Veterinary compositions for use against endoparasites, and their preparation

Abstract: The invention relates to veterinary compositions suitable against endoparasites containing as active ingredient at least one pyrethroid derivative of the general formula I - wherein R and R¹ represent a C₁₋₄ alkyl group or halogen atom, Z represents a group of the general formula a) or b) or c) - H - R² (a) or the isomeric mixture thereof in whatever ratio and optionally a benzimidazole derivative of the general formula II or an aniline derivative of the general formula III - wherein Y represents -O-, -S-, -NH-, -CO-, -SO-, -SO₂- or a valence line, R⁴ represents hydrogen atom, C₁₋₄ alkyl group or C₂₋₅ alkoxycarbonyl group or phenyl group, R⁵ stands for a group of the general formula -NH-COOR⁹ or 4-thiazolyl group, R⁶ stands for hydrogen atom, C₁₋₄ -S-alkyl or -S-phenyl group, R⁷ stands for -NO₂ or -NHR¹⁰ group, R⁸ stands for a group of the general formula -CSNHCOOR¹¹ or -C(NR¹²)NHCOOR¹³ or -COCH₂OR¹⁴, in an amount of 0.5-50 weight%, while optionally the ratio of the active ingredients of the general formulae I and II or III is 1:7-1:1, in addition to the filling, diluting and other auxiliary agents generally used in veterinary therapeutics. The invention relates, furthermore, to a process for the preparation thereof.

Description: The invention relates to veterinary compositions for use against endoparasites, containing as active ingredients a pyrethroid and albendazole. The invention thus provides a veterinary composition for use against endoparasites which contains as active ingredients: (a) alpha-(cyano)-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylic acid-3-phenoxybenzyl ester or any isomeric mixture thereof; and (b) 5(6)-propylthio-2-benzimidazolyl-methylcarbamate, in an amount of 0.5-50 weight %, the ratio of the active ingredients being 1:7-1:1, in addition to the filling, diluting and other auxiliary agents generally used in veterinary therapeutics. The compositions of the invention can be prepared by mixing the active ingredients in an amount of 0.5 to 50 weight % with filling, diluting and other auxiliary agents generally used in veterinary therapeutics, and transformed into veterinary compositions. The active ingredients are used in a form which is suitable for use in the veterinary therapeutics, such as: compositions for oral administration, such as pastes, emulsions, suspensions (drenches), granules, powders, tablets, boluses, furthermore the so-called pour on (more liquid) and spot on (more concentrated) compositions which can be applied on to the skin surface. The pour on and spot on compositions, which are poured onto the intact skin surface, are prepared by dissolving the active ingredient(s) in a suitable solvent or solvent mixture, by suspending or emulsifying. The stability and usability of the individual oral compositions according to the invention is optimal if they are in the form of inoculated lyotropic liquid crystals. The inoculated lyotropic liquid crystalline veterinary compositions of the invention contain the above described active ingredients having a particle size under 100 µm in an amount of 0.5-50 weight%, 5 to 55 weight% of surfactants containing at least 8 carbon atoms, 0 to 67 weight% of water or an aqueous solution of non-surfactants, 0 to 40 weight% of water immiscible, water miscible or partly miscible solvents or a mixture thereof, or a water immiscible or partly miscible organic solvent solution of non-surfactants, 0 to 60 weight% of co-surfactants or mixtures thereof and optionally other additives, where the total amount of water, water miscible, immiscible or partly miscible solvents and the co-surfactants is 15 to 94.5 weight%. These compositions may be prepared by inoculating the other ingredients with the active ingredients having a particle size under 100 µm. If desired, further additives are then added to the composition obtained. As surfactants ionic (anionic and cationic) and/or non-ionic and/or amphoteric tensides may be used; as anionic tensides the salts of carboxylic acids (such as fatty acid soaps); sulphates (such as alkylsulphates, e.g. sodiumdodecylsulphate); salts of sulphonic acids, such as alkylbenzensulphonates; phosphates, such as alkylphosphates and the salts thereof; the esters of ethoxylated fatty alcohols formed with inorganic acids (preferably with sulphuric acid, phosphoric acid) and the salts thereof; as cationic tensides ammonium salts (such as cetyl-trimethylammoniumhalogenides), quaternary nitrogen containing compounds (such as N--alkyl-pyridinium salts); alkylamines or the salts of adducts formed of alkyl amines or alkylamides with ethyleneoxide (such as oxyethylated coconut fatty acid amide); as non-ionic tensides fatty acid esters of multivalent alcohols (such as oxyethylated dianhydrosorbit-stearates-O-phosphoric acid trialkyl ester); ethylene oxide adducts (such as fatty acid-polyethylene-glycolesters, fatty alcohol-ethyleneoxide-adducts, adducts of alkylphenols formed with ethyleneoxide, alkyl-phenolpoly(glycolether)); adducts of alkylamines or alkylamides formed with