A pharmaceutical composition, medicated drinking water, their use and method of preparing medicated drinking water

Abstract

The subject according to the invention is a pharmaceutical composition comprising at least one isoxazoline compound of formula (I) or a salt or solvate thereof and a pharmaceutical acceptable carrier, administered orally via drinking water, comprising an ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7-21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH and a surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules. The subject according to the invention is also a medicated drinking water comprising the composition according to the invention, use of the composition and water according to the invention and a method for preparing the water according to the invention.

Description

[0001] A pharmaceutical composition, medicated drinking water, their use and method of preparing medicated drinking water

[0002] The invention relates to the field of pharmaceutical compositions and medicated drinking waters comprising isoxazolines, their use in animals and their method of preparation.

[0003] Isoxazolines are known in the art and compounds of this class are known to be active against parasites in animals. Although different routes of administration are known, the administration of the active ingredients via drinking water systems to intensively reared animals such as pigs and poultry is beneficial because it allows simultaneous administration to a large number of animals during a defined time period. Accordingly, isoxazolines and compositions comprising such compounds adapted for administration to animals via a drinking water system are being developed and marketed. An example is the composition which is the subject of patent EP3082867, the entire text of which is hereby incorporated by reference.

[0004] The composition according to EP3082867 - as described - solves the problems of stability and availability of the active substance in the composition and drinking water system. However, the invention according to EP3082867 and other similar solutions also have limitations and disadvantages. Firstly, the excipients used there are not permitted in feeds in the territory of the European Union, due to the lack of full toxicological studies. Meanwhile, according to the feed law, animal feed should be properly tested and permitted as it can affect animals by, among others, generating unknown metabolites are potentially toxic. Even compounds that are not toxic can produce toxic metabolites. For example, the key solvent for EP3082867 - diethylene glycol monoethyl ether - has not been tested. Therefore, substances that are not compliant with feed law pose a risk to the safety of animals, people and the environment, and the biodegradability and toxicity of such substances and their metabolites are unknown. This is particularly important due to the large-scale use of the product within a single farm and globally. Pharmaceutical ingredients also negatively affect the price of the product. At the same time, it is obvious to the expert, and EP3082867 additionally confirms it that the development of a stable and effective composition for use in a complex drinking water system is a complicated and inventive process.

[0005] Therefore, the aim of the present invention is to provide an alternative pharmaceutical composition comprising an isoxazoline, which solves the previous technical problems - stability (especially in terms of segregation and sedimentation) and ensures appropriate effectiveness (especially after dilution in drinking water). And at the same time, it is based on ecologically, safety and financially acceptable ingredients, which are approved for use in the European Union. These and other technical problems are solved by the present invention, and in addition it unexpectedly improves the solubility of the composition according to the invention in drinking water for animals, improves stability, has a beneficial effect on the preparation process and administration of the composition and the costs associated with it. The invention directly excludes substances that are inconsistent with feed law or untested, especially those used as main excipients in EP3082867 (e.g. diethylene glycol monoethyl ether and polysorbate surfactant).

[0006] The subject of the present invention is a pharmaceutical composition comprising at least one isoxazoline of formula (I) wherein

[0007] R1= halogen, CF3, OCF3, CN, n = integer from 0 to 3, preferably 1 , 2 or 3,

[0008] R2= Ci-C3-haloalkyl, preferably CF3or CF2CI,

[0009] T = 5- or 6-membered ring which is optionally substituted by one or more radicals Y,

[0010] Y = methyl, halomethyl , halogen, CN, NO2, NH2-C=S or two adjacent radicals Y form together a chain, especially a three- or four-membered chain;

[0011] Q= X-NR3R4or 5-membered N-heteroaryl ring which is optionally substituted by one or more radicals;

[0012] X = CH2, CH(CH3), CH(CN), CO, CS,

[0013] R3= hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylammocarbonylmethyl, haloethylammocarbonylcyclopropyl,

[0014]

[0015] S’ . I! RS.12 R:-13 R 4 R*-15 wherein

[0016] ZA= hydrogen, halogen, cyano, halomethyl (CF3); R4= hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl ; or R3and R4together form a substituent selected from the group consisting of: or a salt or solvate thereof, and a pharmaceutically acceptable carrier, administered orally via drinking water, characterized in that it comprises an ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7- 21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH, a surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 ethylene oxide molecules. Preferably, the composition according to the invention is characterized in that the isoxazoline compound is fluralaner .

