Injectable veterinary composition and uses thereof

Abstract

An injectable veterinary pharmaceutical composition comprising the combination of an isoxazoline compound and a macrocyclic lactone as a solution in a carrier comprising a pharmaceutically acceptable gel forming agent, a pharmaceutically acceptable solvent, and a release modifying agent.

Description

[0001] INJECTABLE VETERINARY COMPOSITION AND USES THEREOF

[0002] FIELD

[0003] The present invention relates to injectable veterinary pharmaceutical compositions comprising the combination of an isoxazoline compound and a physiologically active macrocyclic lactone.

[0004] BACKGROUND

[0005] A number of parasites can infest or infect domestic animals, especially companion animals such as cats and dogs. These parasites are of great nuisance to both the animals and their owners. 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.

[0006] 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 pol oxamer 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.

[0007] 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.

[0008] 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.

[0009] Further, physiologically active macrocyclic lactones are known for controlling parasite infestations. For example, moxidectin is useful for the prevention and treatment of infections and infestations caused by helminths, nematodes, and ectoparasitic arthropods.

[0010] Moxidectin was disclosed in U.S. patent number 4,916,154 and EP 0 525 307 and EP 1 197 207 disclose moxidectin microspheres and injectable compositions and their preparation and their use. Because of bioavailability, efficacy, or dosing convenience concerns, many active ingredients are preferably administered parenterally.

[0011] Furthermore, it is desirable to have a safe, long acting, easy injectable, convenient, composition for these active ingredients.

[0012] SUMMARY

[0013] The present disclosure provides an injectable pharmaceutical composition for use in the treatment or prevention of parasitic infections or infestations in an animal, wherein the injectable composition is a solution and comprises: a) an isoxazoline compound of Formula (I)

[0014] R1 - R5 is H, F, Cl or CF3 X is O or S, preferably O

[0015] Y is selected from wherein

[0016] - denotes the bond to the isoxazoline or isothiazoline

[0017] > denotes the bond to the carbonyl group

[0018] Z is selected from wherein

[0019] - denotes the bond to the carbonyl group; b) a macrocyclic lactone, selected from abamectin, doramectin, eprinomectin, ivermectin, and moxidectin; b) at least one pharmaceutically acceptable gel forming agent, d) at least one pharmaceutically acceptable solvent, e) at least one release modifying agent, and wherein the composition is a solution.

[0020] In another aspect, the present disclosure provides a method for treating or protecting an animal from parasite infestation for a period of about 3 to about 12 months which comprises administering the injectable composition a of the invention to said animal.

[0021] 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. 26009

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 shows the syringeability of different formulations measured by the force required to pass through 18G needle.

[0024] The blood plasma concentration of the different formulation over 360 days is shown in Figure 2 for fluralaner and Fig. 3 for moxidectin. Figure: Plasma Fluralaner (A) and Moxidectin concentration after subcutaneous administration of each solution (in-situ gel) formulations. Data represented as mean plasma concentration of 6 dogs.

[0025] DETAILED DESCRIPTION

[0026] It is an unmet veterinary medical need to protect animals, especially companion animals for a long time with a single injection against the most important parasites.

[0027] This means a long-term protection against ectoparasites such as fleas, ticks and mites and helminth parasites, such as heartworm and certain gastrointestinal helminths. 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 dosage form, comprising one or more active agents from a different antiparasitic class.

[0028] In particular, an advantageous injectable pharmaceutical composition for veterinary application is desirable, that enables a single injection to provide efficacious concentration levels of both classes of active compounds, an isoxazoline compound as well as a macrocyclic lactone such as moxidectin, in blood plasma of the treated animals over an extended period. Specifically, a feasible injectable composition that allows the effective and safe release of an effective amount of an isoxazoline compound as described above as well as a macrocyclic compound such as moxidectin in a combined composition safely and effectively over a prolonged time would be desirable.

[0029] For high efficacy and bioavailability of pharmaceuticals, it may be necessary to reach high serum levels of active substances in a short time, which requires dosage forms that are released quickly. Besides the duration of action there are further desirable features for such injectable veterinary compositions such as: easiness of application (syringeability), the possibility to sterilize the composition and / or the absence of side effects such as local injection site reaction and systemic side effects following administration.

[0030] Another object is to provide a composition ensuring a stable content of the active ingredients in such dosage forms, especially the macrocyclic compound such as moxidectin. 26009

[0031] 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 12 months release of the active ingredients, and the formulation is safe with acceptable injection site reaction.

[0032] The Applicant has addressed the problems of the prior art by identifying injectable compositions that are a solution , that should provide a minimal burst release. A higher burst release can cause injection site reactions, unwanted systemic toxicity due to overdose, and unpredictable performance in-vivo and should be therefore minimized.

[0033] Preferably the injectable composition can be injected using no larger than an 18G needle and is physically and chemically stable for at least 6 months.

[0034] The injectable compositions of the present invention have been surprisingly discovered to be stable and effective against a broad spectrum of ectoparasites, and endoparasites for an extended period of time, e.g., a period from three (3) to twelve (12) months while exhibiting favorable properties.

[0035] 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) one or more macrocyclic lactone, selected from abamectin, doramectin, eprinomectin, ivermectin, and moxidectin; c) at least one pharmaceutically acceptable solvent, d) at least one release modifying agent, and e) at least one pharmaceutically acceptable gel forming agent, wherein the composition is a solution.

