The prepared preparation has good biocompatibility, stable physical and chemical properties, and good sustained-release effect. The agent is injected subcutaneously, and is used once. Up to 50-90 days or longer.

 The key technologies for preparing sustained-release injections containing HCO drug-loaded particles are as follows:

 (1) Adjust the sustained-release effect of the preparation by adjusting the ratio of HCO to the drug in the drug-loaded microparticles.

(2) Controlling the maintenance time of the drug effect by changing the dosage. (3) By adjusting the ratio of HCO to the drug, while ensuring the desired sustained-release effect, the specific gravity of the drug-loaded microparticles is as close as possible to the specific gravity of the liquid medium, which helps maintain the stability of the preparation.

 (4) By adjusting the specific gravity of the medium to be close to the specific gravity of the drug-loaded microparticles, the stability of the preparation can still be ensured under the condition that less suspending agent is added. The specific gravity of the preparation medium can be adjusted by adding an appropriate amount of organic substances, such as adding a smaller specific gravity of ethanol or dimethylacetamide, or adding a larger specific gravity of 1, 2-propanediol, glycerol, acetal glycerol, or triple pear Alcohol and so on.

Summary of the Invention

 The preparation composition of the present invention is as follows:

 a. Active ingredient / hydrophobic carrier material solid dispersion particles;

 b. Liquid dispersion medium;

 c. Other auxiliaries can be added to the preparation, including surfactants, suspending agents, antioxidants and local pain relief agents;

 d. Other anthelmintics can also be added to form compound preparations.

 The preparation method of the preparation of the present invention is as follows:

Method (1 Mixing a low-boiling organic solvent or a micronized active compound (such as a macrolide insect repellent or N-phenylpyrazole insect repellent) with the melted HCO, and stir Then, quickly lower the temperature to below 45 ° C to solidify, and then naturally dry or dry under reduced pressure, remove the solvent, and pulverize the obtained active ingredient I HCO solid dispersion to less than 250 μm to obtain the active ingredient / solid dispersion particles ( Drug-loaded microparticles); quantitatively take the drug-loaded microparticles prepared above, add non-ionic surfactants, and add an appropriate amount of water to prepare a viscous After the thick liquid, colloid mill is used to further grind the fineness of the drug-loaded particles to less than 100 μm, and then add water-soluble antioxidants, preservatives and water for injection to the final volume.

 Method (2): Supersaturated active ingredient solution (with or without suspending agent) or a solution containing a high concentration of anti-parasite drugs (with or without suspending agent) or micronized active ingredient with melted or Dissolved HCO or other hydrophobic carrier materials are mixed uniformly, with or without non-ionic surfactants, and then controlled at a certain temperature, mixed with water or other liquids with poor ability to dissolve active ingredients under stirring conditions, and the solids in the system will be dispersed. After the body is formed, grind, add the remaining medium, and if necessary, add other additives (such as non-ionic surfactants, suspending agents, antioxidants, etc.) to obtain the active dispersion / hydrophobic carrier material solid dispersion. Release injection. Or, the solid body in the system is separated, dried, and pulverized, and then a liquid medium is added to disperse and homogenize to obtain a suspension injection.

 The antiparasitic drugs or active ingredients include antiprotozoal drugs, antihelmintic drugs and antiparasitic drugs; preferably macrolide insect repellents (Avermectin abamitin, Ivermectin ivermectin, Emma Emamectin, eprinomectin, doramectin, moxidectin), salicylanilide antiparasitic drugs (preferably chlorocyanamide and its sodium salt), organic monument antiparasitic Insecticides, tetraimidazoles (such as levamisole), N-phenylpyrazole insect repellents (such as fipronil), insect growth regulators (such as fenprobenil, cyclopromazine), and triazines (Such as Diclazuril, Baiqiuqing).

