RU2799591C2 - Injectable isoxazoline pharmaceutical compositions and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to an injectable pharmaceutical composition containing particles of an isoxazoline compound of formula (I)

Formula (I)

where R¹ represents halogen; n is 2; R² represents CF₃; T represents a 6-membered ring which is optionally substituted with one or more Y radicals; Y represents methyl; Q represents X-NR³R⁴; X represents CO; R³ represents CH₂-C(O)NHCH₂CF₃; R⁴ represents either hydrogen or a salt thereof, and a pharmaceutically acceptable excipient, wherein the isoxazoline compound has a volume-weighted particle size distribution D50 measured by a static light scattering instrument, from 50 microns to 150 microns, where the isoxazoline compound is suspension in the composition, also refers to a method for treating or preventing infestation of an animal, comprising administering to an animal in need thereof an effective amount of an injectable pharmaceutical composition, also relates to a kit for treating or preventing infestation of an animal, wherein the kit comprises two or more containers of a) a solid crystalline isoxazoline compound; b) a carrier medium containing a pharmaceutically acceptable excipient capable of forming a suspension with compound a); and c) instructions for combining the solid crystalline isoxazoline compound with a vehicle prior to injection, wherein for the solid crystalline isoxazoline compound, the particle size D50 is 75 microns to 130 microns and the particle size D10 is 30 microns to 50 microns, and also applies to a method of treating or preventing infestation of an animal with parasites, comprising administering a kit to an animal requiring it.

EFFECT: group of inventions provides a composition that demonstrates the desired bioavailability and duration of action, while causing minimal irritation at the injection site.

23 cl, 7 ex, 9 tbl, 4 dwg

Description

Background of the invention

Isoxazoline compounds are known in the art, and these compounds and their use as antiparasitic agents are described, for example, in US patent application US 2007/0066617 and international patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809 , WO 2009/024541, WO 2009/003075, WO 2010/070068 and WO 2010/079077, the contents of which, as well as references cited in these documents, are incorporated by reference. This class of compounds is known to have excellent activity against ectoparasites, ie parasitic insects and acarids such as fleas and ticks.

Examples of isoxazoline compounds are carbamoylbenzamide phenylisoxazoline (CBPI) compounds. A specific example of a CBPI compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl )-methyl]-benzamide (CAS RN [864731-61-3]) - USAN fluralaner.

fluralaner

The CBPI compound fluralaner is described in patent application WO 2005/085216.

WO2015/048371 describes long acting injectable compositions containing spirocyclic isoxazoline compounds, one biopolymer and at least one carrier, solvent or excipient.

WO2016/138339 describes long acting injectable formulations containing at least one isoxazoline active agent, a poloxamer and a co-solvent. Formulations that are suspensions or particle size of isoxazoline are not described.

WO2016/164487 describes sustained release injectable veterinary formulations containing at least one isoxazoline active agent, a pharmaceutically acceptable polymer and a solvent for use against parasites. Formulations that are suspensions or isoxazoline particle size are not described.

US Pat. No. 9,609,869 describes insecticidal compounds based on isoxazoline derivatives for use in the control of agricultural, horticultural, animal and pet pests. Formulations for injection or administration to animals are not described.

US Patent Application Publication No. 2017/0239218 describes long acting injectable pest control compositions containing at least one isoxazoline active agent, liquid PEG and/or neutral oil. Formulations that are suspensions or particle size of isoxazoline are not described.

None of these references discloses a solution to the problem of identifying injectable isoxazoline compositions with long-term efficacy against parasites and a reduced risk of irritation at the injection site.

The essence of the invention

Thus, the present invention relates to injectable isoxazoline compositions with long-term effectiveness against parasites and a reduced risk of irritation at the injection site.

One embodiment of the invention is an injectable pharmaceutical composition containing particles of an isoxazoline compound of formula (I)

Формула (I),

Formula (I),

Where

R ¹ is halogen, CF ₃ , OCF ₃ or CN;

n is an integer from 0 to and including 3, preferably 1, 2 or 3:

m is 1 or 2;

R ² is C ₁ -C ₃ haloalkyl, CF ₃ or CF ₂ Cl;

T is a 5 or 6 membered ring or bicycle which is optionally substituted with one or more Y radicals;

Y is methyl, halomethyl, halogen, CN, NO ₂ , NH ₂ -C=S, or two neighboring Y radicals together form a chain;

Q is X-NR ³ R ⁴ , NR ⁵ -NR ⁶ -XR ³ , XR ³ or a 5-membered N-heteroaryl ring which is optionally substituted with one or more radicals;

X is CH ₂ , CH(CH ₃ ), CH(CN), CO, CS;

R ³ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methylamino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl , (N, N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,

Where

Z ^A is hydrogen, halogen, cyano or halomethyl (CF ₃ );

R ⁴ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

R ⁵ is H, alkyl or haloalkyl;

R ⁶ is H, alkyl or haloalkyl;

or where R ³ and R ⁴ together form a substituent selected from the group consisting of:

,

,

,

,

,

,

And

,

,

or a salt or N-oxide thereof and a pharmaceutically acceptable excipient, wherein the isoxazoline compound has a volume-weighted particle size distribution D50, as measured by a static light scattering instrument, of about 25 microns to about 250 microns.

A further embodiment is a method of treating or preventing infestation of an animal, comprising administering to an animal in need thereof an effective amount of the above injectable pharmaceutical composition.

Description of figures

Figure 1 - Mean plasma concentrations of fluralaner in dogs following subcutaneous administration of large particle fluralaner suspensions.

Figure 2 - Mean plasma concentrations of fluralaner to demonstrate the effects of irradiation and the absence of poloxamer.

Figure 3 - Mean plasma concentrations of fluralaner from injectable formulations with different particle size distributions.

Figure 4 - Mean plasma concentrations of fluralaner to determine the effect of different concentrations of NaCMC and poloxamer, as well as D50 of different particle sizes.

Detailed description

It has been found that the injectable compositions of the invention, containing particles of isoxazoline compounds with a certain particle size, demonstrate the desired bioavailability and duration of action, while causing minimal irritation at the injection site. The compositions also provide desirable safety profiles for warm-blooded animals and birds. In addition, it has been found that a single administration of such compositions usually provides strong activity against one or more parasites (for example, ectoparasites, for example, fleas, ixodid ticks or mites), while, as a rule, provides a rapid onset of activity, a long duration activities and/or desired security profiles.

The invention also relates to methods for treating or preventing parasitic infections and infestations in animals, comprising administering an effective amount of injectable compositions containing an antiparasitic effective amount of at least one isoxazoline compound with defined particle sizes, together with a pharmaceutically acceptable excipient. Surprisingly, it has been found that the isoxazoline-containing compositions of the invention described herein exhibit superior broad spectrum efficacy against harmful parasites (e.g., ectoparasites such as fleas and ticks) more rapidly and over a longer period of time than others. injectable compositions containing known isoxazoline active agents known in the art, showing minimal irritation at the injection site.

The pharmaceutical composition of the present invention may be administered by subcutaneous or intramuscular injection. Intravenous injection is also possible.

Definitions

Isoxazoline compounds are known in the art, and compounds of this class are known to have excellent activity against infestation by parasites such as ticks and fleas. Variants of various isoxazoline compounds of the present invention are presented below.

Injection site irritation is the damage produced at the injection site and surrounding tissue when an animal receives an injection of a pharmaceutical composition. Such lesions may include edema, discoloration of the skin, and tissue necrosis. Although some injection site irritation is unavoidable in some animals, injection site swelling greater than 2 x 2 cm that persists for more than two to three days is considered unacceptable by veterinarians and pet owners. Minimal injection site irritation means injection site irritation that is less than 2×2 cm and persists for less than two to three days. This standard is generally accepted by veterinarians and their clients for animals receiving injections such as rabies vaccine.

As used herein, particle size data are volume-weighted, measured using conventional particle measurement techniques well known to those skilled in the art, such as static light scattering (also known as laser diffraction), image analysis, or sieving. A more detailed discussion of methods for measuring particle size is given below.

