Injectable pharmaceutical compositions and uses thereof

Abstract

To provide an injectable veterinary composition for the sustained release of isoxazoline compounds and moxidectin over a long duration.SOLUTION: An injectable veterinary composition comprises: moxidectin microspheres comprising from about 50 wt.% to about 99 wt.% of fat, wax or mixture thereof, and 0.01-10 wt.% of an anti-oxidant; and particles of an isoxazoline compound represented by Formula (I), wherein the moxidectin microspheres and isoxazoline compound particles are suspended in an aqueous carrier comprising one or more suspending agents, one or more wetting agents and / or one or more preservatives, and water.SELECTED DRAWING: None

Description

[Background technology]

[0001] Isoxazoline compounds are known in the art, and these compounds The compounds and their use as antiparasitic agents are described, for example, in U.S. Patent Application US2007 / 000944. 66617, and International Patent Applications WO2005 / 085216 and WO2007 / 079 162, WO2009 / 002809, WO2009 / 024541, WO2009 / 0 03075, WO2010 / 070068 and WO2010 / 079077 (The disclosures of which and the references cited therein are incorporated by reference.) This class of compounds is known to have excellent activity against ectoparasitic arthropods. It is being done.

[0002] WO2015 / 048371 describes a spirocyclic isoxazoline compound, a biocompatible compound, and a Long-acting injectable compositions comprising a molecule and at least one carrier, solvent or excipient has been disclosed.

[0003] WO2016 / 138339 describes a compound containing at least one isoxazoline active agent, poloxamer, A long-acting injectable formulation is disclosed containing summers and cosolvents.

[0004] WO2016 / 164487 describes at least one EP1311266A1 - Sustained release injection comprising an isoxazoline active agent of the formula (I), a pharmaceutically acceptable polymer and a solvent - Google Patents Possible veterinary formulations are disclosed.

[0005] U.S. Patent No. 9,609,869 describes pests associated with agriculture, horticulture, livestock, and companion animals. Insecticidal compounds based on isoxazoline derivatives for use in the control of It is being done.

[0006] U.S. Patent Application Publication No. 2017 / 0239218 describes a method for producing a compound comprising at least one isoxazoline compound. Long-acting formulations to combat parasites, including phosphorus-active agents, liquid PEG, and / or neutral oils An injectable composition is disclosed.

[0007] Recently, another ectoparasitic compound has been described: 2-chloro-N-(1-cyanocyclopropane). propyl)-5-[1'-methyl-3'-(1,1,2,2,2-pentafluoroethyl) -4'-(trifluoromethyl)[1,5'-bi-1H-pyrazol]-4-yl]benzoate Zuamide; Tigolanel (Tigola) disclosed in WO2019 / 012377 ner) (CAS RN 1621436-41-6).

[0008] Moxidectin has been shown to be effective against helminths, nematodes, mites and worms, especially when administered parenterally to animals. Prevention and treatment of infections and infestations caused by endo- and ectoparasitic arthropods It is an active ingredient useful for treatment.

[0009] Moxidectin is disclosed in U.S. Patent No. 4,916,154. 307 and EP1197207 describe moxidectin microspheres and injectable compositions. The present invention discloses methods for preparing and using the compounds of the present invention.

[0010] An advantageous injectable pharmaceutical composition for veterinary applications is one in which both The effective concentration level of the active compounds (moxidectin and isoxazoline compounds) was measured once. This allows the drug to be provided over a long period of time with a single injection.

[0011] In addition to the duration of release for such compositions, the technical properties of the injectable veterinary formulations characteristics, such as ease of application (injectability and resuspension), and side effects (localized after administration) The absence of adverse reactions (injection site reactions and systemic side effects) and the sterilizability of the formulation are important features. do.

[0012] Therefore, the effective amounts of the isoxazoline compound and moxidectin in the combined preparation technically feasible methods that allow for the effective and safe release of It would be desirable to have an injectable formulation available. This would allow for separate injections and reactions. This will allow the use of these new compounds in conditions where repeated administration is undesirable. The composition also has the advantage that the excipients do not interfere with the moxidectin microspheres and are stable. The manufacturer should ensure that the product provides a moxidectin content of 100mg / kg or more. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US2007 / 0066617 [Patent Document 2] WO2005 / 085216 [Patent Document 3] WO2007 / 079162 [Patent Document 4] WO2009 / 002809 [Patent Document 5] WO2009 / 024541 [Patent Document 6] WO2009 / 003075 [Patent Document 7] WO2010 / 070068 [Patent Document 8] WO2010 / 079077 [Patent Document 9] WO2015 / 048371 [Patent Document 10] WO2016 / 138339 [Patent Document 11] WO2016 / 164487 [Patent Document 12] U.S. Patent No. 9,609,869 [Patent Document 13] U.S. Patent Application Publication No. 2017 / 0239218 [Patent Document 14] WO2019 / 012377 [Patent Document 15] U.S. Patent No. 4,916,154 [Patent Document 16] EP0525307 [Patent Document 17] EP1197207 Summary of the Invention [Problem to be solved by the invention]

[0014] Thus, there is provided a method for treating isoxazoline compounds and moxidexide which overcomes one or more limitations of the prior art. There is a need for injectable pharmaceutical compositions for the extended release of steroids. [Means for solving the problem]

[0015] Thus, the present invention provides a compound that has long-term efficacy against parasites, safety, physical and chemical stability, and isoxazoline compounds and An injectable composition comprising moxidectin microspheres is provided.