[0017] Preferably, the composition according to the invention is characterized in that it comprises from 0.01% to 5% by weight of fluralaner .

[0018] Preferably, the composition according to the invention is characterized in that the weight ratio of ester to surfactant is from 5:95 to 95:5.

[0019] Preferably, the composition according to the invention is characterized in that the composition additionally comprises a solvent, an ether, an antifoaming agent, a preservative and / or an antioxidant, preferably vitamin E.

[0020] Preferably, the composition according to the invention is characterized in that the ester is ethyl acetate.

[0021] Preferably, the composition according to the invention is characterized in that the surfactant is macrogolglycerol ricinoleate ethoxylated with 36 ethylene oxide molecules.

[0022] The subject according to the invention is also a medicated drinking water characterized in that it comprises a mixture of the composition according to the invention and water.

[0023] Preferably, the water according to the invention is characterized in that it comprises from 0.001 to 1 mg / ml of the isoxazoline compound according to the invention.

[0024] The subject according to the invention is also the composition according to the invention or the water according to the invention, characterized in that it is for use in the prevention or treatment of parasite infestations of animals.

[0025] Preferably, the composition or the water for use according to the invention is characterized in that the animals are selected from pigs and poultry.

[0026] More preferably, the composition or the water for use according to the invention is characterized in that the animals are laying hens.

[0027] Preferably, the composition or the water for use according to the invention is characterized in that the parasite infestation is a mite infestation.

[0028] More preferably, the composition or the water for use according to the invention is characterized in that the mite infestation is an infestation with Dermanyssus sp. or Ornithonyssus sp.

[0029] Finally, the subject according to the invention is also a method of preparing the water according to the invention characterized in that the composition according to the invention is diluted by administration through a dosing pump system in a water system or by mixing with water in a medication tank.

[0030] The invention comprises the use of racemic mixtures, for example, equal amounts of enantiomers of such isoxazoline compounds as described above. Furthermore, the use according to the invention includes isoxazoline compounds that are enriched compared to the racemic mixture in an enantiomer of Formula 1 . Also included are essentially pure enantiomers of such isoxazoline compounds. When enantiomerically enriched, one enantiomer is present in greater amounts than the other, and the extent of enrichment can be defined by the expression enantiomeric excess ("ee"), which is defined as (2x-1 )-100%, where x is the mole fraction of the dominant enantiomer in the mixture (e.g., an ee of 20% corresponds to a 60:40 ratio of enantiomers). Preferably, the compositions for use in the invention have at least a 50% enantiomeric excess; more preferably at least a 75% enantiomeric excess; even more preferably at least a 90% enantiomeric excess; and most preferably at least a 94% enantiomeric excess of the more active isomer. Of particular note are enantiomerically pure embodiments of the more active isomer. Isoxazoline compounds as described above can comprise additional chiral centers. The use of this invention comprises racemic mixtures as well as enriched and essentially pure stereo configurations at these additional chiral centers. The reference to isoxazoline compound in this specification includes enantiomers, salts, and solvates as well as N-oxides thereof which can be prepared by conventional methods.

[0031] By "treating" or "treat" or "treatment" is intended, the application or administration of a composition according to the invention to an animal that has a parasite infestation for the eradication of the parasite or the reduction of the number of the parasites infesting such animal. The effect of the composition according to this invention can be e.g. ovicidal, larvicidal and / or adulticidal or a combination thereof. The effect can manifest itself directly, i.e. killing the parasites either immediately or after some time has elapsed, for example when molting occurs, or by destroying their eggs, or indirectly, e.g. reducing the number of eggs laid and / or the hatching rate.

