WO2003086469A1

WO2003086469A1 - Ethyl cellulose-containing veterinary sustained release injection

Info

Publication number: WO2003086469A1
Application number: PCT/CN2003/000202
Authority: WO
Inventors: Yuwan Wang; Zhende Pan; Xiaoxi Dai; Yan Xue
Original assignee: Eco Animal Health Ltd
Priority date: 2002-03-19
Filing date: 2003-03-19
Publication date: 2003-10-23
Also published as: AU2003227165A1; CN1444925A

Abstract

A veterinary sustained release injection comprises of ethyl cellulose (EC) and therapeutical drugs. The injection characterizes that EC doesn't disperse in form of drug-loading particles, such as microspheres or microcapsules present in the medium of the injection, but dissolves or swells in the medium. When it contacts with water or fluid, hydrophorbic drug present in it combines with EC to form semisolid mass. Thus, the diffusion of active ingredients is limited to achieve sustained release. The present formulation is suitable for subcutaneous injection with slow release in a long period.

Description

Veterinary long-acting injection preparation containing ethyl cellulose TECHNICAL FIELD

The present invention provides a veterinary sustained-release injection, consisting of ethyl cellulose (EC) and a therapeutic drug. Background technique

Our experiments show that when using ethyl cellulose with other hydrophobic media or with a hydrophilic solvent that dissolves ethyl cellulose to prepare a formulation carrier containing injections containing certain therapeutic drugs, it has clinically exhibited unexpected long growth. Time activity. Therefore, the subject matter of the present invention is to describe the preparation of veterinary sustained-release injections using ethyl cellulose as the main body, and the present invention will explain the related therapeutic drugs and other ingredients of the formulation, as well as possible principles.

The ethyl cellulose (EC celose) used in the present invention is a commercially available product and has been described in detail in the relevant literature (ed. Zheng Junmin, Medical Polymer Materials Science, China Medical Science and Technology Press, 2000 Years, pp. 108-110). In pharmaceutical preparations, EC is mainly used to form solid dispersions with a sustained release effect, and is used to prepare oral solid preparations. In recent years, people have used EC as a sustained release embedding material to prepare drug-containing particles (microspheres or microspheres). ) For the preparation of sustained (controlled) release injections, the preparation method is as follows: the drug is embedded or dispersed with EC to make drug-containing particles (less than 20 μιη), and the drug-containing particles are dispersed in a liquid medium shield as injections (Goshen editor, modern new dosage forms of new technology, people's Medical Publishing House, ^{^2002,} p. 85; PING can wait, modern Pharmacy, China Medical Science and technology Publishing House, 1998, 625, 655 Pages; Edited by Lu Bin, New Drug Dosage Forms and Technologies Surgery, People's Medical Publishing House, 1998, 169, 254, 307, 521; Liao Gongtie, editor, targeted drug preparation, Sichuan Science and Technology Press, 1997, pp. 153-156). Summary of the Invention

Instead of preparing the active ingredient and EC into drug-loaded microparticles (microspheres or microspheres), the preparation of the present invention uniformly mixes the active ingredient and EC in the liquid medium constituting the preparation. The EC in the preparation exists in a dissolved or swollen state. The active ingredient may be in a dissolved state or present in a solid particulate state (particle size less than 50 μm). When the formulation is exposed to water (in vitro test) or body fluid (injected into the body), the lipophilic active ingredients, EC and hydrophobic medium are "wrapped" together to form one or several "lumps" of varying sizes with greater viscosity. Therefore, the "contact area" of the active ingredient with water or body fluid is significantly reduced, and the release of the active ingredient is "certainly limited" due to the hydrophobicity of the "clumps" and the semi-curing or curing effect, thereby achieving the Purpose of active ingredients slowing.

The EC-containing sustained-release injections of the present invention may further include animal and plant waxes such as beeswax and carnauba wax, hydrogenated vegetable oils, and glycerin fatty acid ester compounds in a solid state at normal temperature. Under certain conditions, their presence can partially limit the curing of the EC and ensure that the drug is released at a more "effective" rate.