[0016] One embodiment of the present invention is an injectable veterinary composition comprising: (a) about 50% by weight to about 99% by weight of a fat, wax, or mixture thereof and 0.01% by weight of moxidectin microspheres containing 10% to 10% by weight of an antioxidant; and (b) Formula (I) [ka]

[0017] [During the ceremony, R 1 = halogens, CF3, OCF3, CN; n=an integer of 0 to 3, preferably 1, 2, or 3; R 2 =C1-C3-haloalkyl, preferably CF3 or CF2Cl; T=5-12 membered monocyclic or bicyclic ring system optionally substituted with one or more radicals Y ; Y=methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent adjacent radicals Y together form a chain (in particular a 3- or 4-membered chain); Q=X-NR 3 R 4 or a 5-membered N-heterocyclic group optionally substituted with one or more radicals aryl ring; X=CH2, CH(CH3), CH(CN), CO, CS; R 3 = hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, meth oxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl ethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethy haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, Methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, proton cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halomethylaminocarbonylcyclopropyl, [ka]

[0018] [where Z A = hydrogen, halogen, cyano, halomethyl (CF3)]; R 4 = Hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethene methylcarbonyl, ethylcarbonyl, propylcarbonyl, propoxymethyl methylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, Aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, di Methoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl yl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl; Or, R 3 and R 4 together, [ka]

[0019] forming a substituent selected from the group consisting of Particles of an isoxazoline compound represented by the formula: wherein the moxidectin microspheres and isoxazoline compound particles are one or more suspensions. The composition is suspended in an aqueous carrier comprising a turbidifying agent, one or more humectants and / or one or more preservatives, and water. are.

[0020] A further embodiment is a method of treating or preventing a parasitic infestation in an animal, wherein wherein the method comprises administering to an animal in need of such treatment or prevention an injectable veterinary composition as described above. This includes administering a substance.

[0021] A further embodiment is a method of making the injectable veterinary composition, comprising: The method comprises the following steps: (a) preparing isoxazoline particles (preferably by crystallization); (b) Melting the fat, wax or mixture thereof and adding moxidectin and optionally An antioxidant is added and the microspheres are sprayed (preferably by spinning disk atomization). and optionally sieving to obtain moxidectin microparticles. the stage of preparing the fair; (c) The moxidectin microspheres obtained in step (b) are mixed with the ibuprofen obtained in step (a). placing the mixture in a first container together with the isoxazoline particles; (d) dissolving excipients, including suspending agents, wetting agents and / or preservatives, in water and adding the mixture to a second container; preparing an aqueous carrier by placing in; (e) Transfer the aqueous carrier from the second container (d) to the first container (c), shake and prepare a ready-to-use solution. The solids are recycled by forming a ready-to-use suspension. The configuration stage.

[0022] A further embodiment is a kit, wherein the kit comprises: (a) Particles of the isoxazoline compound represented by the above formula (I) and the above moxidectin a first container containing a solid mixture of cross-spheres; (b) a second emulsion containing one or more suspending agents, wetting agents, and / or preservatives and an aqueous carrier containing water; a container; and (c) Before subcutaneous or intramuscular injection into animals, the moxidectin microspheres and instructions for reconstituting the isoxazoline compound particles with said aqueous carrier; Includes.

[0023] Further embodiments include the use of such compounds to treat or prevent parasitic infestations in animals. A method of using the kit, wherein the method comprises administering the reconstituted suspension to an animal. By administering by subcutaneous or intramuscular injection. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a scanning electron micrograph of 10% moxidectin in glyceryl tristearate microspheres (GTS). [Figure 2] Figures 2 and 3 show plasma levels of moxidectin (2) and fluralaner (3) after subcutaneous administration to dogs. [Figure 3] Figures 2 and 3 show plasma levels of moxidectin (2) and fluralaner (3) after subcutaneous administration to dogs. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention has long-term efficacy against parasites, safety, and physical and chemical stability. and isoxazoline compounds and moxidex with reduced risk of injection site irritation. An injectable composition comprising the cin microspheres is provided.

[0026] The physical stability of the injectable suspension is determined by the precise amount of isoxazolidinone in one general formulation. Accurate injection of a homogenous suspension containing both Zolin compounds and moxidectin The present inventors have developed two different solid components: The densities of isoxazoline (crystalline) particles and moxidectin microspheres are different (this (This makes it difficult to provide a uniform suspension.) Chemical stability in formulations is particularly challenging for moxidectin.

[0027] causing settling or floating or foaming of suspended particles which may affect the accuracy of dosing. It can be easily resuspended in aqueous carrier by gentle shaking without A stable suspension should be formed where possible.

