Injectable veterinary composition for cattle

Abstract

An injectable veterinary pharmaceutical composition comprising an isoxazoline compound as a solution.

Description

INJECTABLE VETERINARY COMPOSITION FOR CATTLETECHNICAL FIELDThe present invention relates to a ready-to-use isoxazoline injectable solution composition, as well as to its use in the treatment and / or control of ectoparasitic infestations of animals. The present invention also relates to a method for treatment and / or control of ectoparasitic infestations of animals.BACKGROUNDSeveral pests and parasites can infest or infect livestock animals such as cattle, goats, buffalo, camels, pigs, and sheep. These pests and parasites are of great nuisance to the animals and can also lead to huge financial losses in the livestock creation field, particularly in the beef and dairy industries.Ectoparasites of animals such as ticks, mites, lice, and flies irritate the animals and can cause disease, either by themselves, or by carrying vector transmitted pathogens. Livestock animals such as cattle or sheep are affected by different parasites e.g. by ticks, biting and chewing lice and hematophage biting flies and blow flies.Especially important ectoparasites of cattle are ticks, e.g. Rhipicephalus microplus (cattle tick), R. decoloratus, R. annulatus, and the Amblyomma cajennense complex of species. Infestation by ticks can cause significant economic loss in livestock due to poor quality hide, poor quality meat / tissue, reduced weight gain and reduced milk production.For instance, ticks and other ectoparasites are responsible for high losses in Brazilian cattle farming, one of the main economic activities of agribusiness in the country.The losses caused by ectoparasites to Brazilian cattle farming are estimated around 13 billion dollars per year. These data demonstrate the high impact of ectoparasites, especially ticks without even considering issues such as the animal’s welfare.Furthermore, ticks are additionally responsible world-wide for the transmission and spread of many diseases. They are carriers of bacterial (e.g. Rickettsia), viral and protozoal diseases and cause tick-paralysis and tick-toxicosis.For instance, diseases such as anaplasmosis and babesiosis, which can be fatal, are tick-borne diseases affecting livestock animals such as cattle.The administration of parasiticides to animals, especially to livestock, such as cattle, is a very labour-intensive work and causes stress and loss of body weight to the animals. It requiresfrequent handling of livestock animals, which is undesirable, especially in feedlots and on pasture.Albeit treatment with existing products such as macrocyclic lactones, e.g. doramectin (Dectomax® , Zoetis) or ivermectin (Ivomec® of Boehringer Ingelheim) could be an option, the major obstacle is that tick populations are currently resistant to these active ingredients, they have not been shown to be sufficient to satisfactorily control tick infestation in cattle.Optimal compositions should be efficacious, have a quick onset of activity and a long duration of activity to avoid the necessity of frequent reapplications in cattle.Additionally, the compositions should also be safe to the host animal and the care takers and have desirable bioavailability and spectrum of coverage.Furthermore, an optimal composition should be ready-to-use and is chemically and physically stable, sufficiently easy to apply.Furthermore, it should not leave residues in the parts of the animals that are for human consumption for an extended period, resulting in a long withdrawal period before an animal can be slaughtered.There is a need for new compositions for the control of parasitic infestations in livestock animals, especially cattle.Thus, there is a need in the art for injectable compositions for controlling parasites in livestock animals, particularly in cattle, which avoid one or more of the drawbacks mentioned above. Therefore, the invention solves at least one general problem and several specific problems.Isoxazoline compounds are known in the art and the preparation of these compounds and their use as an antiparasitic are described, for example, in US patent application US 2007 / 0066617 and international patent applications WO 2005 / 085216, WO 2007 / 079162, WO 2009 / 002809, WO 2009 / 024541 , WO 2009 / 003075, WO 2009 / 080250, WO 2010 / 070068, WO 2010 / 079077 and WO 2011 / 124998.Several isoxazoline parasiticides were described specifically for veterinary use in the prevention or treatment of infestations by ectoparasites in companion animals such as dogs and cats, such as fluralaner (CAS registry number: 864731-61-3), afoxolaner (CAS RN: 1093861-60-9), lotilaner (CAS RN: 1369852-71-0), and sarolaner (CAS RN: 1398609-39-6).Injectable formulations of isoxazoline compounds have been described.WO 2015 / 048371 discloses long-acting injectable compositions comprising spirocyclic isoxazoline compounds, one biopolymer and at least one carrier, solvent or excipient.WO 2016 / 138339 discloses long-acting injectable formulations for comprising at least one isoxazoline active agent, a poloxamer and a co-solvent.WO 2016 / 164487 discloses extended-release injectable veterinary formulations comprising at least one isoxazoline active agent, a pharmaceutically acceptable polymer and a solvent for use against parasites.U.S. patent No. 9,609,869 discloses insecticidal compounds based on isoxazoline derivatives for use in controlling pest associated with agriculture, horticulture, animal husbandry and companion animals.US patent application publication No. 2017 / 0239218 discloses long-acting injectable compositions for combating parasites comprising at least one isoxazoline active agent, a liquid PEG and / or a neutral oil.SUMMARYThe present disclosure provides an injectable pharmaceutical composition, wherein the injectable composition comprises: a) an isoxazoline compound of Formula (I)R1 - R5 is H, F, Cl or CF3X is O or S, preferably Owherein denotes the bond to the isoxazoline> denotes the bond to the carbonyl group Z is selected fromwherein- denotes the bond to the carbonyl group; wherein the isoxazoline of Formula (I) is fluralaner. b) at least one copolymer of polylactides and polyglycolides that has a lactide to glycolide ratio of 50:50 to 85:15 (weight: weight). d) at least one pharmaceutically acceptable solvent and e) glyceryl triacetate (triacetin), wherein the composition is a solution.In another aspect, the present disclosure provides a method for treating parasite infestation or protecting an animal from parasite infestation which comprises administering the injectable composition of the invention to said animal.In accordance with the first aspect of the present invention, it has been discovered that the inventive compositions generally show desirable bioavailability and duration of efficacy, while causing minimal irritation at the injection site. The compositions also provide desirable safety profiles toward the treated animal. In addition, it has been discovered that a single administration of such compositions generally provides potent activity against one or more parasites, while also tending to provide fast onset of activity, long duration of activity, and / or desirable safety profiles.The summary of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 shows the Viscosity of composition 8 for accelerated stabilityFIG. 