In summary, the injection of the present invention disperses the active ingredient in a medium containing EC in a dissolved or swollen state, and the formulation is subjected to a "drug embedding" process (formation of a semi-cured or cured hydrophobic "mass after injection into the body tissues). Block "), which is one of the outstanding features of the present invention.

The clinical characteristics of the preparation of the invention are: the sustained (controlled) release effect is significant, such as containing 15% Awei The preparation of bacteriocin of the present invention (see Example 1), with a single injection, the duration of effect can be up to 80-120 days. In certain media, when the EC content and drug concentration are increased to a certain level, the retention period can reach 2QQ days or longer.

The therapeutic drugs (active ingredients) involved in the present invention are all commercially available drugs, which are described in some drug books and related patents. The therapeutic drugs involved in the present invention include those water-insoluble or slightly water-soluble antiparasitic drugs, antibacterial drugs, growth-promoting drugs, and non-steroidal anti-inflammatory drugs (NASIDS). .

Specifically, antiparasitic drugs refer to those water-insoluble or slightly soluble anti-helminthic drugs, anti-ectoparasite drugs, and antiprotozoal drugs (Zhang Zhongqiu, Zheng Ming, editor, Handbook of Animal and Poultry Drugs, China Agricultural University Press, 2000, pp. 86-129). Several drugs with wide applications and great economic value are particularly preferred for use in the preparations of the present invention, which include: macrolide insect repellents (avermectin abamectin, ivermectin ivermectin doramectiru mo Oxysporine moxidectin, eprinomectiru (emamectin), salicylanilides (closantel, cysalamide, rafoxanide), benzimidazoles (prosomidin) albendazole, propionite, albendazole oxide, netobimin, fenben ¹⁷ da " ¹ fenbendazole, offen ¹ ¾ ^p oxfendazole, trichlorobenda trilabendazole), four flavor sitting equine insecticide levamisole), substituted p-benzyl methyl derivatives (^ imidacloprid), ^p- quinidine and praziquantels, insect growth regulators (triflumuron, tr if lumuron, diflubenzuron, dif lubenzuron, H-exhausted urea lufenuron, women and insects face methoprene, phenoxycarb ^ b ^v A f pyr iproxyfen, cyromazine), N-phenylpyrazoles (fipronil f iproni l), organophosphorus drugs (dichlorvos dichlorvos, dichlorvos tr ichlorphon ^ harosezon haloxon, chlorpyr ifos, napthalophos> phosim phoxim, bisthion fenthion, malathion malathion, dermatid brick ronneK worm poison cobblestone coumaphos).

The growth-promoting drugs are mainly zearalenone and sex hormones (estrogens, progestins, and androgens); progesterone, estradiol phenylacetate, and nortriandenone acetate are preferred.

Non-steroidal anti-inflammatory drugs are described in some pharmacological monographs, medicinal manuals, and other books (Wen Wensheng, edited by Li Anliang, Medicinal Chemistry, Higher Education Press, 1999, pages 348-375), including antipyretic Analgesics, anti-inflammatory drugs, such as salicylic acid, pyrazolone, arylalkanoic acid, acetic acid, benzothiazine and so on. These anti-inflammatory drugs can inhibit cyclooxygenase (C0X ), Thereby interfering with the biosynthesis of prostaglandins to function, therefore, the present invention also includes COX-2 inhibitors. Included in the present invention are those non-steroidal anti-inflammatory drugs that are water-insoluble or slightly water-soluble or can be chemically modified to be water-insoluble. Anti-inflammatory drugs that are preferably used in the preparations of the invention include indomethacin indomethacin, ketoprofen ketoprof en, meloxican meloxican, naproxeru naproxeru caproprofen caprofen, panolac ketorolac, flunixin f lunixin, diclofenac diclofenac

The above drugs are described in patent WO99 / 27906.