[0032] "Prophylaxis" or "prevention" means that a new infestation of the animal with parasites is prevented by killing adult parasites and any development / larval stage, that is able to infest the host, before infestation of the host or directly after infestation of the protected host or by preventing generation of offspring of the parasites e.g. reducing the number of eggs laid and / or the hatching rate. An "effective amount," is the amount or quantity of an isoxazoline compound that is required to alleviate or reduce parasite numbers on an animal and / or in an animal’s environment e.g. the house / building, and / or to inhibit the development of parasite infections in an animal, in whole or in part. This amount is readily determined by observation or detection of the parasite numbers either on the animal on in an animal’s environment (e.g. by a trap) both before and after administering an isoxazoline compound via drinking water to such animals e.g. the parasite count is reduced, after a first administration, by 5% to 100%.

[0033] Hence, one aspect of the current invention is the pharmaceutical composition according to the invention comprising such composition for use in the prevention or treatment of parasite infestations. Such parasite infestations can be either infestations by ectoparasites or endoparasites. In one embodiment the parasite infestation that is prevented or treated is an ectoparasite infestation.

[0034] The composition according to the invention is preferably administered by systemic administration routes. "Systemic administration" is an administration at a site remote from a site wherein at least a portion of the target parasites reside. With systemic administration, at least a portion of the compound reaches the target parasite via the animal recipient’s bloodstream, other body fluids (lymph fluids), and / or tissues (e.g., skin or fat tissue). Typically, the parasite ingests the compound along with the animal recipient’s blood, other body fluids, and / or tissue. Systemic administration may be achieved in several forms, e.g. oral, parenteral or topical.

[0035] It has been shown that the pharmaceutical compositions according to the invention, which comprise the isoxazoline compounds described herein, and in particular fluralaner, are stable and effective in the prevention and treatment of parasite infestations in animals. Particularly preferably, no precipitation of the isoxazoline compound has been observed after dilution of the composition according to the invention in drinking water, and the composition according to the invention itself has increased stability, especially in comparison with the pure substance. It has also been shown that the solubility of the active substance is greater and that the stability of the composition according to the invention is greater despite the increased concentration of the active substance. This in turn has a positive effect on the cost of production, transport and thus the price of the product. At the same time, the invention solves the problem of untested and / or non-compliant feed excipients and therefore also the risk of toxicity and biodegradability of the substances and their metabolites. It has also been shown that such compositions are suitable for the preparation of medicated water according to the invention, which is sufficiently stable and can be distributed homogeneously in the system to enable the administration of an effective amount of the isoxazoline compounds to animals via drinking water systems. Finally, it surprisingly turned out that the composition according to the invention and the medicated drinking water according to the invention have additional insectrepellent properties and are also more acceptable to animals and humans. Example 1

[0036] The required quantity of surfactant, solvent and excipients were weighed, mixed and homogenized until a visually homogeneous mixture was obtained. Such a pharmaceutical composition can be prepared by methods known in the art. Such methods include, for example, various known mixing, dissolving and emulsifying methods. In one embodiment, the active ingredient (isoxazoline compound) was added to the surfactant / solvent mixture under deflocculated paddle stirring and the mixture was stirred under deflocculated paddle stirring until visually homogenous mixture was obtained (complete dissolution). The following compositions (concentrated solutions) comprising 5% w / w of the isoxazoline compound were prepared in this manner. Table I is presented for fluralaner, but the tests were successfully repeated for other isoxazolines, results of which are not presented here for clarity. Other particularly preferred isoxazolines include afoxolaner, sarolaner, fluralaner and lotilaner. The composition according to the invention comprises fluralaner and / or the other isoxazolines alone or in combination without departing from the scope according to the invention. Table I. Composition of the tested samples of the compositions according to the invention

[0037] The solutions were stable for at least 12 months at 25°C / 60%RH and 40°C / 75%RH.

[0038] What is worth emphasizing - the composition according to the invention is just as stable as the one disclosed in EP3082867 despite dissolving 5x more active substance. This provides a 5x more concentrated composition according to the invention, reducing production and transport costs.

[0039] Rokacet R 36 P is a macrogolglycerol ricinoleate ethoxylated with 36 ethylene oxide molecules. According to the calculations of the inventor, which were also confirmed experimentally, it is possible to use a macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules. And instead of ethyl acetate, it is possible to use another ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7-21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH.