2 shows the Viscosity of composition 8 for long-term stabilityFIG. 3 shows the Density of composition 8 for accelerated stabilityFIG. 4 shows the Density of composition 8 for long-term stabilityFIG. 5 shows the Fluralaner Assay of composition 8 for accelerated stabilityFIG. 6 shows the Fluralaner Assay of composition 8 for long-term stabilityFIG. 7 shows the syringeability of composition 6, 7 and 8, compared with placebo (no fluralaner)DEFINITIONSThe following definitions are relevant in connection with the embodiments of the present invention.As used herein and throughout “long acting” refers to a duration of activity that extends beyond a week. Preferably beyond two weeks, three or four weeks, about one month, two months or 3 months, or alternatively, 12 weeks.The present invention is particularly useful for mammalian animals such as cattle, sheep, goat, camels, buffalo, and pigs, especially when they are livestock animals, kept for meat and / or milk. In one embodiment the animals are cattle animals.In this specification, cattle animals or bovine animals are ruminant mammals of the genus Bos and include but are not limited to steers, heifers, cows (lactating and non-lactating), calves, bulls, and buffalo. Preferred are beef cattle, i.e. cattle animals kept for meat.“Control” includes treatment and protection of animals from parasite infestation .By "treating" or "treat" or "treatment" or “control” is intended the application or administration of the veterinary composition to a livestock animal, such as cattle animal that has been diagnosed to have an ectoparasitic infestation or is in danger of being infested by a parasite.The effect of the treatment on the parasite can be e.g. ovicidal, larvicidal 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.“Protection or protect ” means that a new infestation of the animal, such as cattle, by parasites is prevented by killing adult parasites and any development / larval stages, that are able to infest the host, before infestation of the host is established or, by killing or inhibiting the parasites when they infest an animal that has been treated with the veterinary composition as described herein, thus preventing generation of offspring of the parasites e.g. reducing the number of eggs laid and / or the hatching rate. In some embodiments, an effective amount of the composition of the invention achieves at least 50% efficacy against the target parasite. In other embodiments, an effective amount of the active agent achieves at least 80%, or at least 90% efficacy against the target parasites. The skilled person is aware on the methods of calculating the efficacy, e.g. using standard methods such as disclosed in WAAVP and VICH Guidelines .“Protection period” means the time, expressed in days or weeks after the treatment, that the veterinary composition will prevent or control an infestation of the treated animal by ectoparasites.“Withholding period” means the time, expressed in hours or in days after the treatment, that the milk or meat or edible parts of animal carcasses (meat or especially beef) obtained from a treated animal needs to be discarded and not used for human consumption due to potential active ingredient residue levels.As used herein, an “active pharmaceutical ingredient “or “active ingredient”, or “pharmaceutically active ingredient” or “pharmaceutically acceptable active ingredient” is a substance used in a pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, including an infestation by parasites or to have direct effect in restoring, correcting or modifying physiological functions in humans or animals. In the context of the invention, the active ingredient is a isoxazoline compound of formula (I), especially fluralaner.As used herein, “composition” and “formulation” “veterinary composition” and “veterinary formulation” are to be interpreted as synonyms and refer to a combination of one or more active ingredients and excipients (inactive substances). The composition of the current invention is an injectable liquid and the skilled person is aware of the requirements for a composition to be a liquid injectable veterinary composition.An "effective amount" is the amount or quantity of an isoxazoline compound as described above that is required to treat or prevent ectoparasitic infestations of animals, i.e. to alleviate or reduce ectoparasites numbers on an animal, and / or to inhibit the development of parasite infestations on an animal.As used herein and unless otherwise indicated, the terms “a” and “an” are taken to mean “one”, “at least one” or “one or more”. Unless otherwise required by context, singular terms used herein shall include pluralities and plural terms shall include the singular.Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”. Words using the singular or plural number also include the plural or singular number, respectively. Additionally, the words “herein,” “above” and “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application.