EA040232B1 - USE OF INJECTABLE DELAYED RELEASE PREPARATIONS CONTAINING ISOXAZOLINE ACTIVE SUBSTANCE - Google Patents

Description

Cross-reference to related applications

This application claims the priority claimed in U.S. Provisional Application No. 62/144,871, filed April 8, 2015, which is incorporated herein by reference.

The field of technology to which the invention belongs

The present invention describes sustained release injectable preparations containing at least one isoxazoline active ingredient, a pharmaceutically acceptable polymer and a solvent; the use of these drugs against parasites (including ectoparasites (eg, fleas or ticks) and/or endoparasites) and methods for preventing or treating parasitic infections and infestations in animals.

Prior Art

Animals such as mammals and birds are often susceptible to parasitic infestations/infections. Such parasites can be ectoparasites such as fleas, ticks and parasitic flies, and endoparasites such as nematodes and other worms. Domesticated animals such as cats and dogs are often infected with one or more of the following ectoparasites:

fleas (eg Ctenocephalides spp. such as Ctenocephalides felis and the like);

parasitiform mites (eg Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., etc.);

acariform mites (eg Demodex spp., Sarcoptes spp., Otodectes spp., etc.);

lice (eg Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.);

mosquitoes (Aedes spp., Culex spp., Anopheles spp. etc.) and flies (Hematobia spp., Musca spp., Stomokcus spp., Dermatobia spp., Cochliomyia spp. etc.).

Fleas are a problem because not only do they negatively affect the health of the animal or person, but they also cause a lot of psychological stress. Moreover, fleas also transmit pathogenic agents such as tapeworm (Dipylidium caninum) to animals and humans.

Similarly, parasitiform mites are also harmful to the physical and/or psychological health of an animal or human. However, the most serious problem associated with parasitiform mites is that they are carriers of pathogenic agents that affect both humans and animals. Major diseases that can be transmitted by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsiosis (eg Rocky Mountain spotted fever). Parasitiform mites also release toxins that cause inflammation or paralysis in the host. Sometimes these toxins can be fatal to the host.

Similarly, farm animals are also susceptible to parasitic infestations. For example, cattle can become victims of a large number of parasites. The dominant parasite of cattle in some regions are parasitiform mites of the genus Rhipicephalus, especially those of the species microplus (ringed tick), decoloratus and annulatus. Parasitiform mites such as Rhipicephalus microplus (formerly Boophilus microplus) are difficult to control as they lay their eggs in pastures for farm animals. This species of parasitiform mite is considered a single host mite and, in its immature and adult stages, is on the same animal until the female is fertilized and falls off the host to lay eggs in the environment. The life cycle of such mites is approximately 3-4 weeks. In addition to cattle, Rhipicephalus microplus can infect buffalo, horses, donkeys, goats, sheep, deer, pigs, and dogs. Stressing animals like this can reduce productivity and damage hides, and it also spreads diseases such as babesiosis (bovine piroplasmosis) and anaplasmosis.

Animals and humans also suffer from endoparasitic infections, including, for example, helminthiasis caused by parasitic worms classified as cestodes (tapeworms), nematodes (roundworms) and flukes (flatworms or flukes). These parasites negatively affect animal nutrition and cause great economic losses in raising pigs, sheep, horses and cattle, as well as negatively affecting domestic animals and poultry. Other parasites found in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius, and parasites that are found in blood vessels or other tissues and organs, including filarial worms and additional intestinal stages of Strogyloides, Toxocara and Trichinella.

Recently, isoxazole- and isoxazoline-containing compounds have been shown to be effective against parasites that infect animals. For example, US Pat. No. 7,964,204 (issued to DuPont, incorporated herein by reference in its entirety) describes isoxazoline compounds having the following formula (I) that exhibit activity against ectoparasites and/or endoparasites:

- 1 040232

O - NA ⁶ ^

^w (I)

In addition, published patent applications US 2010/0254960 A1, WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 A1, US 7951828 & US 7662972, US 2010/0137372 A1, US 2010/017 US 2011/0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1 and WO 2007/075459 A2, and US Pat. Other published patent applications that describe various other parasiticidal isoxazoline compounds and formulations containing them include WO 2007/079162 A1, WO 2008/154528 A1, WO 2009/002809 A2, WO 2011/149749 A1, WO 2014/439475 A1, US 8,466,115, WO 2012/120399, WO 2014/039484, WO 2014/189837 (Zoetis) and WO 2012 120135 A1 (Novartis). WO 2012/089623 describes isoxazoline topical formulations containing glycofurol. WO 2013/039948 A1 describes topical veterinary compositions containing at least one isoxazoline active ingredient, and WO 2013/119442 A1 describes oral veterinary compositions, such as soft chewable compositions, which contain at least one isoxazoline active ingredient.

In addition to topical and oral dosage forms, it is sometimes possible to formulate active ingredients in sustained release injectable preparations, depending on, for example, the physicochemical properties of the individual active ingredient. Such properties include, for example, solubility, bioavailability, etc. In some cases, it is possible to introduce the active ingredients into sustained release formulations containing a pharmaceutically acceptable polymer that controls the release of the active ingredient from the formulation in the animal body over an extended period of time. The meaning of sustained release drugs in veterinary medicine is the subject of Terminology Challenges: Defining Modified Release Dosage Forms in Veterinary Medicine by Marilyn N. Martinez, Danielle Lindquist and Sanja Modric (Journal of Pharmaceutical Sciences, vol. 99, no. 8, August 2010) . The definition proposed in the article of a sustained release dosage form as a dosage form that is manufactured in such a way as to release the active substance contained in it over an extended period of time is consistent with the use of this term in the present description, where the components of the preparation make the release characteristics of the active substance, and not the properties the active substance itself, responsible for the long-term effect of the drug. For example, US Pat. Nos. 6,733,767 and 8,362,086 describe long acting injectable formulations containing a bioactive agent such as, for example, avermectin or milbemycin and a bioacceptable polymer. US Pat. No. 5,330,768 describes degradable polymeric drug delivery materials made by blending hydrolyzable polymers (eg, poly(L-lactic acid)), nonionic surfactants, and block copolymers of polyethylene oxide and polypropylene oxide.

Fluorinated compounds, such as some of the isoxazoline compounds described in the formulations of the present invention, often present additional challenges when compared to their non-fluorinated counterparts when such compounds are formulated in sustained release injectable formulations because the presence of fluorinated groups makes it more difficult to achieve the desired release characteristics of the compound. from polymer matrices forming a depot. Fluorinated organic compounds are highly hydrophobic. This is partly due to low surface energies, which make such compounds less wettable. See, for example, N.L. Jarvis and W.A. Zisman, Surface Chemistry of Fluorochemicals, U.S. Naval Research Laboratory, Washington, D.C. (1965). This property makes it difficult to wet polymers such as poly(L-lactic acid), which slows down the degradation of this polymer and slows down the release of the fluorinated compound from the depot.

Despite the known compositions containing isoxazoline active ingredients alone or in combination with other active ingredients described in the above documents, there is a need for veterinary compositions and methods with improved efficacy, bioavailability and spectrum of activity for protecting animals from endoparasites and/or ectoparasites. More specifically, there is a need to develop a long-acting injectable formulation containing an isoxazoline compound that has good bioavailability and provides a high level of efficacy against ectoparasites (eg, fleas and ticks) for a long time (eg, 3 to 12 months), while the same time is characterized by less irritation at the injection site in the animal.

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Inclusion by reference.

Any of the aforementioned applications and all documents cited in or in the course of their consideration (documents cited in the application), and all documents or references in documents cited in the description, and all documents cited or referred to in this document (documents cited in herein) and all documents cited or referenced in documents cited herein, together with all manufacturer's instructions, descriptions, datasheets and data sheets for any products mentioned in this document or in any document incorporated by reference herein are incorporated herein by reference and may be used in the practice of the invention.

Citation or mention of any document in the present description is not an admission that such document is considered prior art for the present invention.

The essence of the invention

The present invention describes novel and innovative sustained release injectable formulations for the treatment or prevention of parasitic infections or infestations in an animal, comprising an antiparasitic effective amount of at least one isoxazoline active ingredient, a pharmaceutically acceptable polymer, and optionally a diluent. In one embodiment, the sustained release injectable formulations of the present invention comprise an antiparasitic effective amount of at least one isoxazoline active ingredient, a pharmaceutically acceptable biodegradable polymer, and a solvent. As used herein, the term poloxamer means a block copolymer of ethylene oxide and propylene oxide. As used herein, poloxamers that are not copolymerized with other pharmaceutically acceptable polymers are considered solvents or surfactants and not a pharmaceutically acceptable polymer. invention. Also in the context of this document, liquid polyethylene glycols (PEGs) not copolymerized with other pharmaceutically acceptable polymers are considered a solvent and are not considered a pharmaceutically acceptable polymer.

According to the present invention, it has been found that the sustained release injectable formulations of the present invention generally show the desired bioavailability and duration of action. In addition, the sustained release injectable preparations of the present invention do not cause undesirable irritation at the injection site in the animal. The described compositions also have the desired safety profile in warm-blooded animals and birds. In addition, it has been found that a single administration of such formulations generally provides sufficient activity against one or more parasites (eg, ectoparasites) while providing a rapid onset of action, duration of action, and/or a desired safety and release profile.

The present invention encompasses the use or veterinary use of isoxazoline compositions for the treatment or prevention or prophylaxis of parasitic infections and infestations in animals (wild or domestic), including farm and pet animals such as cats, dogs, horses, chickens, sheep, goats, pigs. , turkeys and cattle, with the aim of ridding said host animals of parasites commonly found in such animals.

The present invention also describes methods of treating or preventing parasitic infections and infestations in animals, comprising administering an effective amount of sustained release injectable preparations containing an antiparasitic effective amount of at least one isoxazoline compound together with a pharmaceutically acceptable polymer and solvent. Surprisingly, the innovative isoxazoline-containing sustained release injectables described in the present invention have been found to exhibit a broader spectrum of efficacy against harmful parasites (e.g., ectoparasites such as fleas and ticks) while acting faster and for longer periods of time. compared to other injectable formulations containing isoxazoline active ingredients known in the art, while showing acceptable irritation characteristics at the injection site.

The present invention also describes the use of isoxazoline in the preparation of sustained release injectable preparations for the treatment or prevention of parasitic infections in animals.

In one embodiment, the present invention describes sustained release injectable preparations containing antiparasitic effective amounts of at least one isoxazoline having the following formula (I), in combination, and a pharmaceutically or veterinarily acceptable polymer and solvent, where the variables B ¹ , B ² , В ³ , R ¹ , Y and Q have

- 3 040232 the values given in this text and the asterisk indicates that the carbon atom is quaternary. Р—-N

(I)

In other embodiments, the sustained release injectable formulations of the present invention contain effective amounts of at least one isoxazoline active ingredient having the formula:

CF ₃ (Ilf) where the variables R ² , R ⁴ , R ⁵ and n for each formula have the values specified in the present text.

In some embodiments, the sustained release injectables and methods described include 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3isoxazolyl]-N-[2- oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (a compound having the formula (IIc)) as an active substance. These compounds are described in US Pat.

In a preferred embodiment, the present invention describes sustained release injectable formulations for the treatment or prevention of a parasitic infection or infestation in or within an animal, comprising:

a) 5 to 20% (w/w) of an isoxazoline compound of formula (IIa)

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(PA) or a pharmaceutically acceptable salt thereof, wherein R ² is independently halogen, C1- _C6 alkyl, or C1- _C6 haloalkyl;

R ⁴ is H or C ₁ -C ₆ -αkyl;

R ⁵ is C1-C ₄ alkyl optionally substituted with one or more R ⁷ ; And

R ⁷ is C ₂ -C ₇ -alkylcarbonyl, C ₂ -C ₇ -alkoxycarbonyl, C ₂ -C ₇ -alkylaminocarbonyl, C ₃ -C ₉ -dialkylaminocarbonyl, C ₂ -C ₇ -haloalkylcarbonyl, C ₂ -C ₇ - haloalkoxycarbonyl,

C ₂ -C ₇ haloalkylaminocarbonyl, C ₃ -C ₉ dihaloalkylaminocarbonyl;

n is 0, 1 or 2;

b) 1 to 30% (w/w) of a pharmaceutically acceptable polymer which is a copolymer of polylactides and polyglycolides having a lactide to glycolide ratio of 40:60 to 85:15 (w:w); And

c) 40 to 85% (w/w) of a solvent selected from cyclic carbonate, dimethyl isosorbide, poloxamer, glycerol ester, triglyceride, liquid polyethylene glycol and alcohol, or mixtures thereof;

where the sum of all components in the composition is 100% (w/w).

In other embodiments, the long-acting injectable formulations may further comprise one or more additional active ingredients with systemic activity. Systemic active agents may include, but are not limited to, isoxazoline active agents of various structures, neonicotinoid systemic agent, 1-N-arylpyrazole systemic agent, macrocyclic lactones such as avermectin and milbemycin, cyclic depsipeptide such as emodepside or PF1022A or analogues thereof, benzimidazoles, imidazothiazoles, tetrahydropyrimidine active ingredient, organophosphate active ingredient, levamisole, paraherquiamide and/or marcfortine, praziquantel, closantel, chlorsulon, pyrantel, spinosyn or spinosynode, amine acetonitrile active ingredient, aryloazol-2-yl cyanoethyl , a systemic insect growth regulator. In one embodiment, sustained release injectable formulations contain at least one macrocyclic lactone, including (but not limited to) avermectins or milbemycins. In some embodiments, the avermectins or milbemycins are eprinomectin, ivermectin, abamectin, selamectin, doramectin, milbemectin, milbemycin D, milbemycin oxime, or moxidectin.

In other embodiments, the described compositions and methods comprise at least one of the following: thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole, albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel, praziquantel, closantel, chlorsulon, an aminoacetontrile active ingredient, or aryloazol-2-yl cyanoethylamine.

In another embodiment, the described compositions and methods include at least a cyclic depsipeptide active ingredient, including (but not limited to) emodepside and PF1022A, or analogues thereof.

It is an object of the present invention not to include in the present invention any previously known product, method of preparation, or method of using a product, so that Applicants retain and waive rights to any previously known product, method, or method. It should also be noted that the present invention does not include within its scope any product, method of making a product, or method of using a product that does not comply with the written description and requirements of the USPTO (35 U.S.C. §112, first paragraph) or EPO (Article 83 of the EPC), so that Applicant retains and waives any prior art product, method of making a product, or method of using a product.

These and other embodiments are described in, or appear to follow from, the following detailed description.

Detailed description of the invention

The present invention describes new and innovative sustained release injectable formulations for the treatment or prevention of parasitic infections or infestations in an animal, comprising an antiparasitic effective amount of at least one isoxazoline compound, a pharmaceutically acceptable polymer, and optionally a solvent or mixture of solvents.

The present invention also describes methods and uses for the treatment and/or prevention

- 5 040232 parasitic infections and infestations in animals, comprising administering to an animal in need thereof a sustained release formulation containing an antiparasitic effective amount of at least one isoxazoline compound, a pharmaceutically acceptable polymer, and optionally a solvent or mixture of solvents.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising an antiparasitic effective amount of an antiparasitic effective amount of at least one isoxazoline compound and an effective amount of at least one additional systemic active ingredient. , a pharmaceutically acceptable polymer, and optionally a solvent or mixture of solvents.

In a preferred embodiment of the present invention, the pharmaceutically acceptable polymer is a pharmaceutically acceptable biodegradable polymer.