[0040] The isoxazoline compound used in the embodiments can therefore be generally represented as a compound of formula (I) wherein

[0041] R1= halogen, CF3, OCF3, CN, n = integer from 0 to 3, preferably 1 , 2 or 3,

[0042] R2= Ci-C3-haloalkyl, preferably CF3or CF2CI,

[0043] T = 5- or 6-membered ring which is optionally substituted by one or more radicals Y,

[0044] Y = methyl, halomethyl , halogen, CN, NO2, NH2-C=S or two adjacent radicals Y form together a chain, especially a three- or four-membered chain;

[0045] Q= X-NR3R4or 5-membered N-heteroaryl ring which is optionally substituted by one or more radicals;

[0046] X = CH2, CH(CH3), CH(CN), CO, CS,

[0047] R3= hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, wherein

[0048] ZA= hydrogen, halogen, cyano, halomethyl (CF3);

[0049] R4= hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl; or R3and R4together form a substituent selected from the group consisting of:

[0050] In a preferred embodiment, the isoxazoline compound disclosed above is present in the composition according to the invention in quantity up to 5% by weight. Such a pharmaceutical composition is also referred to as a "concentrated pharmaceutical composition" or as a "concentrated solution". In a preferred embodiment, the isoxazoline compound is fluralaner. In a particularly preferred embodiment, fluralaner is present in the composition according to the invention in quantity from 0.01% to 5% by weight.

[0051] The ester derived from a saturated or unsaturated alcohol from CH3OH to CioH7-2iOH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH is generally present in the composition according to the invention in quantity of about 5 % to about 95% by weight of the carrier. In some embodiments, the ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7-21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH is present in quantity from about 10% to 75% by weight, from about 15 % to about 60 % by weight, from about 20% to about 55%, or from about 25% to about 50% by weight, or about 12.5%, 25%, or 37.5% by weight of the carrier.

[0052] In one preferred embodiment, the composition further comprises at least one additional solvent. In one preferred embodiment, the composition further comprises ethyl lactate. In some embodiments, the ethyl lactate is present in quantity from about 10% to about 50% by weight or from about 10% to about 40% by weight or about 12.5%, 25%, or 37.5% of the carrier. Preferably, the ratio of the ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7-21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH to the additional solvent, such as ethyl lactate, is about 75% / 25% w / w. In another preferred embodiment, the additional solvent is a pyrrolidone solvent, such as 2 pyrrole. In some embodiments, 2 pyrrole is present in quantity from about 10% to about 30% by weight, or about 12.5% or 25% by weight of the carrier.

[0053] Surfactants in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules have shown preferable properties in the composition according to the invention. Generally, one or a combination of more than one surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules may be present. On contact with water, a surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules forms micelles around the isoxazoline compound, which is dissolved in an ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7-21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH and keeps the isoxazoline compound dissolved in an aqueous medium. Esters additionally allow to lower the dissolution temperature and density of the composition, and thus improve the manufacturing process and its costs.

[0054] In a particularly preferred embodiment, the surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules is macrogolglycerol ricinoleate ethoxylated with 36 ethylene oxide molecules.

[0055] The surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules is present in the composition in quantity from about 5% to about 95% by weight of the carrier. In some embodiments, the concentration of the surfactant in form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules is from about 5% to about 89% by weight, from about 30% to about 80% by weight, from about 50% to about 75% by weight, or about 75% by weight of the carrier. In a preferred embodiment, the weight ratio of the ester to the surfactant is from 5:95 to 95:5. In a preferred embodiment, the ratio of the ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7-21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH to the surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules is < 50:50% w / w, preferably 15 / 85, 20 / 80, 25 / 75, 30 / 70, 35 / 65, 40 / 60% w / w. In one embodiment the ratio is preferably about 25 / 75% w / w. It has been found that this gives particularly stable compositions with increased solubility of the active ingredient.