The hydrophobic carrier material includes animal wax, vegetable wax, alkane compounds in a solid state below 45 ° C, fatty acids or fatty acid ester compounds in a solid state below 45 ° C, and Esters of mono- or polyhydric alcohols, hydrogen Chemical vegetable oil, rosin and its derivatives, ethyl cellulose, polyethylene, polyvinyl butyral; hydrogenated castor oil (HCO), Brazilian wax, ethyl cellulose, rosin pentaerythritol ester, etc. are preferred Rosin esters, which can be used in combination of two or more.

 The liquid dispersion medium or the solvent for preparing a supersaturated solution of the active ingredient or the liquid having poor solubility to the active ingredient includes: water, a hydrophilic organic liquid, and an ester compound; preferably water, 1, 2-propanediol, and polyethylene Alcohol, glycerol, acetal glycerol, dimethylacetamide, N-methylpyrrolidone, benzyl benzoate, triacetin. The low-boiling organic solvents are acetone, ethyl acetate, ethanol, and the like. During the preparation of the preparation, the above-mentioned hydrophilic organic liquid medium is used in combination with water to obtain better results.

 The nonionic surfactant is a pharmaceutically usable nonionic surfactant; polyoxyethylene sorbitan fatty acid ester (Tween series), sorbitan fatty acid ester (Span series), and castor oil polymer are preferred. Oxyethylene ether (EL series); they can be used alone or in combination. Especially choose Span, Tween series emulsifiers.

 The suspending agent is preferably carboxyfluorenyl cellulose (sodium), fluorenyl cellulose, xanthan gum, polyvinylpyrrolidone. Polyethylene glycol, sodium alginate, propylene glycol sodium alginate, etc. with a molecular weight greater than 1000. These suspending agents are well known in the art.

HCO has good "affinity" with hydrophobic antiparasitic drugs such as ivermectin (IVM for short). Therefore, the present invention specifically selects HCO as a solid dispersion medium to prepare solid dispersion particles containing antiparasitic drugs. The content of antiparasitic drugs in the range of 5-90% (W / W) and HCO content of 10-95% (W / W); the antiparasitic drugs constituting the solid dispersion particles may be one or more than one; OK in HCO solid dispersion particles Add ethyl cellulose or rosin pentaerythritol ester;

The HCO solid dispersion particles are combined into a compound sustained-release preparation.

 The preferred formulation composition and preparation method of the present invention are:

 Formulation A: Sustained-release injection containing ivermectin / HCO drug-loaded microparticles

 (1) Preparation composition:

 a, IVM 0.5-10% (W / V)

 b, HCO 1-25% (WV)

 c. Polyvinylpyrrolidone 0-10% (WV)

 d. Difluorenylacetamide or N-fluorenyl-pyrrolidone or 1, 2-propanediol or acetal glycidyl or two or more in combination 5-30% (V / V)

 e. Phenyl alcohol 1% (V / V)

 f, water or water / glycerin and additives to 100% (V / V)

 (2) Preparation method: IVM and polyvinylpyrrolidone (with or without addition) are heated and dissolved with 1,2-propanediol or other solvents, and then mixed with the melted HCO, added with water and ground, and after being shielded, the remaining medium and Additive to final volume.

 Formulation B: slow-release injection containing IVM / HCO drug-loaded microparticles

 (1) Composition of preparation:

a, IVM 0.5-5% (W / V) b, HCO 1-15% (W / V) c, non-ionic surfactant 5-20% (V / V) d, 1, 2-propanediol or glycerin Alcohol 0-30% (VV) e. Water-soluble antioxidant 0.1-0.5% (W / V) f. Phenyl alcohol 1-2% (V / V)

 g, water to 100% (V / V)

(2) Preparation method: Take IVM plus 2 times of ethyl acetate to heat and dissolve, mix thoroughly with the melted HCO, quickly cool to below 40 ° C, and solidify the IVM and HCO into a solid dispersion, dry or reduce it naturally Press to dry, remove ethyl acetate, and pulverize the obtained IVM / HCO solid dispersion into particles below 250 μm to obtain the fine powder of IVM / HCO solid dispersion; take the fine powder of IVM / HCO solid dispersion and add non-ionic surfactant Wetting, adding colloid mill after adding water, grinding to IVM I HCO coagulation: the particle size is less than 150 μηι, adding water to the final volume to obtain a sustained-release injection containing IVM / HCO solid dispersion particles.

