EP2054064A2

EP2054064A2 - Transdermal application of triazines for controlling coccidia infections

Info

Publication number: EP2054064A2
Application number: EP07801543A
Authority: EP
Inventors: Iris Heep; Hans-Christian Mundt
Original assignee: Bayer Animal Health GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2006-08-16
Filing date: 2007-08-08
Publication date: 2009-05-06
Also published as: CA2660762C; JP5340936B2; BRPI0716404A2; CR10618A; DE102006038292A1; CO6150133A2; AU2007286507A1; IL196864A; JP2010500385A; SV2009003169A; RU2484825C9; NZ574885A; GT200900031A; UA98117C2; RU2484825C2; IL196864A0; WO2008019785A2; MX2009001516A; CN101505756A; WO2008019785A3

Abstract

The invention relates to the transdermal application of triazines such as toltrazuril or ponazuril for controlling coccidia infections in animals and humans.

Description

Transdermal use of triazines to combat coccidial infections

The present invention relates to the transdermal use of triazines such as toltrazuril or ponazuril for controlling coccidial infections in animals and humans.

Coccidioses are common in animals, parasitic infectious diseases. Protozoa of the genera Eimeria, Isospora, Neospora, Sarcosporidium and Toxoplasma spread coccidioses worldwide. For example, infections of pigs with coccidia of the genus Isospora or of cattle with coccidia of the genus Eimeria are economically significant. Injections with Isospora suis have only been recognized in recent years as a cause of follicular diarrhea and intensively researched. As a rule, an infection takes place from the environment to the piglets or from piglets to piglets via oocysts, each of which contains two sporocysts with two sporozoites each. The multiplication of the parasite stages takes place in the epithelial cells of the small intestine villi, the existence of extraintestinal stages in the liver, spleen and lymph nodes is discussed. The clinical manifestation of the disease includes a necrotic, inflammatory destruction of the intestinal epithelial cells with villi atrophy and thereby digestive and absorption disorders. Characteristic of an acute illness is a watery, whitish to yellow diarrhea, which occurs mostly in the 2nd to 3rd week of life. Infected piglets have a reduced weight gain. The treatment and therapy of the disease have so far been insufficiently resolved. Antibiotics are ineffective, sulfa drugs are recommended, but therapy usually comes too late. Other treatment options are contradictory: By administration of e.g. Monensin, amprolium or furazolidone could not be prevented in experimentally infected piglets a disease. In recent studies, in some farms, despite good hygiene, up to 92% of all litters were identified as Isospora suis.

Triazines, in particular toltrazuril and ponzazuril, and their action against coccidia are known from a number of publications, see, inter alia. DE-OS 27 18 799 and DE-OS 24 137 22. From WO 99/62519 semi-solid aqueous preparations of Toltrazuril-sulfone (Ponazuril) are known. It is also known that, in particular, toltrazuril is suitable for the treatment of coccidiosis (for example Isospora suis) in pigs. See for example the following publications: Do not forget coccidiosis, Update on Isosporosis in piglets. Part I, Pig Progress volume 17, No2, 12-14; Mundt., H.-C, A. Daugschies, V. Letkova (2001): be aware of piglet coccidiosis. Part II, Pig Progress volume 17, No 4, 18-20; Mundt, H.-C, G.-Pl Martineau, K. Larsen (2001): control of coccidiosis Part III, Pig Progress volume 17, No 6, 18-19.

Coccidioses in cattle due to infections with various pathogenic Eimeria spp. (eg E. bovis and E. Zürnii) express themselves as diarrheal diseases of varying severity (bloody diarrhea with mortality). The transdermal application of drugs is particularly easy and convenient in animals. Compared to traditional oral administration, it is also advantageous in animals because transdermal application is associated with less stress on the animals. However, as it is often difficult to develop satisfactory transdermal formulations, transdermal application in the control of coccidial infections has heretofore not been common in practice. Commercial products of this type are thus far not available.

WO 96/38140, DE 10049468 or WO 00/37063 describe agents against coccidiosis in animals. In addition to other types of application, the external application is mentioned there in general form.

However, it is also known that the skin of different animal species differs significantly and therefore is not necessarily comparable in different animal species. Thus, it can not be assumed that an active substance transdermally in any animal species or even in humans, if this was found only on one animal species.

It has now been found that triazine active substances are also effective systemically as a transdermally administered formulation against coccidial infections, above all in animals, in particular mammals and, in particular, farmed mammals (agricultural livestock).