[0056] Moreover, the composition according to the invention may comprise other inactive ingredients, excipients, carriers and vehicles known to those skilled in the art. In a preferred embodiment, the composition according to the invention also comprises an antifoaming agent, such as, for example, simethicone, sodium oleate, sodium caprylate or mixtures thereof. The antifoaming agent is present in a sufficient concentration to prevent foam formation when the composition according to the invention is diluted with water. Simethicone may be present in a concentration of from about 0.001% by weight to about 0.005% by weight of the carrier. In another preferred embodiment, the composition according to the invention comprises an ether. In yet another preferred embodiment, the composition according to the invention comprises a preservative. The preservative is known to those skilled in the art and may be, for example, benzyl alcohol, sodium butyl paraben, sodium methyl paraben, sodium propyl paraben and mixtures thereof. It is generally present in an quantity of from about 0.01 % to about 3% by weight of the carrier. In a further preferred embodiment, the composition according to the invention comprises an antioxidant. The antioxidant is an antioxidant known to those skilled in the art and may be, for example, butylated hydroanisole, butylated hydrotoluene, tocopherol (vitamin E) and its derivative as a-tocopherol polyethylene glycol succinate, and mixtures thereof. It is generally present in a quantity of from about 1% to about 10% by weight of the carrier.

[0057] Example 2

[0058] Sebsequently, from the above samples, the composition defined in Table II was selected as particularly preferable in terms of stability, and then its solubility in purified water was tested at five concentrations (% by weight) - sample A: 0.1 , sample B: 1 .0, sample C: 2.0, sample D: 4.0 and sample E: 10.0. The turbidity and the presence of precipitate were visually assessed at 7 time points at 25°C / 60%RH: 1 hour, 4 hours, 8 hours, 16 hours, 24 hours, 36 hours and 48 hours after dissolution. In none of the samples was turbidity or precipitate observed at the time tested (up to 48 hours). Thus, the composition according to the invention dissolves completely in water and is stable for the typical period of administration in the form of medicated drinking water. Table II. Qualitative and quantitative composition of the preferred embodiment of the composition according to the invention

[0059] Example 3

[0060] The pharmaceutical composition according to the invention is intended for use in the preparation of a medicated drinking water for administering a drug to an animal via the drinking water. The medicated drinking water is generally a drinking water that comprises a pharmaceutically active ingredient and water. Such medicated drinking water was prepared by mixing and diluting a quantity (volume) of the pharmaceutical composition according to the invention with water to a required concentration of the isoxazoline compound that provides an effective amount of the isoxazoline compound for the number of animals treated with a volume of drinking water that substantially corresponds to the volume that is consumed by the animals during the treatment period.

[0061] A prediluted (micellar) solution which can be used for the preparation of a medicated drinking water as described above can be prepared from the composition according to the invention as described above (concentrated solution) by mixing with a defined volume of drinking water. Such prediluted solution can be further diluted in 1 to 5 steps to prepare a medicated drinking water. Such prediluted solution comprises 1 to 85% v / v water, especially 1 , 5, 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80 or 85%.

[0062] In one embodiment, the composition according to the invention, in particular according to examples 1 and 2, was administered in a medication tank by diluting the composition according to the invention in water. In another embodiment, the composition according to the invention was diluted by administration through a dosing pump system in a water system. Thus, one aspect according to the invention is a method for preparing medicated drinking water, wherein the pharmaceutical composition is diluted by injection through a dosing pump system in a water system or by mixing with water in a medication tank. In this way, the pharmaceutical composition is made available during the treatment period to one animal; or at the same time to a group of animals or to all animals in one stable (hen house) or farm by means of medicated drinking water.

[0063] The pharmaceutical composition according to the invention is delivered to the target animal through a selected drinking water system by mixing and diluting the composition with drinking water in a central water tank or a separate medication tank and storage tank. Alternatively medicated drinking water can be prepared by injecting the composition according to the invention continuously into a high or low pressure ring system for drinking water distribution, using a dosage dispenser or dosing pump system or proportioner medication system. Dosing pump systems rely on a pump that delivers measured amounts of a concentrate into the water pipes at a typical dilution of 1 -5%.