 Formulation C: Sustained-release injection of fipronil / HCO drug-loaded microparticles

 Preparation method (1): take fipronil and dissolve it with acetone, add it to an aqueous solution with or without PVP under stirring conditions to rapidly crystallize, centrifuge or filter, remove water / acetone, and obtain the fipronil ^ The powder is dispersed in the melted HCO. When it is cooled to semi-solidified, it is ground with water, and then (or without) non-ionic surfactant, and the remaining medium is added to the final volume, so that the micronized powder containing fipronil is obtained. Release injection.

 Preparation method (2): Dissolve fipronil with a small amount of an injectable solvent to make a supersaturated solution or a high-concentration solution, and then mix it with the melted HCO uniformly. Then, under the conditions of controlling temperature and stirring speed, Mix with water to solidify, grind, homogenize, add (or not) non-ionic surfactants, and add the remaining medium to the final volume.

Preparation method (3): Dissolve fipronil with a solvent having a boiling point of less than 100 ° C (such as acetone) to prepare a supersaturated solution, and then mix it with the melted HCO and mix, and cool under stirring. However, it is solidified to obtain a fipronil / HCO solid dispersion, which is naturally dried or pulverized after drying under reduced pressure to obtain fine particles of fipronil / HCO solid dispersion. The solid dispersion fine powder is taken and dispersed in a medium to obtain Sustained-release injection containing micronized fipronil / HCO solid dispersion.

 The particularly preferred formulation composition and preparation method of the present invention are:

 Formulation A: Sustained-release injection containing 2-10% IVM 16-20% HCO drug-loaded microparticles (1)

 a, IVM 2-10% (W / V)

 b, HCO 6-20% (WV)

 c. Dimethylacetamide or 1,2-propanediol or formalin or glycidol 5-30 (V / V)

 d, benzyl alcohol 1% (V / V)

 e. Sodium thiosulfate 0.2-0.4% (WA

 f. Glycerol 0-10% (VV)

 g, water and additives to 100% (V / V)

 (2) Preparation method: Dissolve IVM with diamidoacetamide or 1,2-propanediol or other solvents, and then mix with the melted HCO, mix and grind with glycerin and water (through colloid mill or use other milling methods) ), After homogenization, add water and additives to the final volume.

Formulation B: Sustained-release injection containing fipronil / HCO drug-loaded microparticles, the preparation method is to use fipronil 1-3 times the solvent (acetone, ethanol, 1, 2-propanediol, acetaldehyde glycerol, difluorene Acetacetamide or N-fluorenyl-pyrrolidone) is dissolved, mixed with the melted HCO uniformly, and then under the conditions of controlled temperature and stirring speed, mixed with water to solidify, grind, homogenize, add the remaining medium and Additive to final volume. The slow-release preparation containing the antiparasitic drug according to the present invention is injectable or oral, and is used to prevent and treat animal parasitic diseases. The subcutaneous injection is selected, and the dosage is 0.4-4 mg (macrolide deworming drug). ) / Per kilogram of body weight, the suitable dosage is: 0.7-1.5mg macrolide insect repellent per kilogram of body weight.

detailed description

 The following describes the preparation of the present invention with examples, but the examples do not limit the scope of the present invention, and the scope and core content of the present invention are determined according to the claims.

 Example 1.

 (1) Take 100glVM and 0.5g BHT / BHA, add 170ml ethyl acetate, dissolve it under reflux, and then add it to 200g of melted HCO. Under stirring conditions, quickly cool down and solidify to obtain HCO / IVM solid dispersion. body.

 (2) The HCO / IVM solid dispersion prepared above is dried under reduced pressure and pulverized to 150 μm or less to obtain HCO / IVM (2: 1) solid dispersion particles.

 (3) Quantitatively weigh 300 g of HCO / IVM (2: 1) solid dispersion particles, add 350 g of Tween-80 and 350 g of Span-80, mix well and add 1-1.5 L of water for injection, mix well, pass colloid mill to obtain milk Paste.