ethyleneoxide, poly(propylenglycols)-ethyleneoxide-adducts, alkyl(polyethylenglycolether)-O-phosphorus acid triesters; as amphoteric tensides, preferably the inner salts of betaines or phophorus acid derivatives formed with choline can be used. As solvent water, aliphatic and/or aromatic solvents, such as mineral oils and ketones of low molecular weight, mono or multivalent alcohols and esters, plant and animal oils C₁₋₆ saturated or unsaturated and above C₆ unsaturated carboxylic acids can be used. As co-surfactants alcohols, ketones and esters, containing one or more polar group(s), such as fatty alcohols (e.g. i-octanol, dodecanol) can be used. In the inoculated liquid crystalline compositions of the invention preferably a mixture of ionic and non-ionic surface active agents is used as surface active agent in a total amount of 6-10 weight%. The veterinary compositions of the invention can preferably be used against the insects and arthropodous erdoparasites of different domestic and farm animals as well as in diagnosis. Helminthoses arising and often frequent among farm animals cause significant economic damage. According to estimates the gross profit in the cattle and sheep population is by 20-40 US $ less per capita than would be expected on the basis of the genetic abilities. Among the economic losses the damage caused by parasites have an increasingly greater role in addition to the animal keeping, feeding and other veterinary problems. The endoparasites take the nutritive material necessary for their survival and multiplication from the host. The production of farm animals and sometimes even their life is exposed to danger. The scope of the active ingredients used by the protection against nematodes is wide. These are for example phenotiazine, benzimidazoles, imidazoles, pyrimidines, pyridines, ivermectin, different organic phosphate esters, piperazine, isothiocyanate, certain substituted phenols and salicylanilides. The protection against internal parasites is extremely difficult because of the condition that in addition to nematodes, trematodes and cestodes livestock can be infected also by articulata. The articulata belonging to the species of Dipteras are e.g. the horse bot flies (Gastrophilidae) causing the bottenness of horses, the gad-flies causing the gad-fly larva disease of cattle skin (Hypodermatidae) and the gad-flies (Oestridae) causing the gad-fly larva disease of snouts of sheep. The current anthelmintics - except ivermectin - are, however, ineffective against Dipteras. Therefore per os administered phophate ester type insecticides are used against these flies by themselves or combined with an anthelmintic. Such a composition is Rintal Plus (Bayer), which is a mixture of a probendazole - namely phebantel - and trichlorfon in a ratio of 1:5 with an active ingredient content of 42.7 weight%. An analogous composition is Combotel. Another composition containing mebendazole and trichlorfon in a ratio of 8.8:40 is Telmin B. The composition Equizole-B (Merck) contains also thiabendazole and trichlorfon in a ratio of 44:40. Mixtures of oxybendazole:trichlorfon are used in similar manner in ratios of 1:3.5 (Vet. Med., 1985, April p.68) and 1:3 (Vet. Rec., 1986, Sept., p. 294). Another phophate ester, dichlorvos (Astrobot), is also widely used. Such compositions are Equigard and Equigel (Squibb). The organic phosphate ester insecticides effective for colinerg synapses are, however, not selective and their oral administration is therefore very hazardous. Their therapeutic index is so low that even a double overdose has a toxic effect. As it is known, horses are sensitive to treatment with trichlorfon (Vet. Med., 1985, April, p. 68), resulting in diarrhoea, frequent defecation and urination. The treatment of animals in poor health and bad condition is therefore contraindicated. Among insecticides pyrethroids have developed fastest during the last decades. Already more than 20 active ingredients are at the disposal of agricultural, veterinary and sanitarian use. But compositions containing a pyrethroid as active ingredient usable against the endoparasite articulata of farm animals are unknown. The possible reason for this is that pyrethroids, as insecticides effective against adult flies and having knock down activity, are known and no practical importance has been attached to their activity against larvae of flies and worms. One of the most important characteristics of the pharmaceutical compositions is the quotient of toxic and therapeutic dosage, the so-called therapeutic index characterising the safety of use. The higher is this value, the smaller is the risk in use, and the more selective is the active ingredient. In view of the unfavourable selectivity of the current active ingredients against endoparasite articulata, the aim was to develop a composition the effectivity of which is better and the therapeutic index of which is higher. For this purpose the activity of several pyrethroid insecticides has been tested by themselves or in combination with different benzimidazole type anthelmintics on flies (Musca domestica). Considering the complete larval development it was found that several (in themselves