[0064] In a preferred embodiment, the medicated drinking water according to the invention is administered by a dosing pump system in the water system by diluting the composition according to the invention in water. A non-limiting example of such a pump system is an electronic dosing pump system, such as the KONTI-DOS from Buerkert, or a mechanical dosing pump, such as the DOSATRON® water-driven dosing pump, or the DOSMATIC® water-driven dosing pump. The variety of field installations also concerns the water supply systems themselves: dead end or closed loop systems in different lengths with different pipe materials (e.g. PVC, galvanized iron) and the drinkers which are adapted to the target animals such as bell drinkers, nipples.

[0065] In one embodiment, 10 ml of the composition according to the invention was used and then diluted with water in a ratio of about 1 :200 to provide a medicated drinking water comprising an isoxazoline compound, e.g. fluralaner, in a concentration of 0.001 to about 1 mg / ml, preferably from about 0.05 to about 0.5 mg / ml. In one embodiment, the medicated drinking water has a concentration of between 0.002 and 0.2 mg / ml of the isoxazoline compound. In another specific embodiment for fluralaner, the concentration in the medicated drinking water is calculated to provide a target amount of fluralaner per body weight (BW) of the poultry being treated in the range of about 0.1 mg to about 2 mg of fluralaner per kilogram of body weight per day. Such amount was present in the volume of drinking water normally consumed by the poultry being treated over a period of 2 to 24 hours, preferably 4-5 to 8 hours.

[0066] Example 4

[0067] The efficacy of the composition according to the invention (Examples 1 and 2) administered orally in the form of a medicated drinking water according to the invention (Examples 2 and 3) for the prevention and treatment of red mite (Dermanyssus gallinae) in laying hens was studied. Twenty hens Gallus domesticus) were divided into two groups: A (n = 10) and B (n = 10). Each hen in both groups was infected with 10 red mites (Dermanyssus gallinae). Group A received a total dose of 1 mg fluralaner / kg body weight, but divided into two doses (0.5 mg / kg body weight 2 times). Group B received a single dose of 1 mg fluralaner / kg body weight (without dividing the dose in time). Due to ethical restrictions and the availability of literature data, the experiment did not include control groups (negative and positive). A person skilled in the art will predict without additional inventive thought or know from the scientific literature the results for negative and positive controls of similar preparations (including from EP3082867) without the need to replicate the experiments.

[0068] The drinking water consumption of each group was measured three days prior to administration of the composition and the medicated drinking water according to the invention in order to calculate the average daily water consumption. The medicated drinking water according to the invention was prepared by diluting the composition according to the invention (10 mg / ml) in water, as shown in the table below, to the calculated concentration of fluralaner. The number of live parasites on the hens was then assessed visually over a period of 22 days after the administration.

[0069] Table III. Efficacy of the composition and medicated water according to the invention in time

[0070] As apparent from Table III, the composition and the medicated drinking water according to the invention were well tolerated by the chickens. It also proves the pharmaceutical composition can be effectively used in the control of arthropod parasite infestations in animals. A rapid onset of action of the preparation was demonstrated in both groups. Splitting the dose (group A) resulted in a later and slower return of the parasite infestation.

[0071] In one embodiment, the pharmaceutical composition is used for treatment or prevention of parasite infestations in animals, especially farm animals (e.g., cattle, poultry, and pigs) by means of isoxazoline compounds, e.g., fluralaner, via drinking water systems. The skilled person is aware of a wide range of animals in need of treatment or prevention of parasite infections and on which the composition or water according to the invention can be used. These include, in particular, but are not limited to, pig, cattle, horse, goat, sheep, cat, dog, poultry and fish. In a preferred embodiment, the animals to which the composition or water according to the invention is administered are selected from pigs and poultry.

[0072] The administration of the pharmaceutical composition via medicated drinking water as defined earlier is especially useful in types of fowl animals that are kept on a commercial scale, such as, laying hens, rearing pullets or replacement chickens, layer breeders, broiler chicken, and broiler rearing pullets and breeders. However, the administration of the pharmaceutical composition via medicated drinking water as defined earlier can be also used in other types of poultry, such as e.g. turkey, geese, ducks, pigeons, quails or pheasants. The administration to poultry animals that are kept for breeding or egg laying that are kept longer than approximately 8 weeks is preferred. This includes such poultry animals that currently do not (yet) lay eggs (such as e.g. replacement chickens). In a particularly advantageous embodiment, these animals were laying hens. The term "laying hen" or "layer" is a common term for adult females, chickens (common domestic fowl Gallus domesticus), which are primarily kept for laying eggs. Such eggs are generally used for consumption as human food. The administration of the pharmaceutical composition through the medicated drinking water according to the invention is particularly useful in poultry and pigs. In the case of poultry, it is particularly useful in chickens and turkeys.

