DE102007061262A1 - New use of tribendimidine - Google Patents

Abstract

The present invention relates to the use of tribendimidine for controlling endoparasites in farm animals.

Description

The The present invention relates to the use of tribendimidine for the control of endoparasites in livestock.

Tribendimidine, a symmetrical diamidine derivative of amidine sheath, has been known for about 20 years and is being developed in China as a broad-spectrum anthelmintic for human use (see, for example: Ren, HN et al. Chin. J. Parasitol. Parasite. Dis. 5 (1987) 262-264 ; Keizer, J. et al. Antimicrob. Agents Chemother. 51 (2007) 1096-1098 ).

Amidantel is known as a potent anthelmintic for dogs ( Wollweber H et al. Drug Research / Drug Research 29 (1) 31-32 ; DE-OS-20 29 298 ). The use in humans against Ancylostoma duodenale is described in Rim HJ et al. The Korean Journal of Parasitology 18 (1) 24-36 ,

The Use of tribendimidine to combat endoparasites in livestock has not yet been described.

The present invention therefore relates to:
The use of tribendimidine for the manufacture of medicaments for the control of endoparasites in farm animals.

According to a further aspect, the invention relates to:
A method of controlling endoparasites in farm animals by administering to the subject farm animal the amount of tribendimidine required to control endoparasites.

Tribendimidine has the following structural formula (1):

Tribendimidine and its synthesis are known. A manufacturing method is described, for example Yao RH, Chen YQ (1986) "Synthesis of Tribendimidine and its substituted analogues as new anthelmintic agents." Annual Report of Institute of Parasitic Diseases, Chinese Academy of Preventive Medicine, 1986, pp. 199-202 ,

There Tribendimidine has basic centers, it may as well be used as a salt. For the inventive Use only pharmaceutically acceptable salts in question, in particular correspondingly favorable toxic properties to have. Due to the basic properties of tribendimidine come Salts with acids in question, such as. As salts with inorganic Acids, for example hydrochlorides, hydrobromides, dihydrosulfates or phosphates, salts with organic carboxylic acids or organic sulfonic acids, for example formates, acetates, Trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates or para-toluenesulfonates.

Other pharmaceutically acceptable forms of the active ingredient, such as. Hydrates, other solvates etc. can of course also be used.

Tribendimidin is used according to the invention for controlling pathogenic endoparasites used in animal husbandry and Animal breeding occur in livestock. By fighting The pathogenic endoparasites are said to be disease, deaths and performance reductions (eg in the production of meat, Milk, wool, hides, eggs, honey, etc.), so that by using the active ingredients a more economical and easier animal husbandry is possible.

The pathogenic endoparasites include helminths, in particular cestodes, trematodes, nematodes. Examples include:
From the order of Pseudophyllidea z. For example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diplogonorus spp.
From the order of Cyclophyllidea z. For example, Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosma spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Anhyra spp., Bertiella spp., Taenia spp. , Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
From the subclass of Monogenea z. B: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.
From the subclass of Digenea z. Eg, Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp. , Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhloccelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus Spp., Catatropis spp., Plagiorchis spp., Prosthogonism spp., Dicrocoelium spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp., Metagonimus spp.
From the order of Enoplida z. Trichuris spp., Capillaria spp., Trichlomosoides spp., Trichinella spp.
From the order of Rhabditia z. For example: Micronema spp., Strongyloides spp. From the order of Strongylida z. B: Strongylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp. , Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus Spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp. , Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp.
From the order of Oxyurida z. Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
From the order of Ascaridia z. Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
From the order of Spirurida z. Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
From the order of Filariida z. E.g., Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.
From the group of Gigantohynchida z. For example, Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

Prefers is the fight against tapeworms, z. Eg Taenia spp ..

Also preferred is the control of nematodes, such. B .:
From the order of Rhabditia z. For example: Micronema spp., Strongyloides spp.
From the order of Strongylida z. B: Strongylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostromum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp. , Globocephalus spp., Syngamus spp., Cyathostomum spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp. , Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp., Cylicocyclus spp., Cylicodontophorus spp.
From the order of Oxyurida z. Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
From the order of Ascaridia z. Ascaris spp., Parascaris spp., Anisakis spp., Ascaridia spp.
From the order of Spirurida z. Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.
From the order of Filariida z. E.g., Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.