[0036] In the current invention provides the isoxazoline compound of Formula (I) Formula (I)

[0037] R1 - R5 is H, F, Cl or CF3

[0038] X is O or S, preferably O

[0039] Y is selected from wherein denotes the bond to the isoxazoline or isothiazoline

[0040] > denotes the bond to the carbonyl group

[0041] Z is selected from wherein

[0042] - denotes the bond to the carbonyl group

[0043] Isoxazoline compounds for use in the current invention of Formula (I) are

[0044] Formula (I)

[0045] R1 - R5 is H, F, Cl or CF3 X is O or S, preferably O

[0046] Y is selected from wherein

[0047] - denotes the bond to the isoxazoline or isothiazoline > denotes the bond to the carbonyl group

[0048] Z is selected from 26009 wherein

[0049] - denotes the bond to the carbonyl group

[0050] In an alternative embodiment the injectable composition comprises the isoxazoline compound of Formula (I) as sole active ingredient. In such embodiment the injectable veterinary pharmaceutical composition comprises an isoxazoline compound as described in this application, b) at least one pharmaceutically acceptable solvent, c) at least one release modifying agent, and d) at least one pharmaceutically acceptable gel forming agent, wherein the composition is a solution.

[0051] The 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.

[0052] 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]-l -naphthal ene-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-

[0053] (tri fluoromethyl)- l,2-oxazol-3yl]-N-[2-oxo-2-[(2, 2, 2-trifluoroethylamino]ethyl]naphthalene-l -or afoxolaner. Afoxolaner is for example disclosed in WO 2007 / 079162. In one embodiment the isoxazoline compound is Esafoxolaner, in another embodiment umifoxolaner

[0054] In 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'-((5 S)- (5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H- spiro[azetidine-3,l'-isobenzofuran]-l-yl)-2-(methylsulfonyl)ethan-l-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-tri chi orophenyl)-5-(tri fluoromethyl)-

[0055] 4.5-dihydroisoxazol-3-yl]thiophene-2-carboxamide (CAS RN: 1369852-71-0). This compound is known as lotilaner.

[0056] In one preferred embodiment of the invention and / or embodiments thereof a compound used as alternative to the isoxazoline compound is 2-chloro-N-(l-cyanocyclopropyl)-5-[l-[2-methyl-5- (l,l,2,2,2-pentafluoroethyl)-4-(trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]benzamide (CAS RN 1621436) This compound is known as tigolaner.

[0057] 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.

[0058] 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).

[0059] In one preferred embodiment of the invention and / or embodiments thereof the isoxazoline is 4- [5-(3,5-di chi orophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thi etan-3- yl)benzamide (CAS RN 1164267-94-0) that was disclosed in WO 2009 / 0080250.

[0060] 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.

[0061] 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.

[0062] Especially preferred is fluralaner (corresponding to 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-

[0063] 4.5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide) which is represented by In one embodiment

[0064] 9

[0065] Formula (II).

[0066] In a preferred embodiment of the invention and / or embodiments thereof, the present composition comprises fluralaner, in an amount of about 0.1% by weight to about 50.0% by weight, preferably of about 1.0% by weight to about 45% by weight, more preferably of about 2.0 % by weight to about 35% by weight, even more preferably of about 3% by weight to about 30% by weight, in particular of about 6% by weight to about 23% by weight, especially about 8% by weight to 15% by weight, based on the total weight of the composition.

[0067] 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.

[0068] 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 / 075591 and

[0069] 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.

[0070] 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.

[0071] Stereoisomers and polymorphic forms

[0072] As noted above, it will be appreciated by those of skill in the art that certain compounds within the compositions of the invention may exist and be isolated as optically active and racemic forms. Compounds having one or more chiral centers, including at a sulfur atom, may be present as single enantiomers or diastereomers or as mixtures of enantiomers and / or diastereomers.

[0073] In addition, compounds within the compositions of the invention may include one or more chiral centers, which results in a theoretical number of optically active isomers. 26009

[0074] Where compounds within the compositions of the invention include n chiral centers, the compounds may comprise up to 2n optical isomers. The present invention encompasses compositions comprising the specific enantiomers or diastereomers of each compound as well as mixtures of different enantiomers and / or diastereomers of the compounds of the invention that possess the useful properties described herein. In addition, the invention encompasses compositions comprising one or more conformational isomers (e.g. rotamers) as well as mixtures of conformational isomers.

[0075] Parasiticidal macrocyclic lactones include avermectins such as abamectin, doramectin, eprinomectin, ivermectin, latidectin, , and milbemycins such as, moxi dectin.. In one embodiment the composition comprises one or more macrocyclic lactone, selected from abamectin, doramectin, eprinomectin, ivermectin, and moxidectin.

[0076] In one preferred embodiment the composition according to the invention comprises moxidectin. The macrocyclic lactone compounds are known in the art and can easily be obtained commercially or through synthesis techniques known in the art. Reference is made to the widely available technical and commercial literature.

[0077] In an embodiment of the invention and / or embodiments thereof, the composition comprises eprinomectin as (al) physiologically active macrocyclic lactone and fluralaner, alternatively (S)-fluralaner, as (b) the isoxazoline compound of Formula (I).