[0028] Furthermore, the final composition to be injected remains stable over the entire period of use after being subjected to resuspension / reconstitution. It is important that the material remains physically (and chemically) stable.

[0029] Furthermore, the injection is safe for the animal after injection and does not cause any side effects, especially tolerability. Advantageously, it does not cause irritation at the injection site.

[0030] The composition is administered by injection, so that the composition is administered by generally accepted and known procedures. It is even more important that it can be sterilized.

[0031] The present invention provides such an advantageous composition.

[0032] Isoxazoline compounds are known in the art and include compounds of this class. The compound is known to have excellent activity against infestations by parasites such as ticks and fleas. Various isoxazoline compound embodiments for use in the present invention include: The details are described below.

[0033] Injection site irritation occurs at the injection site and surrounding tissues when an animal receives an injection of a pharmaceutical composition. Such damage can be swelling, discoloration of the skin, and tissue necrosis. Although injection site irritation may be unavoidable in some animals, veterinarians and animal owners should Injection site swelling greater than 2 x 2 cm lasting more than 3 days is generally considered unacceptable. Minimal injection site irritation is defined as an injection site irritation that is less than 2 x 2 cm and lasts less than 2-3 days. This standard applies to veterinarians and generally accepted by its clients.

[0034] As used herein, the particle size data reported is based on static light scattering (LAS) methods well known in the art, such as laser diffraction, image analysis, or sieving. The particle size is measured by conventional particle techniques. Further explanations are provided below.

[0035] Injectable means that the suspension can be easily dispensed from the ampoule / vial / container into a syringe with a needle. The suspension can then be withdrawn from such a syringe through a needle and injected intramuscularly ( This means that it can be injected intravenously (im) or subcutaneously (sc) (e.g., 18 gauge). Ji).

[0036] The particle size of the active ingredient in the suspension can affect resuspendability and injectability. i.e., the particle size is large enough to prevent compaction or caking and to facilitate resuspension. But it has to be small.

[0037] Pharmaceutically acceptable excipients are inert substances that form a vehicle or medium for a pharmaceutical product.

[0038] A parasitic "infestation" refers to the presence of a number of parasites that pose a risk to humans or animals. Presence can be in the environment, for example in animal bedding, on the animal's skin or fur. The insult referred to may be present within the animal body, for example within the blood or another organ. In the case of an invasion within a tissue, the term "invasion" is also intended to be synonymous with the term "infection." , where the term "infection" is used as commonly used in the art unless otherwise indicated. as understood by the

[0039] Aqueous suspensions are mixed with aqueous liquids, including water or water-miscible liquids, but are not soluble in the aqueous liquid. " refers to a composition containing particles that are not coated.

[0040] The liquid aqueous vehicle is the solvent (or solvents) in which the active agent is formulated and / or administered. is an aqueous carrier or inert medium used as a diluent.

[0041] Reconstitutable (or resuspendable) formulations are those in which the liquid vehicle is in one container and one or more The solid active ingredients are in separate containers, and the two containers are mixed at some point before administration to the animals. The contents of the container are combined to form the final formulation of a solution or suspension.

[0042] Reconstitution is the process of adding a liquid / diluent to dry ingredients to form a solution or suspension. It is a process.

[0043] The aqueous liquid vehicle may contain several excipients for the formulation, such as one or more aqueous diluents, These may include a suspending agent, one or more wetting agents, one or more preservatives, and the like.

[0044] The pharmaceutical compositions of the present invention are useful in the control of ectoparasites, i.e. in humans and domestic animals and Arthropods harmful to companion animals or diseases in humans and livestock and companion animals They are particularly valuable in the control of arthropods that spread or act as vectors of

[0045] Important arthropod parasites - ectoparasites (insect and acarine pests) are discussed further below. This will be described in more detail below.

[0046] Biting insects include, for example, Hypoderma sp. in cattle. .), Gastrophilus in horses and in rodents Migratory dipterans such as Cuterebra sp. ous) larvae, as well as all types of biting fly and mosquito species, e.g., blood-sucking Examples of adult flies include the horn fly or Haematobia nigricans. Haematobia irritans, horse fly ) or Tabanus spp., stable fly or Stomoxys calcitrans, black fly (b black fly or Simulium spp., deer fly r fly or Chrysops spp., louse flies se fly) or Melophagus ovinus, Tsetse fly or Glossina sp. p.) and other parasitic fly maggots. Oestrus ovis and Cuter spp. ebra spp.), blow fly or Pha enicia spp.), screwworm or cochliomyia Hominivorax (Cochliomyia hominivorax), cowfly (c attle grub or Hypoderma spp. and free Mosquitoes include Culex spp. lex spp.), Anopheles spp. and Aedes spp. (Aedes spp.), etc.

[0047] Mites include: chicken mites ite), Dermanyssus gallinae; Ich mite or scab mite or scab mite Mange mites (Astigmata), e.g., scabies Acarina species (Sarcoptidae spp.), e.g., Sarcoptes scabiei (Sarcoptes scabiei); mange mite te), for example, Psoroptidae spp., e.g. , Chorioptes bovis, Psoroptes ovis (Psoroptes ovis) and Demodex canis (Demodex cani s); ear mite Otodectes sinotis chiggers, e.g., Trombiculidae species (Tribodoridae) ombiculidae spp.), e.g., North American chiggers American chigger Trombicul alfrezugesi a alfreddugesi).