“About” is used to provide flexibility to a numerical range endpoint by providing that a given value can be “slightly above” or “slightly below” the endpoint without affecting the desired result. The term “about” in association with a numerical value means that the numerical value can vary by plus or minus 5% or less of the numerical value (rounded up to the nearest whole number if the value is not sub-dividable).Throughout this disclosure, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range of this disclosure relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated.Throughout this disclosure, numerical ranges are inclusive of their recited endpoints, unless specifically stated otherwise. All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the rangesand any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.Features of the invention have been described in embodiments in the present application; however, for brevity not all combinations of the features are literally described. Combinations of features as described above are, however, expressly considered to be part of the invention.DETAILED DESCRIPTIONIt is an unmet veterinary medical need to protect animals, especially livestock animals, especially cattle for a long time with a single injection against the most important parasites.This means a long-term protection against ectoparasites such as ticks, lice and mites. In order to keep or alternatively enhance / improve the prophylactic and / or therapeutic effect of an injectable veterinary pharmaceutical composition, it would be desirable to have a long-acting formulation for cattle that reduces the handling of animals,Besides the duration of action there are further desirable features for such injectable veterinary compositions such as: easiness of application (syringeability) and / or the absence of side effects such as local injection site reaction and systemic side effects following administration.Another object is to provide a composition ensuring a stable content of the isoxazoline compound of Formula (I) in such formulation, especially under accelerated test conditions for the stability testing.The inventors of the present invention identified new injectable compositions as described herein with favorable properties that address one or more of such desires. It has been found that the composition provides at least 2 months, preferably about 3 months of efficacy against ticks, and the formulation is safe with acceptable injection site reaction and no other adverse events.The Applicant has addressed the problems of the prior art by providing an injectable composition that is a solution as described in this application.Preferably the injectable composition can be injected using an 18G needle and is physically and chemically stable for at least 6 months, preferably under accelerated conditions.The injectable compositions of the present invention have been surprisingly discovered to have a shelf life for an extended period of time, e.g., a period of at least 18 months while exhibiting favorable properties.The present invention provides for an injectable composition for the treatment and / or prophylaxis of parasitic infections and infestations in or on animals comprising:a) an antiparasitic effective amount of at least one isoxazoline active agent, which is: i) an isoxazoline compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof; and b) at least one copolymer of polylactides and polyglycolides that has a lactide to glycolide ratio of 50:50 to 85:15 (weight: weight). c) at least one pharmaceutically acceptable solvent and triacetin, wherein the composition is a solution.In the current invention provides the isoxazoline compound of Formula (I)Formula (I)R1 - R5 is H, F, Cl or CF3X is O or S, preferably OY is selected fromwherein- denotes the bond to the isoxazoline or isothiazoline> denotes the bond to the carbonyl groupZ is selected fromwherein- denotes the bond to the carbonyl groupIsoxazoline compounds for use in the current invention of Formula (I) areFormula (I)R1 - R5 is H, F, Cl or CF3X is O or S, preferably OY is selected fromwherein denotes the bond to the isoxazoline or isothiazoline i i 111 i i 1111 denotes the bond to the carbonyl groupZ is selected fromwherein denotes the bond to the carbonyl groupThe disclosure in this specification applies for such composition with isoxazoline compounds .In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 4- [5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3). This compound is also known as fluralaner.In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 4- [5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2- [(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalene-carboxamide (CAS RN 1093861-60-9). This compound is also known as a 4-[5-(5-chloro-a,a,a-trifluoro-m-tolyl)-4,5-dihydro-5- (trifluoromethyl)-1 ,2-oxazol-3yl]-N-[2-oxo-2-[(2,2,2-trifluoroethylamino]ethyl]naphthalene-1-or afoxolaner. Afoxolaner is for example disclosed in WO 2007 / 079162. In one embodiment the isoxazoline compound is Esafoxolaner, in another embodiment umifoxolanerIn one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 1- (5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H- spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one, preferably 1-(5'-((5S)-(5- (3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidine- 3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethan-1-one (CAS RN: 1398609-39-6). This compound is known as sarolaner.In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 3- methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[5-(3,4,5-trichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl]thiophene-2-carboxamide, preferably methyl-N-(2-oxo- 2-((2,2,2-trifluoroethyl)amino)ethyl)-5-[(5S)-5(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl]thiophene-2-carboxamide (CAS RN: 1369852-71-0). This compound is known as lotilaner.In one preferred embodiment of the invention and / or embodiments thereof a compound used as alternative to the isoxazoline compound is 2-chloro-N-(1-cyanocyclopropyl)-5-[1-[2-methyl-5- (1 , 1 ,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN 1621436) This compound is known as tigolaner.In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 4H- Cyclopenta[c]thiophene-1 -carboxamide, 3-[(5S)-5-(3,5-dichloro-4- fluorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-N-[2-[(2,2- difluoroethyl)amino]-2-oxoethyl]-5,6-dihydro- (CAS 1414642-93-5). This compound is known as mivorilaner.In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is in another embodiment the compound of Formula (I) is (Z)-4-[5-(3,5-dichlorophenyl)-5- trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 4- [5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed in WO 2009 / 0080250.In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 5- [5-(3,5-dDichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2- [(2,2,2-trifluoroethyl)amino]ethyl]- 2-thiophenecarboxamide (CAS RN 1231754-09-8) that was disclosed in WO 2010 / 070068.In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline compound of Formula (I) is selected from fluralaner, afoxolaner (including es afoxolaner), umifoxolaner, sarolaner, and lotilaner.Especially preferred is fluralaner (corresponding to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl- 4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide) which is represented byFormula (II).In a preferred embodiment of the invention and / or embodiments thereof, the present