 (4) Add an aqueous solution containing sodium thiosulfate and trichloro-tert-butyl alcohol to 4L to the prepared paste to obtain a sustained-release injection containing 2.5% IVM.

 The above operations should be performed under sterile conditions, and the reagents and drugs used should meet the requirements for the preparation of injection solutions.

Example 2. Preparation of a sustained-release injection containing 7% IVM / 14% HCO solid particles. Take 1 kg of IVM and 2 kg of HCO, and heat with dimethylacetamide or 1,2-propanediol to 95. C is dissolved. When the temperature of the solution drops to room temperature and solidifies, 6 L of water is poured into the mouth, ground, and then Tween-80 and Span-80 are added, ground and stirred for 2-4 hours, and then water is added to the final volume. You can also add emulsifier first, then add water, stir and homogenize, and then add the remaining medium to the final volume.

 Example 3. Preparation of a sustained-release injection containing 5% IVM and 15% HCO solid particles. Take lkglVM, add 1,2-propanediol, and dissolve it at 90 ° C. Add 1 kg of HCO. After thawing, add water and glycerol at room temperature when it just solidifies. Triacetate, grind, then add Tween-80 and Span-80, stir for 2-4 hours and add water to the final volume.

 Example 4: Preparation of a sustained-release injection containing 3% IVM / 6% HCO solid particles. Take 1 kg of IVM which has been ultra-pulverized (less than 2 μιη), and add it to a 2 kg HCO solution that has been cooled to about 60 ° C. Add 1 L of 1,2-propanediol / water (1: 1) solution, grind, add OP-10, add water to the final volume.

 Example 5.Preparation of a sustained-release injection containing 6% IVM, 16% EC-6% HCO

 Take IVM3g, EC (RT10) 3g, add 10ml diamidoacetamide, heat to dissolve, add 3g HCO, melt and homogenize, add 20ml water, grind, homogenize, add a certain amount of glycerin or a certain amount of OP-10, add water to the final volume.

 Example 6.Preparation of Sustaining-release Injection

 Take 2 g of fenapyl urea, add 2 ml of difluorenylacetamide, heat to dissolve, add 2 ml of OP-10, add 1 g of HCO, and add 15 ml of water after melting.

 Example 7.Preparation of Sustaining-release Injection

Take lgHCO, add 2 ml of OP-10, heat and melt, then add 2 g of fenfluril fine powder, homogenize, add 10 ml of water, homogenize to obtain. Example 8. Preparation of a sustained-release injection containing 7% IVM 1 14% HCO solid particles. Take 3.5 kg of IVM, dissolve it with 6 L of aldol and heat it to 90 ° C, and mix with 7 kg of melted HCO. Mix in cold water, grind, and add 10 L of 1,2-propanediol solution containing 0.5 L of stupid methanol and 1.5 kg of PVP to obtain it.

 Example 9.Preparation of suspension injection containing HCO / IVM drug-loaded microparticles using triacetin

 Take HCO I IVM (0.5: 1) solid dispersion fine powder, add 3-6 times (weight / volume ratio) glycerol triacetate and 5-20% ethanol / water (2: 1) The solution is prepared as a suspension injection. This preparation is used for the prevention and treatment of animal parasitic diseases, and the subcutaneous injection dose is 1-2 mg IVM / kg body weight. The duration of effect is more than 60 days.

 Example 10.Sustained-release injection containing 10% IVM

 Take 1 g IVM, 1.5 g hydrogenated castor oil, 1 ml dimethylacetamide, dissolve (melt) at 90 °, add 1 ml glycerol, 3 ml water, grind, add 0.3 g PVP K-30, 0.2 ml Tween -80 and 2ml of water.

 Example 11. Sustained-release injection containing 2% avermectin (AVM)

 Take avermectin, add diamidoacetamide to dissolve, then add HCO, melt, pour into water to solidify, filter, and take the solid to obtain a solid body containing AVM / HCO (1: 1), add 1,2-propanediol, ground with a colloid mill, homogenized so that the fineness of the solid dispersion is less than 100 μιη, and then added 1,2-propanediol and water for injection (about 10% of the final volume) to the final volume.