ineffective) benzimidazole derivatives significantly increased the effectivity of pyrethroids. This synergistic interaction was shown not only in the decrease of the therapeutic concentrations but also on the activity of the sublethal doses to the development. The body mass of the larvae has been decreased and from the little aurelias evolved during the long development, often deformed imagos, unsuitable for further multiplication, were hatched out. The synergistic interaction has made possible a decrease of the therapeutic dose of the orally administered insecticide. On the basis of the results of the examinations and toxicity data the therapeutic dose usable for treating bot infection of horses were determined in field trials. Surprisingly it was found that some pyrethroids and pyrethroid + benzimidazole mixtures were so effective against the larvae (bots) of the parasite Gastrophylus species that - considering also their warm blooded toxicity - their selectivity index was by two orders higher than that of the compositions having similar indication field. The therapeutic indexes of current anthelmintics and Transmix, each having insecticidal activity and suitable for per os administration, are shown in Table 1. Anthelmintic/ insecticide Toxicity acute per os LD₅₀ (mg/kg) Therapeutic dose (mg/kg) Therapeutic index (selectivity) Dichlorvos 56 5 11 Trichlorfon 450 30 15 Ivermectin 10 0.2 50 Transmix 5000 2 2500 Example 1 For examining the interaction between benzimidazoles and pyrethroids the larvae of domestic flies in L₃ status (Musca domestica WHO/SRS) were used as model organism. A nutrient suitable for breeding fly larvae was prepared from yeast, milk, bran and water and portioned into plastic glasses. Acetonic strain solution was prepared from the active ingredients and after dilution the amounts necessary for achieving the desired active ingredient concentrations were added to the nutrient in the plastic glasses. The examinations were carried out with total active ingredient concentrations of 1, 5, 10, 50, 100 and 200 ppm in 6 parallel per concentration. Into the plastic glasses containing the treated culture medium 20-20 domestic fly-larvae of L₃ status were placed after weight measurement. The glasses were covered by gauze and after 12 days the hatched imagos were counted. In the control containing only solvent the hatching ratio was 91 %, the average weight of the hatched flies were 18.2 mg. The results are shown in Table 2. Active ingredient Concentration (ppm) 1 5 10 50 100 200 number of hatched imagos (from 120 L₃) Chinmix 90 62 47 27 4 0 Transmix 108 112 89 64 39 18 Albendazole 111 113 107 112 107 109 Chinmix + Albendazole 91 44 25 15 0 0 Transmix + Albendazole 110 95 63 34 21 3 Transmix + Albendazole 106 98 69 44 26 0 Example 2 Fly larvae of L₃ status were grown in identical manner as in Example 1, on a nutriment having a total active ingredient concentration of 5 and 10 ppm. The average body mass of the larvae before hatching and of the imagos after treatment is shown in Table 3. Active ingredients Concentration (ppm) 5 10 average body mass (hatching %) Chinmix 10.3 (53) 7.8 (41) Transmix 12.9 (98) 9.6 (84) Abendazole 18.3 (100) 17.8 (100) Chinmix + Albendazole 7.3 (43) 4.2 (25) Transmix + Albendazole 9.5 (88) 5.6 (61) The data of the Table show that the combinations give an outstanding result not only concerning the mortality values. The treatments with sublethal dose significantly hinder the puparial development which is shown by the decreased body weight of the hatching imagos. The decreased vitality and issue producing of the flies having smaller body weight further increases the effectivity of treatments. Example 3 A trial was carried out in June, 1988 on 24 horses aged 2-5 years (13 geldings, 8 mares, 3 stud horses; types : 8 gidrans and 16 Hungarian halfbreeds). 18 horses divided into two groups (in group A 6, in group B 12) were treated per os with the composition of Example 4 in a dose of 20 g/600 kg (= 10 mg/kg albendazole + 1.5 mg/kg transmix). To the control animals (6 horses) a paste was given which did not contain active ingredient. After the addition of the composition of Example 4 and the control paste with no active ingredient content, all the removed Gasterophylus intestinal larvae were determined in the spontaneously defecated faeces samples for 72 hours. The results are shown in Table 4. Animal group number Total number of collected larvae (pieces) A 6 302L₃ + 24L₄ B 12 48L₃ Control 6 - A + B 18 350L₃ + 24 L₄ Example 4 110 g of saccharose was dissolved in 256.5 g of ion exchanged water at 35 °C. The solution was cooled to 20 °C and 50 g of propyleneglycol, 75 g of Tween 60 (ICI) were added to the solution. To the solution mixed with a stirrer (Vitra Turrex) of high shearing force, 333 g os Albendazole, then 50 g of Transmix were added. When preparing the suspension the mixture was cooled so that the temperature did not exceed 40 °C. To the solution, 12 g of fatty alcohol polyglycolether dissolved in 108 g of paraffin oil and then a solution of 4.5 g of 96 % alcohol and 1 g of Nipagin is added. The suspension is homogenised for 30 seconds by