composition comprises fluralaner, in an amount of about 2.5% by weight to about 30% by weight, preferably of about 5 % by weight to about 25% by weight, more preferably of about 10 % by weight to about 17.5% by weight, even more preferably of about 15% by weight based on the total weight of the composition.The isoxazoline compounds may exist in various isomeric forms. A reference to an isoxazoline compound always includes all possible isomeric forms of such a compound. Unless otherwise stated, a compound structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the compound, as well as compositions comprising fewer than all the possible conformational isomers. In some embodiments, the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.Isoxazoline compounds of Formula (I) can be prepared according to one or other of the processes described e.g., in patent applications US 2007 / 0066617, WO 2007 / 079162, WO 2009 / 002809, WO 2009 / 080250, WO 2010 / 070068, WO 2010 / 079077, WO 2011 / 075591and WO 2011 / 124998 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis.In an embodiment of the invention and / or embodiments thereof, the isoxazoline compound of Formula (I)) is the (S)-enantiomer of afoxolaner (esafoxolaner), umifoxolaner or the (S)- enantiomer of fluralaner.In an embodiment of the invention and / or embodiments thereof, the present composition can be administered in combination with an additional active ingredient. The administration of the additional active ingredient is in the same composition or in separate compositions.The additional therapeutic agent can preferably be a parasiticide or a vaccine, preferably another parasiticide.For the chemical preparation, a person skilled in the art is regarded as having at her / his disposal, inter alia, the entire contents of "Chemical Abstracts" and of the documents cited therein.The injectable composition according to the invention comprises at least one copolymer of polylactides and polyglycolides (PLGA) that has a lactide to glycolide ratio of 50:50 to 85:15 (weight: weight).The molecular weight of copolymer of polylactides and polyglycolides may impact the characteristics of the compositions of the invention. The average molecular weight may be found by techniques familiar to persons of skill in the art, for example, size exclusion chromatography with molecular weight standards, or the like.For example, in some embodiments depending on the active agent and solvents included, one may see an earlier release when the weight average molecular weight range is from about 5 to about 20 kDa (kilo daltons) or from about 7 to about 15 kDa. A later release of the isoxazoline compound of Formula (l)s may be observed when the weight average molecular weight is between about 30 to about 70 kDa.The composition in another embodiment comprises at least two (different) copolymers of polylactides and polyglycolides. A combination of copolymers of polylactides and polyglycolides having different average molecular weights may provide a release rate that combines the effect of the different polymers used.Inherent viscosity (IV) in polymer chemistry is a viscometrical method for measuring molecular weight. It is defined as the ratio of the natural logarithm of the relative viscosity to the mass concentration of the polymer and is based on the flow time of a polymer solution through a narrow capillary.As used herein with respect to the molecular weight range of copolymer of polylactides and polyglycolides the term “low molecular weight” (LMW) refers to an inherent viscosity in the range of 0.05-0.29 dL / g; the term “medium molecular weight” refers to an inherent viscosity in the range of 0.3-0.55dL / g; and high molecular weight refers an inherent viscosity in the range of 0.55-1.0 dL / g.In one embodiment, at least one of the pharmaceutically acceptable copolymers of polylactides and polyglycolides, in the composition of the invention has an inherent viscosity of about 0.1 to about 0.90 dL / g, preferably about 0.40 to about 0.50.In another embodiment the copolymers of polylactides and polyglycolides have an intrinsic viscosity in the range of about 0.1 to about 0.90 dL / g, preferably about 0.15 to about 0.25.In one embodiment, the composition comprises about 0.5 to about 10% % (w / v) of the copolymer of polylactides and polyglycolides, preferably up to about 2%(w / v).The viscosity of the injectable compositions according to the current invention is an important parameter with respect to the ability to easily administer the composition to animal and can be assessed by using Brookfield rheometer or some other type of viscometers such as Ostwald's viscometer or Cone and Plate viscometer.The viscosity of the formulation should be such that no difficulties are faced during its administration when injected. This is also important when the injection is carried out at different temperatures, e.g. if the cattle animals are on pasture or kept in feedlots and are exposed to the outside temperature. Under such different temperature conditions, it is important that the composition according to the invention retains good syringeability.Typically, at a temperature of approximately at 25° C viscosities of about less than 150 centipoises (cPs) are acceptable. Thus, in one embodiment, the viscosity of the compositions of the invention at 25° C is about less than 150 cPs. In other embodiments, the viscosity of the compositions of the invention at 25° C is about less than 140 cPs, less than about 130 cPs or less than about 120 cPs. In other embodiments, the viscosity of the compositions of the invention at 25° C is about less than 110 cPs or less than about 100 cPs. In one embodiment the force to be applied to pass the composition through a 18G needle injectable ranges from 3 N to 50 N, as measured by using a Brookfield rheometer.The composition according to the invention is a solution. A solution is a homogeneous mixture of two or more substances, where one substance (the solute) is dissolved in another (the solvent). The solvents used in the injectable compositions may be a single or a blend or mixture of solvents.The composition according to the invention comprises at least one pharmaceutically acceptable solvent and include triacetin, also known as glycerol triacetate or propane-1, 2, 3-triyl triacetate.Solvents may be used in the compositions of the invention to improve the solubility of the isoxazoline active agent and / or to lower the viscosity of the compositions. In one embodiment, the solvents used in the injectable compositions of the present invention the at least one solvent comprises dimethylacetamide, an