Crucial for a practical transdermal formulation is that a sufficiently high blood level of the active ingredient in the serum is achieved and the active ingredients reach the pathogens. It is desirable to have full effectiveness at conventional dosages.

Surprisingly, we have found that in the case of triazines in transdermal application, full efficacy can be achieved, even if only the usual dosage for oral use is used. Usually, a significantly higher dose must be administered during transdermal administration than, for example, oral administration. The skilled artisan generally anticipates at least a multiple of the oral dose for the dermal application dose (JH Vaile and P. Davis, Topical NSAIDs for musculoskeletal conditions, Drugs, 1998 Nov., 56 (5), 783-799. Graziani, GA Abbiati, E. Dolfini, R. Testa and GP Velo, Pharmacokinetic, Pharmacodynamic, and toxicological properties of naproxen gel in laboratory animals, Current therapeutic research, Sept. 1987, 42 (3), 480-490. Clays, A. Barel, J. Taeymans, Percutaneous Penetration of Drug Use in Physiotherapy, Sports Injuries and Sports Injuries, Sports Physiotherapy, Dec. 1997, 19-23). For example, it has been shown that transdermal formulations of the rabbit, porcine and bovine agents have enabled serum levels to be effective against coccidial infections.

For example, after pour-on administration of toltrazuril formulations, the drug was percutaneously absorbed by all animals. Astonishingly, this happens even in animal species that are less hairy. Little hairy animals, like the pig, ensure the protective function of the outer body cover over a thicker epidermis. It is completely surprising that the active substance is absorbed by this thicker skin and in particular by the skin layer (stratum corneum), which is particularly thick in pigs. In addition, the active ingredient can not, as in other, more hairy species, are absorbed through the numerous hair follicles. So it was surprising that in studies on pigs a massive infection with Isospora suis, the causative agent of Saugferkelcoccidiose, could be controlled by a pour-on treatment with toltrazuril. The efficacy was shown both clinically (reduced diarrheal incidence, better weight development) and parasitic (lower oocyst excretion). In addition, the percutaneous absorption was also detected by detection of the active ingredient and its main metabolite in various body tissues (serum, muscle, skin, liver, kidney).

The invention therefore relates to the use of triazines of the formulas (I) or (II)

or

wherein - A -

R ^{1 is} R ³ -SO ₂ - or R ³ -S-,

R ^{2 is} alkyl, alkoxy, halogen or SO ₂ N (CH ₃ ) ₂ and

R ^{3 is} haloalkyl

R ⁴ and R ⁵ independently of one another represent hydrogen or Cl and

R ^{6 is} fluorine or chlorine.

and their physiologically acceptable salts

for the preparation of agents for the transdermal treatment of coccidial infections in animals or humans.

The triazines are well-known per se as anti-coccidial agents, and the triazine triones, e.g. Toltrazuril and ponazuril as well as the triazinediones such as e.g. Clazuril, diclazuril and letrazuril.

The triazinediones are represented by formula (H):

Clazuril (R ⁴ = Cl, R ⁵ = H, R ⁶ = Cl in formula (II))

Letrazuril (R ⁴ = Cl, R ⁵ = Cl, R ⁶ = F in formula (II)) and

Diclazuril (R ⁴ = Cl, R ⁵ = Cl, R ⁶ = Cl in formula (II)).

Of these 1, 2,4-triazinediones, diclazuril is most preferred.

Particularly preferred according to the invention are the triazinetriones of the formula (I) as active ingredients:

R ² is preferably alkyl or alkoxy each having up to 4 carbon atoms, particularly preferably methyl, ethyl, n-propyl, i-propyl.

R ³ is preferably perfluoroalkyl having 1 to 3 carbon atoms, more preferably trifluoromethyl or pentafluoroethyl.

The preferred triazinetriones are represented by the formula (I):

Toltrazuril (R ¹ = R ³ -S-, R ² = CH ₃ , R ³ = CF ₃ )

Ponazuril (R ¹ = R ³ -SO ₂ -, R ² = CH ₃ , R ³ = CF ₃ ) Combinations with other active substances are also possible, for example with those used for other indications, such as anthelmintics, antibiotics or dermal antiparasitics.

The dosage of the triazine can - as explained above - vary depending on the animal species. Usual dosages are 1 to 60 mg of active ingredient per kg of body weight (mg / kg) of the animal to be treated per day, preferably 5 to 40 mg / kg and particularly preferably 10 to 30 mg / kg.