A pharmaceutically acceptable excipient is an inert substance that forms a carrier or drug vehicle.

Parasitic "infestation" refers to the presence of parasites in quantities that pose a danger to humans or animals. They may be present in the environment, for example, in animal bedding, on the skin or fur of an animal, etc. When said infection occurs within the animal, for example, in the blood or other internal tissues, the term infection is also meant to be synonymous with the term infection. ”, as this term is usually understood in this area, unless otherwise indicated.

Suspension means the state of a substance when its particles are mixed with a liquid (liquid or gas) or solid, but not dissolved in them.

Diluent means a substance used to dilute a mixture, suspension or solution.

The carrier medium is a carrier or inert medium used as a solvent (or diluent) in which the drug is formulated and/or administered.

The pharmaceutical compositions of the invention are of particular value in the control of ectoparasites, ie arthropods that are harmful or spread or act as disease vectors in humans as well as in animals and domestic animals.

Important arthropod ectoparasites (insects and acarids) are described in more detail below.

Stinging insects include, for example, migratory Diptera larvae such as Hypoderma sp. in cattle, Gastrophilus in horses and Cuterebra sp. in rodents, as well as biting flies and mosquitoes of all kinds. For example, blood-sucking adult flies include, for example, the horn fly or Haematobia irritans , the horsefly or Tabanus spp., the autumn fly or Stomoxys calcitrans , the black aphid or Simulium spp., the deer fly or Chrysops spp., the bloodsucker or Melophagus ovinus , the tsetse fly or Glossina spp. Parasitic fly larvae include, for example, nasopharyngeal gadfly ( Oestrus ovis and Cuterebra spp.), blowfly or Phaenicia spp., blowfly larva or Cochliomyia hominivorax , bull botfly larva or Hypoderma spp. and wool worm. Mosquitoes include, for example, Culex spp., Anopheles spp. and Aedes spp.

Ticks include the blood-sucking bird mite, Dermanyssus gallinae ; scabies or horse mites or scabies ( Astigmata ) such as Sarcoptidae spp., eg Sarcoptes scabiei ; scabies, such as Psoroptidae spp., including Chorioptes bovis, Psoroptes ovis and Demodex canis; the ear mite Otodectes cynotis ; trombiculid mites, eg Trombiculidae spp., eg North American trombiculid mites, Trombicula alfreddugesi.

Ixodid ticks include, for example, soft-bodied ticks, including but not limited to Argasidae spp., eg Argas spp. and Ornithodoros spp.; hard-bodied mites including Ixodidae spp. e.g. Ixodes ricinus , Ixodes scapularis , Rhipicephalus sanguineus , Haemaphysalis spp, Dermacentor reticulatus , Dermacentor variabilis, Amblyomma americanum and Boophilus spp.

Lice include, for example, sucking lice, such as Menopon spp. and Bovicola spp.; biting lice, e.g. Haematopinus spp., Linognathus spp. and Solenopotes spp.

Fleas include, for example, Ctenocephalides spp., such as the dog flea ( Ctenocephalides canis ) and the cat flea ( Ctenocephalides felis ); Xenopsylla spp. such as the southern rat flea ( Xenopsylla cheopis ); and Pulex spp. such as the human flea ( Pulex irritans ).

True hemiptera bugs include, for example,Cimicidaeor, for example, a common bed bug (Cimex lectularius);Triatominaespp., including triatomine bugs, also known as kissing bugs; For example,Rhodnius prolixus AndTriatomaspp.

The compositions of the invention are valuable for treating and killing various stages of the life cycle of parasites, including egg, nymph and larval, juvenile and adult stages.

For the avoidance of doubt, references in this document to "treatment" as used herein include references to curative and palliative care, references to "ectoparasite control" include extermination, deterrence, banishment, render harmless, containment, elimination, alleviation, minimization, eradication of harmful organisms on animals and in the environment of animals.

"Controlling an ectoparasite infestation" means alleviating or reducing the number of parasites in and/or on an animal, and/or suppressing the development of a parasitic infestation in or on an animal, in whole or in part.

Prevention prevents the occurrence of a new or incoming infection or infection.

The suppressive effect or "effectiveness" of the compound means that the number of parasites is reduced after the first administration by an amount in the range from 5% to about 100%. Control of arthropods (eg, insects, acarids) can be insecticidal and/or acaricidal. The effect of the compounds of the invention may be, for example, ovicidal, larvicidal, nymphicidal, or an adult-only killing effect, or a combination thereof. The effect may be direct, i.e. killing the parasites either immediately or after some time, such as when molting occurs, or by destroying their eggs, or indirectly, such as reducing the number of eggs laid and/or the rate of hatching.

For in vivo administration of a compound of the invention, an effective amount is synonymous with a "pharmaceutically effective amount", which is a dose or amount that treats or ameliorates the symptoms and/or signs of a parasitic infection or infestation in a treated animal, or reduces the number of parasites in and/or on an animal. , and/or inhibits the development of a parasitic infestation in or on the animal, in whole or in part. This latter amount can also be readily determined by one of skill in the art, for example by observing or detecting changes in the clinical condition or behavior of treated animals, and by observing or detecting relative changes in parasite counts following such treatment.

Systemic administration of drugs means that the target (organ or parasite) is reached through the bloodstream.

Animal means mammals, including domestic animals. Pet means dog, cat or horse.

A reconstituted composition is one in which the carrier medium is in one container and the active ingredient is in another container, and both containers are combined at some point prior to administration.

The carrier medium contains some or all of the formulation auxiliaries such as diluent, wetting agent, antifoam agent, pH control agent, etc.

In one embodiment, the isoxazoline compounds for use in the invention also include pharmaceutically acceptable salts, esters and/or N-oxides. In addition, reference to an isoxazoline compound applies equally to any of its polymorphic forms or stereoisomers.

In one embodiment, a racemic mixture of isoxazoline for use according to the invention containing equal amounts of enantiomers of such an isoxazoline compound as described above can be used in a pharmaceutical composition according to the invention. Alternatively, isoxazoline compounds may be used in the pharmaceutical composition which contain enriched stereoisomers compared to the racemic mixture in one of the isoxazoline enantiomers as defined herein. Also, a substantially pure stereoisomer of such isoxazoline compounds can be used in the pharmaceutical composition. Such enriched or purified isoxazoline stereoisomeric preparations for use in the invention may be prepared by methods known in the art. Examples are chemical processes that use catalytic asymmetric synthesis or separation of diastereomeric salts (see, for example, WO 2009/063910 and JP 2011/051977, respectively).

In one embodiment, isoxazoline for use according to the invention T is selected from

where in T-1, T-3 and T-4 the Y radical is hydrogen, halogen, methyl, halomethyl, ethyl, or haloethyl.

In one embodiment, the isoxazoline for use in the invention, Q is selected from

where R ³ , R ⁴ , X and Z ^A have the meanings defined above, and

Z ^B =

Z ^D =

In one embodiment of the invention, the isoxazoline for use according to the invention is as shown in Table 1.

Table 1:

(R ¹ ) _n R ² R ³ R ⁴ T Y Q Z X 3-Cl, 5-Cl _CF3 CH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ OCH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - CO 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 - T-2 - Q-6 ^ZB -7 CO 3-Cl, 5-Cl _CF3 - - T-2 - Q-7 ^ZB -7 CO 3-Cl, 5-Cl _CF3 - - T-2 - Q-5 ^ZB -7 CO 3-Cl, 5-Cl _CF3 - - T-2 - Q-2 ^ZD -1 CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CC H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CN H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ CH ₃ T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ CH ₃ T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CH ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ SCH ₃ H T-21 - Q-1 - CO

Table 1 (continued):

(R ¹ ) _n R ² R ³ R ⁴ T Y Q Z X 3-Cl, 4-Cl, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH(CH ₃ ) ₂ H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)-cyclopropyl H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH ₂ CH ₃ H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 Cl Q-1 - CH ₂ 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CH ₃ H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (Z) H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (E) H T-1 CH ₃ Q-1 - CO

In one embodiment of the invention, the isoxazoline for use according to the invention is as shown in Table 2.