Example 12. Preparation of a sustained-release injection containing 5% IVM 1 15% HCO Take 5g of IVM, add 10ml of dimethylacetamide and 1ml of phenethyl alcohol, stir to dissolve IVM, add 15g of melted HCO and mix well, mix with 30-40ml of water for injection under stirring, grind, homogenize, Add 10-20 ml of glycerol and an aqueous solution containing 0.3 g of sodium thiosulfate and 3 g of polyvinylpyrrolidone to the final volume.

 Example 13. The preparation of Example 12 was used for the control of nematodes and pruritus in sheep. Select 200 sheep that are naturally infected with nematodes and itch mites, of which 20 are control sheep, and the remaining groups are 60 sheep. Group 1 was injected with the preparation of 1ml / 50kgb.w. Example 12; group 2 was injected with 2ml / 50kg bw The preparation of Example 12; the third group was injected with conventional 1% ivermectin injection 5ml / 50kg, and the above four groups of experimental sheep were mixed and fed.

 Experimental results: (1) The above three groups of drug-treated sheep did not bite on the first 3-5 days after administration, and new hairs appeared on the affected area in about 10-20 days. None of the control groups recovered. (2) Five sheep from each group were dissected on the 20th day after the administration, and the larvae and adults of Haemonchus nematode, Osterema, round-shaped nematode, Cooperia nematode, hairy head nematode, and larvae parasited in the gastrointestinal tract were examined The results showed that the total number of five nematodes detected in the control group was 1483 per / 5 sheep, and no worms were detected in the treatment group. (3) In the drug control group (Group 3), 8 sheep had bitten on the 31st day, and 37 sheep had bitten on the 50th day, and live mites were detected by microscopy; No biting occurred and no live mites were detected; in the first group, four sheep had bites and the live mites were detected on the 55th day; the second group had four sheep had bites and the live mites were detected on the 85th day; It can be seen that a) the preparation of Example 9 has a good sustained-release effect; b) with the increase of the dosage, the holding period is prolonged. (4) On the 95th day, 10 sheep were dissected from each group, and worms were detected in the control group and the third group. The average number of worms was 272 per sheep, and neither group 1 nor group 2 was detected. Nematode body.

Example 14 Blood samples were taken from the sheep in the medication group of Example 13 on the 1st, 2nd, 3rd, 4th, 5th, 6th, 20th, 40th, 60th, 80th, 95th, and 110th days after the administration, and the ivermectin content in the plasma was analyzed. Three sheep. The experimental results show that the peak blood drug time in the medication group is 2-6 days, and the peak blood drug concentrations are 19-23ng / ml in the first group, 24-30ng / ml in the second group, and 85-94ng in the third group. On day 40, the blood concentration of group 1 dropped to 2-4 ng / ml, and the blood concentration of group 3 fell below 1 ng / ml; on day 60, the blood concentration of group 1 decreased to 2 ng / ml. In the following, the blood concentration of the third group dropped to below 0.3 ng / ml, while the blood concentration of the second group was about 5 ng / ml, and the blood concentration on the 95th day remained at 2-3 ng / ml.