[0078] In an especially preferred embodiment of the invention and / or embodiments thereof, the composition comprises moxidectin as (al) physiologically active macrocyclic lactone and fluralaner, alternatively (S)-fluralaner, as (b) isoxazoline compound of Formula (I).

[0079] In an embodiment of the invention and / or embodiments thereof, the composition comprises moxidectin in an amount of about 0.01% by weight to about 1.0% by weight, more preferably of about 0.05% by weight to about 0.85% by weight, even more preferably of about 0.1% by weight to about 0.7% by weight, in particular preferably of about 0.15% by weight to about 0.5% by weight, especially about 0.5% by weight, or alternatively about 0.75% by weight and the isoxazoline compound of formula (I), especially fluralaner in amount of about 0.1% by weight to about 50.0% by weight, preferably of about 1.0% by weight to about 45% by weight, more preferably of about 2.0 % by weight to about 35% by weight, even more preferably of about 3% by weight to about 25% by weight, in particular of about 5% by weight to about 15% by weight, especially about 9% by weight to 12% by weight, based on the total weight of the composition. 26009

[0080] In an embodiment of the invention and / or embodiments thereof, the composition comprises eprinomectin as (al) physiologically active macrocyclic lactone and umifoxolaner, as (b) isoxazoline compound of Formula (I).

[0081] In an embodiment of the invention and / or embodiments thereof, the composition comprises m oxidectin as (al) physiologically active macrocyclic lactone and umifoxolaner, as (b) isoxazoline compound of Formula (I).

[0082] In an embodiment of the invention and / or embodiments thereof, the composition comprises eprinomectin as (al) physiologically active macrocyclic lactone and sarolaner as (b) isoxazoline compound of Formula (I).

[0083] In an embodiment of the invention and / or embodiments thereof, the composition comprises moxidectin as (al) physiologically active macrocyclic lactone and sarolaner as (b) isoxazoline compound of Formula (I).

[0084] In an embodiment of the invention and / or embodiments thereof, the composition comprises eprinomectin as (al) physiologically active macrocyclic lactone and lotilaner as (b) isoxazoline compound of Formula (I).

[0085] In an embodiment of the invention and / or embodiments thereof, the composition comprises moxidectin as (al) physiologically active macrocyclic lactone and lotilaner as (b) isoxazoline compound of Formula (I).

[0086] In an embodiment of the invention and / or embodiments thereof, the present composition can contain an additional therapeutic agent.

[0087] In an embodiment of the invention and / or embodiments thereof, the present composition can be administered in combination with an additional therapeutic agent. The administration of the additional therapeutic agent may be in the same composition or in separate compositions.

[0088] The additional therapeutic agent can preferably be a parasiticide or a vaccine, preferably another parasiticide.

[0089] 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.

[0090] It has been found that the injectable composition according to the invention can be injected as liquid into the animal body, and then, an in situ solid gel is formed. Such system is known as injectable in-situ gelling system. It consists of gel forming agents that are preferably biodegradable polymers dissolved in a biocompatible solvent system. When the liquid polymer system is placed in the body using standard needles and syringes, it solidifies upon contact with aqueous body fluids to form a solid implant. 26009

[0091] Injectable in-situ forming depots comprise possess the advantages of a straightforward manufacturing even for sensitive molecules and ease of application as a liquid.

[0092] . One of the problems with these systems is the possibility of a burst in drug release especially during the first few hours after injection into the body.

[0093] The injectable composition according to the invention comprises at least one pharmaceutically acceptable gel forming agent. The pharmaceutically acceptable gel forming agent is selected from the group consisting of polylactides, polyglycolides, copolymers of polylactides and polyglycolides and cellulose acetate butyrate.

[0094] Alternative pharmaceutically acceptable polymers that can be used as gel forming agents for use in the inventive injectable compositions include, poly caprolactones, polyanhydrides, polyamides, polyurethanes, polyester amides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures therein including copolymers.

[0095] In one embodiment, the pharmaceutically acceptable gel forming agent is a polymer, especially a biodegradable polymer. Examples of biodegradable polymers include, but are not limited to, polylactides, polycaprolactones, polyglycolides, polyorthoesters, polyurethanes,), and copolymers thereof.

[0096] The molecular weight of the pharmaceutically acceptable gel forming agent may impact the characteristics of the compositions of the invention. The average molecular weight of a gel forming agent 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. The molecular weight range of a gel forming agent can impact the physical characteristics of the material and the way that it interacts with the active agent.

[0097] 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 active ingredients may be observed when the weight average molecular weight is between about 30 to about 70 kDa. In some embodiments, a combination of gel forming agent having different average molecular weights may provide a release rate that combines the effect of the different polymers used. 26009

[0098] 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.

[0099] As used herein with respect to the molecular weight range of a pharmaceutically acceptable polymer, the term “low molecular weight” (LMW) refers to polymer with an inherent viscosity in the range of 0.05-0.29 dL / g; the term “medium molecular weight” refers to a polymer with an inherent viscosity in the range of 0.3-0.55dL / g; and high molecular weight refers to a polymer with an inherent viscosity in the range of 0.55-1.0 dL / g.

[0100] In another embodiment, the pharmaceutically acceptable polymer in the composition of the invention will have an inherent viscosity of about 0.10-0.20 dL / g. In another embodiment, the pharmaceutically acceptable polymer in the composition will have an inherent viscosity of about 0.35-0.50.