In one embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) an antiparasitic effective amount of at least one isoxazoline active substance, which is:

i) an isoxazoline compound having the formula (I)

(I) where B ¹ , B ² and B ³ are each independently CR or N;

each R is independently H, halogen, cyano, —NO ₂ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, or alkoxycarbonyl;

R ¹ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

Y is an optionally substituted phenylene, naphthylene, indanylene, 5- or 6-membered heteroarylene, or 8-10-membered fused heterobicyclylene, where the optional substituents are selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN or -NO ₂ and NH ₂ -C(=S)-;

Q is X-NR2R ³ , (-CH2-)(-CH2-)NR ³ , OH, NH2, alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino, thiol, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl or an optionally substituted 5- or 6-membered carbocyclyl, heterocyclyl or heteroaryl ring;

X is (CH ₂ ) _p , CH(CH ₃ ), CH(CN), C(=O) or C(=S);

R ² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R ³ is H, OR ⁷ , NR8R ⁹ or Q ¹ or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; or

R ² and R ³ are combined together with the nitrogen atom to which they are attached to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, said ring being optionally substituted with 1- 4 substituents selected from the group consisting of alkyl, halogen, -CN, -NO2 and alkoxy;

каждый R ⁴ независимо представляет собой галоген, алкил, циклоалкил, алкоксигруппу, алкилтиогруппу, галогеналкилтиогруппу, алкилсульфинил, галогеналкилсульфинил, алкилсульфонил, галогеналкилсульфонил, алкиламиногруппу, галогеналкиламиногруппу, диалкиламиногруппу, дигалогеналкиламиногруппу, циклоалкиламиногруппу, алкилкарбонил, алкоксикарбонил, алкиламинокарбонил, диалкиламинокарбонил, галогеналкилкарбонил, галогеналкоксикарбонил, галогеналкиламинокарбонил, dihaloalkylaminocarbonyl, hydroxy, -NH ₂ , -CN or -NO ₂ ; or Q ² ;

each R ⁵ is independently halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, -CN or -NO2;

- 6 040232 each R ⁶ is independently halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN, -NO ₂ , phenyl or pyridinyl;

R ⁷ is H or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more halogen atoms;

R ⁸ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R ⁹ is H; Q ³ or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; or

R ⁸ and R ⁹ are combined together with the nitrogen atom to which they are attached to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, said ring being optionally substituted with 1 - 4 substituents selected from the group consisting of alkyl, halogen, -CN, -NO ₂ and alkoxy;

Q ¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-, or 10-membered fused bicyclic system optionally containing 1-3 heteroatoms selected from up to 1 O atom, up to 1 S atom, and up to 3 N atoms , each ring or ring system is optionally substituted with one or more substituents independently selected from R ⁵ ;

Q ² is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring is optionally substituted with one or more substituents independently selected from R ⁶ ;

Q ³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring is optionally substituted with one or more substituents independently selected from R ⁶ ; and n is 0, 1, or 2;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant;

f) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In one embodiment of the present invention regarding sustained release compositions containing an isoxazoline compound having formula (I), Y is selected from Y-1, Y-2, Y-3, Y-4, where Z is nitrogen or CH, Y-5 or Y-6 shown below:

In one embodiment of the present invention, comprising an isoxazoline compound having formula (I), the Q group is X-NR2R ³ . In another embodiment

Q is X-NR2R ³ where R ² is H or C1-C3 alkyl and R ³ is C1-C ₃ alkyl optionally substituted with R ⁴ . In another embodiment, Q is X-NR2R ³ where R ² is H and R ³ is C ₁ -C ₃ alkyl optionally substituted with alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl , dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl or dihaloalkylaminocarbonyl. In another embodiment

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Q is X-NR2R ³ where R ² is H and R ³ is C1- _C3 alkyl optionally substituted with alkylthio, haloalkylthio, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl or dihaloalkylaminocarbonyl. In another embodiment, Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ . In another embodiment, Q is -C(O)CH ₂ S(O) ₂ CH ₃ . In another embodiment, Q is -C(O)NHCH ₂ CH ₂ SCH ₃ . In another embodiment, Q is a (-CH2-)(CH2-)N(CO)CH2S(O)2CH3 group.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention (prevention) of parasitic infections and infestations in animals, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having formula (IIa) (Pa) or a pharmaceutically acceptable salt thereof, wherein R ² is independently halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;

R ⁴ represents H or C ₁ -C ₆ -alkyl;

R ⁵ is C1-C ₄ alkyl optionally substituted with one or more R ⁷ ; And

R ⁷ is C ₂ -C ₇ -alkylcarbonyl, C ₂ -C ₇ -alkoxycarbonyl, C ₂ -C ₇ -alkylaminocarbonyl, C ₃ -C ₉ -dialkylaminocarbonyl, C ₂ -C ₇ -haloalkylcarbonyl, C ₂ -C ₇ - haloalkoxycarbonyl, C ₂ -C ₇ haloalkylaminocarbonyl, C ₃ -C ₉ dihaloalkylαminocαrbonyl (eg -CH ₂ C(O)NHCH ₂ CF ₃ ); and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant;

f) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention (prevention) of parasitic infections and infestations in animals, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the formula (IIc) (Ps) or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant;

f) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention (prevention) of parasitic infections and infestations in animals, comprising:

a) an antiparasitic effective amount of an isoxazoline compound having the formula (IId)

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or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant; And

f) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention (prevention) of parasitic infections and infestations in animals, comprising:

a) antiparasitic formula (IIe) an amount of an isoxazoline compound having an effective

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant;

f) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention (prevention) of parasitic infections and infestations in animals, comprising:

a) antiparasitic formula (IIf) an effective amount of an isoxazoline compound having

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant;

f) optionally at least one pharmaceutically acceptable additive, excipient or mixtures thereof.

In another embodiment, the sustained release injectable formulations of the present invention comprise an antiparasitic effective amount of 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-naphthalenecarboxamide (compound having formula (IIc)).

In another embodiment, the pharmaceutically acceptable polymer in the sustained release injectable formulations described above may be a polylacti copolymer

- 9 040232 doves and polyglycolides, and the solvent may be a single solvent, such as, for example, a cyclic carbonate (for example, ethylene carbonate or propylene carbonate), or a mixture of solvents containing, for example, a cyclic carbonate, a glycerol ester (for example, glycerol triacetate) and optionally a poloxamer (eg P-124) which may act as a solvent or surfactant. In another embodiment, the sustained release formulations described above include an antioxidant such as butylated hydroxytoluene.

Compounds having the formula (I), (IIa), (IIc), (IId), (IIe), (IIf) may exist as stereoisomers because a chiral center is present in the molecule. These individual stereoisomers are covered by the structural formulas depicted in this text. Various stereoisomers include enantiomers, diastereomers and atropisomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or exhibit additional beneficial properties as compared to the other enantiomer. In addition, one skilled in the art will know how to separate, enrich and/or selectively obtain the stereoisomer of the isoxazoline compounds described herein. The isoxazoline compounds described in this text contain a quaternary chiral carbon atom in the 5-membered isoxazoline ring (marked with an asterisk (*)); therefore, these compounds contain at least two possible stereoisomers. As an example for compounds having formula (IIc), two possible stereoisomers at the quaternary carbon atom are shown as formula (R)-IIc and (S)-IIc:

The compound having the above formula (S)-IIc has the ^-configuration at the chiral carbon atom, and the compound having the formula (R)-IIc has the ^-configuration.

The images of molecules given in this text follow the standard rules for the representation of stereochemistry. To indicate the stereoconfiguration, bonds emerging from the plane of the figure towards the reader are depicted as solid wedges, where the wide end of the wedge is attached to an atom that rises above the plane of the figure towards the reader. Bonds extending from the drawing plane down from the sheet plane and away from the reader are shown as dotted wedges, where the narrow end of the wedge is attached to the atom located further from the reader. Lines of constant width mean links that are in the opposite or neutral direction relative to the links shown by solid or dotted wedges; lines of constant width also mean bonds in molecules or parts of molecules in which no particular stereoconfiguration is intended to be indicated.

Thus, in another embodiment, the sustained release injectable formulations of the present invention comprise an antiparasitic effective amount of at least one isoxazoline having formulas (I), (IIa), (IIc), (IId), (IIe), (IIf), which is enriched in one of the enantiomers, or a pharmaceutically acceptable salt thereof.

In one embodiment, the sustained release injectable formulations contain an antiparasitic effective amount of at least one isoxazoline having formulas (I), (IIa), (IIc), (IId), (IIe), (IIf), which is enriched in an enantiomer showing a significant in vitro and in vivo activity with a favorable toxicity profile (eutomer), while a compound or composition enriched in the other enantiomer exhibits significantly lower in vitro and in vivo activity (distomer), or a pharmaceutically acceptable salt thereof. In one embodiment of the present invention, the more biologically active enantiomer of a compound having formula (IIc) is considered to be a compound having formula (S)-IIc depicted above, which has the ^-configuration at the chiral carbon atom. Similarly, the more biologically active enantiomers of the isoxazoline compounds having formulas (I), (IIa), (IId), (IIe), (IIf) are considered to have the ^-configuration at the chiral carbon of the isoxazoline ring.

In one embodiment, compounds having formulas (I), (IIa), (IIc), (IId), (IIe), (IIf) present in the compositions of the present invention are enriched in one enantiomer with respect to

- 10 040232 of the other enantiomer in a weight ratio of at least 1.5:1. In another embodiment, compounds having formulas (I), (IIa), (IId), (IIe), (IIf) present in the compositions of the present invention are enriched in one enantiomer in a weight ratio of at least 2:1, at least at least 5:1 or at least 10:1.

In another embodiment, compounds having formulas (I), (IIa), (IId), (IIe), (IIf) present in the compositions of the present invention are substantially pure enantiomers. Thus, in another embodiment, the present invention describes sustained release injectable compositions that contain essentially pure enantiomers of compounds having formulas (I), (IIa), (IIc), (IId), (IIe), (IIf).

In one embodiment, the composition of the present invention contains a compound having formula (I) which is substantially enriched in an enantiomer. By substantially enriched is meant that the weight/weight ratio is at least about 1.5 to 1 or higher in favor of the desired enantiomer. In another embodiment, the sustained release injectable compositions of the present invention comprise a compound having formula (I) that is substantially enriched in the (S)-enantiomer. In another embodiment, the sustained release injectable compositions of the present invention comprise a compound having formula (I) that is substantially enriched in the (R)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formula (I) enriched in the (S)-enantiomer in a weight ratio of at least about 2:1, (S) to (R), or more. In another embodiment, the compositions of the present invention contain a compound having formula (I) enriched in the (S)-enantiomer in a weight ratio of at least about 5:1, (S) to (R), or more. In another embodiment, the compositions of the present invention comprise a compound having formula (I) enriched in the (S)-enantiomer in a weight ratio of at least about 10:1, (S) to (R), or greater. In another embodiment, the compositions of the present invention contain a compound having formula (I) which is substantially pure (S)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formula (I) enriched in the (R)-enantiomer in a weight ratio of at least about 2:1, (R) to (S), or more. In another embodiment, the compositions of the present invention comprise a compound having formula (I) enriched in the (R)-enantiomer in a weight ratio of at least about 5:1, (R) to (S), or greater. In another embodiment, the compositions of the present invention comprise a compound having formula (I) enriched in the (R)-enantiomer in a weight ratio of at least about 10:1, (R) to (S), or greater. In another embodiment, the compositions of the present invention contain a compound having formula (I) which is essentially pure R-enantiomer.

In one embodiment, the composition of the present invention contains a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf), which is significantly enriched in enantiomer. In another embodiment, the sustained release injectable compositions of the present invention comprise a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) that is substantially enriched in the (S)-enantiomer. In another embodiment, the sustained release injectable compositions of the present invention comprise a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) that is substantially enriched in the (R)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) enriched in the (S)-enantiomer in a weight ratio of at least about 2:1, (S) to (R), or more. In another embodiment, the compositions of the present invention contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) enriched in the (S)-enantiomer in a weight ratio of at least about 5:1, (S) to (R), or more. In another embodiment, the compositions of the present invention contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) enriched in the (S)-enantiomer in a weight ratio of at least about 10:1, (S) to (R), or more. In another embodiment, the compositions of the present invention contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf), which is essentially pure (S)-enantiomer.

In another embodiment of the present invention, the compositions contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) enriched in the (R)-enantiomer in a weight ratio of at least about 2:1, (R) to (S), or more. In another embodiment, the compositions of the present invention comprise a compound having formulas (IIa), (IIc), (IId), (IIe), or (IIf) enriched in the (R)-enantiomer in a weight ratio of at least about 5:1, (R) to (S), or more. In another embodiment, the compositions of the present invention contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf) enriched in the (R)-enantiomer in a weight ratio of at least about 10:1, (R) to (S), or more. In another embodiment, the compositions of the present invention contain a compound having formulas (IIa), (IIc), (IId), (IIe) or (IIf), which is essentially pure (R)-enantiomer.

- 11 040232

In one embodiment, the composition of the present invention contains a compound having formula (IIc) which is substantially enriched in an enantiomer. In another embodiment, the sustained release injectable compositions of the present invention comprise a compound having formula (IIc) that is substantially enriched in the (S)-enantiomer. In another embodiment, the sustained release injectable compositions of the present invention comprise a compound having formula (IIc) that is substantially enriched in the (R)-enantiomer.

In another embodiment, the present invention includes racemic mixtures, for example, approximately equivalent amounts of enantiomers having formulas (I), (IIa), (IIc), (IId), (IIe), (IIf).

In the case of enantiomeric enrichment, one enantiomer is present in greater amounts than the other, and the degree of enrichment can be estimated by the enantiomeric excess (ee) value, which is calculated as (2x-l)-100%, where x is the mole fraction of the dominant enantiomer in the mixture (for example, 20% of it corresponds to a 60:40 ratio of enantiomers). In some embodiments, the compositions of the present invention contain compounds that have an enantiomeric excess of at least 50%. In other embodiments, compositions of the present invention contain compounds that have an enantiomeric excess of the more active isomer of at least 75%, an enantiomeric excess of the more active isomer of at least 90%, or an enantiomeric excess of the more active isomer of at least 94%. Of particular note are enantiomerically pure embodiments of the more active isomer (eutomer).

The compounds of the present invention may exist as one or more conformational isomers due to restricted rotation around an amide bond attached to an aryl or heteroaryl ring (eg, an amide bonded to a naphthyl group in formula (IIc)). The present invention includes mixtures of conformational isomers. In addition, the present invention includes compounds that are enriched in one conformer as compared to others.

It should be understood that, in addition to the chiral carbon atom in the isoxazoline ring of compounds having formulas (I), (IIa), (IIc), (IId), (IIe), (IIf), some compounds may include other chiral centers in one or more substitutes. Thus, these compounds will have a greater number of possible stereoisomers (eg, diastereomers). All possible stereoisomers are covered by the sustained release injectable compositions of the present invention.

In another embodiment, the sustained release injectable preparations of the present invention comprise an antiparasitic effective amount of at least one isoxazoline described in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009 /003075, WO 2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617 WO 2008/122375, WO 2014/439475 A1 and WO 2012/120135 A1, all of which are hereby incorporated by reference in their entirety.

In another embodiment, the sustained release injectable formulations of the present invention comprise an antiparasitic effective amount of at least one isoxazoline compound described in WO 2009/02451 A2 and WO 2011/075591 A1, both documents incorporated herein by reference in their entirety.

In one embodiment, the compositions of the present invention may contain from about 5% to about 50% (w/w) of the isoxazoline active ingredient. In another embodiment, the compositions may contain from about 5% to about 30% (w/w) of the isoxazoline active ingredient. In other embodiments, the compositions may contain from about 5% to about 20% (w/w) or from about 5% to about 15% (w/w) of the isoxazoline active ingredient. In another embodiment, the compositions of the present invention may contain from about 10% to about 40% (w/w) or from about 10% to about 30% (w/w) of the isoxazoline active ingredient. In another embodiment, the compositions may contain from about 10% to about 20% isoxazoline active ingredient. In another embodiment, the compositions of the present invention may contain from about 15 to about 40% (w/w), from about 15 to about 35% (w/w), or from about 15 to about 30% (w/w). /wt.) isoxazoline compounds. In another embodiment, the compositions of the present invention contain from about 20 to about 30% (w/w), from about 20 to about 25% (w/w), or from about 25 to about 30% (w/w). wt.) isoxazoline active ingredient.