Claims

Rights request 1. A sustained-release injection containing an antiparasitic drug for veterinary use, characterized in that the antiparasitic drug in the preparation exists in the form of a solid dispersion particle with a hydrophobic carrier material. The antiparasitic drugs include antiprotozoal drugs, antihelminth drugs and antiparasitic drugs; the hydrophobic carrier materials include animal waxes, vegetable waxes, fatty acid ester compounds in a solid state below 45 ° C, 45 Ester compounds, rosin and its derivatives, and ethyl cellulose synthesized from monohydric or polyhydric alcohols in a solid state below ° C.  2. The sustained-release injection according to claim 1, characterized in that:  (1), the antiparasitic drug is preferably a macrolide insect repellent (avermectin abamectin, ivermectin ivermectin, emamectin, eprinomectiru, doramectin, Moxidectin), 7j aniline antiparasitic drugs (preferably cyhalidisalamide and its sodium salt), organophosphorus antiparasitic drugs, tetraimidazole anthelmintic drugs (such as levamisole), N -Phenylpyrazole insect repellents (such as fipronil), insect growth regulators (such as fenprofen, cypromazine), triazines (such as diclazuril, hundred balls) clear).  (2) The hydrophobic carrier material is selected from Hydrogenated Castor Oil (HCO), Brazilian wax, ethyl cellulose, rosin pentaerythritol ester, etc., and they can be used in combination of one or more.  3. The sustained-release injection according to claim 1 and 2, characterized in that: (1) HCO is specifically selected as the solid dispersion medium for preparing solid dispersion microparticles containing antiparasitic drugs, and the content of antiparasitic drugs constituting the microparticles is 5-90% (W / W), HCO content is 10-95% (W / W).  (2) The antiparasitic drugs constituting the solid particles of the solid particles may be one or more than one.  (3) Ethyl cellulose or rosin pentaerythritol ester can be added to the solid dispersion particles containing HCO.  (4) Compound HCO solid dispersion particles containing different antiparasitic drugs can be combined into a compound sustained-release preparation.  (5) There may still be partially dissolved or micronized antiparasitic drugs in the preparation.  4. The method according to claims 1-3, characterized in that the selected formulation composition and preparation method are:  (1) Preparation composition:  a. Solid dispersion particles composed of antiparasitic drugs and HCO or solid dispersion particles composed of antiparasitic drugs with HCO and other hydrophobic carrier materials; b. Water and hydrophilic organic liquid dispersion medium or hydrophobic Liquid medium; c. Other auxiliaries can be added to the preparation, including antioxidants, local pain reducing agents, surface active agents  Sex agents, suspending agents and other stabilizers;  d. Other anthelmintics can also be added to form compound preparations.  (2) The preparation method is preferably the following two methods: Method a: Dissolve a low-boiling organic solvent or a micronized anti-parasite drug, such as a macrolide insect repellent or an N-phenylpyrazole insect repellent, with the melted HCO Mix well, or dissolve or melt the active ingredients and HOC with a low-boiling organic solvent. Under stirring conditions, lower the temperature to below 45 ° C to solidify, and then dry naturally or under reduced pressure. Remove the solvent and remove the solvent. The anti-parasitic drug / HCO solid dispersion is pulverized to a fineness of less than 250 μιη to obtain anti-parasitic drug / HCO solid dispersion particles (drug-loaded particles); the drug-loaded particles prepared above are quantitatively taken with or without non-ion Surfactant, add a small amount of water or other liquids, prepare a viscous liquid, and then grind (such as colloid mill) to make the fineness of the drug-loaded particles less than 150 μιη, and then add antioxidants, preservatives, and local pain relief agents And water for injection or other liquid dispersion medium and auxiliary to the final volume. Or pulverize the dry antiparasitic drug / HCO solid dispersion to a fineness of less than 100 μm, and then disperse it in a liquid dispersion medium and an auxiliary agent, and homogenize to obtain. Method b: Mix the solution or supersaturated solution containing antiparasitic drugs or the micropowder of antiparasitic drugs with melted or dissolved HCO or other hydrophobic carrier