The antibacterial drugs used in the present invention include water-insoluble or water-insoluble or slightly soluble antibiotics and synthetic antibacterial drugs; such as penicillins, semi-synthetic penicillins, cephalosporins, macrolides, aminoglycosides, forests Coamines, tetracyclines, chloramphenicols, Phosphorus-containing polysaccharides, polyethers, neomycin, tiamulin, saidicomycin, primomycin, rifamycin, rifampicin. Preferred synthetic antibacterial drugs include transamines, furans, quinolones, acetoquinone, berberine, quinoxalic acid. These drugs are described in the following literatures: Geng Hongsheng, Wang Shaohua, editor, Practical Therapeutics, People's Medical Publishing House, 1997, pp. 27-133; Tong Wensheng, Li Anliang, Medicinal Chemistry, Higher Education Press, 1999 Years, 537-628; Editor-in-Chief, Ding 4 Ling, Handbook of Animal Drugs, China Agricultural Press, 2000, First Edition, pp. 170-229; Editor-in-Chief, Zhang Zhongqiu and Zheng Ming, Handbook of Animal and Poultry Drug Use, Published by China Agricultural University Press, 2000, pp. 19-75.

The composition of the long-acting injection containing the above therapeutic drugs of the present invention is:

a. Active ingredient G. 1-30% (W / V)

b, EC 0. 1-15% (W / V)

c. Add liquid dispersion medium and co-solvent to 100% (V / V)

d. If necessary, add other auxiliaries, including: such as antioxidants, local pain relief agents, non-ionic surfactants, and other hydrophobic slow carrier materials.

In the above formulation, EC may exist in a dissolved state or in a swollen state. The active ingredient in the preparation may be dispersed in the preparation in a dissolved state, or it may be uniformly dispersed in the preparation in a solid particle state (particle diameter less than 50 μm), or it may be partially dissolved and partially dispersed in the preparation.

The hydrophobic medium described in the above formulation is an organic liquid that can dissolve or swell EC, or can dissolve or swell EC in the presence of a co-solvent, and is safe for animals, preferably ester compounds and lipophilic nonionic surfactants; Particularly preferred are benzyl benzoate, triacetin, vegetable oils or their purified products and derivatives thereof, medium chain fatty acid esters, HLB Polyoxyethylene ether compounds with a value of less than 7.

The co-solvent used in the above formulation is an organic solvent that can dissolve EC or active ingredients. It can be a hydrophilic solvent or a hydrophobic solvent. N-methyl-pyrrolidone, Azone and other N-hydrocarbyl groups are particularly preferred. Azacyclones, dimethylacetamide, acetal glycerol, acetone, ethyl acetate. A small amount of ethyl acetate or acetone can remain in the preparation, or they can be removed from the preparation by distillation under reduced pressure after completing the "solubilizing" effect. The content of N-methyl-pyrrolidone and dimethylacetamide in the preparation should be less than 40% (V / V). The higher the content, the greater the tissue damage at the injection site.

The other hydrophobic carrier materials are semi-solid or solid materials with good biocompatibility and a melting temperature of 45-1 30; animal waxes (such as beeswax), vegetable waxes (such as Brazilian wax), and HC0 are preferred.

The nonionic surfactant is preferably: polyoxyethylene type surfactant, polyhydric alcohol. Type surfactant, polyoxyethylene fatty alcohol ether and polyoxyethylene alkyl phenol ether; the preferred nonionic surfactant For: Polyoxyethylene sorbitan fatty acid ester (Tween series), sorbitan fatty acid ester (Span series), castor oil polyoxyethylene ether (EL series) and alkylphenol polyoxyethylene ether (0P series ) Surfactants, they can be used alone or in combination of two or more.