alcohol, or mixtures thereof. Preferred is a mixture of dimethylacetamide and an alcohol. The alcohol preferably is benzyl alcohol or a mixture of benzyl benzoate and benzyl alcohol .Preferably the alcohol is benzyl alcohol.The composition according to the invention comprises about 1 to about 50 % (w / v) of the at least one solvent.Benzyl alcohol is present between about 1 to about 50 % (w / v), preferably about 1 to about 25 % (w / v), preferably about 2 % (w / v).Dimethylacetamide is present in the composition according to the invention between about 25 to about 35 % (w / v), preferably about 28 to about 32 % (w / v), preferably about 30 % (w / v).In a preferred embodiment the injectable composition according to the invention characterized does not comprise propylene carbonate. The reminder of the composition of the invention (q.s.) is triacetin . Alternatively, the remainder of the composition of the invention (q.s.) is a medium chain triglyceride. The term medium-chain triacylglycerols refers to mixed triacylglycerols of saturated fatty acids with a chain length of 6-10 carbons, i.e., hexanoic acid (C6:0, common name capronic acid), octanoic acid (C8:0, common name caprylic acid), and decanoic acid (C10:0, common name capric acid), dodecanoic acid (C12:0, common name lauric acid).The injectable composition according to the current invention does not comprise propylene carbonate. Propylene carbonate has been specifically tested in the prior art, e.g. in WO2026 / 164487 and it was described to be useful to prepare long-acting injectable solution compositions.The inventors repeated the instructions of WO2016 / 164487 Example 65 using an isoxazoline compound (fluralaner), propylene carbonate, triacetin and poloxamer 124 by mixing, maintaining the same proportion as described in the prior art. However, it was observed that no solution could be formed following the instructions. The composition of the current invention formed a clear solution that is useful as an injectable composition.The injectable compositions of the invention may include additional pharmaceutically acceptable additives or excipients. Pharmaceutically acceptable additives and excipients include, but are not limited to, surfactants, antioxidants, preservatives, pH stabilizing agents (e.g. buffers), and other non-active excipients.The compositions of the invention are made by mixing the appropriate amount of the isoxazoline compound, with the other pharmaceutically acceptable components as described herein and / or excipient to form a composition of the invention. After mixing the isoxazoline compound of formula (I) , PLGAs, and the at least solvent until complete solubilization was achieved, the volume of the composition is adjusted with triacetin.In some embodiments the compositions of the present invention can be obtained by following the method of making these forms described above by the description of making these forms found in general composition text known to those in the art, e.g., Remington- The Science and Practice of Pharmacy (20st Edition).Another aspect of the invention is the injectable veterinary composition of the present invention for use in treating and / or preventing a parasite infestation in an animal, especially a cattle animal.It has been found that a single administration of such compositions generally provides potent activity against parasites, while also tending to provide fast onset of activity, long duration of activity, and / or desirable safety profiles.Another aspect is a method for treating and protecting an animal from parasite infestation, especially a tick infestation, especially by Rhipicephalus ticks for a period of about 2 to about 3 months which comprises administering the injectable composition of the invention to said animal, preferably to a cattle animal. Especially preferred is an administration every 12 weeks, the clinical example shows tick efficacy , especially for Rhipicephalus ticks above 90 % ( even above 95 %) for at least 84 days.This is a significant advancement because it allows infrequent treatment and full protection of the treated animal for the long period of 12 weeks. Alternatively, the animal is protected from ectoparasite infestations for at least 8 weeks, 9 weeks, 10 weeks or 11 weeks, depending on the parasite species. The long-acting protection of cattle animals from ectoparasite infestations, especially tick infestation is an especially preferred embodiment of the current invention, especially preferred is a protection for 12 weeks as this allows a standard procedure in a cattle flock for administration of a product for tick control on a specific workday. An example is that the complete cattle herd is treated on a Monday, every 12 weeks.The composition of the invention has been shown to be especially useful for the control of ticks, especially Rhipicephalus ticks. The composition according to the invention useful against ectoparasites of animals such as ticks, mites, lice, and flies that irritate the animals and can cause disease, either by themselves, or by carrying vector transmitted pathogens. Livestock animals such as cattle are affected by different parasites e.g. by ticks, biting and chewing lice and hematophage biting flies and blow flies. Especially important ectoparasites of cattle ticksare, e.g. Rhipicephalus microplus (cattle tick), R. decoloratus, R. annulatus, and the Amblyomma cajennense complex of species. The composition according to the invention is preferably administered subcutaneously.The concentration of the isoxazoline compound of Formula (I) in the composition needs to be sufficient to provide the desired therapeutically or prophylactically effective amount in a volume that is acceptable for injectable administration depending on the animal treated.In a preferred embodiment of the invention and / or embodiments thereof, the isoxazoline compound of Formula (I), preferably fluralaner, is administered at about from about 0.1 to about 20 mg per kg of animal body weight (bw), more preferably from about 0.5 to about 10 mg per kg of animal body weight, in particular from about 1 to about 2 mg per kg of animal body weight, especially about 1.5 mg / kg bw.Additionally, it turned out that after injection the present injectable composition safe to the animal, shows a desirable bioavailability for the isoxazoline compound of Formula (I) in the composition and duration of efficacy and does not cause inacceptable side effects, especially no inacceptable injection site irritation, wherein the present composition can be administered by subcutaneous injection at different injection sites, such as the neck