Especially preferred is the use of tribendimidine for control Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp. as well as Ascaridia such. B. Parascaris spp.

The farm animals include in particular mammals such. B. Cattle, horses, sheep, pigs, Zie camel, water buffalo, donkey, rabbit, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon.

Fewer preferred for the use according to the invention are the following species that are not mammals, but also belong to the livestock: birds, such as Chickens, geese, turkeys, ducks; Sweet- and saltwater fish such. Trout, carp, eels, reptiles; Insects such. B. honeybee and silkworm.

Under The mammals are recommended for the use of tribendimidine especially the herbivores (herbivores) preferred, so animals, which mainly feed on plants. Particularly preferred is the treatment of ruminants (such as sheep, goats, cattle).

When not ruminant herbivores, the mammals are, as a preferred example, the horses are called. There can Tribendimidine preferably z. B. for the control of Strongylida or in particular of roundworms (Ascaridia), such as. B. Parascaris equorum.

at ruminants may prefer Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp. be fought.

Especially sheep are preferably treated according to the invention.

Also cattle are particularly preferred according to the invention treated.

The Application can be both prophylactic and therapeutic.

The Application of the active substance takes place directly or in the form of suitable Preparations enteral, parenteral, dermal, nasal, by treatment the environment or with the aid of active ingredient-containing moldings such as As strips, plates, tapes, collars, Ear tags, limb bands, marking devices.

The enteral application of the drug happens z. B. orally in the form of Powders, suppositories, tablets, capsules, fasting, potions, Granules, drenches, boluses, medicated feed or drinking water. The dermal application happens z. In the form of diving (dipping), Spraying (spraying), bathing, washing, infusion (pour-on and spot-on) and powdering. The parenteral application happens z. In the form of injection (intramuscular, subcutaneous, intravenously, intraperitoneally) or by implants.

Suitable preparations are:
Solutions such as injectable solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels;
Emulsions and suspensions for oral or dermal use and for injection; semi-solid preparations;
Formulations in which the active substance is processed in an ointment base or in an oil in water or water in oil emulsion base;
Solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; Aerosols and inhalants, active substance-containing moldings.

injection solutions are administered intravenously, intramuscularly and subcutaneously administered.

injection solutions are prepared by adding the active ingredient in a suitable solvent and possibly additives such as solubilizers, Acids, bases, buffer salts, antioxidants, preservatives be added. The solutions are filtered sterile and bottled.

When Solvents may be mentioned: Physiologically acceptable Solvents such as water, alcohols such as ethanol, butanol, Benzyl alcohol, glycerine, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.

The If appropriate, active compounds can also be administered in physiologically acceptable form vegetable or synthetic oils for injection are suitable, solve.

As solubilizers may be mentioned: solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

preservative are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

oral Solutions are applied directly. Concentrates are after previous dilution to the application concentration orally applied. Oral solutions and concentrates are as above produced in the injection solutions, wherein can be dispensed with sterile work.

solutions for use on the skin are dripped, brushed, rubbed in, sprayed on, sprayed on or by dipping (Dipping, bathing or washing) applied. These solutions are described as above for the injection solutions produced.

It may be advantageous to add in the preparation thickener.

thickener are: inorganic thickeners such as bentonites, colloidal silicic acid, Aluminum monostearate, organic thickeners such as cellulose derivatives, Polyvinyl alcohols and their copolymers, acrylates and methacrylates.

gels are applied or painted on the skin or in body cavities brought in. Gels are made by using solutions that produced as described in the injection solutions have been added with so much thickening agent that a clear mass with ointment-like consistency is formed. As a thickener the thickening agents specified above are used.

pour-on formulations are infused or sprayed onto limited areas of the skin, wherein the active ingredient either penetrates the skin and systemically acts or spreads on the body surface.

pour-on formulations are prepared by the active ingredient in suitable skin-friendly Solvents or solvent mixtures dissolved, is suspended or emulsified. Optionally, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, Light stabilizer, adhesive added.