The optimized formulation composition of the present invention is: a. Active ingredient 0.1-30% (W / V)

b. EC 0.1-10% (W / V)

c. Antioxidant 0, 1-1% (W / V)

d. Cosolvent or hydrophilic medium 10-99% (V / V)

e. Benzyl benzoate or glycerol triacetate is added to 100% (V / V) The composition of the formulation further optimized by the present invention is:

Preparation (1):

a. Avermectin 5-12% (W / V)

b. EC 0.5-2% (W / V)

c Antioxidant 0.3-0.5% (W / V)

d. Triacetin 30-75% (V / V)

e. Ethanol or water / ethanol 5-10% (V / V)

g. Phenyl alcohol 1% (V / V)

f. Benzyl benzoate to 100% (V / V)

Preparation (2):

a. Ivermectin 5-20% (W / V) b. EC 1-6% (W / V) c Antioxidant 0.2-0.6% (W / V) d. N-methyl-pyrrolidone or formaldehyde Glycerol or 20-80% (V / V) in combination e. 1% (V / V) in benzyl alcohol f. Triacetin or benzyl benzoate or combined use to add to the (V / V) preparation (3): a. Ivermectin 0.5-3.5% b. Icylamide or sodium cyhalomidide 5-20% (W / V) c. EC 0.2-3% (W / V) d. Antioxidants 0.3-0.5% (W / V) e. Benzyl alcohol or trichloro-tert-butyl alcohol 0.5-1% (V / V) f. N-methyl-pyrrolidone or dimethylacetamide 10-40% (V / V ) g. Benzyl benzoate or 1,2-propanediol or their combined use to 100% (V / V) formulation (4):

a. Indomethacin or ketoprofen diclofenac 5-20% (W / V) b. EC 0.1-2% (W / V) c. N-methyl-pyrrolidone or acetal glycidol or combination Application of 10-50% (V / V) d. Benzyl benzoate or triacetin or combined application to 100% (V / V) For different drugs, the required duration of treatment is different. The present invention changes the holding period of a drug by changing the concentration and existence state (dissolved or particulate state) of EC, hydrophilic liquid medium, hydrophobic liquid medium and drug in the preparation. Decreasing the concentration of EC, the hydrophobic medium and the drug or increasing the concentration of the hydrophilic liquid medium with high solubility to the drug can shorten the duration of the drug; otherwise, it can extend the duration of the drug. Therefore, when preparing long-acting injections with different uses for different active compounds, the ratio between EC / hydrophobic liquid medium / hydrophilic liquid medium in the preparation should be adjusted. At the same time, attention should be paid to the adjustment of the drug concentration and the existing state in order to achieve the required This is the key link in implementing the technology of the present invention. In fact, the ratio of EC, hydrophilic solvent, and hydrophobic medium to the preparation changes from a liquid state to a semi-solid state (lumps) or even after water or body fluids (injected into the body). The change to a solid state has a significant effect. When the hydrophilic solvent that dissolves EC has a low ability to dissolve the drug, the higher the amount added to the formulation, the more beneficial it is for the EC to cure and "wrap" the lipophilic active ingredient. This should be considered when implementing the technology of the present invention. problem. The viscosity of EC and its concentration in the preparation have a greater effect on the viscosity and sustained-release effect of the preparation. The greater the viscosity of EC, the greater the viscosity of the preparation, the poorer the fluidity of the preparation, and the more difficult it is for injection. Choosing an EC with an RT of less than 50 More suitable for use in the formulation of the invention.

The local pain reducing agent used in the preparation of the present invention is a local pain reducing agent commonly used in pharmaceutical preparations. It is edited by Luo Mingsheng and Gao Tianhui, "Pharmaceutical Supplements" (Sichuan Science and Technology Press, January 1999, pages 70-71) As described in more detail, benzyl alcohol and trichlorot-butanol are preferred in the present invention.

The antioxidant used in the preparation of the present invention is an antioxidant commonly used in pharmaceutical preparations, which is described in detail in "Pharmaceutical Supplements" edited by Luo Mingsheng and Gao Tianhui (Sichuan Science and Technology Press, January 1999, pages 56-58). In the description, oil-soluble antioxidants such as BHT, BHA, NDGA, and antioxidants such as phenols, organic sulfurs, and enols are preferred in the present invention. 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. Take 3. 3 kg of Avermectin, dissolve with 6 ml of benzyl benzoate, and then add 2 ml of ethanol. After 10 minutes of reaction, add 11 ml of benzyl benzoate solution containing EC (RT-20) 6%, that is, Get the preparation.