Table 2:

(R ¹ ) _n R ² R ³ R ⁴ T Y Q Z X 3-Cl, 5-Cl _CF3 CH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ OCH ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-CF ₃ , 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-2 - Q-1 - CO 3-Cl, 5-Cl _CF3 - T-2 - Q-6 ^ZB -7 3-Cl, 5-Cl _CF3 - - T-2 - Q-7 ^ZB -7 3-Cl, 5-Cl _CF3 - - T-2 - Q-5 ^ZB -7 3-Cl, 5-Cl _CF3 - - T-2 - Q-2 ^ZD -1 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CC H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CN H T-3 CH ₃ Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 4-F, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-3 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ CH ₃ T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-20 - Q-1 - CO 3- _CF3 , 5- _{CF3 CF3} CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-21 - Q-1 - CO 3-Cl, 5-Cl _CF3 CH ₂ CH ₂ SCH ₃ H T-21 - Q-1 - CO 3-Cl, 4-Cl, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH(CH ₃ ) ₂ H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)-cyclopropyl H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 F Q-1 - CH ₂ 3-Cl, 4-Cl, 5-Cl _CF3 C(O)CH ₂ CH ₃ H T-22 F Q-1 - CH ₂ 3-Cl, 4-F, 5-Cl _CF3 C(O) _CH3 H T-22 Cl Q-1 - CH ₂ 3-Cl, 5-Cl _CF3 CH ₂ C(O)NHCH ₂ CF ₃ H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (Z) H T-1 CH ₃ Q-1 - CO 3-Cl, 5-Cl _CF3 R ³ -1 (E) H T-1 CH ₃ Q-1 - CO

In one embodiment of the invention, isoxazoline for use according to the invention is a compound:

where R ^1a , R ^1b , R ^1c independently of each other represent: hydrogen, Cl or CF ₃ .

Preferably R ^1a and R ^1c are Cl or CF ₃ and R ^1b is hydrogen,

T represents

where Y represents methyl, bromine, Cl, F, CN or C(S)NH ₂ ; n=1 or 2; and Q is as described above.

In one embodiment of isoxazoline as defined herein, R ³ is H and R ⁴ is: -CH ₂ -C(O)-NH-CH ₂ -CF ₃ , -CH ₂ -C(O)-NH-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -CF ₃ or -CH ₂ -CF ₃ .

In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is one or more selected from the group consisting of fluralaner, afoxolaner, lotilaner, or sarolaner.

In one embodiment, the compound of formula (I) is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[(2,2 ,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3 - USAN fluralaner).

In another embodiment, the compound of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2 -oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN - afoxolaner), which was described in WO2007/079162-.

In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is a lotilaner (CAS RN: 1369852-71-0; 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5 -[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide).

In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is sarolaner (CAS RN: 1398609-39-6; 1-(5'-(( 5S )-5-(3,5-dichloro-4-fluorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'-H-spiro(azetidine-3,1'-(2)benzofuran)-1-yl)-2-(methylsulfonyl)ethanone).

In another embodiment, the compound of formula (I) is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl ]-2-methylbenzamide (CAS RN 928789-76-8).

In another embodiment, the compound of formula (I) is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3- yl)benzamide (CAS RN 1164267-94-0), which was described in WO2009/0080250.

In another embodiment, the compound of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2 -oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN - afoxolaner), which was described in WO2007/079162.

In another embodiment, the compound of formula (I) is 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2- oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN 1231754-09-8), which was described in WO2010/070068.

Long acting injectable compositions of the invention include pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, surfactants, antioxidants, preservatives, pH stabilizing agents (eg buffers), and other inactive excipients. In another embodiment, the compositions of the invention may contain from about 0.01% to about 20% (w/v) of pharmaceutically acceptable excipients. In other embodiments, the compositions may contain from about 0.01% to about 5% (w/v), from about 0.1% to about 10% (w/v), or from about 0.1% to about 5% (w/v) pharmaceutically acceptable excipients. In other embodiments, the compositions may contain from about 5% to about 15% (w/v) or from about 5% to about 10% (w/v) of pharmaceutically acceptable excipients. In yet another embodiment, the compositions may contain from about 7% to about 10% pharmaceutically acceptable excipients.

Surfactants may be present in the compositions of the 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%. up to about 10% (w/w). More typically, surfactants may be present at 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 the compositions include, but are not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitol monooleate (Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, D-α-tocopherol 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 glycerinaprylate/caprate (CAPMUL® MCM), 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). include macrogol stearates, polyoxyl stearates, polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters of mixed polyoxyethylene polymers. polyethylene glycols One of the polyethylene glycol hydroxystearates that can be used in the compositions is polyethylene glycol 12-hydroxystearate. In another embodiment, the compositions of the invention may include the surfactant 12-hydroxy polyethylene glycol 15 stearate (Kolliphor® HS 15 from BASF), a mixture of mono- and diesters of 12-hydroxystearic acid with 15 moles of ethylene oxide. Again, these compounds, as well as their amounts, are well known in the art. In another embodiment, the compositions of the invention may include polyoxyl 35 castor oil (Kolliphor® EL) as a surfactant. In other embodiments, the compositions of the invention may include polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) or polyoxyl 60 hydrogenated castor oil as surfactants. Compositions of the invention may also include a combination of surfactants.

The compositions of the invention may contain other inert ingredients such as antioxidants, preservatives or pH stabilizers. These compounds are well known in the art of composition. Antioxidants such as vitamin E, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulphate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol, tert-butyl hydroquinone (TBHQ), benzyl alcohol, and the like. Antioxidants are typically included in compositions of the invention in an amount of from about 0.01% to about 3%, or from about 0.01 to about 2% (w/v), based on the total weight of the composition (w/w). In another embodiment, the compositions contain from about 0.05 to about 1.0% (w/w) of one or a mixture of antioxidants.

Preservatives such as benzyl alcohol are suitably used in the composition in amounts of from about 0.01% to about 10.0%, with about 0.05% to about 5.0% being particularly preferred. Other preservatives include parabens (methylparaben and/or propylparaben), benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurol, phenolphenyloxybenzyl, phenolphenyloxybenzene, phenolphenyloxybenzene phenylmercury acetate, phenylmercury borate , phenylmercury nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Preferred ranges for these compounds include from about 0.01% to about 5%.

Compounds that stabilize the pH of the composition may also be present. Again, such compounds are well known to the person skilled in the art, and it is also known how to use these compounds. 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, especially sodium phosphate or sodium citrate.

Oily suspensions (non-aqueous suspensions) can be prepared by suspending the isoxazoline compound in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin or other pharmaceutically acceptable oils. Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. These compositions may be stabilized by the addition of an antioxidant such as ascorbic acid or other known preservatives.

In yet another embodiment, the oily suspension injectable compositions of the invention include water-immiscible co-solvents. Non-limiting examples of these cosolvents include benzyl benzoate, ethyl acetate, triacetin, lipids, triglycerides, including medium chain triglycerides such as C8-C10 triglycerides such as capric/caprylic acid triglycerides, propylene glycol derivatives (e.g. propylene glycol monolaurate), caprylocaproylpolyoxyl-8 glycerides (labrazol) (a non-ionic water-dispersible surfactant), isopropyl myristate, or a mixture of at least two of these co-solvents.

In another embodiment, the non-aqueous injectable composition of the invention may include neutral oils as a co-solvent. Neutral oils are triglycerides of fractionated vegetable fatty acids with a chain length of C8 to C10. The two commercially available products are known as MIGLYOL® 810 and MIGLYOL® 812. In another embodiment, the neutral oil is a C8 and C10 chain length fractionated vegetable fatty acid triglyceride in combination with linoleic acid (about 4-5%). The commercially available product is known as MIGLYOL® 818. In yet another embodiment, the neutral oil is an ester of C8 and C10 fractionated vegetable fatty acids glycerol in combination with succinic acid. The commercially available product is known as MIGLYOL® 829. In another embodiment, the neutral oil may be a propylene glycol diester of C8 and C10 chain length saturated vegetable fatty acids. The commercially available product is known as MIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In another embodiment, the co-solvent may be a mixture of two or more neutral oils.