of the animal or the base of the ear. Furthermore, the residues in the edible tissues are not present for an extended period.A subcutaneous administration can for example be carried out by a syringe. In one embodiment a syringe with a 18 gauge needle is used. It is important that the compositions according to the invention have good syringeability.The term “syringeable” describes a solution that can be easily drawn from an ampoule / vial / container with a needle into a syringe and subsequently injected from such a syringe through the needle (e.g. 18 Gauge needle) intramuscularly (im) or subcutaneously (sc), preferably subcutaneously.It turned out that when the present injectable veterinary composition is used in treating and / or preventing a parasite infestation in an animal, the treated animal suffers minimal injection site irritation and a good syringeability was observed. Injection site irritation is an injury produced at the injection site and surrounding tissue, when an animal receives an injection of a pharmaceutical composition. Such injury can be swelling, skin discoloration and tissue necrosis.The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.EXAMPLESThe following compositions were prepared.Compositions 1 to 3 are comparative examples. Compositions 4 to 8 are according to the current invention.Example 1 (comparative)Component Concentration (%w / v)Fluralaner 5.00Dimethylacetamide 30.00Cottonseed oil QsExample 2 comparative)Component Concentration (%w / v)Fluralaner 4,00Dimethylacetamide 30.00Cottonseed oil QsExample 3 comparative)Component Concentration (%w / v)Fluralaner 10.00Dimethylacetamide 30.50Benzyl Alcohol 1.00Medium-chain Qs triglyceridesThe comparative compositions of Examples 1 and 2 were not suitable injectable compositions. In Examples 1 and 2, after completion of the formulation, phase separation was observed, indicating physical instability. The formulation in Example 3 was physically stable without initial phase separation. However, in clinical trials with the formulation of Example 3 a shorter duration of effectiveness against ticks was observed.Example 4Component Concentration(%w / v)Fluralaner 10,00Dimethylacetamide 30.50PLGA 502A 2.00Benzyl Alcohol 1.00Triacetin QsExample 5Component Concentration(%w / v)Fluralaner 5.00Dimethylacetamide 30.00PLGA 502A 2.00Benzyl Alcohol 1.00Triacetin QsExample 6Component Concentration(%w / v)Fluralaner 5.00PLGA 502A 1.00PLGA 50 5A 1.00Dimethylacetamide 30.50Benzyl Alcohol 2.00Triacetin qsExample 7Component Concentration(%w / v)Fluralaner 10.00PLGA 502A 1.00PLGA 50 5A 1.00Dimethylacetamide 30.50Benzyl Alcohol 2.00Triacetin qsExample 8Component Concentration(%w / v)Fluralaner 15.00PLGA 502A 1.00PLGA 50 5A 1.00Dimethylacetamide 30.50Benzyl Alcohol 2.00Triacetin qs PLGA of the following grades were used in the compositions:Table 1: PLGA propertiesCompound D / L Lactide Glycolide Inherent Viscosity MW Range(0,5% CHCI3, 25°C) (Mw, kDa, PSSTD)PLGA 502A 50 50 0.15-0.25 05-20PLGA 50 5A 50 50 0.40-0.50 42-65The injectable compositions according to the invention were prepared by mixing the isoxazoline, PLGAs, and benzyl alcohol in dimethylacetamide until complete solubilization was achieved, followed by adjusting the volume with triacetin.Table 2: Physicochemical characterization of example 6, 7 and 8.The stability under accelerated conditions was investigated for composition Example 8. It remained stable throughout the entire accelerated stability study (6 months) at 40°C / 75% RH and has been stable for at least 18 months in the ongoing long-term stability study at 30°C / 75% RH. This stability is demonstrated by the viscosity (Figures 1 and 2), density (Figures 3 and 4), and assay results (Figures 5 and 6). The syringeability test was performed to verify the impact of fluralaner increase on the force necessary for applying the injectable composition (Figure 7).Efficacy data:Biological Experiment 1 :Efficacy of Formulation Example 8 after subcutaneous injection in the control of Rhipicephalus (Boophilus) microplus in naturally infested bovine animals of pure breed or crossbreeds in Southeast region of Brazil.The study was randomized, conducted in a blinded manner, consisting of three groups. This study was conducted in Brazilian Southeast region. A total of 9 male and / or female cattle naturally infested by ticks were allocated to the experimental groups, as described in table 5 below. The counts were performed on one side of the animal, and the same side used for the pre-treatment counts was used in the post-treatment counts.Table 3: Experimental designRhipicephalus (Boophilus) microplus counts were performed on one side of each animal on days -3, -2, -1 (pre-treatment), 1 , 3, 5, 7, 10, 14, 21 , 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 and 98 (post- treatment). Ticks measuring between 4.5 and 8.0 mm were quantified. The side that was used(left side) for the first tick count on Day -3 was maintained in the other counts performed throughout the study.Formulation Example 8 administered at 1.5 mg of fluralaner per kg BW registered high average efficacy rates, above 90%, from day 3 to 84 post-treatment at the base of the ear injection, and, from day 5 to 91 post-treatment when administered at the neck.Tick quantifications in cattle naturally infested with ticks reinforce the high anti-tick activity of Formulation Example 8, in the different groups, starting usually at the 3rdday after treatment and maintaining low counts of R. (B.) microplus females until at least the 77thday after treatment, going until Day 91 after treatment administration, depending on the injection site. Lower tick counts (P <0.05) than the negative control group were observed for the Example 8 between the 3rdand the 84thor 91stdays after treatment, depending on the injection site.Table 4: Efficacy against Rhipicephalus (Boophilus) microplus in naturally infested bovinesThe persistent efficacy (> 90% according to WAAVP and VICH Guidelines) observed with the solution injectable formulation (Example 8) was up to 84 days (77 to 84 days). During the studies conducted, no adverse events or any abnormal observations were made in any of the animals receiving the fluralaner solution formulation (Formulation Example 8).The injection site reactions observed consisted of edema ranging from 1 to 5 cm of diameter, selflimiting and with no need for concomitant medication. No abscesses, crusts or signs of pain were observed during all the studies.Comparative example from WO2016 / 164487 / Example 65The methodology used in the test was performed as described in patent application US2021 / 0299104 A1 , page 56, item