Analysis shows that avermectin exists in two states in the preparation, 11-13% of avermectin It exists in a solid state of less than 5 μm, and 2 to 4% of avermectin exists in a dissolved state (molecular state) in the medium, and EC exists in the formulation in a partially dissolved and partially swollen state. It has been clinically shown that for the prevention and treatment of parasites in cattle and sheep, 0.5-lml is injected subcutaneously for every 50 kg of body weight, and the control period can reach 80-120 days.

Example 1: 10 g of ivermectin and 0.3 g of an antioxidant were dissolved in 10 ml of N-methyl-pyrrolidone / 40 ml of glycerol triacetate solution to obtain solution A; 3 g of EC was dissolved in 50 ml of benzyl benzoate to obtain Liquid B; Mix the two liquids and heat them to 60-85 ° C and homogenize to obtain a long-acting injection containing 10% ivermectin.

Example 3: Dissolve 3gEC (RT-10) and 10g Ivermectin in 30ml of Azone, and then add 30ml of benzyl benzoate and 30ml of triacetin to the final volume containing the antioxidant. Long-acting injection of 3% EC, 10% ivermectin.

Example 4: Dissolve 2 g of EC (RT-20), 0.2 g of BHT and 10 g of ivermectin in 30 ml of N-fluorenyl-pyrrolidone, and add 10 g of ivermectin to formaldehyde glycerol solution to 100 ml to obtain 2% EC, 20% ivermectin long-acting injection.

Example 5: Take 2 g of avermectin, add 8 ml of glycerol triacetate to dissolve, then add 1 ml of ethanol / water (2: 1), stir for 1-3 minutes, and then add 10 ml of benzyl benzoate solution containing 0.4 g of EC to The final volume is a long-acting injection containing 10% avermectin. Analysis shows that 7-8% of avermectin in this preparation is dispersed in a solid particulate state (less than 5 μm) in the medium, and 2-3% of avermectin exists in a dissolved state.

Example 6. Take 1. lg of indomethacin, 0.05 g of EC and dissolve it in 2 ml of N-methyl-pyrrolidone / 1 ml of benzyl benzoate, and then add glycerol triacetate to 10 ml to obtain 10% of indomethacin. Long-acting injection. Example 7: Take 5.5 g of ketoprofen, add 5 ml of N-fluorenyl-pyrrolidone to dissolve it, and then add 60 ml of benzyl benzoate solution containing 2.5 g of EC. After mixing, add glycerol triacetate to 100 ml to obtain Long-acting injection containing 5% ketoprofen. This preparation is injected with 2ml per 50kg body weight, and the duration of effect can reach 24-48 hours.

Example 8. Take procaine penicillin to prepare particles smaller than 20 μm, and then disperse it in benzyl benzoate solution and triacetin solution containing 0.4% glyceryl tristearate and EC. The duration of drug activity can reach 72 hours or longer, and its duration is positively correlated with the dose and EC content in the preparation.

Example 9. Take 10 g of ivermectin and 10 g of EC, add 30 ml of N-fluorenyl-pyrrolidone and 50 ml of benzyl benzoate, heat to dissolve, and then add acetal glycidol to the final volume to obtain a homogeneous and transparent Iranian Vitamins 10 ° /. Semi-solid long-acting injection. The preparation is convenient to use. The preparation is extracted with a common syringe (20 gauge needle) and injected subcutaneously, with a duration of up to 120 days.

Example 10.Injection containing 10% imidacloprid

Imidacloprid 10% (W / V)

N-fluorenyl-pyrrolidone 40% (V / V)

EC 5% (W / V) glycerol triacetate to 100% (V / V) Example 11. 5% anthrafloxacin-containing injection Anthrafloxacin 5% (W / V)

EC 1-2.4% (W / V) co-solvent 16% (V / V) benzyl benzoate 40-60% (V / V) glycerol triacetate added to 100% (V / V) Example 12, 10% injection containing gentamicin

Gentamicin 10% (W / V) EC 63% (W / V) Co-solvent 20-40% (V / V) benzyl benzoate or triacetin or N-fluorenyl-pyrrolidone or combination Application to 100% (V / V) Example 13, Injection containing 20% chloramphenicol

Chloramphenicol Fluoride 20% (W / V) EC (RT-10) 1% (W / V)

N-fluorenyl-pyrrolidone 10-30% (V / V) benzyl benzoate or triacetin or glycerol or combination

Adding to 100% (V / V) aseptic operation and aseptic requirements of raw materials and sterility of the final product is necessary for the preparation of injectables. This is a well-known knowledge in the industry. Therefore, in the present invention, There is no description or specific knowledge of how to control the sterility of the preparation of the present invention.