Aqueous suspensions may contain the isoxazoline compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents include natural phosphatide, such as lecithin, or condensates of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensates of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensates of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate or ethylene oxide condensates with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavors, and one or more sweeteners and/or bitters, such as those set forth above.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water may provide the isoxazoline compound when admixed with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

In one embodiment, the isoxazoline compound is suspended in an aqueous suspension wherein the liquid phase (diluent) is water.

In another embodiment, the liquid phase (diluent) of the aqueous suspension comprises water and a co-solvent.

The co-solvents which may be used in the injectable compositions of the invention containing the isoxazoline compound may be individual or may be a mixture of co-solvents.

In one embodiment, the co-solvents used in the aqueous injectable compositions of the present invention include polar solvents that are miscible with water. Non-limiting examples of these cosolvents include ethanol, isopropanol, benzyl alcohol, glycol ethers (for example, including but not limited to diethylene glycol monoethyl ether (for example, including but not limited to diethylene glycol monoethyl ether (DGME, Transcutol®, butyldiglycol, n dipropylene glycol -butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether and the like), liquid polyethylene glycols (PEG) (e.g. PEG 400), propylene glycol, carbonates (e.g. propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide, dimethyl sulfoxide, glycerol formal, or a mixture of at least two of these solvents.

In one embodiment, the compositions of the invention contain a polar protic solvent, including, but not limited to, an alcohol such as ethanol, isopropanol, or glycol, or a glycol ether. In another embodiment, the long acting injectable compositions of the invention comprise a polar aprotic solvent such as N-methyl pyrrolidone, dimethyl isosorbide, dimethylacetamide, dimethyl sulfoxide, or propylene carbonate.

In one embodiment, the isoxazoline compounds may exist in various isomeric forms. Reference to an isoxazoline compound always includes all possible isomeric forms of such a compound. Unless otherwise indicated, a compound structure that does not indicate a particular conformation is intended to cover compositions of all possible conformational isomers of the compound, as well as compositions containing the fewest possible conformational isomers. In some embodiments of the invention, the compound is a chiral compound. In some embodiments of the invention, the compound is a non-chiral compound.

In one embodiment of the invention, the isoxazoline compounds of formula (I) can be prepared according to one or the other method described, for example, in US patent applications 2007/0066617, WO 2007/079162, WO 2009/002809, WO 2009/080250, WO 2010/070068, WO 2010/079077, 2011/075591 and WO 2011/124998, or by any other means within the competence of a person skilled in the art who is an expert in the field of chemical synthesis. For the chemical preparation of the products according to the invention, it is considered that the person skilled in the art has at his disposal, inter alia, the entire contents of the "Chemical Abstracts" and the documents cited therein.

In one embodiment of the invention, the isoxazoline compound in the composition is in suspension. In one embodiment, the suspension is aqueous. Alternatively, the suspension is non-aqueous.

In one embodiment of the invention, the pharmaceutical composition is substantially free of organic solvents.

In one embodiment of the invention, the pharmaceutical composition contains a surfactant/wetting agent. In another embodiment, the surfactant/wetting agent is a poloxamer. Alternatives to poloxamer are other water-soluble/miscible non-ionic surfactants, including sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (polysorbates/tweens), polyoxyethylene castor oil derivatives (cremophors), polyoxyethylene stearates, lecithin, and TPGS ( D-α-tocopheryl polyethylene glycol 1000 succinate). Surfactant/wetting agent is present in the composition in an amount of from about 0.01% wt./about. up to about 0.5% wt./about. or about 0.05% wt./about. up to about 0.1% wt./about.

Poloxamers are non-ionic triblock copolymers consisting of a central hydrophobic polyoxypropylene (poly(propylene oxide)) chain flanked by two hydrophilic polyoxyethylene (poly(ethylene oxide))) chains (see US Pat. No. 3,740,421).

Poloxamer 124 is poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), number 9003-11-6 . Also known as lutrol L44 or Kollisolv P124.

Lutrol F68 is another poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), also known as poloxamer 188 or Kolliphor P188.

Lecithins are mixtures of glycerophospholipids including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid.

In one embodiment of the invention, the pharmaceutical composition contains a suspending agent. In one embodiment of the invention, the suspending agent is sodium carboxymethyl cellulose (NaCMC). In an alternative embodiment of the invention, the suspending agent is methylcellulose or polyvinylpyrrolidone.

In one embodiment of the invention, the pharmaceutical composition contains an antifoam agent. In one embodiment of the invention, the antifoam agent is simethicone. Simethicone is a mixture of α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilylene)] with silicon dioxide.

In one embodiment of the invention, the pharmaceutical composition contains a preservative. In one embodiment of the invention, the preservative is benzyl alcohol. In an alternative embodiment of the invention, the preservative is m-cresol, benzalkonium chloride, methylparaben, or propylparaben.

Injectable pharmaceutical compositions can be prepared by combining and mixing the solid components and then suspending the solid mixture in a diluent.

A method for producing an injectable pharmaceutical composition, including combining particles of isoxazoline with a wetting agent and a diluent.

In one embodiment of the invention, the pharmaceutical composition is a reconstituted solid that is reconstituted with a diluent prior to injection.

In one embodiment of the invention, the diluent is water. In an alternative embodiment of the invention, the diluent is an oil or a solvent with little or no solvent of the isoxazoline compound.

The pharmaceutical composition additionally contains a surfactant/wetting agent. Specific surfactants/wetting agents and surfactant/wetting agent alternatives are discussed throughout this specification and in the examples.

The pharmaceutical composition further comprises additional excipients such as a suspending agent, an antifoaming agent or a preservative. Specific examples of suitable excipients and alternative agents are discussed herein below and in the examples.

Particle size of isoxazoline compounds and measurement

It has been found that the injectable compositions according to the invention, containing particles of isoxazoline compounds with a fixed particle size, have particularly useful properties.

In one embodiment, the isoxazoline compound has a D50 particle size distribution, measured with a static light scatterer, from about 25 microns to about 250 microns, a particle size from about 11 microns to about 250 microns, a particle size from about 50 microns to about 150 micron, particle size from about 75 microns to about 130 microns, particle size from about 90 microns to about 110 microns, particle size from about 30 microns to about 100 microns.

Particle size distribution describes the relative amount of particles present according to size. D10 denotes the particle size distribution, which expresses a size that is less than 10% of the particles. D50 denotes a particle size distribution which expresses a size that is less than 50% of the particles. D90 denotes a particle size distribution which expresses a size that is less than 90% of the particles.

In a particular embodiment, the particle size D10 is about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, or about 80 µm.

In a specific embodiment, the particle size D50 is about 50 µm, about 75 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, or about 150 µm.

In a particular embodiment, the particle size D90 is about 100 µm, about 130 µm, about 150 µm, about 175 µm, about 200 µm, or about 250 µm.

In a particular embodiment, the particle size D10 is from about 20 to 35 microns, the particle size D50 is from about 90 to 105 microns, and the particle size D90 is from about 155 to 175 microns.

In a particular embodiment, the particle size D10 is about 25 to 30 microns, the particle size D50 is about 95 to 100 microns, and the particle size D90 is about 160 to 170 microns.

In a particular embodiment, the particle size D10 is about 10 to 20 microns, the particle size D50 is about 85 to 110 microns, and the particle size D90 is about 170 to 185 microns.

In a particular embodiment, the particle size D10 is about 10 to 15 microns, the particle size D50 is about 95 to 105 microns, and the particle size D90 is about 175 to 180 microns.

In a particular embodiment, the particle size D10 is about 10 to 25 microns, the particle size D50 is about 40 to 60 microns, and the particle size D90 is about 95 to 100 microns.

In a particular embodiment, the particle size D10 is about 15 to 20 microns, the particle size D50 is about 45 to 55 microns, and the particle size D90 is about 90 to 95 microns.

In a specific embodiment of the invention, the particle size D10 is from about 30 to 50 microns and the particle size D50 is from about 70 to 130 microns.