In one embodiment, the compositions of the present invention contain from about 1% to about 40% (w/w) of a pharmaceutically acceptable polymer, including a biodegradable polymer. In other embodiments, the compositions contain from about 1 to about 30% (w/w) or from about 1 to about 20% (w/w) of a pharmaceutically acceptable polymer. In another embodiment, the compositions contain from about 1 to about 15% (w/w) or from about 1 to about 10% (w/w) of a pharmaceutically acceptable polymer. In another embodiment, the compositions contain from about 5% to about 20% (w/w) or from about 5% to about 15% (w/w) of a pharmaceutically acceptable polymer. In another embodiment

- 12 040232 compositions contain from about 10 to about 20% (wt./wt.) or from about 10 to about 15% (wt./wt.) pharmaceutically acceptable polymer. In another embodiment, the compositions contain from about 7 to about 13% (w/w) or from about 8 to about 15% (w/w) of a pharmaceutically acceptable polymer. In another embodiment, the compositions of the present invention contain from about 1 to about 7% (w/w), from about 1 to about 5% (w/w), or from about 3 to about 7% (w/w). wt.) pharmaceutically acceptable polymer.

In one embodiment, the compositions of the present invention may contain from about 30% to about 90% (w/w) of a solvent or mixture of solvents. In another embodiment, the compositions of the present invention may contain from about 40% to about 90% (w/w) of a solvent or mixture of solvents. In another embodiment, the compositions contain from about 40 to about 80% (w/w), from about 50 to about 80% (w/w), or from about 45 to about 80% (w/w) solvent or mixture of solvents. In another embodiment, the compositions of the present invention contain from about 60 to about 80% (w/w) or from about 65 to about 80% (w/w) of a solvent or mixture of solvents. In another embodiment, the compositions may contain from about 65 to about 75% (w/w) or from about 70 to about 80% (w/w) of a solvent or mixture of solvents.

In another embodiment, the compositions of the present invention may contain from about 0.01% to about 10% (w/w) of a pharmaceutically acceptable additive, excipient, or mixtures thereof. In other embodiments, the compositions may contain from about 0.01 to about 5% (w/w), from about 0.1 to about 10% (w/w), or from about 0.1 to about 5% (wt./wt.) pharmaceutically acceptable additives, excipients or mixtures thereof.

In another embodiment, the compositions of the present invention may contain from about 0.01% to about 5% (w/w) of an antioxidant. In other embodiments, the compositions may contain from about 0.01 to about 3% (w/w) or from about 0.01 to about 2% (w/w) of an antioxidant.

Pharmaceutically acceptable polymers in sustained release injectables include, but are not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, pseudo poly(amides), polyhydroxyalkanoates, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylenexalates, polyalkylene succinates, poly(malic acid), poly(amino acids), poly(methylvinyl ether), poly(maleic anhydride), chitin, chitosan and copolymers, terpolymers or combinations or mixtures thereof, including copolymers of polylactides, polycaprolactones, polyglycolides (for example, poly(lactide-glycolide) and copolymers of polyethylene glycol or methoxy-polyethylene glycol with one or more of polycaprolactone, polylactide, or any of the other polymer groups mentioned above. Also included within the scope of the present invention are derivatives of pharmaceutically acceptable polymers. such as hydroxylated derivatives including polycaprolactone diols and the like.

In one embodiment, the pharmaceutically acceptable polymer is a biodegradable polymer. In another embodiment, the pharmaceutically acceptable biodegradable polymer may have one or more or all of the following characteristics: be biodegradable due to cellular activity, be biodegradable due to the action of liquid components of non-living bodies, be softenable when exposed to heat, but return to its original state when cooled, and be capable of substantially dissolve or disperse in a water-miscible carrier or solvent to form a solution or dispersion. When contacted with an aqueous liquid, the polymer may contribute to the formation of a film-coated or encapsulated liquid or solid (which contains the active ingredient of the present invention). The types of polymers suitable for use in the compositions described herein generally include any polymers having the characteristics described above. Examples of biodegradable polymers include, but are not limited to, polylactides, polycaprolactones, polyglycolides, polyorthoesters, polyurethanes, polyphosphazenes, pseudo poly(amides), and their copolymers.

One skilled in the art will appreciate that the molecular weight of a polymer is not a discrete number, but a range of molecular weights. The average molecular weight of the polymer can be determined by methods known to those skilled in the art, such as gel permeation chromatography with molecular weight standards, and the like. The molecular weight range of a polymer can affect the physical characteristics of the material and its interaction with the active ingredient. Accordingly, the molecular weight range of the polymer can affect the performance of the sustained release composition of the present invention. For example, in some embodiments, depending on the active ingredient and solvents used, an earlier release of the isoxazoline active ingredient can be observed when diapa

- 13 040232 zones weight average molecular weights is from about 5 to about 20 kDa (kilodaltons) or from about 7 to about 15 kDa. Delayed release of the isoxazoline active may occur when the weight average molecular weight is from about 30 to about 70 kDa (e.g., from about 40 to about 70 kDa, or from about 45 to about 60 kDa) or from about 90 to about 200 kDa ( for example, from about 100 to about 150 or from about 105 to about 130 kDa). In some embodiments, a combination of polymers having different average molecular weights can provide a release rate that combines the effect of the different polymers used.

Intrinsic viscosity determination in polymer chemistry is a viscometric method for determining 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 determined by the time of expiration of the polymer solution through a narrow capillary. When used herein in relation to the molecular weight range of a pharmaceutically acceptable polymer, the term low molecular weight (LMW) refers to a polymer having an intrinsic viscosity in the range of 0.05-0.29 dl/g; the term average molecular weight refers to a polymer having an intrinsic viscosity in the range of 0.3-0.55 dl/g; and the term high molecular weight refers to a polymer having an intrinsic viscosity in the range of 0.55-1.0 dl/g. In another embodiment, the pharmaceutically acceptable polymer in the sustained release formulations of the present invention has an intrinsic viscosity of about 0.10-0.20 dl/g. In another embodiment, the pharmaceutically acceptable polymer in sustained release formulations has an intrinsic viscosity of about 0.35-0.50 dl/g.

In some embodiments, the sustained release injectable formulations of the present invention comprise polylactides, polycaprolactones, polyglycolides, and copolymers thereof. In another embodiment, the compositions comprise a polylactide-co-glycolide copolymer (PLGA). PLGA copolymers may have different molecular weight ranges and may also have different wt:wt. lactide to glycolide ratio. This ratio can affect the properties of the copolymer and its interaction with the active substance. Since the lactide group contains an additional methyl group in the side chain compared to the glycolide, this change can affect the conformation of the polymer and change the interaction of the polymer with the isoxazoline active ingredient (and/or other active ingredient combined with isoxazoline). Without wishing to be bound by theory, in one embodiment, compositions of the present invention having a higher ratio of lactide to glycolide (e.g., 75:25 versus 50:50) have stronger hydrogen bonds between the active ingredient and the polymer, resulting in to better solubility of the active substance in vivo. This effect favorably affects the reaction at the injection site and allows higher amounts of the active substance to be included in injectable sustained release formulations, resulting in longer lasting efficacy.

In one embodiment of the present invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is from about 30:70 to about 99:1. In another embodiment of the present invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is from about 40:60 to about 80:15. In another embodiment of the present invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is from about 40:60 to about 60:40. In another embodiment of the present invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is from about 70:30 to about 80:20. In another embodiment of the present invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 50:50. In another embodiment of the present invention, when the pharmaceutically acceptable polymer is PLGA, the ratio of lactide to glycolide is about 75:25.

In some embodiments, the amount of PLGA contained in the sustained release injectable preparation of the present invention is from about 1 to about 30% (w/w). In another embodiment, the compositions contain from about 1 to about 20% (w/w). .) PLGA. In another embodiment, the compositions contain from about 5 to about 20%, from about 8 to about 20% (w/w), or from about 10 to about 20% (w/w) PLGA. In another embodiment, the compositions contain from about 5% to about 15% (w/w) PLGA. In other embodiments, the amount of PLGA contained in the sustained release injectable formulation of the present invention is from about 3% to about 15% (w/w) or from about 10% to about 15% (w/w). In another embodiment, the compositions contain from about 7 to about 13%, or from about 8 to about 15% (w/w) PLGA.

In some embodiments, the implementation of the ratio wt.:weight. PLGA and isoxazoline active ingredient is greater than or equal to about 1:1, for example, from about 1.1:1 to about 20:1; on

- 14 040232 example, from about 1:1 to about 10:1, from about 1.1:1 to about 10:1, or from about 2:1 to about 5:1. In other embodiments, the implementation of the ratio wt.:weight. PLGA and isoxazoline active ingredient is from about 1.2:1 to about 5:1. In another embodiment, the ratio wt.:weight. PLGA and isoxazoline active ingredient is from about 1.2:1 to about 2:1. In another embodiment, the ratio wt.:weight. PLGA and isoxazoline active ingredient is from about 1.2:1 to about 1.3:1.

In other embodiments, the implementation of the ratio wt.:weight. PLGA and isoxazoline active ingredient is from about 1.5:1 to about 1:1.5. In other embodiments, the ratio of isoxazoline active ingredient to PLGA is from about 1.25:1 to about 1:1:25.

The solvents used in the sustained release injectable formulations of the present invention may be individual or may be a mixture of solvents. Non-limiting examples of these solvents include alcohols such as ethanol, 1-propanol, isopropanol, glycol ethers (for example, including but not limited to diethylene glycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, monoethyl ethylene glycol ether, ethylene glycol monomethyl ether, dipropylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), liquid polyethylene glycols (PEGs), including (but not limited to) PEG 200, PEG 300, and PEG 400; propylene glycol, glycerin, glycerol esters including glycerol triacetate (triacetin), cyclic carbonates (e.g. ethylene carbonate and propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide (DMA), dimethylformamide (DMF), caprolactam, glycerol formal, acetone, dimethyl sulfoxide (DMSO), ethyl acetate, ethyl lactate, benzyl benzoate, or a mixture of at least two of these solvents.

In one embodiment, the compositions of the present invention may include one or more poloxamers as a solvent or surfactant. Poloxamers are a family of synthetic block copolymers of ethylene oxide and propylene oxide. Poloxamers may be liquid, milky white pastes or powders and may be represented by the following structure:

where a is an integer from 2 to 130;

b is an integer from 15 to 67 (see US 3740421).

Poloxamers are available from commercial sources such as BASF and Croda. An example of a poloxamer is P-124, which is solid at room temperature. In one embodiment, the P-124 poloxamer has a=12 and b=20. Other poloxamers include P-128 (a=38 and b=29), P-181 (a=3 and b=30), P-188 (a=80 and b=27), P-237 (a=64 and b=37), P338 (a=141 and b=44) and P407 (a=101 and b=56). In some embodiments, the amount of poloxamer, if present, is from about 0.5 to about 20% (w/w). In other embodiments, the implementation of the composition may contain, if present, from about 1 to about 20% (w/w), from about 1 to about 10% (w/w), or from about 1 to about 5% (w/w). In other embodiments, the amount of poloxamer, if present, is from about 1 to about 3% (w/w).

In one embodiment, the compositions of the present invention contain a solvent or solvent mixture that is miscible with water. Solvents that are miscible with water are well known and include certain alcohols, liquid polyethylene glycols (PEGs), certain poloxamers, glycols and glycol ethers, and polar aprotic solvents. Water-miscible alcohols include, but are not limited to, ethanol, isopropanol, n-propanol, solketal (isopropylidene glycerol), or formal glycerin. Polar aprotic solvents include, but are not limited to, amides such as dimethylacetamide, dimethylformamide, 2-pyrrolidone, N-alkylpyrrolidones such as N-methylpyrrolidone and N-octylpyrrolidone, dimethylisosorbide, dimethylsulfoxide, cyclic carbonates including propylene carbonate and ethylene carbonate, and some ketones such as acetone, etc. Glycol ethers include, but are not limited to, diethylene glycol monoethyl ether (DGME, Transcutol®), butyl glycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc. P.

In one embodiment, the sustained release formulations of the present invention contain a polar protic solvent, including (but not limited to) an alcohol such as ethanol, isopropanol, or glycol or glycol ether.

In another embodiment, the sustained release injectable formulations of the present invention contain a polar aprotic solvent such as N-methylpyrrolidone,

- 15 040232 dimethyl isosorbide, dimethylacetamide or propylene carbonate.

In another embodiment of the present invention, the compositions of the present invention comprise water-immiscible solvents (eg, not completely water-miscible, although they may have some water solubility). Non-limiting examples of such solvents include 1-butanol, 2-butanol, 1-pentanol, 3-pentanol, benzyl alcohol, methyl tyl ketone (MEK), triacetin, lipids, triglycerides, including medium chain triglycerides such as C ₈ -C ₁₀ triglycerides such as capric/caprylic triglycerides, propylene glycol derivatives (eg, propylene glycol monolaurate), caprylocaproyl polyoxyl-8-glycerides (Labrasol) (non-ionic water-dispersible surfactant, isopropyl myristate, oils such as castor oil, soybean oil, or other vegetable oils or derivatives thereof, such as epoxidized or hydrogenated vegetable oils such as epoxidized soybean oil or hydrogenated castor oil, or a mixture of at least two of these solvents.

In another embodiment, the composition of the present invention may include neutral oils as a solvent. Neutral oils are triglycerides of fractionated vegetable fatty acids with a chain length of C ₈ to C ₁₀ . Two commercially available products are known as MIGLYOL®810 and MIGLYOL®812. In another embodiment, the neutral oil is C ₈ to C ₁₀ fractionated vegetable fatty acid triglycerides in combination with linoleic acid (about 4-5%). The commercially available product is known as MIGLYOL® 818. In another embodiment, the neutral oil is an ester of glycerol and fractionated C ₈ to C ₁₀ vegetable fatty acids in combination with succinic acid. The commercially available product is known as MIGLYOL® 829. In another embodiment, the neutral oil is a propylene glycol fatty acid ester. In another embodiment, the neutral oil may be a diester of propylene glycol and fractionated vegetable fatty acids with a chain length of C ₈ to C ₁₀ . The commercially available product is known as MIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In another embodiment, the solvent may be a mixture of two or more neutral oils.

It should be understood that mixtures of solvents can be used as a solvent for sustained release injectable preparations. In one embodiment, the compositions of the present invention may contain a mixture of a water-miscible solvent and a water-immiscible solvent. For example, in one embodiment, the solvent may be a mixture of a cyclic carbonate, such as propylene carbonate, with triacetin. Of course, other mixtures of a water-miscible solvent and a water-immiscible solvent are possible. In one embodiment, the water-miscible solvent in the solvent mixture can be a water-miscible alcohol such as ethanol or isopropanol, glycerol formal or solketal, an amide such as 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide or dimethylacetamide, a glycol such as propylene glycol, glycerin or glycol ether.

In another embodiment, the water-immiscible solvent in the solvent mixture may be triacetin, benzyl alcohol, triglyceride, including C ₈ -C ₁₀ triglycerides such as capric/caprylic triglycerides, propylene glycol derivatives (e.g., propylene glycol monolaurate), caprylocaproyl polyoxyl- 8-glycerides (Labrasol); fatty acid propylene glycol diester, and the like.

In one embodiment, the solvent may be a mixture of a water-miscible solvent and a water-immiscible solvent in a weight ratio of from about 10 to 1 to about 1 to 10, water-miscible solvent to water-immiscible solvent. In another embodiment wt.:wt. the ratio of water-miscible solvent to water-immiscible solvent may be from about 5 to 1 to about 1 to 1. In another embodiment, wt:wt. the ratio of water-miscible solvent to water-immiscible solvent may be from about 3 to 1 to about 1 to 1. In another embodiment, wt:wt. the ratio of water-miscible solvent to water-immiscible solvent may be from about 3 to 1 to about 2 to 1, or from about 2 to 1 to about 1 to 1.