The dosage in the transdermal treatment according to the invention may be about equal to or lower than in the oral application. It should be understood by "about the same or lower" that the dermal dosage per day not more than 200%, preferably not more than 150%, more preferably not more than 110%, especially not more than 100% of the corresponding oral dosage at otherwise same conditions.

Toltrazuril is usually dosed during oral administration as follows:

Pig: 20 mg / kg body weight

Beef: 15 mg / kg body weight

Sheep: 20 mg / kg body weight

Poultry: 15 mg / kg body weight

With the exception of poultry, toltrazuril is administered only once per treatment, so that in pigs, cattle and sheep, the dosages given are per day and per treatment. For poultry, the indicated dose is divided into two consecutive days.

Preparations suitable for animals are: solutions, suspensions or emulsions, referred to as so-called spot-on or pour-on (pour-on formulations), e.g. be abandoned on the back or neck of the animals. Solutions are preferred.

Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. If appropriate, further auxiliaries, such as solubilizers, absorption-promoting substances, antioxidants, preservatives, thickeners, adhesives, pH regulators, light stabilizers or dyes are added.

Suitable solvents include: Physiologically acceptable solvents such as water, alcohols, such as monohydric alkanols (eg, ethanol or n-butanol), polyhydric alcohols, such as glycols (eg, ethylene glycol, propylene glycol), polyethylene glycols (eg, tetraglycol), polypropylene glycols, glycerol; aromatic substituted alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol; Esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethyl oleate; Ethers, such as alkylene glycol alkyl ethers (eg, dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether); Ketones such as acetone, methyl ethyl ketone; aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils; Glycerol formal, Solketal (2,2-dimethyl-4-hydroxymethyl-l, 3-dioxolane), N-methylpyrrolidone, 2-pyrrolidone, N, N-dimethylacetamide, glycofurol, dimethylisosorbitol, lauroglycol, propylene carbonate, octyldodecanol, dimethylformamide, and Mixtures of the solvents mentioned.

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

Absorption-demanding substances are

Ionic substances such as e.g. Sodium lauryl sulfate.

Dialkyl sulphoxides, e.g. Dimethylsulfoxide and decylmethylsulfoxide.

Omega-amino acids and their derivatives, e.g. Dodecylazacycloheptan-2-one (Azone®), N-dodecyl-2-pyrrolidone or dodecyloxycarbonylpentylammonium dodecyloxycarbonylpentylcarbamate (Transkarbam 12).

Dipolar aprotic solvents such as e.g. Dimethylacetamide, dimethylformamide, 2-pyrrolidone, N-methylpyrrolidone.

Aliphatic alcohols having 1 to 4 carbon atoms, such as ethanol or isopropanol.

Polyalcohols such as glycerol or polyethylene glycol, propylene glycol, diethylene glycol or dipropylene glycol.

Fatty alcohols, e.g. Dodecanol, oleyl alcohol or isostearyl alcohol.

Esters and amides of organic carboxylic acids: eg short-chain esters, such as ethyl acetate; Fatty acid esters, such as glycerol monolaurate, glycerol monooleate, oleyl oleate, propylene glycol diester of caprylic / capric acid; Amino-containing esters, such as dodecyl-N, N-dimethylamino acetate, or the capsaicin-analogous nonivamide. Emulsifiers of the classes polyoxyethylene fatty alcohol ethers, for example polyoxyethylene glycol monostearate, polysorbates, for example polyoxyethylene 20 sorbitan monooleate or sorbitan fatty acid esters, for example sorbitan malolaurate

Amines such as e.g. dodecylamine

• urea or compounds of urea.

Cyclic acetals, e.g. 2-nonyl-4-hydroxy-methyl-dioxolane, 2-nonyl-1,3-dioxolane.

• fatty acids such as oleic acid or lauric acid.

• Essential oils, in particular from the class of terpenes, such as linolen, limonene, 1,8-cineole, nerolidol (C 15) or menthol.

• Spreading oils such as silicone oils, isopropyl myristate or isopropyl palmitate.

Triglycerides such as medium chain triglycerides of chain length Cg-C _12.

Antioxidants are sulfites or metabisulfites such as potassium or sodium metabisulfite, sodium or potassium disulfide, ascorbic acid, iso-ascorbic acid, ascorbic acid palmitate, gallic acid esters, butylhydroxytoluene, butylhydroxyanisole or tocopherol.