[0048] Ticks include the following: d tick), for example, Argasidae spp., e.g. Argas spp. and Ornithodoro spp. s spp.); hard-bodied ticks, e.g., Ixodidae Species (Ixodidae spp.), e.g., Ixodes ricinus icinus), Ixodes scapularis, Rhipicephalus sanguineus ), Haemaphysalis spp., Dermacentor reticula Dermacentor reticulatus, Dermacentor variabili Squirrel (Dermacentor variabilis), Amblyomma americanum (Amblyomma americanum) and Boophilus species s spp.).

[0049] Lice include: blood-sucking lice, e.g., menopause; Menopon spp. and Bovicola spp. Biting lice, e.g., Haematopinus spp. ), Linognathus spp. and Solenopotes spp. olenopotes spp.).

[0050] Fleas include, for example, Ctenocephus species alides spp.), e.g., dog fleas (Ctenocephalides Ctenocephalides canis and cat fleas flea)(Ctenocephalides felis) Xenopsylla spp., e.g., Xenopsylla spp. Oriental rat flea (Xenopsylla ceopsis) sylla cheopis); and Pulex spp., e.g. For example, the human flea (Pulex irritans) itans)).

[0051] Bedbugs include, for example, the following: idae), or, for example, the common bed bug (Cimex lectularius) Cimex lectularius); Triatomine species atominae spp.), e.g., kissing bugs Also known as the assassin bug (triatomid bug); e.g., Rhodnius Rhodnius prolixus and Triatomine species ma spp.).

[0052] The compositions of the present invention are effective against egg, nymph and larvae stages, The various life stages of the parasite, including juvenile and adult stages It has value for the treatment and control of the cytoplasmic stage.

[0053] For the avoidance of doubt, references herein to "treatment" include As used in the specification, the term "ectoparasite" encompasses reference to curative and palliative treatments. References to "biological control" include killing and repelling pests on animals and in their environments. To deter, expel, disable, prevent, eliminate, mitigate and encompasses minimizing and eradicating.

[0054] Prophylaxis is the stopping of new or subsequent infestations or infections from becoming established.

[0055] "Control of ectoparasite infestation" means to prevent infestation or to prevent the infestation of parasites within an animal and / or Relieving or reducing the number of parasites on an animal and / or preventing or reducing the number of parasites in or on an animal By this is meant inhibiting, in whole or in part, the development of a parasitic infestation on an animal.

[0056] "Control of endoparasite infestation" refers to the control of endoparasites (e.g., mitigating or reducing parasitic populations of parasites (e.g., nematodes and tapeworms) and / or reducing the inhibiting, in whole or in part, the development of parasitic infestations in or on animals; means.

[0057] Effectiveness against endoparasites is assessed by examining the endoparasites (especially helminths) immediately after necropsy of the host animal. can be evaluated by counting

[0058] Reduction of parasite numbers (especially gastrointestinal helminth parasites) may alternatively be attributed to the reduction of fecal eggs or specific In this case, the effective amount of the composition is: To reduce the number of helminth eggs or larvae excreted in the faeces of treated animals before and after treatment. So it is confirmed.

[0059] The compositions of the present invention are administered parenterally via injection. The concentration of the active ingredient in the composition is , in an amount acceptable for injectable administration depending on the animal being treated, to achieve the desired therapeutic or It should be sufficient to provide a prophylactically effective amount.

[0060] The compositions according to the invention may be used to treat helminth infections, for example by combining with a compound selected from the group consisting of: used to treat infections caused by one or more helminths selected from : Ancylostoma spp.; Anec ator spp.); Ascaridia spp.; Ascari Ascaris spp.; Brugia spp.; Buno Bunostomum spp.; Capillar spp. ia spp.); Chabertia spp.; Cooperia spp. (Cooperia spp.); Cyathostomum spp. pp.); Cylicocyclus spp.; Silicodonts Cylicodontophorus spp.; Cylicostephanus spp. species (Cylicostephanus spp.); Craterostomum species (Crate rostomum spp.; Dictyocaulus spp. pp.); Dipetalonema spp.; Dirofilaria spp. species (Dirofilaria spp.); Dracunculus species (Dracunculus s spp.); Enterobius spp.; Filaroi Filaroides spp.; Habronema spp. Haemonchus spp.; Heterakis spp. Heterakis spp.; Hyostrongylus spp. s spp.); Metastrongylus spp. ;Meullerius spp.;Necato spp. r spp.); Nematodirus spp.; Niposto Nippostrongylus spp.; Oesophagostomum Oesophagostomum spp.; Onchocerca spp. erca spp.); Ostertagia spp.; Oki Oxyuris spp.; Parascaris spp. Stephanurus spp.; Strongi Strongylus spp.; Syngamus spp. pp.); Toxocara spp.; Strongyloides spp. Strongyloides spp.);Teladorsagia spp. ia spp.); Toxascaris spp.; Trichyne Trichinella spp.; Trichuris spp. spp.); Trichostrongylus spp. ); Triodontophorous spp.; Uncinaria spp. and / or Wuche reria spp.).