In a specific embodiment of the invention, the particle size D10 is from about 35 to 45 microns and the particle size D50 is from about 90 to 110 microns.

In a specific embodiment of the invention, the particle size D10 is about 40 microns and the particle size D50 is about 100 microns.

Volume-weighted particle size can be measured by sieving, microscopy or laser diffraction (Malvern or Sympatec). Volume-weighted particle size measurement can be performed with the Malvern Mastersizer 2000 with Hydro 2000G measuring cell or with the Horiba LA-910 Laser Diffraction Particle Size Distribution Analyzer. The volume-weighted particle size can be measured with the Sympatec Helos instrument.

When used according to the invention, the isoxazoline compound is present in the pharmaceutical composition in accordance with the invention in an amount in the range between about 0.1 and about 50% wt./about. final pharmaceutical composition according to the invention. Isoxazoline is present in an amount ranging between about 10% and about 45% w/v; between about 20 and about 45% w/v; between about 15 and 35% wt./about., or between about 25% wt./about. and about 35% wt./about., or between about 1% wt./about. and about 12% wt./about., or between about 3% wt./about. and about 9% wt./about. pharmaceutical composition according to the invention.

In one embodiment, the amount of isoxazoline compounds in the pharmaceutical composition in accordance with the invention is about 30% wt./about. pharmaceutical composition according to the invention. In one embodiment, the amount of isoxazoline compounds in the pharmaceutical composition in accordance with the invention is about 7.5% wt./about. pharmaceutical composition according to the invention.

In one embodiment of the invention, the pharmaceutical composition is a ready-to-use composition. That is, it is a composition suitable for injection. In another embodiment, the pharmaceutical composition must be reconstituted prior to injection. For example, the pharmaceutical composition is reconstituted in water prior to injection.

In one embodiment, the pharmaceutical composition is administered in combination with an additional therapeutic agent. The introduction of additional therapeutic agent can be carried out in the same composition or separate compositions. The additional therapeutic agent may be a parasiticide or a vaccine.

In another embodiment, the additional therapeutic agent is another parasiticide. In one embodiment, the parasiticide is a macrocyclic lactone. In one embodiment, the macrocyclic lactone is moxidectin or milbemycin.

Other active ingredients are selected from the group consisting of isoxazoline compounds, avermectins (eg, ivermectin, selamectin, doramectin, abamectin and eprinomectin); milbemycins (moxidectin and milbemycin oxime); probenzimidazoles (eg febantel, netobimine and thiophanate); benzimidazole derivatives such as thiazole, benzimidazole derivatives (eg thiabendazole and cambendazole), benzimidazole carbamate derivatives (eg fenbendazole, albendazole (oxide), mebendazole, oxfendazole, parbendazole, oxibendazole, flubendazole and triclabendazole); imidazothiazoles (eg levamisole and tetramizole); tetrahydropyrimidine (morantel and pyrantel), salicylanilides (eg closantel, oxyclozanide, rafoxanide and niclosamide); nitrophenolic compounds (eg nitroxynil and nitroscanate); benzene disulfonamides (eg clorsulon); pyrazinoisoquinolines (eg praziquantel and epsiprantel); heterocyclic compounds (eg piperazine, diethylcarbamazine and phenothiazine); dichlorphen, arsenic compounds (eg thiacetarsamide, melorsamine and arsenamide); cyclooctadepsipeptides (eg, emodepsid); paraherquamids (eg, derquantel); and aminoacetonitrile compounds (eg monepantel, AAD 1566); amidine compounds (eg, amidantel and tribendimidine), including all pharmaceutically acceptable forms such as salts, solvates or N-oxides. In one embodiment of the invention, moxidectin is present in an amount ranging from about 0.1% w/v. up to about 1.0% wt./about.

An embodiment of the invention is a method of treating or preventing an infestation of an animal, comprising administering to an animal in need thereof an effective amount of the injectable pharmaceutical compositions described above.

In one embodiment, the animal experiences minimal irritation at the injection site. As noted above, minimal injection site irritation means injection site irritation that is less than 2×2 cm and persists for less than two to three days.

In one embodiment, the animal is a pet.

In one embodiment, the pet is a dog or cat.

The optimal amount to be used for best results will, of course, depend on the particular isoxazoline compound used, the species of animal to be treated, the route and composition of administration, and the type and severity of the parasitic infection or infestation. In general, good results are obtained with the isoxazoline compounds of formula (I) when administered from about 0.01 to 200 mg/kg of animal body weight, in one embodiment, from 0.1 to 100 mg per kg of animal body weight, or 0, 5 to 50 mg per kg of body weight of the animal, or from 1 to 30 mg per kg of body weight of the animal, such a total dose is administered at a time or in divided doses.

Those skilled in the art will appreciate that the methods of the present invention may be used in the treatment of diseases and disorders known to be associated with the presence of arthropods, parasites, including, for example, those listed above. Such diseases (parasitosis), for example, result from a severe infestation with a parasite, such as infection of dogs with a large number of ixodid ticks in regions where exposure to ixodid ticks is of such a nature, which leads to significant pathogenic consequences for the animal.

As used herein, the terms "administer" or "administration" refers to the delivery of a compound of formula (I), a salt, solvate or prodrug thereof, or a pharmaceutical composition containing a compound of formula (I), a salt, solvate or prodrug, to an animal for the purpose of controlling with parasitic infection of animals or on animals.

Administration of the compounds of the invention may be intermittent and may be daily, weekly, biweekly, monthly, bimonthly, quarterly, semi-annual, yearly, or even less frequently. The period of time between treatments depends on such factors as the parasites being treated, the degree of infestation, the type of animal, mammal or bird, and the environment in which they are found.

Injectable pharmaceutical compositions may be administered daily, weekly, monthly, semiannually, or annually. Injectable pharmaceutical compositions can be administered every month, every two months, every three months, every four months, every five months, every 6 months, every seven months, eight months, every nine months, every ten months, every eleven months, every twelve months , every 13 months, every 14 months, every 15 months, every 16 months, every 17 months, or every 18 months.

In one embodiment, the injectable isoxazoline pharmaceutical composition is administered with a separate injectable parasiticide composition. In one embodiment, the introduction is simultaneous or sequential.

In one embodiment of the injectable pharmaceutical composition, the particle size D50 of the isoxazole compound is from about 75 microns to about 130 microns, and the particle size D10 is from about 30 microns to about 50 microns.

An embodiment of the invention is a kit for treating or preventing infestation of an animal, wherein the kit contains

two or more containers

a) a solid crystalline isoxazoline compound;

b) a carrier medium containing a pharmaceutically acceptable excipient capable of forming a suspension with compound a); And

c) instructions for combining the solid crystalline isoxazoline compound with the vehicle prior to injection,

where for solid crystalline isoxazoline compound D50 volume-weighted particle size is from about 75 microns to about 130 microns and D10 particle size is from about 30 microns to about 50 microns.

In another embodiment, the isoxazoline compound is fluralaner.

Another embodiment of the invention is a method of treating or preventing infestation of an animal, comprising administering to an animal in need thereof the above kit.

In a further embodiment of the invention, the injectable pharmaceutical composition is reconstituted in a carrier medium.

In a further embodiment, the carrier medium contains a diluent and optionally contains a wetting agent, an antifoam agent, a pH control agent, and/or a suspending agent.