When Solvents may be mentioned: water, alkanols, glycols, Polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters, such as ethyl acetate, Butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as Dipropylene glycol monomethyl ether, diethylene glycol mono-butyl ether, Ketones such as acetone, methyl ethyl ketone, aromatic and / or aliphatic Hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1,3-dioxolane.

dyes are all dyes approved for use in animals that have been dissolved or suspended.

absorption accelerators Substances are z. DMSO, spreading oils such as isopropyl myristate, Dipropylene glycol pelargonate, silicone oils, fatty acid esters, Triglycerides, fatty alcohols.

antioxidants are sulfites or metabisulfites such as potassium metabisulfate, ascorbic acid, Butylhydroxytoluene, butylhydroxyanisole, tocopherol.

Light stabilizers are z. B. substances from the class of benzophenones or novantisoleic acid.

adhesives are z. B. cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.

emulsions can be used orally, dermally or as an injection.

emulsions are either water-in-oil or oil-type in water.

she are prepared by adding the active ingredient either in the hydrophobic or dissolved in the hydrophilic phase and these with the help suitable emulsifiers and optionally further auxiliaries such as Dyes, absorption-promoting substances, preservatives, Antioxidants, light stabilizers, viscosity increasing Substances homogenized with the solvent of the other phase.

As hydrophobic phase (oils) may be mentioned: paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic / capric acid biglycerid, triglyceride mixture with vegetable fatty acid of chain length C _8-12 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated fatty acids which may also contain hydroxyl groups, mono- and diglycerides of C ₈ / C ₁₀ -fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a medium-chain branched fatty acid with saturated fatty alcohols of chain length C ₁₆ -C ₁₈ , isopropyl myristate, isopropyl palmitate, cypryl / capric acid ester of saturated fatty alcohols of chain length C ₁₂ C ₁₈ , isopropyl stearate, oleyl oleyl ester, oleic acid ethyl ester, ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duckbald gland fat, dibutyl phthalate, diisopropyl adipate, the latter related ester mixtures, among others.

fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, Oleyl alcohol.

fatty acids such as As oleic acid and its mixtures.

As hydrophilic phase may be mentioned:
Water, alcohols such. As propylene glycol, glycerol, sorbitol and their mixtures.

As emulsifiers may be mentioned: nonionic surfactants, for. Polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers;
ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;
anionic surfactants such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol orthophosphoric acid ester monoethanolamine salt;
cationic surfactants such as cetyltrimethylammonium chloride.

When Other auxiliaries may be mentioned: viscosity-increasing and the emulsion stabilizing substances such as carboxymethyl cellulose, Methyl cellulose and other cellulose and starch derivatives, Polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, Polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, Polyethylene glycols, waxes, colloidal silica or Mixtures of the listed substances.

suspensions can be used orally, dermally or as an injection. They are made by placing the active ingredient in a carrier liquid if appropriate with the addition of further auxiliary substances, such as wetting agents, Dyes, absorption-enhancing substances, preservatives, antioxidants, Light stabilizer suspended.

When Carrier liquids are all homogeneous solvents and solvent mixtures called.

When Wetting agents (dispersants) are the surfactants specified above called.

When Other auxiliaries are those mentioned above.

semi-solid Preparations may be administered orally or dermally. They differ from the suspensions described above and Emulsions only by their higher viscosity.

to Preparation of solid preparations, the active substance with suitable Carriers optionally with the addition of excipients mixed and brought into the desired shape.

When Carriers are called all physiologically acceptable solid inert materials. As such serve inorganic and organic Substances. Inorganic substances are z. For example, common salt, carbonates such as calcium carbonate, Bicarbonates, aluminas, silicas, clays, precipitated or colloidal silica, phosphates.

organic Substances are z. As sugar, cellulose, food and feed such as milk powder, animal meal, cereal flours and meals, starches.

Excipients are preservatives, antioxidants, dyes, which are already listed above have been.

Further suitable adjuvants are lubricants and lubricants such. Magnesium stearate, Stearic acid, talc, bentonites, disintegrating Substances such as starch or cross-linked polyvinylpyrrolidone, Binders such. As starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

Of the Active ingredient according to the invention can be used in combination be used with other active ingredients.