Synergists of these antioxidants may be: amino acids (e.g., alanine, arginine, methionine, cysteine), citric acid, tartaric acid, edetic acid or its salts, phosphoric acid derivatives or polyhydric alcohols (polyethylene glycol).

Preservatives are: benzyl alcohol, benzalkonium chloride, trichlorobutanol, p-hydroxybenzoate, n-butanol, chlorocresol, cresol, phenol, benzoic acid, citric acid, tartaric acid or sorbic acid.

Thickeners are: inorganic thickeners such as bentonites, silica (e.g., amorphous, colloidal or fumed silica), aluminum stearates, organic thickeners such as cellulose derivatives e.g. Hydroxypropylmethylcellulose 4000, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.

pH-regulating substances are pharmaceutically customary acids or bases. The bases include alkali or alkaline earth hydroxides (eg NaOH, KOH), basic salts such as ammonium Chloride, basic amino acids such as arginine, choline, meglumine, ethanolamines or buffers such as tris (hydroxymethyl) aminomethane, citric acid or phosphate buffer. The acids include, for example, hydrochloric acid, acetic, tartaric, citric, lactic, succinic, adipic, octanoic or linolenic acid and acidic amino acids such as aspartic acid.

Sunscreen agents are e.g. Substances from the class of benzophenones or novantisolic acid.

Dyes are all dyes approved for animal or human use which may be dissolved or suspended.

Emulsions as a pour-on formulation are either of the water-in-oil type or of the oil-in-water type.

They are prepared by dissolving the active substance in one phase and homogenizing it with the aid of suitable emulsifiers and, if appropriate, further auxiliaries, such as dyes, resorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity-increasing substances.

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 acids of chain length C _8-I2 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated, possibly hydroxyl-containing fatty acids, mono- and diglycerides of Cg / Cio 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 the chain length CIG-C, isopropyl myristate, isopropyl palmitate, caprylic / capric acid ester of saturated fatty alcohols of chain length C; _{] 2} -C _lg , isopropyl stearate, oleyl oleate, oleic acid ethyl ester, ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duckbell glands 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, e.g. 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: surfactants (includes emulsifiers and wetting agents), such as

1. nonionic, e.g. polyoxyethylated castor oil, polyoxyethoxylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers,

2. ampholytic, such as di-Na-N-lauryl-.beta.-iminodipropionate or lecithin,

3. anionic, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt,

4. cationic, such as cetyltrimethylammonium chloride.

As further auxiliaries are suitable:

Viscosity-increasing and emulsion-stabilizing substances such as carboxymethylcellulose, methylcellulose 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 as a pour-on formulation can also be applied cutaneously. They are prepared by suspending the active ingredient in a carrier liquid optionally with the addition of further auxiliaries, such as wetting agents, dyes, resorptionsfördemde substances, thickeners, adhesives, preservatives, antioxidants or light stabilizers.

As carrier liquids may be mentioned all homogeneous solvents and solvent mixtures.

As wetting agents (dispersants) may be mentioned:

Surfactants (includes emulsifiers and wetting agents) such as

1. anionic, such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / Dialkylpolyglykolether- orthophosphorsäureester monoethanolamine salt, lignosulfonates or dioctylsulfosuccinate,

2. cationic, such as cetyltrimethylammonium chloride,

3. ampholytic such as di-Na-N-lauryl-β-iminodipropionate or lecithin, 4. Non-ionic, eg polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, Pluronic®.

As further auxiliaries mentioned above.

The active ingredients can also be applied in the form of an aerosol. For this purpose, the active ingredient in a suitable formulation is finely divided under pressure.

Preferred to be mentioned are transdermally administered solutions containing compounds of the formula (I) or (IT) which are characterized in that

a) the active compound is present in a concentration of 0.1-30% by weight, in particular 2-25% by weight and especially 5-20% by weight,

b) they contain optionally substances for regulating the pH

c) optionally containing substances for influencing transdermal absorption in a concentration of 0.1-50% by weight, especially 1-20% by weight and especially 1-10% by weight,

d) they contain, where appropriate, preservatives for adequate preservation, individually or in combination with so-called synergists. The preservatives are usually contained in concentrations of 0.01-5% by weight and especially 0.05-1% by weight.

e) they optionally contain antioxidants in a concentration of 0.1 to 1 wt .-%,

f) the pH of the solution 3-10 is in particular 4-9 and especially 5-8.