[0101] In some embodiments, the composition of the invention comprises gel forming agent being a pharmaceutically acceptable polymer selected polylactides, polyglycolides and copolymers thereof. In another embodiment, the compositions include a poly(lactide-co-glycolide) copolymer ("PLGA"). PLGA copolymers may have different molecular weight ranges and may also have different weight: weight ratios of lactide to glycolide.

[0102] This ratio may affect the properties of the copolymer and the way that it interacts with the active agent. In one preferred embodiment, the compositions of the invention having a higher lactide to glycolide ratio (e.g., 75:25 compared with 50:50) result in an increase in hydrogen bonding between the active agent and the polymer, leading to better solubility of the active agent in vivo. This effect improves the injection site reaction and allows for the extendable release injectable compositions to include a higher amount of the active agent, which will translate to a longer duration of efficacy.

[0103] In one embodiment of the invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 30:70 to about 99: 1. In another embodiment of the invention where the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 40:60 to about 80: 15. In another embodiment of the invention where the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 40:60 to about 60:40. In another embodiment of the invention where the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 70:30 to about 80:20. In another 26009 embodiment of the invention, where the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 50:50.

[0104] In another embodiment of the invention, where the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 75:25.

[0105] In one embodiment, the compositions comprise about 1 to about 30% (w / w) of the gel forming agent . In another embodiment, the compositions comprise about 5 to about 25%, about 8% to about 20% (w / w) or about 10 to about 20%) (w / w). In another embodiment, the compositions comprise a maximum of about 20 to about 25% (w / w) of the gel forming agent, in another preferred embodiment especially about 5, about 10, about 15% or about 20% (w / w) for PLGA or PDLLA (Poly(D,L-lactide), more preferably about 5, or about 10% (w / w) .

[0106] 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.

[0107] Typically, at a temperature of approximately at 25° C viscosities of about less than 150 centipois (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 at25° 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.

[0108] Solvents

[0109] The solvents used in the injectable compositions may be a single or a blend or mixture of solvents.

[0110] Solvents may be used in the compositions of the invention to improve the solubility of the isoxazoline active agent and the macrocyclic lactone and / or to lower the viscosity of the compositions. In one embodiment, the co-solvents used in the injectable compositions of the present invention include polar solvents that are miscible in water.

[0111] Non-limiting examples of these co- solvents include ethanol, isopropanol, glycol ethers (e.g., including, but limited to, diethyleneglycol monoethyl ether (DGME, Transcutol® ), butyl diglycol, dipropylene glycol n- butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol 26009 monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and the like), propylene glycol, glycerin, carbonates (e.g., propylene carbonate or ethylene carbonate), 2-pyrrolidone, substituted 2-pyrrolidones including N-methylpyrrolidone, 1- ethylpyrrolidone, 1-octylpyrrolidone, 1-dodecylpyrrolidone, 1- isopropylpyrrolidone, l-(sec- or t- or n-butyl)pyrrolidone, 1-hexylpyrrolidone, l-vinyl-2- pyrrolidone, 1-cyclohexylpyrrolidone, 1- (2-hydroxyethyl)-pyrrolidone, l-(3- hydroxypropyl)pyrrolidone, 1 -(2 -methoxy ethyl)- pyrrolidone, l-(3-methoxypropyl)pyrrolidone and 1-benzylpyrrolidone; dimethyl isosorbide (DMI), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), glycerol formal or a mixture of at least two of these solvents. In one embodiment, the long-acting compositions of the invention comprise a polar protic solvent. In another embodiment, the polar protic solvent is a glycol, such as glycerol or propylene glycol, or a glycol ether such as diethylene glycol monoethyl ether (Transcutol) or other commonly used glycol ethers such as those described above.

[0112] In another embodiment, the injectable compositions of the invention comprise a polar aprotic solvent including, but not limited to, N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, dimethylsulfoxide or propylene carbonate.

[0113] Solvents include ethyl acetate, triacetin, lipids, triglycerides including medium chain triglycerides such C8 -CIO triglycerides such as capri c / caprilic triglycerides, propylene glycol derivatives (e.g. propylene glycol monolaurate), capryl ocaproyl polyoxyl-8 glycerides (Labrasol) (non-ionic water dispersible surfactant, isopropyl myristate, or a mixture of at least two of these solvents.

[0114] Preferably at least one solvent is an alcohol, a liquid polyethylene glycol, especially PEG that is liquid at room temperature such as PEG 400 , propylene glycol, tetraglycol, diethylene glycol monoethyl ether (Transcutol), glycerol, a glycerol ester, a cyclic carbonate, 2-pyrrolidone, N- methylpyrrolidone, dimethyl isosorbide, dihydrolevoglucosenone (Cyrene), dimethylacetamide, dimethylsulfoxide, glycerol formal, a triglyceride, a propylene glycol diester or a poloxamer or mixtures thereof.

[0115] More preferably at least one solvent is, a liquid polyethylene glycol, propylene glycol, tetraglycol, diethylene glycol monoethyl ether (Transcutol), glycerol, a glycerol ester, 2- pyrrolidone, N-methylpyrrolidone, , dihydrolevoglucosenone (cyrene), dimethylacetamide, dimethylsulfoxide or a propylene glycol diester or mixtures thereof. 26009

[0116] Even more preferred is N-methylpyrrolidone, triacetin, DMSO or dihydrolevoglucosenone (Cyrene) or mixtures thereof , most preferred N-methylpyrrolidone, polyethylene glycol, especially PEG 400 or dihydrolevoglucosenone, ,most preferable N-methylpyrrolidone.