In another embodiment, the solvent may be a mixture of a water-miscible solvent and a water-immiscible solvent in a weight ratio of about 1 to 2 or about 1 to 3, water-miscible solvent to water-immiscible solvent. In another embodiment wt.:wt. the ratio of water-miscible solvent to water-immiscible solvent may be from about 1 to about 5, from 1 to about 7.

In one embodiment, the solvent may be a mixture of a cyclic carbonate (e.g., propylene carbonate) and a glycerol ester (e.g., triacetin) in a weight ratio of from about 10:1 to about 1:1, a cyclic carbonate (e.g., propylenecarbo

- 16 040232 nat) to a glycerol ester (eg triacetin). In one embodiment, the solvent may be a mixture of cyclic carbonate (e.g., propylene carbonate) and glycerol ester (e.g., triacetin) in a weight ratio of from about 5 to 1 to about 1 to 1, cyclic carbonate (e.g., propylene carbonate) to glycerol ester (for example, triacetin). In another embodiment, the solvent may be a mixture of cyclic carbonate (e.g., propylene carbonate) and glycerol ester (e.g., triacetin) in a weight ratio of from about 3 to 1 to about 1 to 1, cyclic carbonate (e.g., propylene carbonate) to glycerol ester (for example, triacetin). In another embodiment, the solvent may be a mixture of a cyclic carbonate (eg, propylene carbonate) and a glycerol ester (eg, triacetin) in a weight ratio of from about 2 to 1 to about 1 to 1, or from about 3:1 to about 2:1 , a cyclic carbonate (eg propylene carbonate) to a glycerol ester (eg triacetin). In other embodiments, the range wt.:wt. the ratio of cyclic carbonate (eg, propylene carbonate) to glycerol ester (eg, triacetin) is from 1.5:1 to about 15:1, or from about 2:1 to about 6:1.

Surfactants may be present in the formulations of the present invention at concentrations of from about 0.1 to about 10% (w/w), from about 1 to about 10% (w/w), or from about 5 to about 10% (w/w). More typically, surfactants may be present in concentrations of from about 0.1 to about 5% (w/w) or from about 1 to about 5% (w/w). Examples of surfactants that can be used in formulations include, but are not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), sodium lauryl sulfate, copolymers of ethylene oxide and propylene oxide (for example, poloxamers such as LUTROL® F87 and the like), polyethylene glycol derivatives of castor oil, including polyoxyl 35 castor oil (Cremophor ® EL), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor® RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride esters including glycerol caprylate/caprate (CAPMUL® MSM), polyglycolized glycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen® 767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleic glycerides (Labrafil ® M-1944CS), PEG 300 linoleic glycerides (Labrafil® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates, including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate, and the like). Polyethylene glycol stearates (synonyms include macrogol stearates, polyoxyl stearates, polyoxyethylene stearates, ethoxylated stearates; CAS 9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters of mixed polyoxyethylene polymers. Polyethylene glycol hydroxystearates are mixtures of mono- and diesters of hydroxystearic acid with polyethylene glycols. One polyethylene glycol hydroxystearate that can be used in the compositions is polyethylene glycol 12-hydroxystearate. In another embodiment, the formulations of the present invention may include the surfactant polyethylene glycol 15 12-hydroxystearate (Kolliphor® HS 15 from BASF), a mixture of mono- and diesters of 12-hydroxystearic acid with 15 moles of ethylene oxide. These compounds, as well as their amounts, are well known in the art. In another embodiment of the present invention, the formulations of the present invention may include polyoxyl 35 castor oil (Kolliphor® EL) as a surfactant. In other embodiments, formulations of the present invention may include polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) or polyoxyl 60 hydrogenated castor oil as surfactants. The formulations of the present invention may also include a combination of surfactants.

The formulations described herein may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. Such compounds are well known in the art. Antioxidants such as vitamin E, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulphate, sodium metabisulphite, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol, t-butyl hydroquinone (TBHQ) and the like. Antioxidants are typically added to the formulation in amounts of from about 0.01% to about 5.0%, based on the total weight of the formulation, particularly preferably from about 0.05% to about 2.0%. In another embodiment, the preparation preferably contains from about 0.05 to about 1.0% (w/w) of an antioxidant.

Preservatives such as parabens (methylparaben, ethylparaben, butylparaben and/or propylparaben) are suitably used in the formulation in amounts of from about 0.01% to about 2.0%, particularly preferably from about 0.05% to about 1.0%. Other preservatives include benzalkonium chloride,

- 17 040232 benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury acetate, phenylmercury borate, phenylmercury nitrate, potassium sorbate, sodium benzoate, sodium propionate , sorbic acid, thimerosal, and the like. Preferred input of these compounds includes the range from about 0.01 to about 5%.

Also within the scope of the present invention are compounds that stabilize the pH value of the formulation. Such compounds are also well known to those skilled in the art, as are their uses. Buffer systems include, for example, systems selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tartaric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycinate, tris , glutamic acid/glutamates and sodium carbonate.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) from about 1% to about 40% (w/w) of a pharmaceutically acceptable polymer;

c) about 40 to 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the above embodiments (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) from about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) from about 40% to 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIe), (IId), (IIe), (IIf));

b) from about 10% to about 40% (w/w) of a pharmaceutically acceptable polymer;

c) from about 30% to 85% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) from about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) about 30 to 85% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01 to about 5.0% (w/w) pharmaceutically acceptable to

- 18 040232 supplements, excipients or mixtures thereof.

In some other embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) from about 12% to about 38% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 40% to about 85% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some other embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) from about 1% to about 20% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 40% to about 85% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 20 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) about 15% to about 40% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 50% to about 80% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 20 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) about 1% to about 10% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 50% to about 80% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 20 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above

- 19 040232 (for example, a compound having any of the formulas (I), (IIa), (IIc), (IId), (IIe), (IIf));

b) from about 15% to about 38% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 60% to about 80% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 20 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf));

b) from about 3% to about 7% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 60% to about 80% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched in the (S) enantiomer;

b) from about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) about 40 to 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched in the (S)-enantiomer;

b) from about 1% to about 28% (w/w) of a pharmaceutically acceptable polymer;

c) about 40 to 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched in the (S)-enantiomer;

b) from about 1 to about 20% (w/w) pharmaceutically acceptable biodegradable

- 20 040232 limes;

c) from about 50% to about 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched in the (S)-enantiomer;

b) from about 5% to about 20% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 60% to about 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched in the (S) enantiomer;

b) about 1% to about 10% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 60% to about 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched in the (S)-enantiomer;

b) from about 3% to about 20% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 70% to about 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some other embodiments, where the compositions contain an isoxazoline active ingredient that is enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched

- 21 040232 (B)-enantiomer;

b) from about 1 to about 5% (w/w) pharmaceutically acceptable biodegradable polymer;

c) from about 70% to about 95% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment of the present invention, when the compositions contain an isoxazoline active substance enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable preparations for the treatment and/or prevention of parasitic infections and infestations in animals, containing:

a) about 10 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched with (B)-enantiomer;

b) from about 8 to about 30% (w/w) pharmaceutically acceptable biodegradable polymer;

c) from about 60% to about 90% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment of the present invention, when the compositions contain an isoxazoline active substance enriched in the more active enantiomer (eutomer), the present invention describes sustained release injectable preparations for the treatment and/or prevention of parasitic infections and infestations in animals, containing:

a) about 10 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds described in the embodiments described above (for example, a compound having any of formulas (I), (IIa ), (IIc), (IId), (IIe), (IIf)), enriched with (B)-enantiomer;

b) from about 3% to about 7% (w/w) of a pharmaceutically acceptable biodegradable polymer;

c) from about 60% to about 90% (w/w) of a pharmaceutically acceptable solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId), (IIe), (IIf)), such as a compound having the formula:

- 22 040232

or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 40% (w/w) of a pharmaceutically acceptable polymer;

c) from about 40% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId), (IIe), (IIf)), such as a compound having the formula:

- 23 040232

(Πά)

(PO, or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) from about 40% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 24 040232

(iif), or a pharmaceutically acceptable salt thereof,

b) from about 10% to about 40% (w/w) of a pharmaceutically acceptable polymer;

c) from about 30% to about 85% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

CI (Ps) about

CI (lid)

- 25 040232 about

Cl (lie)

ABOUT

CF ₃ (W), or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) from about 30% to about 85% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 20 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

CI (Ps) about

CI (lid) about

CI (Pe) about

CF ₃ (Ilf), or a pharmaceutically acceptable salt thereof,

b) from about 15% to about 40% (w/w) of a pharmaceutically acceptable polymer;

- 26 040232

c) from about 50% to about 80% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 20 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

cf ₃ (PO, or a pharmaceutically acceptable salt thereof,

b) from about to about 10% (w/w) of a pharmaceutically acceptable polymer;

c) from about 50% to about 80% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 27 040232

CF ₃ (Ilf), or a pharmaceutically acceptable salt thereof,

b) from about 10% to about 40% (w/w) of a pharmaceutically acceptable polymer;

c) from about 60% to about 85% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 28 040232

or a pharmaceutically acceptable salt thereof,

b) from about 3% to about 7% (w/w) of a pharmaceutically acceptable polymer;

c) from about 60% to about 85% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

CI (Ps) about

CI(IId)

- 29 040232

or a pharmaceutically acceptable salt thereof,

b) from about 12 to about 38% (w/w) PLGA polymer;

c) from about 55% to about 85% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f optionally, from about 0.01 to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 30 040232 or a pharmaceutically acceptable salt thereof,

b) about 1 to about 5% (w/w) PLGA polymer;

c) from about 55% to about 85% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

or a pharmaceutically acceptable salt thereof,

b) about 10 to about 35% (w/w) PLGA polymer;

c) about 60 to about 85% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, an alcohol including ethanol, isopropanol, glycerol formal and solketal, and an amide, and a water-immiscible solvent selected from the group consisting of benzyl alcohol, glycerol ester, triglyceride, and ester propylene glycol;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

- 31 040232

a) about 15 to 30% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

cf ₃ (Ilf), or a pharmaceutically acceptable salt thereof,

b) from about 1 to about 7% (w/w) PLGA polymer;

c) about 60 to about 85% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, an alcohol including ethanol, isopropanol, glycerol formal and solketal, and an amide, and a water-immiscible solvent selected from the group consisting of benzyl alcohol, glycerol ester, triglyceride, and ester propylene glycol;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 32 040232

(5)-IIf, or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 28% (w/w) of a pharmaceutically acceptable polymer;

c) from about 40% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

CI(5)-PS

- 33 040232

or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) from about 40% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In some embodiments, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 34 040232

or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 20% (w/w) of a pharmaceutically acceptable polymer;

c) from about 50% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

or a pharmaceutically acceptable salt thereof,

b) from about 5% to about 20% (w/w) of a pharmaceutically acceptable polymer;

c) from about 60% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes injectable preparations for

- 35 040232 slow release for the treatment and / or prevention of parasitic infections and infections in animals, containing:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 10% (w/w) of a pharmaceutically acceptable polymer;

c) from about 60% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

- 36 040232

or a pharmaceutically acceptable salt thereof,

b) from about 3% to about 20% (w/w) of a pharmaceutically acceptable polymer;

c) from about 70% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 5 to 15% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

(5)-ps

ABOUT

CI(S)-IId

ABOUT

CI(5)-Pe

- 37 040232 about

CF ₃ (X-IIf, or a pharmaceutically acceptable salt thereof,

b) from about 1% to about 5% (w/w) of a pharmaceutically acceptable polymer;

c) from about 70% to about 95% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 10 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

(S)-IIf, or a pharmaceutically acceptable salt thereof,

b) from about 8% to about 28% (w/w) of a pharmaceutically acceptable polymer;

c) from about 60% to about 90% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

- 38 040232

In another embodiment, the present invention describes sustained release injectable formulations for the treatment and/or prevention of parasitic infections and infestations in animals, comprising:

a) about 10 to 20% (w/w) of an isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having formula (I), (IIa), (IIc ), (IId), (IIe), (IIf)), such as a compound having the formula:

cf ₃ (S)-IIf, or a pharmaceutically acceptable salt thereof,

b) from about 3% to about 7% (w/w) of a pharmaceutically acceptable polymer;

c) from about 60% to about 90% (w/w) of a solvent or mixture of solvents;

d) optionally, from about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.01% to about 5.0% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof.

Another embodiment of the present invention is an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting mainly of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) a pharmaceutically acceptable polymer;

c) at least one solvent or mixture of solvents;

d) optionally, an antioxidant;

e) optionally, a surfactant;

f) optionally, at least one pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable preparation for

- 39 040232 slow release for the treatment and / or prevention of parasitic infections and infections in animals, consisting mainly of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) from about 1 to about 30% (w/w) PLGA polymer;

c) about 40 to about 98% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting mainly of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 1 to about 20% (w/w) PLGA polymer;

c) about 40 to about 98% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting mainly of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 5 to about 20% (w/w) PLGA polymer;

c) about 40 to about 90% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting mainly of the following components:

- 40 040232

a) an antiparasitic effective amount of at least one isoxazoline active substance, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 5 to about 15% (w/w) PLGA polymer;

c) about 50 to about 95% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting mainly of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active substance, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 1 to about 10% (w/w) PLGA polymer;

c) about 50 to about 95% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1% to about 5% (w/w) of a pharmaceutically acceptable additive, excipient, or mixture thereof

Another embodiment of the present invention is an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) a pharmaceutically acceptable biodegradable polymer;

c) at least one solvent which is a polar solvent miscible with water;

d) optionally, an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, at least one pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) from about 1 to about 30% (w/w) PLGA polymer;

c) from about 40% to about 98% (w/w) of a water-miscible solvent mixture, and not

- 41 040232 water-miscible solvent, where the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerol, triglyceride, propylene glycol ester, and formal glycerol;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 1 to about 20% (w/w) PLGA polymer;

c) about 40 to about 98% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 5 to about 20% (w/w) PLGA polymer;

c) about 40 to about 90% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N -methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active substance, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 1 to about 10% (w/w) PLGA polymer;

c) about 50 to about 98% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone,

- 42 040232

N-methylpyrrolidone, N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, formal glycerin, triglyceride, propylene glycol ester and formal glycerin;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the present invention describes an injectable sustained release preparation for the treatment and/or prevention of parasitic infections and infestations in animals, consisting of the following components:

a) an antiparasitic effective amount of at least one isoxazoline active ingredient, such as, for example, any of the isoxazoline compounds of the embodiments described above (for example, a compound having any of formulas (I), (IIa), (IIc), (IId ), (IIe), (IIf)), and, optionally, at least one additional active ingredient specified in this document;

b) about 5 to about 15% (w/w) PLGA polymer;

c) about 50 to about 95% (w/w) of a mixture of a water-miscible solvent and a water-immiscible solvent, wherein the water-miscible solvent is selected from the group consisting of cyclic carbonate, dimethyl isosorbide, dimethyl sulfoxide, 2-pyrrolidone, N-methylpyrrolidone , N-octylpyrrolidone, liquid polyethylene glycol, poloxamer, alcohol, solketal and amide, and the water-immiscible solvent is selected from the group consisting of benzyl alcohol, glycerol ester, glycerol formal, triglyceride, propylene glycol ester and glycerol formal;

d) optionally, from about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, from about 0.1 to about 10% (w/w) surfactant;

f) optionally, from about 0.1 to about 5% (w/w) of a pharmaceutically acceptable additive, adjuvant, or mixture thereof.

In another embodiment, the pharmaceutically acceptable polymer in the sustained release injectable formulations described above may be a copolymer of polylactides and polyglycolides, and the solvent may be an individual solvent such as, for example, a cyclic carbonate (e.g., ethylene carbonate or propylene carbonate), or a solvent mixture containing , for example, a cyclic carbonate, an ester of glycerol (eg, glycerol triacetate), and optionally a poloxamer (eg, P-124), which may act as a solvent or surfactant. In another embodiment, the sustained release injectables described above may further include an antioxidant, such as butylated hydroxytoluene (B HT).