As solvents for these preferred solutions, the solvents mentioned above can be used, as preferred examples of solvents N-methylpyrrolidone and dimethylacetamide may be mentioned.

Also substances for influencing the transdermal resorption (so-called "penetration enhancers") have already been mentioned above, preferred examples are: isopropanol, dodecyl-azacycloheptan-2-one (Azone®), limonene and 1,8-cineole.

The antioxidants used in the formulations mentioned are preferably BHA or BHT. The preservatives can be used for sufficient conservation individually or in combination with so-called synergists. Synergists such as citric acid, Tartaric acid, ascorbic acid or the sodium salt of the editic acid are usually present in concentrations of 0.01-1% by weight, especially 0.05-0.15% by weight.

As already mentioned above, the preferred solutions may contain a thickening agent to set the appropriate consistency, usually in concentrations of from 0.5 to 2% by weight. As an example of a preferred thickener is called hydroxypropylmethylcellulose.

Hydrochloric acid (e.g., IN-HCl) or caustic soda (e.g., IN-NaOH) is preferably used to adjust the pH.

Systemic effective pour-on formulations for use on the skin or in body cavities are infused, dripped, brushed, sprayed, rubbed, sprayed or bathed whereby the active ingredient permeates the skin and acts systemically. According to the invention, the use of the smallest possible volume in the form of a pour-on or spot-on application is preferred

The active ingredients are surprisingly low toxicity to warm-blood for combating coccidia according to the invention, which occur in livestock and livestock in livestock, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive strains. By controlling parasitic protozoa, it is intended to reduce disease, fatalities and impairments (for example, in the production of meat, milk, wool, hides, eggs, etc.) so that the use of the active substances makes it possible to achieve more economical and easier animal husbandry.

The coccidia include:

Mastigophora (Flagellata), e.g. Trypanosomatidae e.g. Trypanosoma brucei, T. gambiense, T. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani , L. tropica, such as Trichomonadidae e.g. Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda) such as Entamoebidae e.g. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.

Apicomplexa (Sporozoa) such as Eimereria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E. meleagrimitis, E.misis, E.necatrix, E.ninakohlyakimovae, E.ovis, E.parva, E.pavonis, E. perforans, E.phasani, E.piriformis, E. praecox, E. residua, E. scabra, E.spec, E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidiurn spec., Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I.spec, I. suis, Neospora caninum, N. hugesi, Cystisospora spec., Cryptosporidium spec. as Toxoplasmadidae eg Toxoplasma gondii, such as Sarcocystidae eg Sarcocystis bovicanis, S. bovihominis, S. neurona, S. ovicanis, S. ovifelis, S. spec, S. suihominis as Leucozoidae eg Leucozytozoon simondi, like Plasmodiidae eg Plasmodium berghei, P. falciparum , P. malariae, P. ovale, P. vivax, P. spec., Such as Piroplasmea eg Babesia argentina, B. bovis, B. canis, B. spec., Theileria parva, Theileria spec, as Adeleina eg Hepatozoon canis, H. spec ,

Further Myxospora and Microspora e.g. Glugea spec. Nosema spec.

Furthermore, Pneumocystis carinii, as well as Ciliophora (Ciliata), e.g. Balantidium coli, Ichthiophthirius spec, Trichodina spp., Epistylis spec

Of particular note are those protozoan genera and species that cause subclinical or clinical infections in pigs, in particular: Eimeria debliecki, E. suis, E. scabra, E. perminuta, E. spinosa, E. polita, E. porci, E neodebliecki, Isospora suis, Cryptosporidium, Toxoplasma gondii, Sarcocystis miescheriana, S. suihominis, Babesia trautmanni, B. perroncitoi, Balantidium coli.

The livestock and breeding animals include mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, chinchilla, raccoon, birds, e.g. Chickens, geese, turkeys, ducks, pigeons, ostriches, bird species for home and zoo keeping. It also includes farmed and ornamental fish. Particularly noteworthy are pigs, cattle, sheep and dogs in all species, subspecies and breeds.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

Hobby animals include dogs and cats.