[0061] Another internal parasite that can seriously harm animals is the heartworm. Also known as Dirofilaria immitis The most common hosts are dogs and cats, but other animals such as ferrets and raccoons are also affected. Other animals can also become infected. The parasitic helminth is transmitted by the bite of mosquitoes that carry the larvae of Dirofilaria immitis. Adult worms live in the major blood vessels of the lungs, causing inflammation of the blood vessels and infection of the heart. In advanced infections, the worms can also attack the heart. To invade.

[0062] In a particularly preferred embodiment of the present invention, the composition of the present invention is It is used to treat or prevent infection by Dirofilaria immitis. In another embodiment, the compounds and compositions of the present invention are effective against Dirofilaria repens (D Used to treat or prevent infection with irofilaria repens .

[0063] Control or "efficacy" of a compound is measured by the reduction in parasite populations between 5% and about 100% after the first dose. This means that the amount of arthropods (e.g., insects, mites) is reduced to a range of The effects of the compounds of the present invention may be, for example, ovicidal, insecticidal and / or acaricidal. Larvicidal, nymphicidal and / or It may be an insecticide, an adulticidal or a combination thereof.

[0064] The effect can be direct (i.e., killing the parasite immediately) or over some time. Kill them after a period of time (e.g., when molting occurs) or destroy their eggs. This can be manifested indirectly (e.g., by reducing egg production and / or hatchability) or indirectly (e.g., by reducing egg production and / or hatchability). reduce).

[0065] With respect to in vivo administration of a compound according to the present invention, an effective amount is synonymous with a "pharmaceutically effective amount." This is because the treated animals show no signs of parasitic infection or infestation and / or is a dose or amount that treats or ameliorates symptoms or that has an adverse effect on the animal body and and / or to reduce the number of parasites on animals and / or in or on animals It is a dose or amount that totally or partially inhibits the development of a parasitic infestation. The amount of the compound can also be determined by, for example, observing or detecting changes in the clinical symptoms or behavior of the treated animal. and the relative change in parasite numbers after such treatment. This can be easily confirmed by those skilled in the art by observation or detection.

[0066] Systemic administration of a drug means that it reaches the target (organ or parasite) via the bloodstream. .

[0067] Animal means mammals, including companion animals. Companion animals (or pets) include dogs, , cats or horses, and in particular dogs or cats.

[0068] In one embodiment, the isoxazoline compounds for use in the present invention are The term also includes environmentally acceptable salts, esters and / or N-oxides. Reference to a phosphorus compound refers equally to any polymorphic form or stereoisomer thereof.

[0069] In one embodiment, the pharmaceutical composition according to the present invention comprises an isooxygenase for use in the present invention. Racemic mixtures of the isoxazolines may also be used, with the isoxazoline compound being an equivalent amount of the isoxazoline compound. Includes anantiomers.

[0070] Alternatively, the pharmaceutical composition may comprise an enantiomer of an isoxazoline as defined herein. One of the isomeric forms isoforms containing enriched stereoisomers compared to the racemic mixture. Xazoline compounds can be used.

[0071] Furthermore, pharmaceutical compositions may also be prepared using essentially pure stereoisomers of such isoxazoline compounds. Isomers may also be used. Such enriched or purified stereoisomeric preparations can be obtained by methods known in the art. It can be prepared by

[0072] Examples include chemical processes utilizing catalytic asymmetric synthesis or processes utilizing separation of diastereomeric salts. (See, for example, WO2009 / 063910 and JP201 (See 1 / 051977).

[0073] Particularly preferred is the S-enantiomer.

[0074] In one embodiment of an isoxazoline for use in the present invention, T is [ka] TIFF0007769070000005.tif181151TIFF0007769070000006.tif56151

[0075] wherein in T-1, T-3 and T-4, the radical Y=hydrogen, halogen The aryl group is methyl, halomethyl, ethyl or haloethyl.

[0076] In one embodiment of an isoxazoline for use in the present invention, Q is [ka]

[0077] where R 3 , R 4 , X and Z A is as defined above and ,and, Z B = [ka]

[0078] and Z D = [ka] is.

[0079] In one embodiment, the isoxazolines for use in the present invention are those shown in Table 1. This is exactly as stated. [Table 1] TIFF0007769070000011.tif106170 [Table 2]

[0080] In one embodiment, the isoxazolines for use in the present invention are those shown in Table 2. This is exactly as stated. [Table 3] TIFF0007769070000014.tif79170

[0081] In one embodiment, the isoxazoline for use in the present invention is the compound: [ka]

[0082] [In the formula, R 1a , R 1b , R 1c are each independently hydrogen, Cl or CF3. is.