Claims

Rights request

1. A sustained-release injection consisting of ethyl cellulose (EC) and an active compound, characterized in that the sustained-release carrier system constituting the preparation is composed of EC and other hydrophobic media or affinity with soluble EC It is composed of an aqueous solvent, and EC is dispersed in a medium in a dissolved or swollen state; the composition of the preparation is: a. Active ingredients 0.1-30% (W / V); b. EC 0.1-15% (W / V); c. Cosolvent and liquid dispersion medium are added to 100% (V / V); d. If necessary, add other auxiliaries, including: antioxidants, surfactants, local pain relief agents and other hydrophobic slow-release carrier materials.

2. The preparation according to claim 1, characterized in that the active ingredients are antiparasitic drugs, antibacterial drugs, non-steroidal anti-inflammatory drugs, and growth-promoting drugs; the antiparasitic drugs include Anti-helminthic drugs, anti-parasitic drugs, antiprotozoal drugs; Preferred anti-parasitic drugs include: Macrolide insect repellents (Avermectin abamectin, Ivermectin ivermectin, Daramectin doramectin, Moxidectin> eprinomectin, emamectin), salicylanilides (closantel closantel, rafoxanide), benzimidazoles ^p- albendazoles, propofol, sialyl sulfoxide, albendazole oxide, netobimin, fenben ( ^17- fenbendazole, orfenda oxfendazole, trichlorobenzene, p-trilabendazole), four-amidine anthelmintics (levamisole levamisole) ), pyrazolyl raziquantel ^ ¹¹ Kui one ear down and substituted ^{p-pyrazol-ylmethyl} 4 fouling organisms (e.g., acetamiprid leaching of imidacloprid), insect growth regulators drugs (triflumuron as triflumuron, diflubenzuron insects from dif lubenzuron Urea-lufenuron, Ascaris spp.methoprene, plienoxycarb, p-pyrroxyfen, acetaminox cyromazine), N-phenyl Pyrazoles (Fipronil f iproni l), organic tablets (Dichlorvos dichlorvos, trichlorphon trichlorphon> haroxon haloxon, chlorpyr ifos, naphthol napthalophos phoxim, bismube fenthioru malathion, ronnel and coumaphos); the antibacterial drugs include antibiotics and synthetic antibacterial drugs; the non-body anti-inflammatory drugs include salicylic acid Aminophenol derivatives, indole and indeneacetic acid, heteroarylacetic acid, arylpropionic acid, enolic acid, alkanone, anthranilic acid and other COX-2 inhibitors; indomethacir indomethacir is preferred Fenketoprofen, meloxican meloxican, naproxen naproxen, caproprofen caprofen, homotoric acid ketorolac ^ | ^ Nixin f limixiru diclofenac diclofenac; the growth promoter drugs are mainly Gibberella zeae Alcohols and sex hormones (estrogen, progesterone, and androgens), progesterone, estradiol benzoate, and nortritrienol acetate are preferred. The above active compounds may be composed of two or more compound preparations.

3. The preparation according to claim 1, characterized in that the liquid dispersion medium is a hydrophilic liquid medium or a hydrophobic liquid medium that is highly biocompatible and has the ability to dissolve or swell in EC; a hydrophilic medium Preference is given to 1,2-propanediol and formalin. The hydrophobic medium is selected from ester compounds and lipophilic nonionic surfactants. Particularly preferred are benzyl benzoate, triacetin, vegetable oil or its purified product and its four-fouling organisms, medium chain fatty acid esters, Polyoxyethyl ethers with HLB value less than 7.