Other embodiments of the present invention are any of the sustained release injectables described above wherein: the ratio of PLGA to isoxazoline active ingredient to polylactide-polyglycolide copolymer is from about 1.5:1 to about 1:1.5 (wt:wt. ); the weight average molecular weight of the copolymer of polylactides and polyglycolides is from about 5 to about 20 kDa; and the concentration of the copolymer of polylactides and polyglycolides is from about 8 to about 20% (w/w) (for example, 12.5 or 13% (w/w)). In another embodiment, any of the sustained release injectables described above may further comprise 0.5 to about 20% (w/w) poloxamer (eg, about 1 to about 3% (w/w)). In another embodiment, the polylactide-polyglycolide copolymer may have a lactide to glycolide ratio of about 75:25 (w:w).

The sustained release formulations of the present invention are prepared by adding a solvent or mixture of solvents, non-polymeric excipients (e.g., if present, antioxidants, surfactants, etc.), followed by addition of the active ingredient(s) with stirring. When the active ingredient and inactive excipients are completely dissolved, the pharmaceutically acceptable polymer(s) are added, with stirring until complete dissolution. Of course, the compositions can be prepared by other suitable methods known in the art, provided that the resulting preparation is a homogeneous liquid preparation suitable for use.

As used herein and in the claims, terms such as contains, containing, having, and the like have the meanings assigned to them in US patent law and may mean includes, includes, and the like; terms consisting principally of and consisting principally of also have the meaning prescribed in patent law, and these terms are not exclusive, allowing for the presence of more than what is listed, provided that the essential or new features of what is listed are not changed by

- 43 040232 the absence of more than listed, but excluding options known in the prior art. The term consisting of excludes any element, step, or ingredient not specified in the statement.

Definitions

The terms used in this text have the generally accepted meaning in this field, unless otherwise indicated. The organic moieties referred to in the definitions of the variables present in formula (I) are - like the term halogen - collective terms for lists of individual group members. The prefix C _n -Cm in each case indicates the possible number of carbon atoms in the group.

The term sustained release or sustained release formulation or sustained release composition as used herein means a dosage form prepared in such a way that the active ingredient(s) contained therein become available over a prolonged period of time due to the interaction of the components of the formulation in combination with natural pharmacokinetic or pharmacodynamic characteristics of the active substance(s). This definition is consistent with the use of the term as known and accepted in the veterinary field, according to Terminology Challenges: Defining Modified Release Dosage Forms in Veterinary Medicine' by Marilyn N. Martinez, Danielle Lindquist and Sanja Modric (Journal of Pharmaceutical Sciences, vol. 99, no 8, August 2010).

For example, sustained release formulations of the present invention are understood to provide at least 90% efficacy against fleas and/or ticks for at least 3 months as described herein.

The term animal is used in this text to include all mammals, birds and fish, and also includes all vertebrates. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. They also include the individual animal at all stages of development, including the embryonic and prenatal stages. In some embodiments, animal means non-human animals.

The term substantially pure is used herein to indicate that a compound or enantiomer is at least about 90% (w/w), at least about 95% (w/w), at least about 98 pure. % (w/w) or higher.

The term alkyl refers to saturated linear, branched, cyclic, primary, secondary or tertiary hydrocarbons, including hydrocarbons containing from 1 to 20 atoms. In some embodiments, the alkyl groups include C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₈ , C ₁ -C ₆ , or C ₁ -C ₄ alkyl groups. Examples of C ₁ -C ₁₀ alkyls include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C ₁ -C ₄ -alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups or cycloalkyl, which are covered by the term alkyl, include groups with 3-10 carbon atoms containing one or more fused rings. In some embodiments, the cycloalkyl groups include C ₄ -C 7 or C ₃ -C ₄ cyclic alkyl groups. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The alkyl groups described herein may be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl or dialkylamino, amido, arylamino, alkoxy, aryloxy. , nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thio ester, thio ether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoacid, phosphate, phosphonate, or any other possible functional group that does not inhibit the biological activity of the compounds of the present invention, in an unprotected or optionally protected form, as is known to those skilled in the art, for example, as described in Greene's book, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, incl. herein by reference.

Terms that include the term alkyl, such as alkylcycloalkyl, cycloalkylalkyl, alkylamino, or dialkylamino, are to be understood as containing an alkyl group, as defined above, linked to another functional group, wherein said group is linked to the remainder of the compound via the last listed group, as will be understandable to a person skilled in the art.

The term alkenyl refers to straight and branched carbon chains containing

- 44 040232 at least one carbon-carbon double bond. In some embodiments, alkenyl groups may include C ₂ -C 2o alkenyl groups. In other embodiments, the alkenyl comprises C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , or C ₂ -C ₄ alkenyl groups. In one version of alkenyl, the number of double bonds is 1-3, in another version of alkenyl, the number of double bonds is one or two. Other numbers of carbon-carbon double bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkenyl fragment in the molecule. C ₂ -C ₁₀ alkenyl groups may contain more than one double bond in the chain. Examples include (but are not limited to) ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1 -propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl- 2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl- 1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3- methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl- 4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3- dimethyl 3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1- boutani l, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl- 2-propenyl.

The term alkynyl refers to straight and branched carbon chains containing at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another version of alkynyl, the number of triple bonds is one or two. In some embodiments, the alkynyl groups include C ₂ -C ₂₀ alkynyl groups. In other embodiments, alkynyl groups may include C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , or C ₂ -C ₄ alkynyl groups. Other numbers of carbon-carbon triple bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkynyl moiety in the molecule. C ₂ -C ₁₀ -Alkynyl as used herein refers to linear or branched unsaturated hydrocarbon groups containing from 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1-yl , prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but -2-in-1-yl, n-pent-1-in-1-yl, n-pent-1-in-3-yl, n-pent-1-in-4-yl, n-pent-1 -yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yl -3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4 -yl, n-hex-1-yn-5-yl, n-hex-1-yn6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n -hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3yn-2-yl, 3-methylpent-1 -yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn -1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term haloalkyl refers to an alkyl group, as defined herein, that is substituted with one or more halogen atoms. For example, C1- _C4 haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2- trichloroethyl, pentafluoroethyl, and the like.

The term haloalkenyl refers to an alkenyl group, as defined herein, that is substituted with one or more halogen atoms.

The term haloalkynyl refers to an alkynyl group, as defined herein, that is substituted with one or more halogen atoms.

The term alkoxy refers to the group alkyl-O-, where alkyl has the above meaning. Similarly, the terms alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, and halocycloalkenyloxy refer to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl- O-, cycloalkenyl-O-, halocycloalkyl-O- and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl and halocycloalkenyl are as defined above. Examples of C1- _C6 alkoxy include, but are not limited to, methoxy, ethoxy, C ₂ H ₅ -CH ₂ O-, (CH ₃ ) ₂ CHO-, n-butoxy, C ₂ H ₅ -CH(CH ₃ ) O-, (CH ₃ ) ₂ CH-CH ₂ O-, (CH ₃ ) ₃ CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2- dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, nhexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy, and the like.

- 45 040232

The term alkylthio refers to the group alkyl-S-, where alkyl has the above meaning. Similarly, the terms haloalkylthio, cycloalkylthio, and the like are refer to the haloalkyl-S- and cycloalkyl-S- groups, where haloalkyl and cycloalkyl have the meanings given above.

The term alkylsulfinyl refers to the group alkyl-B(O)-, where alkyl has the above meaning. Similarly, the term haloalkylsulfinyl refers to the group haloalkyl-B(O)-, where haloalkyl has the same meaning as defined above.

The term alkylsulfonyl refers to the group alkyl-B(O)2-, where alkyl is as defined above. Similarly, the term haloalkylsulfonyl refers to the group haloalkyl-8(O) ₂ - where haloalkyl has the same meaning as defined above.

The terms alkylamino and dialkylamino refer to the groups alkyl-NH- and (alkyl) ₂ N-, where alkyl is as defined above. Similarly, the term haloalkylamino refers to the group haloalkyl-NH-, where haloalkyl has the same meaning as defined above.

The terms alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl refer to the groups alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, where alkyl, alkoxy, alkylamino and dialkylamino have the above meanings.

Similarly, the terms haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl and dihaloalkylaminocarbonyl refer to the haloalkyl-C(O)-, haloalkoxyC(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)- groups, where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino have the above meanings.

The term aryl refers to a monovalent carbocyclic group containing from 6 to 14 carbon atoms, having one ring or more fused rings. In some embodiments, the aryl groups include C ₆ -C ₁ o-aryl groups. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. Aryl groups may be unsubstituted or be substituted with one or more substituents selected from the following: halogen atom, cyano group, nitro group, hydroxy group, mercapto group, amino group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, алкоксигруппа, алкенилоксигруппа, алкинилоксигруппа, галогеналкоксигруппа, галогеналкенилоксигруппа, галогеналкинилоксигруппа, циклоалкоксигруппа, циклоалкенилоксигруппа, галогенциклоалкоксигруппа, галогенциклоалкенилоксигруппа, алкилтиогруппа, галогеналкилтиогруппа, циклоалкилтиогруппа, галогенциклоалкилтиогруппа, алкилсульфинил, алкенилсульфинил, алкинилсульфинил, галогеналкилсульфинил, галогеналкенилсульфинил, галогеналкинилсульфинил, алкилсульфонил, алкенилсульфонил, алкинилсульфонил, галогеналкил-сульфонил, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino, alkynylamino, di(alkyl)amino, di(alkenyl)ami no group, di(alkynyl)amino group or trialkylsilyl.

The terms aralkyl or arylalkyl refer to an aryl group that is linked to the remainder of the compound via a diradical alkylene bridge, (-CH ₂ -) _p , where n is 1-12 and where aryl has the meaning given above.

The term heteroaryl refers to a monovalent aromatic group containing 1-15 carbon atoms, preferably 1 to 10 carbon atoms, containing one or more oxygen, nitrogen and sulfur heteroatoms in the ring, preferably 1-4 heteroatoms or 1-3 heteroatoms. The nitrogen and sulfur heteroatoms can optionally be oxidized. Such heteroaryl groups may have one ring (eg, pyridyl or furyl) or multiple fused rings, provided that the point of attachment is on a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl and benzothiophenyl. Heteroaryl rings may be unsubstituted or substituted with one or more of the moieties defined above for the term aryl. The term heteroarylene (where the heteroaryl group is bridged) should be interpreted accordingly.

The terms heterocyclyl, heterocyclic or heterocyclo refer to fully saturated or unsaturated cyclic groups, for example 3-7 membered monocyclic or 4-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic systems which may contain at least one heteroatom in a ring containing at least one carbon atom. Each ring of a heterocyclic group containing a heteroatom may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom in the ring or ring system and may be unsubstituted or substituted with one or more substituents as described above for aryl groups.

Examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imide

- 46 040232 zolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl-2-oxopiperodinoxopinoxy, 2 , azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1dioxothienyl, triazolyl, triazinyl, and the like.

Examples of bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2b]pyridinyl] or furo[2,3b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl) , tetrahydroquinolinyl, and the like. The term heterobicyclylene (wherein the bicyclic heterocyclic group is bridged) should be interpreted accordingly.

Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

The term halogen means fluorine, chlorine, bromine and iodine atoms. The designation halogen (for example, as in the term haloalkyl) refers to all degrees of substitution from single substitution to perhalogen substitution (for example, can be illustrated for methyl: chloromethyl (-CH ₂ Cl), dichloromethyl (-CHCl ₂ ), trichloromethyl (-CCl ₃ )).

The term enriched means that the ratio wt./weight. is at least about 1.05 or higher in favor of one of the enantiomers. Preferably the ratio wt./weight. is at least about 1.05 or higher in favor of the enantiomer that exhibits significant activity in vitro and in vivo (eutomer).

Stereoisomers and polymorphic forms.

Those skilled in the art will appreciate that some of the compounds in the compositions of the present invention may exist and be isolated as optically active and racemic forms. Compounds having one or more chiral centers, including that on the sulfur atom, may be present as single enantiomers or diastereomers, or as mixtures of enantiomers and/or diastereomers. For example, it is well known that sulfoxide compounds may be optically active and may exist as single enantiomers or racemic mixtures. In addition, the compounds in the compositions of the present invention may include one or more chiral centers, which lead to the existence of a theoretical number of optically active isomers. Where the compounds in the compositions of the present invention include n chiral centers, the compounds may have up to 2 ⁿ optical isomers. The present invention encompasses the particular enantiomers or diastereomers of each compound, as well as mixtures of different enantiomers and/or diastereomers of the compounds of the present invention that have the useful properties described herein. In addition, the present invention covers compositions containing one or more conformational isomers (eg, rotamers), as well as mixtures of conformational isomers. Conformational isomers of isoxazoline compounds can result from obstruction of rotation around an amide bond attached to an aryl or heteroaryl ring (eg, an amide bond attached to a naphthyl group in formula (IIc)). Optically active forms can be obtained, for example, by resolution of racemic forms by selective crystallization, synthesis from optically active precursors, chiral synthesis, chromatographic separation using a chiral stationary phase, or by enzymatic resolution.

In addition, the compounds in the compositions of the present invention may exist as hydrates or solvates in which certain stoichiometric amounts of water or solvent are associated with the molecule in crystalline form. Compositions of the present invention may include hydrates and solvates of the active ingredients. In some embodiments, the compositions of the present invention may include up to 15% (wt./wt.), up to 20% (wt./wt.) or up to 30% (wt./wt.) of a certain solid form.

Salt.

Also within the scope of the present invention are acid and base salts of the compounds described herein, where applicable.

The term acid salt/acid salts embraces salts of the compounds with all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment, the acids are linear or branched, saturated or unsaturated

- 47 040232

C1- _C2 o-aliphatic carboxylic acids which are optionally substituted with halogens or hydroxyl groups, or C6- _C12 aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, α-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids containing from 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butanoic acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylstearic acid. Other acids include gluconic acid, glucoheptonic acid and lactobionic acid.

The term salts with bases/basic salts encompasses salts of the compounds with all pharmaceutically acceptable inorganic or organic bases, including alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates. Salts formed with such bases include, for example, alkali or alkaline earth metal salts, including (but not limited to) lithium, sodium, potassium, magnesium, or calcium salts. Salts formed with organic bases include salts with commonly known hydrocarbon and heterocyclic amines, which include, for example, ammonium (NH4+) salts, alkyl- and dialkylammonium salts, and salts with cyclic amines such as morpholine and piperidine salts.

In another embodiment, the sustained release injectable formulations of the present invention comprise an effective amount of at least one isoxazoline, or a pharmaceutically acceptable salt thereof, in combination with at least one other active ingredient. In one embodiment, the sustained release injectable compositions contain an effective amount of at least one isoxazoline compound having formula (I), (IIa), (IIc), (IId), (IIe), (IIf), or a pharmaceutically acceptable salt thereof, in combination with at least one other active substance with systemic activity.

Additional veterinary/pharmaceutical active ingredients may be used in the compositions of the present invention. In some embodiments, additional active ingredients may include, but are not limited to, acaricides, anthelmintics, antiparasitics, and insecticides. Antiparasitic agents may include ectoparasiticidal and/or endoparasiticidal agents.