The Application in combination means either that tribendimidine and one or more other active substances in a common preparation formulated and applied together accordingly. The drug combinations but can also be used separately or in stages become.

Examples

formulation Examples

Example 1 (liquid formulation):

• 1000, 1500 or 2000 mg tribendimidine in 100 ml glycerol formal / glycerol Polyethylenglykolricinoleat (Cremophor ^® EL) in the mixing ratio 40/60 (v / v).

Example 2 (liquid formulation):

• 1000, 1500 or 2000 mg in 100 ml Tribendimidin Cremophor ^® EL / water in a mixing ratio of 1:10 1: 1

Example 3 (liquid formulation):

• 1000, 1500 or 2000 mg in 100 ml Tribendimidin Cremophor ^® EL / water in the ratio 1: 5

Example 4 (liquid formulation):

• 1000, 1500 or 2000 mg in 100 ml Tribendimidin Cremophor ^® EL / water in the ratio 1: 1

Example 5 (solid formulation)

• 1000, 1500 or 2000 mg tribendimidine as a powder, filled in a gelatin capsule

Biological examples

Example A Anthelmintic Effect in sheep

sheep (Merino or Schwarzkopf breed, 25-35 kg body weight) were experimentally infected with 5000 H. contortus L3 larvae, in the case of Trichostrongylus colubriformis with 12,000 L3 larvae, in the case of Cooperia curticei with 30,000 L3 larvae, Teladorsagia circumcincta with 3000 to 10000 L3 larvae and with the formulated Test substance at the end of the prepatency period of the parasite treated. The test compounds were administered orally in either a gelatin capsule or applied by means of a syringe. The anthelmintic efficacy The test substances were used as a function of the reduction of the egg number per Grams of feces measured. This was fresh feces from the experimental animals according to the McMaster method, modified according to Wetzel and edited the egg number is determined. The egg numbers were determined in regular intervals Intervals before and after treatment. The results are shown in the table.

(This assay is described in the literature: G. von Samson-Himmelstjema, A. Harder, T. Schnieder, J. Kalbe, N. Mencke (2000) In vivo activities of the new anthelmintic depsipeptide PF1022A. Parasitol Res. 194-199.) Tribendimidine Mg / kg /% killing of worms Haemonchus contortus 10 / 99.2 Trichostrongylus colubriformis 25 / 99.8 Cooperia curticei 10/95 Ostertagia circumcincta 10/95

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - DE 2029298 A [0003]

Cited non-patent literature

• Ren, HN et al. Chin. J. Parasitol. Parasite. Dis. 5 (1987) 262-264 [0002]
• Keizer, J. et al. Antimicrob. Agents Chemother. 51 (2007) 1096-1098 [0002]
• - Wollweber H et al. Drug Research / Drug Research 29 (1) 31-32 [0003]
• - Rim HJ et al. The Korean Journal of Parasitology 18 (1) 24-36 [0003]
• - Yao RH, Chen YQ (1986) "Synthesis of Tribendimidine and its substituted analogues as new anthelmintic agents." Annual Report of Institute of Parasitic Diseases, Chinese Academy of Preventive Medicine, 1986, pp. 199-202 [0008]

Claims (12)

Use of tribendimidine for the preparation of medicines to combat endoparasites livestock Use according to claim 1, characterized characterized in that the farm animals are herbivores. Use according to claim 1, characterized characterized in that the farm animals are ruminants or horses. Use according to one of the preceding Claims wherein the endoparasites are helminths. Use according to claim 4, wherein the helminths are cestodes, tematodes or nematodes. Use according to claim 5, wherein the helminths are cestodes. Use according to claim 5, wherein the helminths are nematodes. Use according to one of the claims 1 to 5 for the control of Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp. such as from Ascaridia such. B. Parascaris spp. Use according to claim 8 to Control of Strongylida, in particular Haemonchus spp., Trichostrongylus spp., Cooperia spp. and Ostertagia spp., in ruminants. Use according to claim 8 to Fight against Ascaridia, in particular Parascaris spp. in horses. Tribendimidine for use in control of endoparasites in farm animals. Method for controlling endoparasites in livestock, in which one of the relevant farm animal to combat amount of tribendimidine required by endoparasites.