4. The preparation according to claim 1, wherein the co-solvent is an organic solvent that easily dissolves EC or active ingredients, and it can be a hydrophilic or hydrophobic solvent; N-methyl-pyrrolidone and the like are particularly preferred. Pyrrolidone compounds, dimethylacetamide, phenylacetone, Azone and N-hydrocarbyl aziridones, acetone, ethyl acetate.

5. The preparation according to claim 1-4, characterized in that the optimized preparation composition is preparation (1):

a. Active ingredient 2-20% (W / V) b. EC 0.2-6% (W / V) c. Antioxidant 0.3-0.5% (W / V) d. Trichlorot-butanol or benzyl alcohol 0.5 -2% (V / V) e. Ethanol or water / ethanol 5-10% (V / V) f. Benzyl benzoate or glycerol triacetate or used together to add to 100% (V / V) preparation ( 2):

a. Active ingredient 2-20% (W / V) b. EC 0.2-6% (W / V) c Antioxidant 0.3-0.5% (/ V) d. N-methyl-pyrrolidone or difluorenylethyl amides 10-40% (V / V) e 0. 5 trichloro-t-butanol or benzyl alcohol ^{-.. 2% (V /} V) f triacetin or benzyl or phenyl Yue acid diglycidyl or combined formaldehyde use

Add to 1GG% (V / V) 6. The preparation according to claim 5, characterized in that the optimized preparation composition is a. Abamectin 5-12% (W / V)

b. EC 0.5-2% (W / V)

c. Antioxidant 0.3-0.5% (W / V)

d. Triacetin 30-75% (V / V)

e. Ethanol or water / ethanol (1: 2) 5-10% (V / V)

f. Benzyl alcohol 1% (V / V)

g. Benzyl benzoate 100% (V / V)

Preparation (2):

a. Ivermectin 5-20% (W / V) b. EC 1-6% (W / V) c. Antioxidant 0.2-0.

6% (W / V) d. N-fluorenyl-pyrrolidone or acetal glycidol or a combination of 20-80% (V / V) e. 1% benzyl alcohol (V / V) f. Triacetin Or benzyl benzoate or combined use to 100% (V / V) Preparation (3):

a. Ivermectin 0.5-3.5% (W / V) b. Icysalamide or sodium cyhalosalid 5-20% (W / V) c EC 0.2-3% (W / V) d Antioxidant 0.3-0.5% (W / V) e. Benzyl alcohol or trichloro-tert-butyl alcohol 0.5-1% (V / V) f. N-methyl-pyrrolidone or dimethylacetamide 10- 40% (V / V) g. Benzyl benzoate or 1,2-propanediol or their combined use to 100% (V / V)

7. The preparation according to claim 5, characterized in that the optimized formula composition is: a. Indomethacin or ketoprofen or diclofenac 5-20% (W / V) b. EC 0.1-2 % (W / V) c. N-fluorenyl-pyrrolidone or acetal glycidol or combined application 10-50% (V / V) d. Benzyl benzoate or triacetin or combined application to 100 % (V / V)

8. The preparation according to claims 1 and 5-7, characterized in that the active ingredients in the preparation can be dispersed in the preparation medium in a dissolved state, or can be dispersed in the preparation medium in a solid particle state (particle size less than 50 μιη), or It can be partially dissolved and partially dispersed in the formulation medium.

9. The preparation according to claims 1 and 5 to 7, characterized in that 1-10% (W / V) polyvinylpyrrolidone can also be added to the preparation.

10. Sustained-release carrier consisting of EC in a dissolved or swollen state and a hydrophobic liquid dispersion medium or slow-release carrier consisting of EC and a hydrophilic solvent in which EC can be dissolved or EC in a dissolved or swelled state with a hydrophobic and hydrophilic liquid A slow release carrier system combined with a dispersion medium is used for preparing a slow (controlled) release injection for veterinary use; a slow release injection composed of the active ingredient according to claim 1 is preferably applied to the prevention and treatment of animal diseases.