The following examples are intended to illustrate the invention without, however, limiting it: Examples

I. Formulation Examples

Formulation 1

5% ponazuril or toltrazuril 0.1% butylhydroxyanisole ad 100% N-methylpyrrolidone Formulation 2

4% Toltrazuril

0.1% butylhydroxyanisole ad 100% Solketal

Formulation 3

10% ponazuril

2% benzyl alcohol

5% fumed silica (e.g., Aerosil 200) ad 100% dimethylacetamide

Formulation 4

10% Toltrazuril

3% n-butanol

0.1% butylhydroxyanisole ad 100% 2-pyrrolidone Formulation 5

5% Toltrazuril ad 100% Tetraglycol Formulation 6 20% Toltrazuril

0.8% hydroxypropylmethylcellulose 4000

79.2% N-methylpyrrolidone Formulation 7

20% toltrazuril 0.8% hydroxypropylmethylcellulose 4000

79.2% dimethylacetamide Formulation 8

20% Toltrazuril

1% hydroxypropylmethylcellulose 4000 10% isopropanol

69% N-methylpyrrolidone Formulation 9

20% Toltrazuril

1% hydroxypropylmethylcellulose 4000 10% oleic acid

69% N-methylpyrrolidone Formulation 10

5% Toltrazuril

ad 100% N-methylpyrrolidone

Formulation 11

20% Toltrazuril

1% hydroxypropyl methylcellulose 4000

10% dodecylazacycloheptan-2-one (Azone®)

ad 100% N-methylpyrrolidone

Formulation 12

20% Toltrazuril

1% hydroxypropyl methylcellulose 4000

10% limes

ad 100% N-methylpyrrolidone

Formulation 13

20% Toltrazuril

1% hydroxypropyl methylcellulose 4000

10% 1,8-cineole

ad 100% N-methylpyrrolidone

The substances are mixed and stirred until a clear solution is obtained. In this case, antioxidants are first dissolved in the solvent, the active ingredients added and then the

Thickener added. The preparation can also be carried out in a different order, for example by first adding the thickening agent to the solvent, then optionally adding the antioxidant and simultaneously or subsequently adding and dissolving the active ingredient. The solutions may (but need not) be finally filtered and transferred to suitable containers. II. Efficacy studies in animals:

A. Determination of serum concentrations of toltrazuril and ponazuril after pour-on administration in calves and rabbits

On day 0, three calves or rabbits each were administered the formulation of Example 10 externally at a dose of 20 mg per kg (body weight). At the times indicated in the tables, the serum concentrations of toltrazuril and its metabolite ponazuril (toltrazurilsulfone) were determined. The results are shown in Tables 1 and 2.

Table 1: Serum levels of toltrazuril / ponazuril in calves.

<LoQ = below the limit of quantitation [25 μg / L]

Table 2: Serum levels of toltrazuril / ponazuril in rabbits.

The present studies show that toltrazuril is percutaneously absorbed and metabolised after pour-on administration in both rabbits and calves.

B. Effectiveness of Toltrazuril pour-on against artificially induced infections in suckling piglets with Isospora suis:

3 groups of 4 to 11 animals were formed. Group A was infected with oocysts and treated with the Toltrazuril pour-on formulation according to Example 10. Group B was not infected but treated in the same way, with the dosage of Groups A and B being 20 mg / kg body weight, respectively. Group C was infected with oocysts but not treated with toltrazuril. The success of the treatment was determined by controlling the liveweight of the animals. For this purpose, the animals were weighed on different days and determined the weight gain of each animal. The results are shown in Table 3.

Table 3: average live weight per piglet (g)

* at the beginning of the study

As can be seen in Table 3, the weight of the infected Toltrazuril pour-on treated animals of group A is on average 1520 g higher than that of the infected, untreated animals of group C. These values clearly show that the formulation is effective in the desired form.

Claims

claims:

1. Use of triazines of the formulas (I) or (Et)

or

wherein

R ^{1 is} R ³ -SO ₂ - or R ³ -S-,

R ^{2 is} alkyl, alkoxy, halogen or SO ₂ N (CHj) ₂ and

R ^{3 is} haloalkyl

R ⁴ and R ⁵ independently of one another represent hydrogen or Cl and

R ^{6 is} fluorine or chlorine.

and their physiologically acceptable salts

2. Use of compounds of the formula (I) according to claim 1 for the transdermal treatment of pigs, sheep, cattle, dogs and cats.

Use according to claim 2 for the transdermal treatment of pigs.

4. Use according to claim 1 for the transdermal treatment of turkeys, geese or pigeons.

5. Use according to one of the preceding claims, wherein the active ingredient of the formulas (I) or (ET) in the transdermal administration is dosed approximately equal to or lower than in the oral application.

6. Use of toltrazuril according to one of the preceding claims.

7. Use of ponazuril according to one of claims 1 to 5.