[0073] In one embodiment the administration of the pharmaceutical composition via medicated drinking water according to the invention controls the stages of parasitic arthropods, as described above that are present in the environment of poultry animals. The parasitic arthropod stages can be all stages of the lifecycle that are known to the skilled person, i.e. both juvenile stages (development / larval) and adult stages.

[0074] In one embodiment the administration of the pharmaceutical composition via medicated drinking water according to the invention controls arthropods in the environment of poultry animals, and especially broiler chickens that generally do not infest animals directly, but provide harm to the animals, such as e.g. darkling beetles.

[0075] The final isoxazoline compound concentration in the medicated drinking water is depending on the effective amount, the animal body weight, the animal water consumption and the treatment period. In general the effective amount per kg body weight of the animals treated is dictated by the parasitic species infection being treated and is known in the art. The treatment frequency with the pharmaceutical composition via medicated drinking water is depending on the parasite treated or prevented (and its biological lifecycle) and the production cycle of the host animal treated.

[0076] The skilled person will appreciate the wide range of parasites against which the composition or water according to the invention can be used. These include, but are not limited to, fleas (Ctenocephalides fells, Ctenocephalides sp. and the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentorsp., Amblyomma sp., Haemaphysalis sp., Boophilus sp.and the like), and mites (Demodex sp., Sarcoptes sp., Otodectes sp., Cheyletiella sp., Dermanyssus sp, Ornithonyssus spp. and the like), lice ( Trichodectes sp., Felicola sp., Linognathus sp., and the like), mosquitoes (Aedes sp., Culex sp., Anopheles sp., and the like) and flies (Hematobia sp. including Haematobia irritans, Musca sp., Stomoxys sp. including Stomoxys calcitrans, Dermatobia sp., Cochliomyia sp., and the like). In a preferred embodiment, the parasites against which the composition or water according to the invention was used were mites. In a particularly preferable embodiment, the mites were Dermanyssus sp. or Ornithonyssus sp . In one embodiment the pharmaceutical composition via medicated drinking water is administered to treat or prevent a mite infestation. Certain mites migrate from birds, rodents, food material, vegetable matter and house dust and can attack and annoy animals and humans. There are different categories of mites including Northern fowl mites (Ornithonyssus sylviarum), chicken red mites (Dermanyssus gallinae, follicle mites (Demodex folliculorum), itch or scabies mites (Sarcoptes spp., Cheyletiella spp., Psorioptes spp.). In a preferred embodiment the mite infestation is a mite infestation of poultry, especially of Dermanyssus sp. (e.g. D. gallinae) and / or Ornithonyssus sp., especially Ornithonyssus sylviarum.

[0077] The pharmaceutical composition according to the current invention is administered via medicated drinking water at least once, or twice per production cycle of the host animal treated (e.g. laying period in case of laying hens). By this administration of the pharmaceutical composition via medicated water a higher efficacy against the parasites can be achieved, because of the different lifecycle stages of the parasites that can be reached. By such administration regimen the parasite population can be reduced to a level that only causes minimal damage to the animal and minimal production losses. For some parasites, not all stages of the parasites can be reached by a single administration of the pharmaceutical composition via medicated drinking water because specific parasite stages either do not feed on the animal, or are not sufficiently controlled by the administration of the pharmaceutical composition via medicated drinking water. With the administration of a second dose of the pharmaceutical composition via medicated drinking water the parasites can be reached, that developed (following the lifecycle of the parasites) from not susceptible, or difficult to reach parasite stages, e.g. that matured from the juvenile stages of the parasites (such as eggs, nymphs or pupae) during this period.