materials uniformly, with or without non-ionic surfactants, and control a certain temperature, When mixed with water or other antiparasitic drugs and liquids with poor HCO solubility under stirring conditions, the antiparasitic drugs will aggregate with HCO or with other hydrophobic carrier materials to form solid dispersion particles. The obtained solid dispersion was further prepared into a formulation by the following three routes. (A): homogenize the liquid containing the solid dispersion particles described above, so that the fineness of the solid dispersion particles is less than 150 μηι, and then add the remaining medium and auxiliary agent; The liquid is filtered or centrifuged. The obtained solid is added to the liquid dispersion medium and ground. When the fineness of the solid is less than 150 μm, the dispersion medium and auxiliary are added to the final volume to obtain a suspension injection. (C): drying the obtained solid, pulverizing it to less than 150 μηι, adding it to a liquid dispersion medium and an auxiliary, homogenizing, and preparing a suspension injection. 5. The preparation according to claim 4, characterized in that:  (1), the hydrophilic or hydrophobic liquid dispersion medium, or a solvent for preparing a solution or a supersaturated solution containing an anti-parasite drug, or a liquid medium having a poor ability to dissolve an anti-parasite drug includes: water, 1, 2-propanediol, polyethylene glycol, glycerol, acetal glycerol and its homologs, dimethylacetamide, N-fluorenylpyrrolidone, benzyl benzoate, triacetin, synthetic or Fatty acid ester compounds extracted from plants.  (2) The low-boiling organic solvent is: ethanol, acetone, ethyl acetate, dichloromethane or trichloromethane.  During the preparation of the formulation, the above liquid dispersion medium or solvent may be used in combination of two or more.  (3) The suspending agent and other stabilizers are pharmaceutically acceptable suspending agents and other stabilizers; preferred suspending agents and other stabilizers include: fluorenyl cellulose, carboxymethyl cellulose and Sodium salt, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium alginate, propylene glycol sodium alginate, sodium polyacrylate, sorbitol, mannitol, sodium metabolite, polyvinylpyrrolidone, polyvinyl alcohol, molecular weight greater than 1000 Polyethylene glycol, xanthan gum.  (4) The surfactant is a pharmaceutically usable nonionic surfactant; preferred nonionic surfactants include: glycerin fatty acid ester, polyglycerol fatty acid ester, sucrose ester, sorbitan higher fat Acid ester Span, polyoxyethylene desorbide higher fatty acid ester condensate Tween, polyoxyethylammonium higher fatty acid condensate Myrjs, polyoxyethylene and higher fatty alcohol condensate Brijs, pingpingjia Pargal, emulsifier OP, Polyoxyethylene castor oil condensate, polyoxyethylene hydrogenated castor oil condensate, Pluronic Pluronic. (5), the local pain reducing agent is preferably phenethyl alcohol, trichloro-tert-butyl alcohol, proca Caffeine, tetracaine or lidocaine.  (6) The antioxidant is a water-soluble antioxidant or an oil-soluble antioxidant; preferably, an antioxidant containing a gram element is used.  6. Particularly preferred is one or more of 1, 2-propanediol, glycerol, acetal glycidol, difluorenylacetamide or N-fluorenylpyrrolidone in a certain volume ratio or weight with water. The ratio combination is used to prepare the formulation according to claim 4; a solid dispersion microparticle composed of a macrolide insect repellent or an N-phenylpyrazole insect repellent and HCO is particularly selected and dispersed in the above-mentioned In a biocompatible liquid medium, a sustained-release injection is prepared.  7. The method according to claims 1-6, characterized in that the preferred formulation composition and preparation method are as follows:  Formulation A: Ivermectin / HCO-loaded drug ^: sustained release injection of granules  (1) Composition:  a, Ivermectin 0.5-10% (W / V) b, HCO 1-25% (W / V) c, dimethylacetamide or N-methyl-pyrrolidone or 1, 2-propanediol or formaldehyde Glycerin or more than one combination of 5-30% (V / V)  d, Phenyl alcohol 1% (V / V) f, water and additives or water and glycerol and additives to 100% (V / V) (2) Preparation method: Dissolve ivermectin and polyvinylpyrrolidone (with or without addition) with 1, 2-propanediol or dimethylacetamide or other solvents, and then mix with the melted HCO, add water or add glycerin and After water, grind and homogenize, add the remaining medium And additives to final volume.  