EXAMPLES

Example 1 Fluralaner Ready-to-Use Injectable Suspension

Table 3

Example Composition % w/v (norm) API Size (Volume Weighted Particle Size) 1AA 7.5% fluralaner, 0.25% NaCMC,
0.1% lutrol, 2% benzyl alcohol, 0.2 simethicone, 0.7% sodium phosphate, HCl, qs H ₂ O Micronized (approx. 5 µm) 1A 7.5% fluralaner (afi), 0.25% NaCMC (suspending agent), 0.1% lutrol L-44 (wetting agent), 2% benzyl alcohol (preservative), 0.2% simethicone (antifoaming agent), 0.7% Na phosphate, HCl, H ₂ O 10 µm (non-micronized) 1B 7.5% fluralaner (afi), 0.25% NaCMC (suspending agent), 0.1% lutrol, 2% benzyl alcohol, 0.7% Na phosphate, HCl, H ₂ O 10 µm (non-micronized) 1C 7.5% fluralaner (afi), 0.25% NaCMC (suspending agent), 0.1% lutrol, 2% benzyl alcohol, 0.7% Na phosphate, HCl, H ₂ O 10 µm (non-micronized) 1D 7.5% fluralaner (afi), 0.25% NaCMC (suspending agent), 0.1% lutrol, 2% benzyl alcohol, 0.7% Na phosphate, HCl, H ₂ O 40 µm(non-micronized) 1E 7.5% fluralaner (afi), 0.5% NaCMC (suspending agent), 0.1% lutrol, 2% benzyl alcohol, 0.2% simethicone (antifoaming agent), 1.5% Na citrate, HCl, H ₂ O 10 µm (non-micronized) 1F 7.5% fluralaner (afi), 0.5% NaCMC (suspending agent), 1% lecithin (wetting agent), 2% benzyl alcohol, 0.2% simethicone (antifoaming agent), 1.5% Na citrate, HCl , _H2O 10 µm (non-micronized) 1G 7.5% fluralaner (afi), 0.5% NaCMC (suspending agent), 0.1% lutrol, 2% BA, 1.5% Na citrate, HCl, H ₂ O 10 µm (non-micronized) 1H 7.5% fluralaner (afi), 0.5% NaCMC (suspending agent), 1% lecithin, 2% BA, 1.5% Na citrate, HCl, H ₂ O 10 µm (non-micronized) 1I 7.5% fluralaner (afi), 0.5% NaCMC (suspending agent), 0.1% lutrol, 2% benzyl alcohol, 0.2% simethicone (antifoaming agent), 0.7% Na phosphate, HCl, H ₂ O 30 µm(non-micronized) 1J 7.5% fluralaner (afi), 2.5% NaCMC (suspending agent), 0.1% lutrol (surfactant/wetting agent), 1.5% benzyl alcohol, 0.05% simethicone (antifoaming agent) , _H2O 100 µm(non-micronized) Placebo 7.5% Flur (micronized), 0.25% NaCMC,
0.1% lutrol, 2% benzyl alcohol, 0.2 simethicone, 0.7% sodium phosphate, HCl, qs H2O No fluralaner

To obtain the composition of example 1A, the following procedure was used

1. Loading ~80% of the total volume of water for injection.

2. The suspending agent (sodium carboxymethyl cellulose (NaCMC)) was added and mixed in the overhead mixer for ~5 minutes.

3. The mixture was further mixed with a homogenizer until no agglomerates

4. Wetting agent (poloxamer 124) was added and mixed in the overhead mixer until smooth.

5. Preservative (benzyl alcohol (BA)) was added and mixed in the overhead mixer until smooth.

6. Sodium phosphate was added and mixed in the overhead mixer until smooth.

7. Added fluralaner and mixed with homogenizer until no agglomerates.

8. Gently mix the antifoam (simethicone) with an overhead mixer until smooth (5 minutes).

9. The pH of the mixture was adjusted to pH 7.0-7.4 by adding HCl. Mix gently with an overhead mixer until smooth (5 minutes).

10. Water QS was added to the final mass for injection and then gently mixed with an overhead mixer until smooth (5 minutes).

11. The resulting composition was packaged in injection vials and sealed with a cork.

12. The vials were autoclaved for 15 minutes at 121°C.

Similar methods were used to obtain the compositions of examples 1AA, 1B-1J and placebo. Batch sizes ranged from 50 ml to 1000 ml. The volume-weighted particle size of the fluralaner crystals (API) was measured using static light scattering (laser diffraction) (Sympatec Helos) to determine the particle size distribution.

Example 2 - Evaluation of reaction at the injection site

The injection sites were checked before starting treatment on the day of treatment, 30 minutes after administration, one day after administration, and then at intervals of 2-3 days to three weeks after administration. If the dog showed an injection site reaction at the time of evaluation, the Study Director could decide on additional evaluation time points. If a dog showed an injection site reaction at the last scheduled evaluation times, additional evaluations were performed on a separate dog at 2-3 day intervals until the reactions resolved.

The insertion sites were first examined for swelling, erythema, or other findings. Regardless of whether results were observed, the insertion sites were gently palpated for swelling, pain, and fever. The following scoring system was used:

Erythema, fever and pain:

o 0=no reaction,

o 1=weak reaction,

o 2=moderate reaction,

o 3=strong reaction.

Edema:

o size (measured with graduated equipment): length×width×height

o consistency: hard/soft

o moves freely: yes/no

o connection with the surrounding tissue: discrete / diffuse

Other observations at injection sites (eg, crusts, wounds, scratches) were recorded in descriptive terms.

Each study group consisted of 6-10 dogs. The placebo group did not receive fluralaner. The data below presents the number of dogs with irritation at the injection site, a description of the size of the irritation in cm, and the duration of the irritation.

Table 4 Irritation at the injection site

Example Day 0-2 Day 3-5 Day 7-9 Day 12-14 Day 18-19 Day 20-21 1AA
(5 µm) tumor eliminated, 2 dogs
swelling (3.8×.8), 1 dog swelling returned, 1 dog
swelling (2.8×3.6), 1 dog tumor eliminated, 1 dog swelling (3×4),
2 dog 1A
(10 µm) 3×3.2,
1 dog 1.8×2,
1 dog 3×3.2,
1 dog 1.8×2,
1 dog Back to normal
1 dog 2.5×3,
1 dog 3×3.2,
1 dog 1.8×2,
1 dog 1B
(10 µm) 2×2,
2 dogs Returned to normal No No 1C
(10 µm) 1.5×2,
7 dogs 4 dogs unclear 1D
(40 µm) 2×1,
6 dogs 4 dogs unclear 1E
(10 µm) 1×1,
2 dogs 1×1,
2 dogs 1×1,
2 dogs 1F
(10 µm) 2×4,
1 dog 2×4.1 dogs 2×4.1 dogs 2×4.1 dogs 1G
(10 µm) 0.5×0.5,
1 dog 0.5×0.5,
1 dog 0.5×0.5,
1 dog 1H
(10 µm) 1×1,
2 dogs 1×1.2 dogs 1×1,
2 dogs 1I
(10 µm) 2×1,
1 dog No 1J
(100 µm) 1×1,
1 dog (30 min) No placebo tumor eliminated, 1 dog tumor eliminated, 1 dog tumor eliminated, 1 dog

These data indicate that irritation at the injection site of the formulation with the smaller fluralaner particle size was greater than in patients with the larger particle size. In particular, formulation 1AA, in which fluralaner was micronized to a particle size of about 5 µm, caused irritation at the injection site with large swelling that persisted for 12-14 days, while formulation with larger particles 1J (particle size 100 µm) caused slight swelling that lasted only a short time. It was similar to the reaction of the placebo group.

Example 3 - Pharmacokinetic Study

Study A: Fluralaner 7.5% suspension with 5 micron particles (Example 1AA) and Fluralaner 7.5% suspension with 40 micron particles (Example 1D) were administered subcutaneously in a single dose of 15 mg/kg body weight ( BW) eight beagle dogs each. The local tolerance of the study samples was evaluated at intervals up to 28 days after administration. Blood samples for determination of fluralaner plasma concentrations were collected before treatment, at 2 hours and 8 hours, and at 1, 2, 3, 5, 7, 10, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140 and 154 days after treatment.

Study B: Fluralaner 7.5% 100 micron suspension (Example 1J) was administered subcutaneously at a single dose of 10 mg/kg body weight to three beagle dogs. The local tolerance of the study samples was evaluated at intervals up to 28 days after administration. Blood samples for determination of fluralaner plasma concentrations were collected before treatment and 1, 3, 5, 7, 10, 14, 21, 28, 35, 49, 56, 63 and 70 days after treatment.