using a high shearing force. The composition shows a microscopic picture characteristic of lyotropic liquid crystals. The agents used in the specification correspond to the following active ingredients: ivermectin: dihydro-avermectin B₁ febantel: (2-(2-methoxyacetamido)-4-(phenylthio)phenyl)-imidocarbonyl-dimethyl-dicarbamate trichlorofon: 2,2,2-trichloro-1-hydroxyethyl-phosphonic acid dimethylester mebendazole: 5(6)-benzoyl-benzimidazole-N-methylcarbamate thiabendazole: 2-(4¹-thiazolyl)-benzimidazole oxybendazole: 5(6)-propoxybenzimidazole-N-methylcarbamate dichlorvos: 2,2-dichlorovinyl-phosphonic acid dimethylester albendazole: 5(6)-propylthio-benzimidazole-N-methylcarbamate transmix: α-cyano-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylic acid-3-phenoxybenzylester 1RtransS and 1StransR enantiomer pair chinmix: α-cyano-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylic acid-3-phenoxybenzylester a mixture of the enantiomer pairs of 1RcisS + + 1ScisR and 1RtransS + 1StransR in a ratio of 55:45 - 25:75.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, NL A veterinary composition for use against endoparasites which contains as active ingredients: (a) alpha-(cyano)-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylic acid-3-phenoxybenzyl ester or any isomeric mixture thereof; and (b) 5(6)-propylthio-2-benzimidazolyl-methylcarbamate, in an amount of 0.5-50 weight %, the ratio of the active ingredients being 1:7-1:1, in addition to the filling, diluting and other auxiliary agents generally used in veterinary therapeutics. A composition according to claim 1 which is in the form of an inoculated lyotropic liquid crystalline composition containing the active ingredients in a particle size under 100 µm, and contains 5 to 55 weight % of surfactants containing at least 8 carbon atoms, 0 to 67 weight % of water or an aqueous solution of non-surfactants, 0 to 40 weight % of water immiscible, water miscible or partly miscible solvents or mixtures thereof, or a water immiscible or partly miscible organic solvent solution of non-surfactants, 0 to 60 weight % of co-surfactants or mixtures thereof and optionally other additives, where the total amount of water, water miscible, immiscible or partly miscible solvents and the co-surfactants is 15 to 94.5 weight %. A composition according to claim 2, characterised in that the surface active component is a mixture of ionic and non-ionic surface active agents and the total surface active agent content is between 6 and 10 weight %. A process for preparing a veterinary composition according to any preceding claim, which comprises mixing the active ingredients with the other ingredients of the composition. The use of the active ingredients (a) and (b) as defined in claim 1 in the manufacture of veterinary compositions for use against endoparasites. Claims for the following Contracting States : ES, GR A process for preparing a veterinary composition for use against endoparasites which contains as active ingredients: (a) alpha-(cyano)-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-carboxylic acid-3-phenoxybenzyl ester or any isomeric mixture thereof; and (b) 5(6)-propylthio-2-benzimidazolyl-methylcarbamate, in an amount of 0.5-50 weight %, the ratio of the active ingredients being 1:7-1:1, in addition to the filling, diluting and other auxiliary agents generally used in veterinary therapeutics, which comprises mixing the active ingredients with the other ingredients of the composition. A process according to claim 1 in which the ingredients are mixed so as to form an inoculated lyotropic liquid crystalline composition. A process according to claim 2 in which the active ingredients have a particle size under 100 µm. A process according to claim 3 in which a solution containing 5 to 55 weight % of surfactants containing at least 8 carbon atoms, 0 to 67 weight % of water or an aqueous solution of non-surfactants, 0 to 40 weight % of water immiscible, water miscible or partly miscible solvents or mixtures thereof, or a water immiscible or partly miscible organic solvent solution of non-surfactants, 0 to 60 weight % of co-surfactants or mixtures thereof and optionally other additives, where the total amount of water, water miscible, immiscible or partly miscible solvents and the co-surfactants is 15 to 94.5 weight %, is inoculated with the active ingredients, and if desired further additives are added to the composition obtained. A process according to claim 4, in which the surface active component is a mixture of ionic and non-ionic surface active agents and the total surface active agent content is between 6 and 10 weight %. The use of the active ingredients (a) and (b) as defined in claim 1 in the manufacture of veterinary compositions for use against endoparasites.

Inventors: GROSCH JANOS, MARMOROSI KATALIN, NAGY LAJOS, PAP LASZLO, SARKOZY PETER, SZEGO ANDRAS, SZEKELY ISTVAN, GROSCH, JANOS, MARMOROSI, KATALIN, NAGY, LAJOS, PAP, LASZLO, SARKOZY, PETER, SZEGO, ANDRAS, SZEKELY, ISTVAN
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1989
Main classification: A61K31
IPC codes: C07D209, A61K31, C07D307, C07C69, C07D235, A61P33