[0117] In one embodiment, the compositions of the invention may comprise about 0.5% to about 85% (w / w) of a solvent.

[0118] In another embodiment, the compositions of the invention may comprise about 10% to about 75% (w / w) or about 15 to about 50% (w / w) of a solvent.

[0119] In still another embodiment, the compositions may comprise about 1% to about 45% (w / w), about 5% to about 50% (w / w), about 5% to about 40% (w / w) or about 5% to about 35% (w / w) of a solvent.

[0120] In other embodiments, the compositions of the invention may comprise about 1% to about 20% (w / w), about 2% to about 15% (w / w) or about 2% to about 10% (w / w) of the solvent.

[0121] Preferably the release modifying agent is a protic solvent including, but not limited to, an alcohol such a Cl -C6 alcohol, preferably selected from ethyl alcohol, benzyl alcohol and benzyl benzoate or mixtures thereof, especially a mixture of benzyl alcohol and benzyl benzoate.

[0122] It has been found that especially the release modifying agent benzyl benzoate positively influences the release rate of the active ingredients.

[0123] In one embodiment, the compositions of the invention may comprise about 0.5% to about 35% (w / w) of the release modifying agent. In another embodiment, the compositions of the invention may comprise about 2% to about 15% (w / w) or about 12 50% (w / w).

[0124] In one embodiment the injectable composition comprises about 10 to about 65 % (w / w) of benzyl benzoate, preferably between about 10% and 30% (w / w), most preferred about 10 % w / w.

[0125] In one embodiment the injectable composition comprises less than 5% (w / w) of water.

[0126] The inventive formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers.

[0127] These compounds are well known in the formulation art. Antioxidants such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfite, n- propyl gallate, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene), BHA and citric acid, monothioglycerol, tert-butyl hydroquinone (TBHQ), and the like, may be added to the present formulation.

[0128] The antioxidants are generally added to the formulation in amounts of from about 0.01 to about 1.0%, based upon total weight of the formulation. 26009

[0129] 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.

[0130] The compositions of the invention are made by mixing the appropriate amount of the active agents, and, optionally, an antioxidant, pharmaceutically acceptable additive and / or excipient to form a composition of the invention. 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).

[0131] Method of treatment

[0132] Another aspect of the present invention is the injectable veterinary composition of the present invention for use in treating and / or preventing a parasite infestation in an animal. The composition of this invention is administered parenterally via an injection.

[0133] A parasite infestation refers to the presence of parasites in numbers that pose a risk to humans or animals.

[0134] It has been shown in the Example that the composition of the invention results in effective blood plasma concentration of moxidectin and fluralaner for an extended period, for more than 6 months.

[0135] This means the present injectable composition achieves an effective extended-release effect of a physiologically active macrocyclic lactone (al) and the isoxazoline compound according to Formula (I) or the compound according to Formula (II) against ectoparasites (such as fleas, ticks and mites) and endoparasites, such as worms (helminths).

[0136] The invention also provides a method for introducing and maintaining blood levels of a physiologically active macrocyclic lactone (al) and an isoxazoline compound according to Formula (I), especially fluralaner in animals for an extended period of time and a method for the prevention or treatment of infections and infestations caused by helminths, nematodes, and ectoparasitic arthropods in animals.

[0137] Additionally, it turned out that after injection the present injectable composition safe to the animal, shows a desirable bioavailability for the active ingredients 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 or intramuscular injection. 26009

[0138] In one embodiment the composition of the current invention is administered by subcutaneous or intramuscular injection to an animal.

[0139] In addition, it has been discovered that a single administration of such compositions generally provides potent activity against one or more parasites (e.g., ectoparasites such as fleas, ticks or mites), while also tending to provide fast onset of activity, long duration of activity, and / or desirable safety profiles.

[0140] Finally, the new injectable composition allows the use of these compounds under conditions, where separate injections and a repeated administration is not desirable.

[0141] 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.

[0142] Another aspect is a method for treating or protecting an animal from parasite infestation for a period of about 3 to about 12 months which comprises administering the injectable composition of the invention to said animal, preferably to a dog or cat, preferably a dog. .

[0143] As far as the injectable veterinary composition is concerned, the same applies as described above. The same applies to parasites and parasite infestation.

[0144] An endoparasite which seriously harms animals is Dirofilaria immitis, also known as heartworm. The most common hosts are dogs and cats but other animals such as ferrets and raccoons may also be infected. The parasitic worm is transmitted by the mosquito bites, which carry the heartworm larvae. The adult worms live in the major blood vessels of the lung, causing inflammation of the blood vessels and potentially resulting in heart damage and early death. In advanced infections, the worms enter the heart as well.

[0145] In a particularly preferred embodiment of the invention, the compositions of the invention are used to treat or prevent an infection by Dirofilaria immitis. In another embodiment the compounds and compositions of the invention are used to treat or prevent an infection by Dirofilaria repens.