The initial absorption of all formulations is comparable in the first days, indicating a similar onset of action. The 100 micron suspension at 10 mg/kg body weight shows a lower plasma profile, which is more favorable in terms of the safety of the target animal. At the same time, plasma concentrations are high enough to suggest sufficient efficacy against ixodid ticks. The 40 micron suspension compared to the micronized suspension administered at the same dose shows higher plasma concentrations after day 84 and is expected to provide longer term efficacy against ixodid ticks.

In general, the larger particle provides sufficient blood levels of fluralaner to demonstrate long-term efficacy against ixodid ticks, while at the same time showing a lower risk of adverse events such as injection site irritation.

Example 4 - Efficiency study

Example 4A

Dose characteristics studies were conducted to determine the effective dose using Rhipicephalus sanguineus and Amblyomma americanum in dogs. Doses of 10, 15 and 20 mg fluralaner/kg body weight have been evaluated. These studies included an untreated control group and three fluralaner treatment groups with 8 to 10 dogs in each group. Individual dogs were infested with 50 ixodid ticks of each species before treatment and again on certain days after treatment. Efficacy was determined by counting live ixodid ticks on all dogs approximately 48-72 hours post infection and calculating % effectiveness or % reduction in live ixodid ticks compared to the untreated control group. The results of one of the current studies are presented in tables 5 and 6.

Table 5 Efficacy of Fluralaner Injectable Suspension Administered at Fluralaner 10, 15, or 20 mg/kg BW Against R. sanguineus Ixodes Ticks in Dogs ^{a, b} Research Day Bite counts from fluralaner dose (mg/kg) % Fluralaner Dose Efficacy (mg/kg) 0 10 15 20 10 15 20 2 32.3 26.4 20.3 12.3 18.2 37.2 62.0 14 21.5 0.3 0.0 0.0 98.8 100 100 32 28.8 0.0 0.0 0.0 100 100 100 62 24.1 0.0 0.0 0.0 100 100 100 92 30.6 0.0 0.0 0.0 100 100 100 123 30.5 0.1 0.1 0.0 99.5 99.6 100 153 29.4 0.9 0.0 0.0 97.1 100 100 183 31.4 0.6 0.0 0.3 98.2 100 99.1 212 31.1 0.3 0.1 0.1 99.1 99.6 99.6 242 32.6 1.9 0.5 0.0 94.3 98.5 100 274 34.9 0.6 0.3 0.1 98.4 99.3 99.6 302 30.7 2.6 0.6 0.0 91.6 98.0 100 333 32.1 4.1 0.1 0.3 87.1 99.6 99.2 363 33.7 5.5 1.3 83.7 96.3 392 27.6 12.4 12.0 55.1 56.5 ^a Counts are arithmetic averages of live ixodid ticks and % efficacy was calculated using arithmetic averages.
^b Counts were made 48 hours after treatment or infection.

Table 6. Efficacy of Fluralaner Injectable Suspension administered at 10, 15, or 20 mg fluralaner/kg bw against A. americanum ixodid ticks in dogs ^{a, b} Research Day Bite counts from fluralaner dose (mg/kg) % Fluralaner Dose Efficacy (mg/kg) 0 10 15 20 10 15 20 2 25.8 22.8 20.3 15.6 20.2 28.9 45.2 14 20.4 0.4 0.4 1.0 98.2 98.2 95.1 32 20.3 0.0 0.0 0.0 100 100 100 62 19.8 0.1 0.0 0.0 99.3 100 100 92 17.9 0.1 0.0 0.0 99.2 100 100 123 13.6 0.9 0.0 0.4 93.7 100 96.9 161 31.8 4.3 2.0 2.3 86.5 93.7 92.8 183 25.5 6.6 1.6 0.2 74.2 93.6 99.3 212 26.6 8.4 5.9 7.4 68.3 77.9 72.3 ^a Counts are arithmetic averages of live ixodid ticks and % efficacy was calculated using arithmetic averages.
^b Counts up to and including day 161 were performed 48 hours after treatment or infection. Counts on days 183 and 212 were 72 hours later

The examples tested the effectiveness of Amblyomma americanum and Rhipicephalus sanguineus as these parasite species are known to be dose limiting ixodid ticks (i.e. an effective dose against these ixodid ticks would also be effective against other ixodid tick species) and what to expect from these data that efficacy against fleas (greater than 90% mortality) can be achieved by administering a composition comprising the isoxazoline compounds of formula (I) at least as long as there is activity against Amblyomma americanum and Rhipicephalus sanguineus .

Therefore, the compositions of the present invention are effective in controlling flea infestations in domestic animals, especially dogs and cats, for at least Amblyomma americanum and Rhipicephalus sanguineus , i.e., for at least 90 days.

Example 4B

The results of additional dose characterization studies are summarized. These studies evaluated three doses (10, 15 and 20 mg/kg) in adult dogs. Prepared injectable suspension preparations of fluralaner are indicated in Example 1J above. One study tested efficacy against Rhipicephalus sanguineus ixodid ticks (see Table 7). In a second study, efficacy against fleas was evaluated approximately 6 months after treatment in dogs (see Table 8).

Table 7 Efficacy of Fluralaner Injectable Suspension Administered at Fluralaner 10, 15, or 20 mg/kg BW Against R. sanguineus Ixodes Ticks in Dogs ^{a, b} Research Day Bite counts from fluralaner dose (mg/kg) % Fluralaner Dose Efficacy (mg/kg) 0 10 15 20 10 15 20 2 40.8 27.6 15.3 20.8 32.2 62.6 49.1 9 38.5 6.0 3.0 1.8 84.4 92.2 95.5 16 37.3 1.5 2.3 1.1 96.0 94.0 97.0 thirty 35.5 2.5 1.9 1.8 93.0 94.7 95.1 58 31.1 1.5 1.1 1.4 95.2 96.4 95.6 86 38.6 1.1 1.9 1.4 97.1 95.1 96.4 114 47.3 0.1 0.5 0.4 99.7 98.9 99.2 142 41.6 0.1 0.1 0.3 99.7 99.7 99.4 170 38.8 0.1 0.4 1.5 99.7 99.0 96.1 184 40.9 0.3 0.8 0.8 99.4 98.2 95.1 212 38.6 2.0 1.9 0.6 94.8 98.2 98.4 ^a Counts are arithmetic averages of live ixodid ticks and % efficiency is calculated using arithmetic averages.
^b Counts were made 48 hours after treatment or infection.

Table 8 Efficacy of Fluralaner Injectable Suspension 10, 15, or 20 mg fluralaner/kg bw against the Ctenocephalides felis flea in dogs ^{a, b} Research Day Flea count from fluralaner dose (mg/kg) % Fluralaner Dose Efficacy (mg/kg) 0 10 15 20 10 15 20 187 89.4 0.0 0.0 0.0 100 100 100 ^a Counts are arithmetic averages of live fleas and % efficiency was calculated using arithmetic averages.
^b Counts were made 24 hours after infection.

The results of these studies demonstrated the efficacy of fluralaner injectable suspension againstR. sanguineusduring for at least 7 and 12 months, respectively.

The 15 and 20 mg/kg doses have also been shown to be effective up to 6 months post-injection against A. americanum .

All three doses have been shown to be 100% effective in reducing the number of live fleas on dogs 6 months after treatment. The efficacy against fleas is expected to last 12 months as fleas have been shown to be more sensitive to fluralaner than ticks. This is especially true of the dose limiting species R. sanguineus and A. americanum .

Example 5 - Fluralaner Reconstitutable Injectable Formulations

Additional examples of an injectable suspension formulation of fluralaner were formulated as reconstituted formulations. The following method was used to obtain composition 5A

A. Carrier medium

1. Loading ~80% of the total volume of water for injection.

2. Suspension agent (sodium carboxymethyl cellulose (NaCMC)) was added and mixed in the overhead mixer for ~5 minutes.

3. The mixture was further mixed with a homogenizer until no agglomerates

4. Wetting agent (Poloxamer 124) was added and mixed with an overhead mixer until smooth.

5. Preservative (benzyl alcohol (BA)) was added and mixed with an overhead mixer until smooth.

6. Sodium phosphate was added and mixed in the overhead mixer until smooth.

7. Gently mix in the antifoam agent (simethicone) with an overhead mixer until smooth (5 minutes).

8. The pH of the mixture was adjusted to pH 7.0-7.4 by adding HCl. Mix gently with an overhead mixer until smooth (5 minutes).