[0078] In the embodiment, the composition according to the invention was administered in the medicated drinking water 6 days apart. However, theoretical calculations based on the results obtained indicate that without departing from the scope of the invention and without compromising the effectiveness, the composition according to the invention in the medicated drinking water can also be administered 7, 8, 13, 14 and 15 days apart. Especially preferred is the administration of the pharmaceutical composition via medicated drinking water approximately 7 days or 14 days apart (depending on the parasite lifecycle and production cycle of the host animal) once or twice during a production cycle. Especially preferred is the administration 7 days apart.

[0079] During animal studies, it was unexpectedly discovered that on top of the ester’s effects of on stability and solubility - which is purposes the composition according to the invention comprises them in the first place - the esters improve the organoleptic properties and thus the preparation’s acceptability by both animals and humans. The observations show that animals were more willing to drink the medicated water according to the invention, and the workers praised the possibilities of esters to mask unpleasant odors. An additional preferable effect of repelling insects was also noted, which should be associated with the repellent properties of some esters (especially those derived from acetic acid, e.g. ethyl acetate has a raspberry smell). Therefore, the composition according to the invention can repel more insects such as mosquitoes, ticks and flies.

Claims

Claims:

1. A pharmaceutical composition comprising at least one isoxazoline of formula (I)Formula (I), whereinR1= halogen, CF3, OCF3, CN, n = integer from 0 to 3, preferably 1 , 2 or 3,R2= Ci-C3-haloalkyl, preferably CF3or CF2CI,T = 5- or 6-membered ring which is optionally substituted by one or more radicals Y,Y = methyl, halomethyl, halogen, CN, NO2, NH2-C=S or two adjacent radicals Y form together a chain, especially a three- or four-membered chain;Q= X-NR3R4or 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;X = CH2, CH(CH3), CH(CN), CO, CS,R3= hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl , haloethylaminocarbonylcyclopropyl,RwhereinZA= hydrogen, halogen, cyano, halomethyl (CF3);R4= hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl; or R3and R4together form a substituent selected from the group consisting of:or a salt or solvate thereof, and a pharmaceutically acceptable carrier, administered orally via drinking water, characterized in that it comprises an ester derived from a saturated or unsaturated alcohol from CH3OH to C10H7- 21OH and a saturated, unsaturated or branched acid from HCOOH to C10H7-21COOH, a surfactant in the form of macrogolglycerol ricinoleate ethoxylated with from 30 to 50 of ethylene oxide molecules.

2. The composition according to claim 1 , characterized in that the isoxazoline compound is fluralaner.

3. The composition according to any of claims 1 to 2, characterized in that it comprises from 0.01 % to 5% by weight of fluralaner.

4. The composition according to any of claims 1 to 3 characterized in that the weight ratio of the ester to the surfactant is from 5:95 to 95:5.

5. The composition according to any of claims 1 to 4, characterized in that the composition additionally comprises a solvent, an ether, an antifoaming agent, a preservative and / or an antioxidant, preferably vitamin E.

6. The composition according to any of claims 1 to 5, characterized in that the ester is ethyl acetate.

7. The composition according to any of claims 1 to 6, characterized in that the surfactant is macrogolglycerol ricinoleate ethoxylated with 36 ethylene oxide molecules.

8. Medicated drinking water characterized in that it comprises a mixture of the composition according to any of claims 1 to 7 and water.

9. The water according to claim 8, characterized in that it comprises from 0.001 to 1 mg / ml of the isoxazoline compound according to claim 1 or 2.

10. The composition according to any of claims 1 to 7 or the water according to any of claims 8 to 9, characterized in that it is for use in the prevention or treatment of parasite infestations in animals.

11. The composition or the water for use according to claim 10, characterized in that the animals are selected from pigs and poultry.

12. The composition or the water for use according to claim 11 , characterized in that the animals are laying hens.

13. The composition or the water for use according to any of claims 10 to 12, characterized in that the parasite infestation is a mite infestation.

14. The composition or the water for use according to claim 13, characterized in that the mite infestation is an infestation with Dermanyssus sp. or Ornithonyssus sp.

15. A method for preparing the water according to any of claims 8 to 9, characterized in that the composition according to claim 1 to 7 is diluted by administration through a dosing pump system in a water system or by mixing with water in a medication tank.

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