[0146] Macrocyclic lactones are especially useful to control heartworm (Dirofilaria spp.) infestations in animals, especially pets or companion animals, especially in dogs or cats.

[0147] The concentration of the active ingredients 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.

[0148] The injectable veterinary composition is administered parenterally, in particular by subcutaneous or intramuscular injection to the animal. A subcutaneous or intramuscular injectable administration can for example be carried out by a syringe. 26009

[0149] The compositions according to the invention have good syringeability.

[0150] 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.

[0151] In a preferred embodiment of the invention and / or embodiments thereof, the dosage regime of the injectable veterinary composition is, monthly, semiannually or annually.

[0152] Preferably the injectable pharmaceutical compositions may be administered every month, every two months, every three months, every four months, every five months, every six months, every seven months, eight months, every nine months, every ten months, every eleven months, every twelve months, every 13 months, every 14 months, every 15 months, every 16 months, every 17 months or every 18 months, in particular once every six months or once every twelve months. Especially preferred is an administration every 6 months. Preferred is also an administration or every 12 months. In one embodiment the dosage regime is at least once every six months or once every twelve months.

[0153] This provides a long- term protection of animals from both ectoparasites, especially fleas and ticks, and endoparasites, especially heartworm and / or gastrointestinal helminths. Especially preferred is long term protection against heartworm infestation.

[0154] Of benefit is the possibility to apply the injectable composition of the invention together with the annual vaccination against infectious diseases such as distemper, influenza, rabies and other vaccines with conventional antigens.

[0155] In a preferred embodiment of the invention and / or embodiments thereof, the animal is a pet. A pet (also referred to as companion animal) can be regarded as an animal generally living in or close to the habitation of its owner. Examples of pets include, but are not limited to, dogs, cats, rabbits, guinea pigs and birds such as budgies and parrots.

[0156] In one embodiment the animal is a dog or cat.

[0157] In a more preferred embodiment of the invention and / or embodiments thereof, the animal is a dog.

[0158] In a preferred embodiment of the invention and / or embodiments thereof, the isoxazoline compound of Formula (I), preferably fluralaner, and / or the compound according to Formula (II) is administered at about 0.01 to about 200mg / kg body weight of the animal, preferably from about 0.1 to about lOOmg per kg of animal body weight, more preferably from about 0.5 to about 26009

[0159] 50mg per kg of animal body weight, in particular from about 1 to about 30 mg per kg of animal body weight.

[0160] In a preferred embodiment of the invention and / or embodiments thereof, the physiologically active macrocyclic lactone, preferably moxidectin is administered at about 0.01 to about 10 mg / kg body weight of the animal, preferably from about 0.1 to about 5 mg per kg of animal body weight.

[0161] 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.

[0162] 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.

[0163] Though some injection site irritation is inevitable in some animals, injection site swelling of more than 2 x 2 cm that further persists for more than two to three days is generally considered to be unacceptable by veterinarians and animal owners.

[0164] Another aspect of the present invention is a method for treating and / or preventing a parasite infestation in an animal comprising administering to a subject in need thereof a therapeutically effective amount of the injectable veterinary composition according to the present invention . Again, as far as the injectable veterinary composition are concerned, the same applies as described above. The same applies to parasites and parasite infestation.

[0165] Thus, the invention provides a method of treating and / or preventing a parasite infestation which comprises administering to an animal a therapeutically effective amount of the injectable veterinary composition of the present invention or using the kit according to the present invention.

[0166] 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.

[0167] In another embodiment, the compositions of the present invention have an efficacy of at least about 50% against ectoparasites for about 3 months, or longer, preferably about 12 months. In still another embodiment, the compositions of the invention provide an efficacy of at least about 90% against ectoparasites for 3 months or longer, preferably about 12 months. 26009

[0168] In yet another embodiment, the compositions of the present invention of the invention provide an efficacy of at least about 95% against ectoparasites for 3 months or longer, preferably about 12 months.

[0169] In other embodiments, the long-acting compositions of the invention have an efficacy of at least about 90% against ectoparasites including, but not limited to, fleas, ticks, mites or parasitic flies, of about 7 months or longer, about 8 months or longer or about 9 months or longer, about 10 months or longer, about 11 months or longer or about 12 months.

[0170] In other embodiments, the compositions of the invention have an efficacy of at least about 90% against ectoparasites including, but not limited to, fleas, ticks, mites and parasitic flies, of about 10 months or longer, about 11 months or longer or even about 12 months or longer, preferably about 12 months.

[0171] Definitions

[0172] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0173] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry are those well-known and commonly employed in the art.

[0174] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0175] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable).

[0176] 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 ranges and 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.

[0177] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds. The term "comprise," or variations thereof such as "comprises" or "comprising," are to be read to indicate the inclusion of any recited integer (e.g., a feature, element, characteristic, property, method / process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method / process steps or limitations) but not the exclusion of any other integer or group of integers.

[0178] The term “animal” is used herein to include all mammals, birds and fish and also include all vertebrate animals. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep .

[0179] The term “essentially pure” is used herein to indicate that a compound or an enantiomer is at least about 90% pure, at least about 95%, at least about 98% pure, or higher.

[0180] By the term “enriched” is meant when the weight: weight ratio is at least approximately 1.05 or higher in favor of the enantiomer that displays significant in vitro and in vivo activity (the eutomer).