9. QS was added to the final mass for injection, and then gently mixed with an overhead mixer until smooth (5 minutes).

10. The resulting composition was packaged in injection vials and sealed with a cork.

11. The vials were autoclaved for 15 minutes at 121°C.

B. Active ingredient

1. Solid fluralaner was added to the vial and sealed.

2. The vial has been permanently sterilized by gamma irradiation.

C. Formation of the reconstituted injectable composition

1. Add vehicle from vial A to vial of active ingredient B and shake.

2. The resulting suspension is ready for injection.

Similar procedures were used to prepare the formulations of Examples 5B-H. Batch sizes ranged from 50 ml to 1000 ml.

The volume-weighted particle size of the fluralaner crystals (API) was measured by static light scattering (laser diffraction) (Sympatec Helos) to determine the particle size distribution.

The composition of formulations 5A-H is shown in Table 9.

Table 9

Example Substance % w/v API size in µm (volume-weighted particle size) D10/D50 5A LPS Fluralaner 15.00 20/100 Sodium CMC (Blanose 7M8 SF PH) 2.00 Poloxamer 124 0.10 benzyl alcohol 2.00 Simethicone emulsion 0.20 Sodium phosphate (dibasic dihydrate) 0.70 Hydrochloric acid (1n) needed to adjust the pH Water for injection QS 5B As in 5A, excluding API size 40/100 5C API size 50/130 5D Irradiated as in 5A except no poloxamer 40/100 5E As in 5B, excluding 2.3% NaCMC 40/100 µm 5F As in 5B, excluding 0.05% poloxamer 40/100 µm 5G As in 5B, excluding API size D50 is 77 µm 5H As in 5B, excluding API size D50 is 116 µm

Example 6 Pharmacokinetic Study of Fluralaner Reconstituted Injectable Formulations

The evaluation of the pharmacokinetic properties of the compositions of example 5 was carried out as described in example 3, except as noted below.

Example 6A:

Sample formulations 5B (fluralaner, D50=100 microns, 15% suspension, 5B (irradiated) and 5D (irradiated, no poloxamer) were injected subcutaneously at a single dose of 20 mg/kg body weight to eight, sixteen and sixteen beagle dogs, respectively. the tolerance of the test products was assessed at intervals up to 21 days after administration.Blood samples for determination of fluralaner plasma concentrations were collected before treatment, after 8 hours and after 1, 3, 5, 7, 10, 14, 21, 28, 35, 42, 49 , 56, 70, 84, 98, 112, 126, 140, 154, 168 and 182 days after treatment.

See figure 2.

Example 6B:

Formulation samples 5A (fluralaner 100 microns (D10=20, D50=100) 15% suspension), 5B fluralaner 100 microns (D10=40, D50=100) 15% suspension and 5C (fluralaner 130 microns ( D10=50, D50=130) (15% suspension) was administered subcutaneously as a single dose of 20 mg/kg body weight to 10 beagle dogs each. plasma was collected before treatment, at 8 hours, and at 1, 3, 5, 7, 10, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126, 140, 154, 168 and 182 days after treatment.

See figure 3

Example 6C:

Formulation samples 5B (100 micron fluralaner, 15% suspension), 5E (100 micron fluralaner, 15% suspension with 2.3% NaCMC), 5F (100 micron fluralaner, 15% suspension with 0 05% poloxamer), 5G (fluralaner 77 micron) 15% suspension) and 5H (fluralaner suspension 116 micron) were administered subcutaneously once at a dose of 20 mg/kg body weight to 10 beagle dogs each. The local tolerability of the test products was evaluated at intervals up to 21 days after administration. Blood samples for determination of fluralaner plasma concentration were collected before treatment, after 8 hours and after 1, 3, 5, 7, 10, 14, 21, 28, 35, 42, 49, 56, 70, 84, 98, 112, 126 , 140, 154, 168 and 182 days after treatment.

See figure 4

Example 7 - Evaluation of reaction at the injection site of reconstituted formulations

The evaluation of the compositions according to Example 5 was carried out as described in example 2.

These formulations were evaluated during the pharmacokinetic experiments described in Example 6. During the evaluation of the formulations of Example 5, there were no significant injection reactions.

Claims (41)

1. An injectable pharmaceutical composition containing particles of an isoxazoline compound of formula (I)

Formula (I), Where R ¹ is halogen; n is 2; R ² is CF ₃ ; T is a 6-membered ring which is optionally substituted with one or more Y radicals; Y is methyl; Q is X-NR ³ R ⁴ ; X is CO; R ³ is CH ₂ -C(O)NHCH ₂ CF ₃ ; R ⁴ is hydrogen or a salt thereof, and a pharmaceutically acceptable excipient, where the isoxazoline compound has a volume-weighted particle size distribution D50, measured by a static light scattering instrument, from 50 microns to 150 microns, where the isoxazoline compound is in suspension in the composition. 2. An injectable pharmaceutical composition according to claim 1, wherein the particle size distribution D50 is from 75 microns to 150 microns. 3. An injectable pharmaceutical composition according to claim 1 or 2, wherein the particle size distribution D50 is between 90 microns and 110 microns. 4. An injectable pharmaceutical composition according to any one of claims 1 to 3, wherein the isoxazoline compound is fluralaner. 5. Injectable pharmaceutical composition according to any one of claims 1 to 4, in which the isoxazoline compound is present in an amount ranging from 5% wt./about. up to 50% w/v 6. Injectable pharmaceutical composition according to claim 5, in which the isoxazoline compound is present in an amount in the range from 25% wt./about. up to 35% w/v 7. Injectable pharmaceutical composition according to claim 5, in which the isoxazoline compound is present in an amount in the range from 5% wt./about. up to 10% w/v 8. An injectable pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is to be reconstituted in a carrier medium. 9. An injectable pharmaceutical composition according to any one of claims 1 to 8, wherein the composition further comprises another parasiticide compound. 10. An injectable pharmaceutical composition according to claim 9, wherein the parasiticide compound is a macrocyclic lactone. 11. An injectable pharmaceutical composition according to claim 10 wherein the macrocyclic lactone compound is selected from moxidectin and milbemycin. 12. An injectable pharmaceutical composition according to claim 11, wherein the parasiticide compound is moxidectin. 13. Injectable pharmaceutical composition according to claim 12, in which moxidectin is presented in an amount in the range from 0.1% wt./about. up to 1.0% w/v 14. An injectable pharmaceutical composition according to any one of claims 1 and 3-12, wherein the volume-weighted particle size distribution D50 is from 75 microns to 130 microns and the particle size D10 is from 30 microns to 50 microns. 15. A method of treating or preventing infestation of an animal, comprising administering to an animal in need thereof an effective amount of an injectable pharmaceutical composition according to any one of claims 1-14. 16. The method of claim 15 wherein the animal experiences minimal irritation at the injection site. 17. The method according to any one of claims 15, 16, wherein the animal is a pet. 18. The method of claim 17 wherein the pet is a dog. 19. The method of any one of claims 15-18, wherein the injectable isoxazoline pharmaceutical composition is administered with a separate injectable parasiticide composition. 20. The method of claim 19, wherein the administration is simultaneous or sequential. 21. A kit for treating or preventing infestation of an animal, where the kit contains two or more containers: a) a solid crystalline isoxazoline compound as defined in claim 1; b) a carrier medium containing a pharmaceutically acceptable excipient capable of forming a suspension with compound a); And c) instructions for combining the solid crystalline isoxazoline compound with the vehicle prior to injection, where for a solid crystalline isoxazoline compound D50 volume-weighted particle size is from 75 microns to 130 microns and D10 particle size is from 30 microns to 50 microns. 22. The kit of claim 21 wherein the isoxazoline compound is fluralaner. 23. A method of treating or preventing infestation of an animal with parasites, comprising administering to an animal in need of this kit according to claim 21 or 22.

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