Veterinary pharmaceuticals that can be incorporated into the compositions of the present invention are well known in the art (see, for example, Plumb' Veterinary Drug Handbook, ^5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, ^9th Edition, (January 2005)) and include (but are not limited to) acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitrecin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogensulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdenate, amoxicillin, clavulanate, Bnapotassium, deoxytrecholate lipid base, ampicillin, amprolium, antacids (oral), antivenin, apomorphion, apramycin sulfate, ascorbic acid, aspraginase, aspirin, atenolol, atipamezole, atracurium besilate, atropine sulfate, aurnofin, aurothioglucose, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, boldenone undecylenate, bromides, bromocriptine, bufinorenzylate, bufinorenzylate, bufinorenzylate, bufinorenzylate, bunocryptine, , butorphanol tartrate, cabergoline, salmon calcitonin, calcitrol, calcium salts, captopril, carbenicillin indanyl sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetan, disodium натрий, цефподоксим проксетил, цефтазидим, цефтиофур натрий, цефтиофур, цефтиаксон натрий, цефалексин, цефалоспорины, цефапирин, активированный уголь, хлорамбуцил, хлорамфеникол, хлордиазэпоксид, хлордиазэпоксид +/- клидиниум бромид, хлортиазид, хлорфенирамина малеат, хлорпромазин, хлорпропамид, хлортетрациклин, хорионический гонадотропин (hCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium, dipotassium clorazepate, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosyntropine, cyclophosphamide, cycloheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dextranase, diamoxane, dexamethasone, dexpanthenol, dextranaz, diamoxane, dexamethasone (oral), dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol

- 48 040232 (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine, disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, doxycycline, edetate calcium disodium, calcium EDTA, edrophonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynic acid/ethacrynate sodium, ethanol (alcohol), etidronate sodium , etodolac, etomidate, pentobarbital euthanasia, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine, fluorouracil (5FU), fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepisol (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, ge ntamycin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine, glyburide, glycerin (oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (oxyglobin®), heparin, hydroxyethyl starch, hyaluronate sodium, hydrazalin, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropionate, impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin, interferon alfa-2a (human recombinant), iodide (sodium/potassium ), ipecac (syrup), sodium ipodate, iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose, levprolide, levamisole, levitiracetam, levothyroxine sodium, lidocaine , lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechloretam in, meclizine, meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomin, melatonin, meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin, methadone, methazolamide, methenamine mandelate/hippurate, methimazole, methionine, methocarbamol sodium, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxol, mexiletine, mibolerlone, midazolam, milbemycin oxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxondro, dexmanno, morphine sulfate , narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin sodium, oxazepam, o xybutynin chloride, oxymorphone, oxytetracycline, oxytocin, disodium pamidronate, pancrelipase, pancuronium bromide, paromomycin sulfate, parosetin, penicillamine, commonly known penicillins, penicillin G, penicillin V potassium, pentazocine, pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline, pergolide mesylate, phenoxybenzamine, phenylbutazone, phenylephrine, phenylpropanolamine, sodium phenytoin, pheromones, parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulphated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone/prednisone, primidone, procainamide, procarbazine, prochlorperazine, propanteline bromide, propionic acne bacteria injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium bulk laxative, pyridostigmine bromide, pyrylamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin, s-adenosyl methionine ( SAMe), saline/hyperosmotic laxative oe, selamectin, selegiline/1-deprenyl, sertraline, sevelamer, sevoflurane, silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodium thiosulfate, growth hormone, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer , succinylcholine chloride, sucralphate, sufentanyl citrate, sulfachloropyridazine sodium, sulfadiazine/trimethroprim, sulfadimentoxin, sulfadimentoxin/ormethroprim, sulfasalazine, taurine, tepoxaline, terbinaflin, terbutaline sulfate, testosterone, tetracycline, thiabedazole, thiacetarsamide sodium, trimethiopenthioguamine, thioputhioguamine , thyrotropin, tiamulin, ticarcilin disodium, tiletamine/zolazepam, tilmoxin, thiopronin, tobramycin sulfate, tocainide, tolazolon, telfenamic acid, topiramate, tramadol, trimcinolone acetonide, trientine, trilostane, trimepraxine tartrate with prednisolone, tripelennamine, tylosin, valprosiol, , vanadium, vancomycin, vasopressin, vecuronium bromide, vera pamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zonisamide, and mixtures thereof.

In one embodiment of the present invention, arylpyrazole compounds known in the art, such as phenylpyrazoles, can be combined with isoxazoline compounds in the sustained release injectable compositions of the present invention. Examples of such phenylpyrazole compounds include (but are not limited to) fipronil, pyriprol, ethiprol and those described in US Pat. Nos. 6,001,384; 6010710; 6083519; 6096329; 6174540; 6685954 and 6998131 (all incorporated herein by reference, each issued by Merial, Ltd., Duluth, GA).

- 49 040232

In another embodiment of the present invention, one or more macrocyclic lactones, which act as an acaricide, anthelmintic and insecticide, can be added to the compositions of the present invention.

Macrocyclic lactones include, but are not limited to, avermectins such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and ML-1,694,554, and milbemycins such as milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadektin. Also included are the 5-oxo and 5-oxime derivatives of the listed avermectins and milbemycins.

Macrocyclic lactone compounds are known in the art and can be easily prepared commercially or by synthetic procedures known in the art. Reference is made to the widely available technical and commercial literature. For avermectins, ivermectin and abamectin, reference can be made, for example, to the work of Ivermectin and Abamectin, 1989, by M.N. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag, or Albers-Schonberg et al. (1981), Avermectins Structure Determination, J. Am. Chem. Soc., 103, 4216-4221. Regarding doramectin, one may consult Veterinary Parasitology, vol. 49, no. 1, July 1993, 5-15. With regard to milbemycins, reference may be made to, inter alia, Davies H.G. et al., 1986, Avermectins and Milbemycins, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis Of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Patent Nos. 4134973 and EP 0677054.

Macrocyclic lactones are natural compounds or their semi-synthetic derivatives. The structures of avermectins and milbemycins are closely related, for example, they share a complex 16-membered macrocyclic lactone ring. Natural avermectins are described in US Pat. No. 4,310,519 and 22,23-dihydroavermectin compounds are described in US Pat. No. 4,199,569 (both incorporated herein by reference). Mention should also be made, among others, of US Pat. Nos. 4,468,390; 5,824,653; 237086. Natural milbemycins are described in US Pat. No. 3,950,360, as well as in various references cited in The Merck Index ^12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in International Nonproprietary Names for Pharmaceutical Substances (INN), WHO Drug Information, vol. 17, no. 4, p. 263-286 (2003). Semi -synthetic derivatives of the above classes of compounds are well known in this area and described, for example, in US patents No. 5077308, 4859657, 4963582, 4855317, 4871719, 4874749, 4427663, 4310519, 505596,497371.1.1.

In another embodiment, the present invention describes sustained release formulations of the present invention containing 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N -[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (a compound of formula (IIc)) in combination with a macrocyclic lactone active ingredient.

In another embodiment, the present invention describes sustained release formulations of the present invention containing 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N -[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (compound having formula (IIc)) in combination with ivermectin, eprinomectin, selamectin, milbemycin oxime or moxidectin.

In another embodiment, the present invention describes sustained release formulations of the present invention containing 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5dihydro-5-(trifluoromethyl)-3-isoxazolyl]-M -[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide enriched in the (S)-enantiomer or substantially pure (S)-enantiomer (compound having the formula (S )-IIc), in combination with the active substance, which is a macrocyclic lactone.

In another embodiment, the present invention describes sustained release formulations of the present invention containing 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5dihydro-5-(trifluoromethyl)-3-isoxazolyl]-M -[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide enriched in the (S)-enantiomer or substantially pure (S)-enantiomer (compound having the formula (S )-IIc), in combination with ivermectin, eprinomectin, selamectin, milbemycin oxime or moxidectin.

In another embodiment, the present invention encompasses an injectable sustained release formulation comprising an isoxazoline compound in combination with systemic compounds from the class of acaricides or insecticides known as insect growth regulators (IGRs). Compounds belonging to this group are well known to those skilled in the art and represent a wide variety of different classes of chemical compounds. These compounds exhibit activity by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in US Pat.

- 50 040232

In one embodiment, the IGR is a compound that is a mimic of juvenile hormone. Examples of juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, and 4-chloro-2-(2-chloro-2methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3( 2H)-on.

In one embodiment, the sustained release injectable formulations of the present invention comprise an effective amount of at least one isoxazoline having the formula (I), (IIa), (IIc), (IId), (IIe), (IIf), or a pharmaceutical formulation thereof. an acceptable salt in combination with methoprene or pyriproxyfen.

In another embodiment, the IGR compound is a chitin synthesis inhibitor. Chitin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenoside, teflubenzuron, triflumoron, nofaluron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl) phenylurea, 1-(2,6-difluorobenzoyl)-3(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro -4-trifluoromethyl)phenylurea.

In another embodiment of the present invention, insecticides that kill adult insects and mites can also be added to the sustained release formulations of the present invention. These include pyrethrins (which include cynerin I, cynerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof) and pyrethroids and carbamates including (but not limited to) benomyl, carbanolate, carbaryl, carbofuran, metthiocarb , metolcarb, promacyl, propoxur, aldicarb, butocarboxym, oxamyl, thiocarboxym and thiophanox. In one embodiment, the compositions may include permethrin in combination with an isoxazoline active ingredient.

In some embodiments, the sustained release formulations of the present invention may include one or more antinematode agents, including (but not limited to) actives from the following classes: benzimidazoles, imidazothiazoles, tetrahydropyrimidines, or organophosphates. In some embodiments, the compositions may include benzimidazoles, including but not limited to thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, and its o,o-dimethyl analog.

In other embodiments, the sustained release formulations of the present invention may include imidazothiazole compounds including (but not limited to) tetramizole, levamisole, and butamisole. In other embodiments, the sustained release formulations of the present invention may include tetrahydropyrimidine active ingredients, including (but not limited to) pyrantel, oxanthel, and morantel.

Suitable organophosphate active ingredients include, but are not limited to, coumaphos, trichlorfon, haloxon, naphtalophos and dichlorphos, heptenophos, mevinphos, monocrotophos, tetraethyl pyrophosphate, and tetrachlorvinphos.

In other embodiments, sustained release formulations of the present invention may include the antinematode compounds phenothiazine and piperazine as neutral compounds or as various salts, diethylcarbamazine, phenols such as disophenol, arsenic compounds such as arsenamide, ethanolamines such as bephenia, tenium closylate and methyridine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate and dithiazanin iodide; isothiocyanates, including bitoscanate, sodium suramin, phthalofin, and various natural substances, including (but not limited to), hygromycin B, a-santonin, and kainic acid.

In other embodiments, the sustained release formulations of the present invention may include anti-trematode agents. Suitable antitrematode agents include, but are not limited to, miracils such as miracil D and mirazan, praziquantel, epsiprantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, gycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenolic compounds, known in the art, including hexachlorophene, bithionol, bithionol sulfoxide and menichlorofolane; various salicylanilide compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide, and closantel; triclabendazole, diamphenetide, clorsulon, getolin and emetine.

Anticestodic compounds can also advantageously be used with sustained release formulations of the present invention including, but not limited to, praziquantel, epsiprantel and arecoline in various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.

In other embodiments, the sustained release formulations of the present invention may include other active ingredients effective against arthropod parasites. Suitable active ingredients include, but are not limited to, bromocyclene, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothione, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthione, diemtoate, dioxathion, ethion , famfur, fenitrothion, fenthion, phosphpyrate, iodophenphos, malathion, naled, fosalon, phosmet, foxim, propetamphos, ronnel, styrophos, alletrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate,

- 51 040232 flucitrinate, permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanatoacetate, metroprene, monosulfiram, pyrenonyl butoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DETA, dimethyl 1, and compounds 5а,6,9,9а,9b-hexahydro-4а(4Н)-dibenzofurancarboxaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7а-tetrahydro-4,7-methano-1Н- isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5pyridine dicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

The antiparasitic agent that can be combined with the isoxazoline compounds in the sustained release formulations of the present invention may be a biologically active peptide or protein, including (but not limited to) depsipeptides that work at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin family. receptors, leading to paralysis and death of parasites. In one embodiment, the depsipeptide is an emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86). In another embodiment, the depsipeptide is PF1022a or a derivative thereof.

In other embodiments, the sustained release injectable formulations of the present invention may include an active ingredient from the neonicotinoid class of pesticides. Neonicotinoids bind and inhibit specific insect nicotinic acetylcholine receptors. In one embodiment, the neonicotinoid insecticidal agent that can be combined with an isoxazoline compound to form a sustained release injectable formulation of the present invention is imidacloprid. Imidacloprid is a well-known neonicotinoid active ingredient and is the key active ingredient in Bayer Animal Health's Advantage®, Advantage® II, K9 Advantix® and K9 Advantix® II topical parasiticide products and in the oral soft chew Advantus™ from Piedmont Animal Health. Means from this class are described, for example, in US patent No. 4742060 or in EP 0892060.

In another embodiment, the sustained release injectable formulations of the present invention may include nitenpyram, another active ingredient in the neonicotinoid class of pesticides. Nitenpyram has the chemical structure shown below and is the active ingredient in the oral product CAPSTAR™ Tablets marketed by Novartis Animal Health.

ΗΝ _χ

Nitenpyram is active against adult fleas when administered daily via oral tablet. Nitenpyram works by disrupting normal nerve transmission and leading to the death of the insect. Nitenpyram has a very fast onset of action against fleas. For example, CAPSTAR™ Tablets begin their effects on fleas within 30 minutes of administration and are intended to be used once a day. However, activity for nitenpyram is only known when administered orally as a systemic parasiticide, as in the case of CAPSTAR™ Tablets.

In some embodiments, the insecticidal agent that can be combined with the sustained release formulations of the present invention is semicarbazone, such as metaflumizone.

In another embodiment, the sustained release formulations of the present invention may preferably contain a combination of isoxazoline compounds known in the art. Such active agents are described in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/0260 2521 and US 2007/0066617 and WO 2008/122375, which are all incorporated herein by reference in their entirety.

In another embodiment of the present invention, nodulisporic acid and its derivatives (a class of known acaricidal, anthelmintic, antiparasitic and insecticidal agents) can be added to the sustained release formulations of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described in, for example, US Pat. Nos. 5,399,582; 5,962,499; The formulations may include one or more of the known nodulisporic acid derivatives, including all stereoisomers such as those described in the patents cited above.

In another embodiment, anthelmintic compounds from the aminoacetonitrile (AAD) class, such as monepantel (ZOLVIX) and the like, can be combined with sustained release formulations of the present invention. These compounds are described, for example, in WO 2004/024704 and US Pat. No. 7,084,280 (incorporated by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature, vol. 452, 13 March 2008, 176-181.

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The compositions of the present invention may also include aryloazol-2-yl cyanoethylamino compounds such as those described in Soll et al. No. 7964621, which is incorporated into the present text by reference.

The sustained release injectable formulations of the present invention can also be combined with paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds that contain a spirodioxepinoindole core with activity against certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492 ). In addition, a structurally related family of marcfortines such as marcfortines A-C are also known and can be combined with the preparations of the present invention (see J. Chem. Soc. Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977). Further information on paraherquamid derivatives can be found, for example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432, US Pat. 5,703,078 and US Pat. No. 5750695, the full content of each of which is incorporated into the present text by reference.

In another embodiment of the present invention, the compositions may include the active ingredient spinosyn produced by the soil actinomycete Saccharopolyspora spinosa (see, for example, Salgado V.L. and Sparks T.C, The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance in Comprehensive Molecular Insect Science, vol. 6, pp. 137-173, 2005), or a semi-synthetic spinosyn active ingredient. Spinosyns are commonly referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of these components or their combination can be used in the compositions of the present invention. The spinosyn compound may be a 5,6,5-tricyclic system fused with a 12-membered macrocyclic lactone, a neutral sugar (rhamnose) and an amino sugar (forosamine). These and other natural spinosyn compounds, including 21-butenyl spinosyn produced by Saccharopolyspora pagona, which can be used in the compositions of the present invention, can be obtained by enzymatic methods according to methods known in the art. Other spinosyn compounds that can be used in the compositions of the present invention are described in US patent No. 5496931;5670364;5591606; 5571901; 5202242; 5767253; 5840861; 5670486; 5631155 and 6001981, the entire content of each of which is incorporated into this text by reference. Spinosyn compounds may include, but are not limited to, spinosyn A, spinosyn D, spinosad, spinetoram, or a combination thereof. Spinosad is a combination of spinosyn A and spinosyn D, while spinetoram is a combination of 3'-ethoxy-5,6-dihydrospinosine J and 3'-ethoxyspinosyn L.