[0854] ,. This item details the preparation process as follows: “The following extended-release injectable formulations were prepared by mixing the following ingredients. Unless otherwise indicated, the concentration of each component is expressed as percent (%) weight per weight (w / w), and MW refers to weight average molecular weight.”The tested formulation corresponded to Example 65, Group 6, in which the compound of Formula (S)-llc was replaced by fluralaner in the same proportion, while all other components were maintained at the proportions described in the example.The described method proved inadequate for obtaining a feasible injectable formulation, as the resulting product exhibited a high viscosity of 448.1 cPs and with the presence of clumps, which may cause the needle blocks during the application. Also, such high viscosity is inadequate for subcutaneous administration, since it requires greater force for injection, potentially causing discomfort to the animal, as reported by Watt et al., 2019.ReferencesRussell P. Watt, Hetal Khatri, Andrew R.G. Dibble, Injectability as a function of viscosity and dosing materials for subcutaneous administration, International Journal of Pharmaceutics, Volume 554, 2019, Pages 376-386, ISSN 0378-5173, https: / / doi.orq / 10.1016Zi.iipharm.2018.11.012.The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

26WHAT IS CLAIMED IS:

1. An injectable pharmaceutical composition, wherein the injectable composition comprises: a) an isoxazoline compound of Formula (I)R1 - R5 is H, F, Cl or CF3X is O or S, preferably OY is selected fromwherein - denotes the bond to the isoxazoline> denotes the bond to the carbonyl groupZ is selected fromwherein- denotes the bond to the carbonyl group; wherein the isoxazoline of Formula (I) is fluralaner. b) at least one copolymer of polylactides and polyglycolides that has a lactide to glycolide ratio of 50:50 to 85:15 (weight: weight); c) at least one pharmaceutically acceptable solvent and triacetin, wherein the composition is a solution.