[0181] The term “treatment” as used herein refers to reversing, alleviating, inhibiting the parasite infestation. Prevention / protection is stopping a new or incoming infestation or infection from establishing.

[0182] For an in vivo administration of the composition according to the invention, an effective amount is synonymous with a "therapeutically or prophylactically effective amount", which is the dose or amount that prevents or treats / ameliorates symptoms and / or signs of parasite infection or infestation by the treated animal or prevents a parasite infestation or reduces parasite numbers in and / or on an animal and / or to inhibits the development of parasite infestation in or on an animal, in whole or in part at a reasonable benefit / risk ratio applicable to any medical treatment.

[0183] This is a sufficient amount of a composition of the invention to reduce the number of parasites infesting the animal compared to untreated animals.

[0184] In some embodiments, an effective amount of the composition of the invention achieves at least 50% efficacy against the target parasite.

[0185] In other embodiments, an effective amount of the active agent achieves at least 80%, or at least 90% efficacy against the target parasites. 26009

[0186] Preferably, an effective amount of the active ingredients will achieve at least 95%, at least 98% or 100% efficacy against the target parasites.

[0187] The terms “prevent”, “prevention” or “prophylaxis” “protection” are intended to mean the administration of the compositions of the present invention to the animal before the parasitic infestation has occurred in order to keep said infestation from occurring.

[0188] Administration of the compositions at recommended regular intervals effectively prevents new parasitic infestations or infections in animals by killing new parasites that attack an animal before they can multiply to establish an infestation. EXAMPLES

[0189] 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.

[0190] 26009

[0191] Example 1 : Preparation of injectable solution of Fluralaner and Moxidectin

[0192] A batch of Fluralaner and Moxidectin injectable solution formulation was prepared by dissolving ingredients to form a clear solution. Briefly, BHT was first dissolved in NMP, benzyl alcohol mixture followed by addition of Fluralaner and Moxidectin. The mixture was then stirred to dissolve the APIs at room temperature to until form a clear solution. The Poly(D,L-lactide-co- glycolide (PLGA) polymer and benzyl benzoate were then added directly into the mixture and stirred at room temperature until form a clear solution. The formulations were characterized by visual appearance, clarity, visible particles, and presence of undissolved API.

[0193] TABLE 1 1IV: inherent viscosity; 2QS: Quantity sufficient.

[0194] In addition, different molecular weight of PLGA polymers with variable polymer concentrations were tested. The solution formulations were characterized by appearance, and syringeability. The result indicated that all formulations were slight yellow clear liquid without precipitation or visible particles.

[0195] TABLE 2

[0196] QS: Quantity sufficient; IV: inherent viscosity.

[0197] The syringeability tests were performed under a fixed flow rate through 18G needle to compare the force required for different compositions. The force (N) was measured by texture analyzer. As expected, formulations with higher concentration or higher molecular weight PLGA or PDLLA polymers required higher force to inject through the needle. However, a non-linear relationship was observed with the increase of polymer concentration in the formulation. In general, formulations require > 80 N force is considered to be difficult to inject, while the maximum acceptable injection force to be <40 N. (Ref. doi.org / 10.1016 / j.ijpharm.2018.11.012). The results (Figure 1 ) indicated that formulations with up to 30% polymer are acceptable for subcutaneous injection.

[0198] Example 2: Feasibility of using alternative solvent(s)

[0199] A feasibility test was performed to explore alternative solvents to for the composition according to the invention using a Fluralaner and Moxidectin injectable solution formulation and identify more pharmaceutically acceptable solvent system.

[0200] TABLE 3 26009

[0201] QS: Quantity sufficient; IV: inherent viscosity.

[0202] The dogs were monitored for 28 days, and the tested formulations were found to have acceptable injection site reaction and can be considered as safe for subcutaneous injection in dogs. Example 3 : Local tolerance test after subcutaneous injection in dogs

[0203] A study was designed to determine the local tolerance of different formulations containing Fluralaner and Moxidectin after subcutaneous administration in dogs. Briefly, 0.05 mL / kg body weight of each formulation were injected subcutaneously in beagle dogs. Dogs were observed at least 5 times approximately 10 minutes apart starting from one hour after test article administration, and then hourly until 4 hours after completion of test article administration for scratching at the administration sites, or other observations (e.g., rubbing, rolling, biting). The injection sites were also inspected one day following administration, and then every 2-3 days until completion of the study until day 18. TABLE 4: Selected formulations for in-vivo tolerance test after subcutaneous injection in dogs 26009

[0204] PLGA: Poly (D, L-lactide-co-glycolide); PDLLA: Poly(D, L-lactide); BHT: Butylated hydroxytoluene; NMP: N-methyl-2-pyrrolidone; CAB: Cellulose acetate butyrate; SAIB: Sucrose acetate isobutyrate;

[0205] Example 4: In-vivo PK study in dogs Eight different solutions of Fluralaner and Moxidectin were selected for in-vivo PK study in dogs.

[0206] TABLE S

[0207] BHT: Butylated hydroxytoluene; NMP: N-methyl-2-pyrrolidone.