Formulation B: Sustained-release injection containing ivermectin / HCO drug-loaded microparticles  (1) Composition:  a. Ivermectin (IVM) 0.5-5% (W / V)  b, HCO 1-15% (W / V)  c. Nonionic surfactant 5-20% (V / V)  d, 1, 2-propanediol or glycerol 0-30% (V / V)  e. Water-soluble antioxidants 0.1-0.5% (W / V)  f, Phenyl alcohol 1-2% (V / V)  g, water up to 100% (V / V)  (2) Preparation method: Take 2 times of IVM plus ethyl acetate to dissolve it, mix thoroughly with the melted HCO, quickly cool it to below 40 ° C, solidify the IVM and HCO into a solid dispersion, dry naturally or reduce the pressure Dry, remove ethyl acetate, and pulverize the obtained IVM / HCO solid dispersion into particles less than 250 μηι to obtain IVM I HCO solid dispersion fine powder; take the IVM / HCO solid dispersion fine powder, and infiltrate with nonionic surfactant After adding water, the colloid mill was used to grind the fineness of IVM I HCO particles to less than 100 μτη, and drool and suspending agent were added to the final volume to obtain a sustained-release injection containing IVM I HCO solid dispersion particles. If necessary, add a small amount of 1,2-propanediol or glycerol.  Formulation C: Fipronil / HCO-loaded drug ^ A granule sustained-release injection, there are three preferred methods of preparation: Method (1): Disperse fipronil in melted HCO. When it is cooled to semi-solidified, grind it with water, then add or not add non-ionic surfactant, add the remaining medium and suspension To the final volume to obtain a sustained release injection containing fipronil.  Method (2): Dissolve fipronil with a small amount of an injectable solvent to make a supersaturated solution or a high-concentration solution, mix it with the melted HCO, and then control the temperature and the stirring speed. Mix with water to solidify, grind, homogenize, add or not add non-ionic surfactants, add remaining medium and suspending agent to final volume.  Method (3): Prepare a supersaturated solution by dissolving fipronil with a solvent having a boiling point of less than 100 ° C (such as acetone), and then mix it with the melted HCO, and then cool it under stirring to solidify it. The HCO solid dispersion can be pulverized after natural drying or drying under reduced pressure to obtain fine particles of fipronil / HCO solid dispersion. Take the solid dispersion fine powder, disperse it in a liquid medium, and homogenize to obtain fipronil / Sustained-release injection of HCO solid dispersion particles.  8. The preparation according to claim 7, characterized in that a particularly preferred preparation composition and preparation method are:  (1) Preparation composition:  a, Ivermectin 2-10% (W / V)  b. Hydrogenated castor oil (HCO) 3-16% (W / V)  c. Difluorenylacetamide or 1,2-propanediol or acetal glycidol or a combination of 3-30 (V / V)  d. Phenyl alcohol 1% (V / V)  e. Shike sodium ketosodium 0.2-0.4% (W / V)  f. Glycerol 0-30% (VV) g. Water for injection and auxiliaries are added to 100% (VV) (2) Preparation method: Dissolving ivermectin with dimethylacetamide or other solvents, and then mixing with the melted HCO, mixing with glycerol and water for injection, grinding, homogenizing, adding ^ < Sodium thiosulfate water for injection and adjuvant to final volume.  9. The method according to claim 4 and 5, characterized in that the preferred formulation composition and preparation method are:  (1) Composition of preparation:  a. Avermectin / HCO (1: 1) solid dispersion 7-14% (W / V) b. Water for injection 10-20% (V / V)  c. Phenyl alcohol 1% (V / V)  d. Sodium thiosulfate 0.3% (W / V)  e, 1, 2-propanediol to 100% (V / V)  (2) Preparation method:  Take the micronized avermectin / HCO solid dispersion, add an appropriate amount of 1, 2-propanediol to prepare a thick liquid, colloid mill, grind to a paste, add the remaining dispersion medium and additives, and mix to obtain.  10. The preparation according to claim 8 and 9, characterized in that the preparation is either injectable or orally, and is used to prevent and treat animal parasitic diseases. Subcutaneous injection is selected, and the dosage is 0.4-4 mg per kg of body weight. (Active ingredient), the suitable dosage is 0.7-2mg ivermectin or avermectin / kg body weight, once used, the control period can be maintained for 50-90 days or longer.