[0083] Preferably, R 1a and R 1c is Cl or CF3, and R 1b is hydrogen the law of nature, T is [ka]

[0084] TIFF0007769070000017.tif66153

[0085] where Y is methyl, bromine, Cl, F, CN, or C(S)NH; 1 or 2; and Q is as described above.

[0086] In one embodiment of the isoxazoline defined herein, R 3 is H and R 4 is -CH2-C(O)-NH-CH2-CF3, -CH2-C(O) -NH-CH2-CH3, -CH2-CH2-CF3 or -CH2-CF3.

[0087] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is fluralaner, af The compound is at least one selected from the group consisting of oxolaner, lotilaner, and sarolaner. In another embodiment of the pharmaceutical composition according to the present invention, the isoxazoline compound is fluralaner, azotoxin, One or more selected from the group consisting of foxolaner, tigolaner, lotilaner, and sarolaner Above.

[0088] 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]-benz amide (CAS RN 864731-61-3, USAN Fluralaner).

[0089] 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 afoxolaner (CAS RN 1093861-60-9, USAN-afoxolaner) be.

[0090] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is lotilaner (CAS RN: 1369852-71-0; 3-methyl-N-[2-oxo-2-(2,2,2 -trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichloro (trifluorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl] thiophene-2-carboxamide).

[0091] 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-dihydroisoxo Sazol-3-yl)-3'-H-spiro(azetidine-3,1'-(2)benzofuran )-1-yl-2-(methylsulfonyl)ethanone).

[0092] In another embodiment, the compound of formula (I) is (Z)-4-[5-(3,5-dichloro-2-(2-methyl-2-propanol)-2-yl]-4-[ ... (chlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl [(methoxyimino)methyl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 9 28789-76-8).

[0093] 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)benzene The compound is azuramide (CAS RN 1164267-94-0).

[0094] 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 afoxolaner (CAS RN 1093861-60-9, USAN-afoxolaner) be.

[0095] In another embodiment, the compound of formula (I) may be 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(tri ... fluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[( 2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide ( CAS RN 1231754-09-8).

[0096] In an alternative embodiment, the isoxazoline compound is 2-chloro-N-(1-cyano) chloropropyl)-5-[1'-methyl-3'-(1,1,2,2,2-pentafluoroethylene (ethyl)-4'-(trifluoromethyl)[1,5'-bi-1H-pyrazol]-4-yl ]benzamide; tigolanel (CAS RN 1621436-41-6). [ka]

[0097] The isoxazoline compounds used in the present invention can exist in various isomeric forms. A reference to a compound for use always includes all possible isomeric forms of such compound. Includes.

[0098] In one embodiment, the racemic form of the isoxazoline compound is present in the composition according to the present invention. In another embodiment, the S-enantiomer is present.

[0099] In certain preferred embodiments, the S-enantiomer of fluralaner is present.

[0100] In another preferred embodiment, the isoxazoline compound of formula (I) is afoxazoline. It is the (S)-enantiomer of solaner (also called esafoxolaner).

[0101] One important aspect of the present invention is to provide a method for treating isoxazoline compound particles at a temperature above about 40°C (preferably Preferably, the molybdenum is dissolved in a fat, wax, or mixture thereof having a melting point (above about 50°C). It is combined in aqueous suspension with stable microspheres containing xydectin.

[0102] These moxidectin microspheres can withstand gamma or electron irradiation without significant degradation. It can be sterilized by beam.

[0103] Microspheres are small particles with a diameter of 1-10 cm, composed of a polymeric wax or other protective material. It is a small spherical particle of 00 μm. Preferred stable moxidectin compounds for use in injectable formulations according to the present invention are The cross-spheres are, by weight, about 75% to 95% by weight of fat, wax or a mixture thereof. Preferably, the microspheres contain about 1-25% moxidectin and about 0.0 Contains 1-1% antioxidants.

[0104] In an alternative embodiment, the composition comprises a mixture of different macrocyclic lactone compounds (e.g., The compounds described herein include, but are not limited to, avermectins or milbemycins. In some embodiments, the avermectin or microspheres Rubemycin is a compound that includes eprinomectin, abamectin, ivermectin, selamectin, and mitomectin. Rubemectin, milbemycin D, or milbemycin oxime.

[0105] In one embodiment, the composition comprises a combination of fluralaner and eprinomectin, or fluralaner A combination of Ranel and milbemycin oxime, selamectin, or moxidectin include.

[0106] In one embodiment, the composition comprises a combination of afoxolaner and eprinomectin, or Combination of foxolaner and milbemycin oxime, selamectin, or moxidectin Includes matching.

[0107] In one embodiment, the composition comprises a combination of sarolaner and eprinomectin, or a combination of sarolaner and eprinomectin. Contains a combination of milbemycin oxime, selamectin, or moxidectin .

[0108] In one embodiment, the composition comprises a combination of lotilaner and eprinomectin, or Milbemycin oxime, selamectin or Milbemycin oxime, selamectin or a combination of moxidectin.

[0109] Injectable compositions generally need to be sterilized before administration to an animal. X-ray or electron beam irradiation is an effective sterilization process for eliminating microbial contaminants. do.