[0208] The blood plasma concentration of the different formulation over 360 days is shown in Figure 2 for fluralaner and Fig. 3 for moxidectin. 26009

[0209] TABLE 6: The PK parameters are presented in the table below 26009

[0210] The PK parameters indicated that the total fluralaner plasma concentrations varied within expectation, while the mean moxidectin plasma concentrations were also varied with significantly higher Cmax concentrations. The 365 days PK profiles showed that the Clast of fluralaner were between 78-108 ng / mL, while Clast for moxidectin were between 0.12-0.57 ng / mL, which are considered to be effective against fleas-ticks and heartworm respectively. In overall, the PK profiles indicated that solution (in-situ gel) formulations achieved effective plasma concentration of fluralaner and moxidectin for 365 days. 26009

[0211] Example 5: Stability of Fluralaner and Moxidectin injectable solutions

[0212] The stability study was conducted at 40°C / 75%RH in clear type I glass vials sealed with rubber stoppers and aluminum crimped. Additional vials were placed at 30°C / 65%RH but tested only after observing any degradation at 40°C / 75%RH. * 30°C samples were tested only at 6 month time point to compare when Moxidectin degradation was observed at 40°C; PLGA: Poly(D,L-lactide-co-glycolide); PDLLLA: Poly(D, L-lactide); Higher than 100% assay results can be attributed to several factors including but not limited to the sample uniformity, sample preparation, and analytical method variability.

[0213] However, the analytical assay variabilities were not significantly different from assay at time zero and cannot be clearly concluded as degradation.

[0214] The stability results indicated that formulations are physically stable over 6 months. There was no chemical degradation for Fluralaner over 6 months, while 4-9% assay loss was observed for Moxidectin at 40°C / 75%RH. The assay loss of Moxidectin was less at 30°C / 65%RH at 6 months indicated a temperature dependent degradation of Moxidectin. 26009

[0215] 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.

[0216] 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

WHAT 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 group Z is selected from34wherein- denotes the bond to the carbonyl group; b) a macrocyclic lactone, selected from abamectin, doramectin, eprinomectin, ivermectin, and moxidectin; c) at least one pharmaceutically acceptable gel forming agent, d) at least one pharmaceutically acceptable solvent, e) at least one release modifying agent selected from benzyl alcohol and benzyl benzoate or mixtures thereof., and wherein the composition is a solution.

2. The injectable composition according to claim 1, wherein the isoxazoline of Formula (I) is selected from the group consisting of fluralaner, afoxolaner,esafoxolaner, umifoxolaner, tigolaner, lotilaner or sarolaner.

3. The injectable composition according to claim 2, wherein the isoxazoline of Formula (I) is fluralaner.

4. The injectable composition according to any one of claims 1-3, comprising about 5 to about 30 % (w / w) of the compound of Formula (I).

5. The injectable composition according to any one of claims 1-4, wherein the macrocyclic lactone is moxidectin.

6. The injectable composition according to any one of claims 1-5, wherein the at least one pharmaceutically acceptable gel forming agent is selected from the group consisting of polylactides, polyglycolides, copolymers of polylactides and polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones,35polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride), cellulose acetate butyrate, chitin and chitosan.

7. The injectable composition according to any one of claims 1-6, wherein the at least one pharmaceutically acceptable gel forming agent is selected from the group consisting of polylactides, polyglycolides, copolymers of polylactides and polyglycolides and cellulose acetate butyrate.

8. The injectable composition according to claim 7, wherein the least one pharmaceutically acceptable gel forming agent is a copolymer of polylactides and polyglycolides and has a lactide to glycolide ratio of 50:50 to 85: 15 (weight: weight).

9. The injectable composition according to claim 7 or 8, 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 0.26 to about 0.82, more preferably about 0.41 to about 0.86.

10. The injectable composition according to any one of claims 1-9, comprising about 2 to about 40% % (w / w) of the at least one pharmaceutically acceptable gel forming agent, preferably up to about 25%(w / w) or up to about 30% (w / w).

11. The injectable composition according to any one of claims 1-10, wherein the at least one solvent is an alcohol, a liquid polyethylene glycol, propylene glycol, tetraglycol, diethylene glycol monoethyl ether (Transcutol), glycerol, a glycerol ester, a cyclic carbonate, 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide, , dihydrolevoglucosenone (Cyrene), dimethylacetamide, dimethylsulfoxide, glycerol formal, a triglyceride, a propylene glycol diester or a poloxamer or mixtures thereof.

12. The injectable composition according to claim 11, wherein the at least one solvent is an alcohol, a liquid polyethylene glycol, propylene glycol, tetraglycol, diethylene glycol monoethyl ether, glycerol, a glycerol ester, 2-pyrrolidone, N-methylpyrrolidone, , dihydrolevoglucosenone, dimethylacetamide, dimethylsulfoxide or a propylene glycol diester or mixtures thereof.2600913. The injectable composition according to any one of claims 1-11, wherein the release modifying agent is a benzyl benzoate or a mixture of benzyl benzoate and benzyl alcohol, comprising about 10 to about 30 % (w / w) of benzyl benzoate.

14. The injectable composition according to any one of claims 1-11, comprising from about 5 to about 30 % (w / w) of a copolymer of polylactides and polyglycolides and benzyl benzoate or a mixture of benzyl benzoate and benzyl alcohol, comprising about 10 to about 30 % (w / w) of benzyl benzoate.

15. A method for treating or protecting an animal from parasite infestation for a period of about 3 to about 12 months which comprises administering the injectable composition of any one of claims 1 - 13 to said animal.

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