In general, the additional active ingredient is included in the sustained release formulations of the present invention in an amount of from about 0.1 μg to about 1000 mg. More commonly, the additional active ingredient may be formulated in an amount of from about 10 μg to about 500 mg, from about 1 to about 300 mg, from about 10 to about 200 mg, or from about 10 to about 100 mg.

In other embodiments of the present invention, the additional active ingredient may be included in the composition in such an amount as to provide a dosage of from about 5 μg/kg to about 50 mg/kg of animal weight. In other embodiments, the additional active ingredient may be included in the composition in an amount sufficient to provide a dosage of about 0.01 to about 30 mg/kg, about 0.1 to about 20 mg/kg, or about 0.1 to about 10 mg/kg animal weight. In other embodiments, the additional active ingredient may be present at a dosage of from about 5 to about 200 μg/kg, or from about 0.1 to about 1 mg/kg of animal weight. In another embodiment of the present invention, the additional active ingredient is present at a dosage of from about 0.5 to about 50 mg/kg.

In one embodiment, sustained release formulations of the present invention, which contain at least an isoxazoline active ingredient, a pharmaceutically acceptable polymer, and a solvent, have surprisingly been shown to be stable and effective against a wide range of ectoparasites, and possibly also endoparasites if another active ingredient is formulated. , over an extended period of time; for example a period of 3 to 12 months, while demonstrating excellent properties in relation to the injection site.

Dosage forms may contain from about 0.5 mg to about 5 g of the combination of active ingredients. More typically, the amount of active ingredient(s) in the compositions of the present invention is from about 1 mg to about 3 g. In another embodiment, the amount of active ingredient(s) in the compositions is from about 20 mg to about 3 g. In another embodiment, the amount of active ingredient(s) present in the compositions is from about 20 mg to about 2 g, from about 20 mg to about 1.5 g, or from about 20 mg to about 1 g. In other embodiments, the amount of active ingredient

- 53 040232 stve (substances) in the compositions is from about 20 to about 500 mg, from about 30 to about 200 mg or from about 50 to about 200 mg. In another embodiment, the amount of active ingredient(s) present in the compositions is from about 50 mg to about 2 g, from about 50 mg to about 1 g, or from about 50 to about 500 mg. In another embodiment of the present invention, the amount of active ingredient(s) is from about 100 mg to about 2 g, from about 100 mg to about 1 g, or from about 100 to about 500 mg.

In another embodiment, the amount of active ingredient(s) is from about 1 to about 500 mg of active ingredient, from about 1 to about 100 mg, or from about 1 to about 25 mg. In other embodiments, the amount of active ingredient present in the composition is from about 10 to about 50 mg, or from about 10 to about 100 mg. In other embodiments, the amount of active ingredient present in the composition is from about 50 to about 200 mg, from about 100 to about 300 mg, from about 100 to about 400 mg, from about 200 to about 500 mg, from about 300 to about 600 mg, about 400 to about 800 mg, or about 500 to about 1000 mg.

Compositions of the present invention are prepared by mixing appropriate amounts of the active ingredients, a pharmaceutically acceptable polymer, a solvent and optionally an antioxidant, a pharmaceutically acceptable additive and/or an excipient, to form a preparation of the present invention. In some embodiments, the preparations of the present invention can be prepared according to the methods for preparing such forms described in sources well known in the art, for example, Remington - The Science and Practice of Pharmacy ( ^21st Edition) (2005), Goodman &Gilman's The Pharmacological Basis of Therapeutics ( ^11th Edition) (2005) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems ( ^8th Edition), edited by Allen et al., Lippincott Williams & Wilkins, (2005).

Methods of treatment.

In another aspect of the present invention, a method for preventing or treating a parasitic infection/infestation in an animal is described, comprising administering to the animal a sustained release injectable formulation comprising an effective amount of at least one isoxazoline compound, a pharmaceutically acceptable polymer, and a diluent. The formulations of the present invention have long-term efficacy against ectoparasites (eg, fleas and ticks), and in some embodiments where the compositions include an additional active ingredient, they may also have activity against endoparasites that infect animals.

In one embodiment, the present invention describes methods of treating or preventing a parasitic infection or infestation in companion animals, comprising administering to the animal a sustained release injectable formulation containing an effective amount of at least one isoxazoline active ingredient. Ectoparasites against which the methods and compositions of the present invention are effective include, but are not limited to, fleas, ticks, itchs, mosquitoes, flies, and lice. In some embodiments, where the formulations of the present invention include one or more additional active ingredients that are active against internal parasites, the described compositions and methods of the present invention may also have activity against endoparasites, including (but not limited to) cestodes, nematodes, hookworms and roundworms from the digestive tract of animals and humans.

In one embodiment of ectoparasite treatment, the ectoparasites are one or more insects or arachnids, including members of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodecte and Felicola.

In another embodiment of the treatment for ectoparasites, the ectoparasites belong to the genera Ctenocephalides, Rhipicephalus, Dermacentor and/or Ixodes. Treated ectoparasites include, but are not limited to, fleas, ticks, itchs, mosquitoes, flies, lice, blowflies, and combinations thereof. Particular examples include (but are not limited to) fleas of dogs and cats (species of the genus Ctenocephalides such as Ctenocephalides felis, Ctenocephalides canis, etc.), ticks (species of the genus Rhipicephalus, Ixodes, Dermacentor, Amblyomma, etc.) and itch (species of the genus Demodex, Sarcoptes, Otodectes, etc.), lice (species of the genus Trichodectes, Cheyletiella, Linognathus, etc.), mosquitoes (species of the genus Aedes, Culex, Anopheles, etc.) and flies (species of the genus Haematobia, including Haematobia irritans, species of the genus Musca, Stomoxys, including Stomoxys calcitrans, species of the genus Dermatobia, Cochliomyia, etc.).

Additional examples of ectoparasites include, but are not limited to, ticks of the genus Rhipicephalus, especially microplus (ringed tick), decoloratus, and annulatus species; myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochliomvia hominivorax (carrion green); sheep myases such as Lucilia sericata, Lucilia cuprina (known in Australia, New Zealand and South

- 54 040232

Africa as blowfly strike), true flies, namely those in which adults are parasitic, such as Haematobia irritans (small cow fly) and Stomoxys calcitrans (common fly); lice such as Linognathus vituli etc.; and pruritus such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art to be harmful and dangerous to animals and humans. They include, for example, the larvae of migrating Diptera.

In some embodiments, the composition may also be used to treat endoparasites such as helminths selected from the group consisting of Anaplocephala, Ancylostoma, Necator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostomum , Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Angiostrongylus and Trichostrongylus, among others.

In one embodiment, the present invention provides methods for treating and preventing parasitic infections and infestations in animals (wild or domestic), including farm and pet animals such as cats, dogs, horses, birds (including chickens), sheep, goats, pigs. , deer, turkeys and cattle, with the aim of ridding said host animals of parasites commonly found in such animals.

In one embodiment, the present invention describes methods and compositions for the treatment or prevention of parasitic infections and infestations in pets, including (but not limited to) cats and dogs. The disclosed methods and compositions are particularly effective in preventing or treating flea and tick parasitic infections in cats and dogs.

In another embodiment, the methods and compositions of the present invention are used to treat or prevent parasitic infections and infestations in cattle or sheep. In the treatment of farm animals such as cattle or sheep, the disclosed methods and compositions are particularly effective against Rhipicephalus (Boophilus) microplus, Haematobia irritans (small blood stinger), Stomoxys calcitrans (common stinger), and sheep myiasis such as Lucilia sericata, Lucilia cuprina (known in Australia, New Zealand and South Africa as blowfly strike).

The terms "treat" or "treat" are intended to mean administering the sustained release preparation of the present invention to an animal that is suffering from a parasitic infection in order to kill parasites or reduce the number of parasites infesting the treated animal. It should be noted that the compositions of the present invention can be used for prophylaxis similar to parasitic infestation.

The terms prevent, prevention or prophylaxis are intended to mean administering the sustained release formulation of the present invention to an animal before a parasitic infestation or infection occurs, so that said infestation or infection does not occur.

The formulations of the present invention are administered in parasiticide effective amounts suitable for reducing the population of particular parasites to the desired extent, as described below. In each aspect of the invention, the compounds and compositions of the present invention can be used against a single species of parasites or against combinations thereof.

By the term antiparasitic effective amount is meant an amount of a composition of the present invention sufficient to kill or reduce the number of parasites infecting an animal. In some embodiments, an effective amount of the active ingredient achieves at least 70% effectiveness (% reduction from control samples) against target parasites. In other embodiments, the implementation of the effective amount of the active substance achieves at least 80% or at least 90% effective against given parasites. Preferably, the effective amount of the active ingredient is at least 95%, at least 98% or 100% effective against the target parasites.

In general, a dosage of from about 0.001 mg to about 100 mg per kg of body weight, in a single dose or in several divided doses, over a period of 1 to 5 days will suffice, but of course there may be cases where higher or lower dosages, and such cases are also included in the scope of the present invention. One of skill in the art is skilled in determining the specific dosage regimen for each host and parasite.

In some embodiments, for pets, the dosage of the isoxazoline active ingredient administered from the sustained release injectable formulations of the present invention is from about 0.1 mg to about 50 mg per kg of body weight. More typically, the dosage of the isoxazoline active ingredient administered is from about 0.5 to about 40 mg/kg, or from about 0.5 to about 30 mg/kg of body weight. In another embodiment, the dosage of the isoxazoline active ingredient administered is about 10 to about 40 mg/kg, about 15 to about 35 mg/kg, or about 20 to about 30 mg/kg of body weight. In another embodiment, the dosage of the isoxazoline active ingredient is between

- 55 040232 about 20 to about 25 mg/kg of body weight.

In other embodiments, the dosage administered may be lower, depending on the animal and the isoxazoline administered. For example, if the composition contains the more active enantiomer of the isoxazoline compounds, a lower dosage may be administered. In some embodiments, the implementation of the dosage is from about 0.1 to about 30 mg/kg of body weight. In another embodiment, the dosage may be from about 0.1 to about 20 mg/kg, or from about 0.1 to about 10 mg/kg of body weight. In other embodiments, the dosage may be from about 1 to about 20 mg/kg of body weight, or from about 1 to about 10 mg/kg. In another embodiment, the dosage may be from about 5 to about 20 mg/kg, or from about 10 to about 20 mg/kg of body weight. In another embodiment, the dosage may be from about 10 to about 30 mg/kg of body weight.

In other embodiments, for the treatment of farm animals such as cattle or sheep, the dosage of the isoxazoline active ingredient administered may be from about 0.1 to about 40 mg/kg of body weight. More typically, the dosage administered is about 1 to about 30 mg/kg, about 1 to about 20 mg/kg, or about 1 to about 10 mg/kg of body weight. In another embodiment, the dosage may be from about 10 to about 25 mg/kg, from about 15 to about 30 mg/kg of body weight, or about 20-30 mg/kg of body weight.

In another embodiment, the sustained release formulations of the present invention provide an efficacy against fleas and/or ticks of at least 90% or greater for about 6 months or more. In another embodiment, the sustained release formulations of the present invention provide an efficacy against fleas and/or ticks of at least 95% or greater for about 6 months or more. In another embodiment, the sustained release formulations of the present invention provide an efficacy against fleas and/or ticks of at least 90% or greater for about 9 months or more. In another embodiment, the sustained release formulations of the present invention provide an efficacy against fleas and/or ticks of at least 90% or greater for about 12 months or more. In another embodiment, the sustained release formulations of the present invention provide flea and/or tick efficacy in cats and dogs of at least about 90% for 2 months or more. In another embodiment, the sustained release formulations of the present invention provide flea and/or tick efficacy in cats and dogs of at least about 95% for 3 months or more. In another embodiment, the compositions provide about 95% effectiveness for about 5 months or longer.

In another aspect of the present invention, a kit for treating or preventing parasitic infections in an animal is described, which comprises a sustained release formulation of the present invention and a syringe or dispenser.

Examples

The present invention is further described with reference to the following non-limiting examples, which further illustrate the invention and are not intended and should not be interpreted as limiting the scope of the present invention.

Examples of drugs.

The sustained release injectables listed below were prepared by mixing the ingredients. Unless otherwise indicated, the concentration of each component is expressed as a percentage (%) by weight (wt./wt.) and MW means the average molecular weight.

Example 1

A compound having the formula (Ps) 26%

PLGA with average mol. weight (MMW) (50:50) 1%

Propylene carbonate 50.9%

Triacetin 22.2%

VNT 0.02%.

Example 2

A compound having the formula (Ps) 26%

Low Molecular Weight (LMW) PLGA (50:50) 5%

Propylene carbonate 48.0%

Triacetin 21.0%

VNT 0.02%.

- 56 040232

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11.

A compound having the formula (Ps) 26% MMWPLGA (50:50) 5% propylene carbonate 48.0% Triacetin 21.0% vnt 0.02%. A compound having the formula (Ps) 20% MMWPLGA (50:50) 3% propylene carbonate 53.9% Triacetin 23.1% VNT 0.02%. A compound having the formula (Ps) 26% MMWPLGA (50:50) 3% propylene carbonate 49.7% Triacetin 21.3% VNT 0.02%. A compound having the formula (Ps) 20% LMWPLGA (50:50) 5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%. A compound having the formula (5)-PS 20% MMWPLGA (50:50) 5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%. A compound having the formula (S)-IIc 10% LMWPLGA (50:50) 5% propylene carbonate 59.5% Triacetin 25.5% VNT 0.02%. A compound having the formula (L')-Ps 10% LMWPLGA (50:50) 2.5% propylene carbonate 61.25% Triacetin 26.25% VNT 0.02%. A compound having the formula (Ps) 20% LMWPLGA (50:50) 7% propylene carbonate 51.1% Triacetin 21.9% VNT 0.02%. A compound having the formula (Ps) 20% MMWPLGA (50:50) 5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%.

- 57 040232

Example 12.

Example 13

A compound having the formula (Ps) 20%

High molecular weight (HMW) PLGA (75:25) 5%

Propylene carbonate 52.5%

Triacetin 22.5%

ΒΗΤ 0.02%.

A compound having the formula (Ps) 15%

HMW PLGA (75:25) 5%

Propylene carbonate 56%

Triacetin 24%

VNT 0.02%.

Example 14

A compound having the formula (Ps) 20%

LMW PLGA (50:50) 5%

Propylene carbonate 75%

VNT 0.02%.

Example 15

A compound having the formula (Ps) 20%

LMW PLGA (50:50) 5%

Propylene carbonate 73%

Paul oxamer 124 2%

VNT 0.02%.

Example 16

A compound having the formula (Ps) 20%

LMW PLGA (50:50) 5%

Propylene carbonate 55%

Paul oxamer 124 20%

VNT 0.02%.

Example 17.

A compound having the formula (Ps) 20%

HMW PLGA (50:50) 5%

Propylene carbonate 52.5%

Triacetin 22.5%

VNT 0.02%.

Example 18.

A compound having the formula (Ps) 20%

HMW PLGA (50:50) 5%

Propylene carbonate 51.1%

Triacetin 21.9%

Paul oxamer 124 2%

VNT 0.02%.

Example 19.

A compound having the formula (Ps) 12.5% HMW PLGA (75:25) 12.5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%.

Example 20.

Compound having the formula (5)-11c 12.5%

HMW PLGA (75:25) 12.5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%.