[0110] However, moxidectin readily degrades when irradiated, resulting in loss of its biological activity. This destructive and degradative response to irradiation is due to the specific moxidectin-containing This precludes the use of gamma radiation or electron beams as a means of sterilizing the composition.

[0111] Moxidectin microspheres have been shown to improve the stability of the active ingredient as shown in Example 2. It can be sterilized by irradiation for injection without adverse effects on the The microspheres have a melting point above about 40°C, with about 50% to 99% by weight of the microspheres being above about 40°C. a fat, wax or mixture thereof, about 1% to 50% moxidectin and about 0.01 to 10% Containing or consisting essentially of 10% antioxidants.

[0112] The injectable pharmaceutical composition provides effective sustained delivery of moxidectin and isoxazoline compounds. Achieve the release effect.

[0113] The present invention further provides moxidectin and isoxazoline compounds (especially moxidectin) A method for introducing steroids (e.g., fluralaner and fluralaner) into an animal body and measuring their blood levels in the animal body Also provided are methods for maintaining the cells for long periods of time; and methods for preventing helminths, nematodes, and mites in animals. and to prevent or treat infections and infestations caused by endoparasitic and ectoparasitic arthropods. A method is also provided.

[0114] In one embodiment, moxidectin is present in the injectable veterinary composition at a concentration of about 0.01 wt. % to about 1.0% by weight.

[0115] In a specific embodiment, the injectable composition of the present invention contains 15% fluralaner and 0.1 Contains 7% moxidectin.

[0116] Waxes and fats suitable in the compositions of the present invention generally have a temperature above 40°C, preferably Or, it has a melting point higher than 50°C.

[0117] As used herein, the term "low" refers to "Hawley's The Cond ensed Chemical Dictionary, Eleventh Edit As described in the "Pyrolysis of Polyethylene Glycol" (Pyrolysis of Polyethylene Glycol), it is defined as a high molecular weight, low melting point organic mixture or compound. It is solid at room temperature and is generally fatty in composition except that it does not contain glycerides. is similar to

[0118] Some are hydrocarbons; others are esters of fatty acids and alcohols. is a saturated or unsaturated long-chain C 10 -C 24 Fatty acids, alcohols, esters, salts, esters These include waxes, esters, or mixtures thereof. They are classified as lipids. However, since it is not a polymer compound, it is not considered to be part of the plastic family. I can't.

[0119] Common properties of these waxes include: water repellency; smooth feel; They are non-toxic and free of unpleasant odors and colors. They are flammable and have excellent dielectric properties. They are soluble in most organic solvents and insoluble in water. The main types are: A.Natural 1. Animal (beeswax, lanolin, shellac wax, China wax) 2. Plants (Camauba, Candelilla, Bayberry, Sugarcane) B. Minerals 1. Fossils or earth wax (ozokerite, ceresin, montan) 2. Petroleum wax (paraffin, microcrystalline) (coarse wax or sweat wax) D.Synthesis 1. Ethylenic Polymers and Polyol Ether Esters ("Carbowax") 2. Chlorinated naphthalenes ("Halowax").

[0120] As used herein, the term "fats" refers to fatty acids such as stearic acid and palmitic acid. Glyceryl esters of higher fatty acids are defined as such esters and their mixtures. Compounds that are solid at room temperature and exhibit a crystalline structure are examples of lard and tallow.

[0121] The term "fat" usually refers specifically to triglycerides, while "lipid" is an all-inclusive term. nothing.

[0122] The fat is preferably a long-chain C 12 -C 22 Triglyceryl esters of fatty acids (e.g., Stearate, palmitate, laurate, myristate, arachidate and behenate ) and mixtures thereof; those with a melting point above 50°C are most preferred.

[0123] Glyceryl tristearate is the most preferred fat in the practice of this invention.

[0124] Antioxidants suitable in the practice of the present invention include those which stabilize the moxidectin compound. Included are all antioxidants known in the art to be suitable for use in the preparation of medicaments.

[0125] The antioxidants of the present invention are used to retard oxidation, staling, rancidity, and gum formation, respectively. Defined as organic compounds added to rubber, natural fats and oils, food, gasoline and lubricants Rubber antioxidants are generally di-, 8-naphthyl-p-phenylenediamine. Amine and aromatic amine types such as phenyl-, 8-naphthylamine.

[0126] Many antioxidants are substituted phenolic compounds (butylated hydroxyanisole, Di-tert-butyl-p-cresol and propyl gallate). Food antioxidants The inhibitors are effective at very low concentrations and not only slow down rancidity but also provide vitamins and essential nutrients. Protects nutritional value by minimizing fatty acid breakdown.

[0127] The moxidectin microspheres of the present invention can be sterilized using gamma radiation or electron beam. and can maintain shelf life without significant loss of biological activity. Moxidectin generally degrades readily, especially when irradiated, resulting in loss of its biological activity. Lose a lot.