2. The injectable composition according to any one of claim 1 , comprising about 5 to about 30 % (w / v) of the compound of Formula (I), preferably about 15% w / v.

3. The injectable composition according to any one of claims 1-2, wherein the copolymers of polylactides and polyglycolides have a lactide to glycolide ratio of 50:50 (weight: weight).

4. The injectable composition according to any one of claims 1-3, wherein the copolymers of polylactides and polyglycolides have an intrinsic viscosity in the range of about 0.1 to about 0.90 dL / g, preferably about 0.15 to about 0.25.

5. The injectable composition according to any one of claims 1-4, comprising copolymers of polylactides and polyglycolides that have an intrinsic viscosity of about 0.40 to about 0.50.

6. The injectable composition according to any one of claims 1-5, wherein two or more copolymers of polylactides and polyglycolides are present that have a different intrinsic viscosity.

7. The injectable composition according to any one of claims 1-6, comprising about 0.5 to about 10% % (w / v) of the copolymer of polylactides and polyglycolides, preferably up to about 2%(w / v).

8. The injectable composition according to any one of claims 1-7, wherein the at least one solvent comprises an alcohol, dimethylacetamide, or mixtures thereof.

9. The injectable composition according to any one of claims 1-8, wherein the alcohol is benzyl alcohol or a mixture of benzyl benzoate and benzyl alcohol.

10. The injectable composition according to any one of claims 1-9, wherein the composition comprises triacetin.

11. The injectable composition according to any one of claims 1-10, wherein the alcohol is benzyl alcohol.

12. The injectable composition according to any one of claims 1-11, characterized in that the composition does not comprise propylene carbonate.

13. The injectable composition according to any one of claims 1-12 comprisingFluralaner . 2.5 to 20.0 % w / vDimethylacetamide ...20.0 to 40.0 % w / vPLGA . 0.5 to 20.0 % w / vBenzyl Alcohol . 0.5 to 20.0% w / vTriacetin . q.s. to 100 % w / v.

14. The injectable composition according to any one of claims 1-13 comprisingFluralaner . 15.0% w / vDimethylacetamide 30.5% w / vPLGA 502A . 1.0% w / vPLGA 50 5A . 1.0% w / vBenzyl Alcohol . 2.0% w / vTriacetin . q.s. to 100 % w / v.

15. A method for treating a parasite infestation of cattle or protecting a cattle animal from parasite infestation for a period of about 12 weeks which comprises administering the injectable composition of any one of claims 1 - 13 to said animal, wherein the parasite infestation is a tick infestation, especially an infestation by Rhipicephalus ticks.

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