- 58 040232

Example 21. A compound having the formula (Ps) 12.5% HMW PLGA (75:25) 12.5% Propylene carbonate 52.5% Triacetin 22.5% BHT 0.02%. Example 22. A compound having the formula (Ps) 12.5% HMW PLGA (75:25) 20% Propylene carbonate 47.5% Triacetin 20.3% BHT 0.02%. Example 23. A compound having the formula (Ps) 12.5% HMW PLGA (75:25) 15% Propylene carbonate 50.7% Triacetin 21.8% BHT 0.02%. Example 24. A compound having the formula (Ps) 12.5% HMW PLGA (75:25) 12.5% Propylene carbonate 51.1% Triacetin 21.9% Poloxamer 124 2% BHT 0.02%. Example 25. A compound having the formula (Ps) 12.5% LMW PLGA (75:25) 12.5% Propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%. Example 26. A compound having the formula (Ps) 12.5% LMW PLGA (50:50) 12.5% Propylene carbonate 52.5% Triacetin 22.5%

ΒΗΤ 0.02%.

Examples of performance tests.

The following examples demonstrate the efficacy of the sustained release injectable compositions of the present invention against ectoparasites in domestic and farm animals.

Example 27.

A study was conducted to determine the plasma concentration of the isoxazoline compound (IIc) in dogs over time after a single subcutaneous injection of the sustained release preparations of the present invention. Accordingly, the sustained release preparations of Examples 1, 2, and 3 were administered to dogs at a dosage of 25 mg/kg on day 0. The plasma concentration of compound (IIc) was measured at regular intervals to determine if the concentration of this compound was sufficient to control fleas. . Compound (IIc) blood concentration strongly correlates with flea efficacy (see, for example, Letendre et al., Veterinary Parasitology, 201 (2014), 190-197). Thus, a concentration of about 20 ng/ml of compound (IIc) is known to be effective in controlling fleas in dogs (EC ₉₀ 23 ng/ml). In the present study, it was found that the concentration of compound (IIc) was above 20 ng/ml for at least 180 days after administration. Accordingly, the sustained release formulations of Examples 1, 2 and 3 can be expected to be highly effective in controlling fleas in dogs for at least 180 days.

Example 28.

In another experiment, the concentration of compound (IIc) in blood plasma was measured in dogs after one

- 59 040232 multiple subcutaneous injections of the sustained release preparations of Examples 4 and 5. The concentration of compound (Ps) was found to be above 20 ng/ml for at least 5 months (154 days) after administration. Thus, the sustained release formulations of Examples 4 and 5 can be expected to be highly effective in controlling fleas in dogs for at least 5 months.

Example 29.

In a separate experiment, the plasma concentration of the isoxazoline compound (Ps) was measured in dogs after a single subcutaneous injection of the sustained release formulations of Examples 4 and 5. Compound (Ps) was found to be above 20 ng/mL for at least 7 months (28 days) after administration.

Example 30. A compound having the formula (Ps) 26% PLGA (50:50) (MW ~52 kDa) 1% Propylene carbonate 22.16% Triacetin 50.8% VNT 0.02% Example 31. A compound having the formula (Ps) 26% PLGA (50:50) (MW ~9 kDa) 5% Propylene carbonate 20.95% Triacetin 48.03 VNT 0.02% Example 32. A compound having the formula (Ps) 26% PLGA (50:50) (MW ~52 kDa) 5% Propylene carbonate 20.95% Triacetin 48.03 VNT 0.02% Example 33. A compound having the formula (Ps) 20% PLGA (70:30) (MW -52 kDa) 3% Propylene carbonate 53.89% Triacetin 23.09% VNT 0.02% Example 34. A compound having the formula (Ps) 26% PLGA (70:30) (MW ~52 kDa) 3% Propylene carbonate 49.69% Triacetin 21.29% VNT 0.02% Example 35. A compound having the formula (Ps) 20% PLGA (50:50) (MW~9) 5% Propylene carbonate 52.5% Triacetin 22.5% VNT 0.02% Example 36. The compound having the formula (5)-PS 20% PLGA (50:50) (MW~9) 5% Propylene carbonate 52.5% Triacetin 22.5% VNT 0.02%

-60040232

Example 37.

Example 38.

Example 39.

Example 40.

Example 41.

Example 42.

Example 43.

Example 44.

Example 45.

A compound having the formula (S)-IIc 10% PLGA (50:50) (MW-9) 5% propylene carbonate 59.5% Triacetin 25.5% vnt 0.02% A compound having the formula (5)-PS 10% PLGA (50:50) (MW~9) 2.5% propylene carbonate 61.25% Triacetin 26.25% VNT 0.02% A compound having the formula (Ps) 20% PLGA (50:50) (MW - 9) 7% propylene carbonate 51.1% Triacetin 21.9% VNT 0.02% A compound having the formula (Ps) 20% PLGA (50:50) (MW-52) 5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02% A compound having the formula (Ps) 20% PLGA (75:25) (MW-111-115) 5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02% A compound having the formula (Ps) 15% PLGA (75:25) (MW-111-115) 5% propylene carbonate 56% Triacetin 24% VNT 0.02% A compound having the formula (Ps) 20% PLGA (50:50) (MW-9) 5% propylene carbonate 75% VNT 0.02% A compound having the formula (Ps) 20% PLGA (50:50) (MW-9) 5% propylene carbonate 73% Poloxamer 124 2% VNT 0.02% A compound having the formula (Ps) 20% PLGA (50:50) (MW-9) 5% propylene carbonate 55% Poloxamer 124 20% VNT 0.02%

- 61 040232

Example 46.

A compound having the formula (Ps) 12.5%

PLGA (75:25) (MW-111-115) 12.5%

Propylene carbonate 52.5%

Triacetin 22.5%

VNT 0.02%

Example 47.

A compound having the formula (Ps) 12.5%

PLGA (75:25) (MW-111-115) 20%

Propylene carbonate 47.7%

Triacetin 20.3%

VNT 0.02%

Example 48.

A compound having the formula (Ps) 12.5%

PLGA (75:25) (MW -111-115) 15%

Propylene carbonate 50.7%

Triacetin 21.8%

VNT 0.02%

Example 49.

A compound having the formula (Ps) 12.5%

PLGA (75:25) (MW-111-115) 12.5%

Propylene carbonate 51.1%

Triacetin 21.9%

Poloxamer 124 2%

VNT 0.02%

Example 50.

A compound having the formula (Ps) 12.5%

PLGA (75:25) (MW-9) 12.5%

Propylene carbonate 52.5%

Triacetin 22.5%

VNT 0.02%

Example 51.

A compound having the formula (Ps) 12.5%

PLGA (50:50) (MW-9) 12.5%

Propylene carbonate 52.5%

Triacetin 22.5%

VNT 0.02%

Example 52.

The compound having the formula (5)-PS 12.5%

PLGA (75:25) (MW-111-115) 12.5%

Propylene carbonate 52.5%

Triacetin 22.5%

VNT 0.02%

Example 53.

A compound having the formula (Ps)

PLGA (50:50) (MW-9)

propylene carbonate

Triacetin

VNT

12.5%

12.5%

52.5%

22.5%

0.02%

- 62 040232

Example 54.

Example 55.

Example 56.

Example 57.

Example 58.

Example 59.

Example 60.

Example 61.

A compound having the formula (S)-IIc 12.5% PLGA (50:50) (MW~9) 12.5% propylene carbonate 52.5% Triacetin 22.5% vnt 0.02% A compound having the formula (S)-IIc 12.5% PLGA (50:50) (MW~52) 12.5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02% A compound having the formula (S)-IIc 12.5% PLGA (50:50) (MW~111-115) 12.5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02% A compound having the formula (5)-PS 12.5% PLGA (50:50) (MW~9) 12.5% propylene carbonate 51.1% Triacetin 21.9% Poloxamer-124 2% VNT 0.02% A compound having the formula (5)-PS 12.5% PLGA (75:25) (MW~9) 15% propylene carbonate 50.7% Triacetin 21.8% VNT 0.02% A compound having the formula (5)-PS 12.5% PLGA (75:25) (MW~9) 12.5% propylene carbonate 52.5% Triacetin 22.5% VNT 0.02% A compound having the formula (5)-PS 12.5% PLGA (50:50) (MW 9) 12.5% propylene carbonate 63.7% Triacetin 11.3% VNT 0.02% A compound having the formula (5)-PS 12.5% PLGA (50:50) (MW~52) 12.5% propylene carbonate 51.1% Triacetin 21.9% Poloxamer-124 2% VNT 0.02%

-

Claims (21)

Example 62. A compound having the formula (Ps) 26% PLGA (50:50) (MW~52) 1% Propylene carbonate 50.82% Triacetin 22.2% BHT 0.02% Example 63. A compound having the formula (Ps) 26% PLGA (50:50) (MW 9) 5% Propylene carbonate 48.03% Triacetin 20.95% VNT 0.02% Example 64. A compound having the formula (Ps) 26% PLGA (50:50) (MW-52) 5% Propylene carbonate 48.03% Triacetin 20.95% Examples of efficiency. Example 65. The following example demonstrates the efficacy of the long acting injectable compositions of the present invention against ectoparasites in companion animals (dogs). Prepared compositions for the test groups described in the table. With the exception of dosage, all values in the table are expressed in % (w/w). Group Compound having formula (S)-IIc PLGA (75:25) (MW -9) ¹ PLGA (75:25) (MW -52) ¹ PC ² Triacetin P-124 ³ BHT Dose (mg/kg) 1 — — 12.5 61.21 26.27 — 0.02 - 2 12.5 — 12.5 51.05 21.92 2 0.02 12.5 3 12.5 — 12.5 52.46 22.52 — 0.02 12.5 4 12.5 — 15 49.31 21.17 2 0.02 12.5 5 12.5 15 — 50.71 21.77 — 0.02 12.5 1 6 1 12.5 - 12.5 51.06 21.92 2 0.02 6.25 ¹ Weight average molecular weight (kDa). ² Propylene carbonate. ³ Poloxamer 124. Thirty beagle dogs were tested to determine the efficacy of the sustained release injectable compositions of the present invention (compositions from test groups 2-6 described above) against fleas (Ctenocephalides felis) for at least 180 days after administration. Formed six test groups of five dogs each, each test group received one injection of the above drug sustained release (group 1 serves as control). All dogs were injected on day 0. Each animal was challenged with C. felis on days 6, 34, 69, and 111. Fleas were counted at removal on days 7, 35, 70, and 112. Fleas were also counted for groups 5 and 6 on day 190. The percentage reduction (also referred to as efficacy) in fleas was 100% for all test groups (i.e. groups 2-6) up to day 112. The percentage reduction in fleas on day 190 was 96.9% for group 5 and 100.0 % for group 6. Plasma concentration. Plasma concentrations of the isoxazoline compound having the formula (S)-IIc were determined by taking individual blood samples from each animal at specific time points after a single subcutaneous injection of the above sustained release formulations. It was found that the concentration of the compound having formula (S)-IIc was above 50 ng/ml 183 days after administration, indicating that the compositions of test groups 2-6 are effective against fleas and ticks. Despite the detailed description of the various embodiments of the present invention, it should be understood that the invention described above is not limited to the specific details given above in the description, since many variations thereof are possible without departing from the essence and scope of the present invention. CLAIM 1. The use of an isoxazoline compound of formula (IIa) for the manufacture of an injectable sustained release composition for the treatment or prevention of a parasitic infection, or - 64 040232 infection on an animal or in an animal body, where the composition contains: a) from 5 to 20% (w/w) of an isoxazoline compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R ² is independently halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl; R ⁴ represents H or C ₁ -C ₆ -alkyl; R ⁵ is C1-C4 alkyl optionally substituted with one or more R ⁷ ; R ⁷ is C2- _C7 alkylcarbonyl, _C2 - _C7 alkoxycarbonyl, _C2 - _C7 alkylaminocarbonyl, _C3 - _C9 dialkylaminocarbonyl, _C2 - _C7 haloalkylcarbonyl, _C2 - _C7 haloalkoxycarbonyl , C ₂ -C ₇ haloalkylaminocarbonyl, C ₃ -C ₉ dihaloalkylaminocarbonyl; and n is 0, 1, or 2; b) 1 to 30% (w/w) of a pharmaceutically acceptable polymer which is a copolymer of polylactides and polyglycolides having a lactide to glycolide ratio of 40:60 to 85:15 (w:w); And c) from 40 to 85% (w/w) of a solvent selected from cyclic carbonate, dimethyl isosorbide, poloxamer, glycerol ester, triglyceride, liquid polyethylene glycol and alcohol, or mixtures thereof, where the sum of all components in the composition is 100% (weight ./weight.). 2. The use of an isoxazoline compound of formula (IIc), (IId), (IIe) or (IIf) for the manufacture of an injectable sustained release composition for the treatment or prevention of a parasitic infection or infestation in or in an animal, wherein the composition contains: a) 5 to 20% (w/w) of an isoxazoline compound of formula (IIc), (IId), (IIe) or (IIf): - 65 040232 or a pharmaceutically acceptable salt thereof; b) 1-30% (w/w) of a pharmaceutically acceptable polymer which is a copolymer of polylactides and polyglycolides having a ratio of lactide to glycolide from 40:60 to 85:15 (wt:wt); And c) 40-85% (w/w) of a solvent selected from cyclic carbonate, dimethyl isosorbide, poloxamer, glycerol ester, triglyceride, liquid polyethylene glycol and alcohol, or mixtures thereof, where the sum of all components in the composition is 100% (wt. /weight.). 3. Use of an isoxazoline compound according to claim 1, wherein the compound is a compound of formula (IIc) or a pharmaceutically acceptable salt thereof. 4. The use of an isoxazoline compound according to claim 1, wherein the isoxazoline compound is - 66 040232 (5)-IIc or a pharmaceutically acceptable salt thereof. 5. Use of an isoxazoline compound according to claim 1 or 2, wherein the solvent is a cyclic carbonate. 6. Use of an isoxazoline compound according to claim 1 or 2, wherein the solvent is a solvent mixture containing a cyclic carbonate and a glycerol ester. 7. The use of an isoxazoline compound according to claim 6 wherein the ratio of cyclic carbonate to glycerol ester is from 1.5:1 to 15:1 (w/w). 8. The use of an isoxazoline compound according to any one of pi. 1-3, where the cyclic carbonate is propylene carbonate. 9. Use of an isoxazoline compound according to any one of claims 1 to 3, wherein the glycerol ester is triacetin. 10. Use of an isoxazoline compound according to any one of claims 1 to 3, wherein the solvent is a mixture containing propylene carbonate and triacetin. 11. Use of an isoxazoline compound according to claim 6, wherein the solvent mixture further comprises a poloxamer. 12. The use of an isoxazoline compound according to claim 11, wherein the mixture contains 0.5 to 20% (w/w) poloxamer. 13. The use of an isoxazoline compound according to claim 1 or 2, where the ratio of the copolymer of polylactides and polyglycolides to the isoxazoline compound having the formulas (Pa), (Ps), (IId), (He) or (IIf) is from 1.5: 1 to 1:1.5 (wt:wt). 14. The use of an isoxazoline compound according to claim 13, wherein the weight average molecular weight of the copolymer of polylactides and polyglycolides is between 5 and 20 kDa. 15. The use of an isoxazoline compound according to claim 1 or 2, wherein the composition further comprises an effective amount of a macrocyclic lactone. 16. The use of an isoxazoline compound according to claim 15 wherein the macrocyclic lactone is abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin, or nemadectin. 17. Use of an isoxazoline compound according to claim 1 or 2, wherein the composition treats or prevents flea or tick infestation for 3-12 months. 18. Use of an isoxazoline compound according to claim 1 or 2, wherein the composition treats or prevents flea or tick infestation for 5-6 months. 19. Use of an isoxazoline compound according to claim 1 or 2, wherein the composition treats or prevents flea or tick infestation for 6 months or more. 20. The use of an isoxazoline compound according to claim 1 or 2, wherein the composition is for the treatment or prevention of a parasitic infection or infestation in or in an animal, which is a dog, cat, sheep or cattle. 21. The use of an isoxazoline compound according to claim 1 or 2, wherein the composition is for the treatment or prevention of a parasitic infestation, which is a flea and/or tick infestation. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2