[0128] Antioxidants suitable for use in the microsphere compositions of the present invention include: Tocopherol, ascorbic acid, ascrovir palmitate, fumaric acid, malic acid, Sodium corbate, sodium metabisulfate, n-propyl gallate, BHA (butyl hydroxybenzoate) butylated hydroxyanisole), BHT (butylated hydroxytoluene), monothioglycerol hydroxyquinone, 6-ethoxy-1,2-dihydro-2,2, 4-trimethylquinoline, with butylated hydroxytoluene being the preferred antioxidant is.

[0129] In certain embodiments, the antioxidant is generally present in an amount of from about 0.01 to about 0.1% by weight of the total formulation. It is added to the formulation in an amount of about 2.0%, with about 0.05 to about 1.0% being particularly preferred.

[0130] The microsphere compositions of the present invention can be sterilized using gamma radiation or electron beam. This allows for shelf life to be maintained without significant loss of biological activity.

[0131] Microspheres for use in the compositions of the present invention may contain moxidectin, an antioxidant The agent and optionally other excipients are mixed with the melted fat, wax or mixture thereof, and then and then subjecting the resulting mixture to various techniques such as emulsifying or spraying, or The mixture is mechanically treated with melted fat, wax or a mixture thereof, and then, for example, centrifuged. The resulting mixture is cooled using a disk to form microspheres. It can be prepared by

[0132] Alternatively, a mixture of active ingredients, antioxidants, excipients and fats, waxes and mixtures thereof with oils. The mixture is cooled to form a solid which can then be separated by procedures such as grinding, milling, and the like. It can be processed as follows.

[0133] The stable microspheres of the present invention are dispersed in a pharmaceutically and pharmacologically acceptable aqueous solution. to obtain a sustained release composition for parenteral administration.

[0134] Excipients such as surfactants, salts, buffers or mixtures thereof may be used in the formulation of the vehicle of the present invention. It can be included inside.

[0135] The amount of excipient suitable for use in the present invention ranges from about 0.1% to 20% by weight. be.

[0136] Preferably, the cellulose derivative (e.g., carboxymethyl cellulose) is The vehicle comprises about 1 to 5% by weight of the vehicle, and inorganic salts (e.g., NaCl) are present in the vehicle. Contains about 0.1 to 2% by weight.

[0137] Sustained blood levels of the active compound are effective against helminths, nematodes, mites and endoparasitic and Related to the protection or treatment of warm-blooded animals against infections and infestations by ectoparasitic arthropods do.

[0138] Maintaining blood levels indicates a slow release of the active ingredient.

[0139] The present invention relates to the administration of moxidectin and isoxazoline compounds (particularly fluralaner) to animals. and using the compositions herein to introduce and maintain levels in the bloodstream of Includes.

[0140] Isoxazoline compound particles and moxidectin microparticles having a defined particle size The injectable compositions of the present invention, including spheres, are effective in preventing irritation at the injection site while minimizing irritation. These compounds have been found to exhibit desirable bioavailability and duration of efficacy.

[0141] The compositions further have desirable safety profiles for warm-blooded and avian recipients. It also provides feel.

[0142] Furthermore, a single administration of such a composition generally provides protection against one or more parasites (e.g., ectoparasites). While providing potent activity against living organisms (e.g., fleas, ticks, or mites), tend to provide a rapid onset of activity, a long duration of activity, and / or a desirable safety profile It was also found that there is a trend.

[0143] The present invention further provides methods for treating or preventing parasitic infections and infestations in animals. wherein the method comprises providing an antiparasitic effective amount of at least one granular material having a defined particle size. One isoxazoline compound and moxidectin microspheres were administered in a pharmaceutically acceptable carrier. The method comprises administering an effective amount of an injectable composition containing the compound together with an excipient.

[0144] Surprisingly, the compositions of the present invention described herein are superior to those known in the art. Compared to other injectable compositions available, Superior broad spectrum efficacy against insects (e.g., fleas and ticks) faster and longer lasting sustained duration while at the same time causing minimal irritation at the injection site was found.

[0145] The pharmaceutical compositions of the present invention can be administered by subcutaneous or intramuscular injection.

[0146] The long-acting injectable compositions of the present invention comprise a pharmaceutically acceptable excipient.

[0147] Pharmaceutically acceptable excipients include, but are not limited to, surfactants, antioxidants, These include agents, preservatives, pH stabilizers (e.g., buffers) and other inactive excipients.

[0148] In another embodiment, the compositions of the present invention comprise from about 0.01% to about 20% (w / v) of a pharmaceutically acceptable salt. Acceptable excipients may be included.

[0149] In another embodiment, the composition comprises from about 0.01% to about 5% (w / v), from about 0.1% to about 10 % (w / v) or about 0.1% to about 5% (w / v) of a pharmaceutically acceptable excipient. In another embodiment, the composition may comprise about 5% to about 15% (w / v) or about 5% to about 1 It may contain 0% (w / v) of pharmaceutically acceptable excipients.

[0150] In yet another embodiment, the composition comprises about 7% to about 10% of a pharmaceutically acceptable excipient. It can include.

[0151] The surfactant may be present in the composition of the present invention in an amount of about 0.1% to about 10% (w / w), about 1% to about It may be present at a concentration of 10% (w / w) or from about 5% to about 10% (w / w). The surfactant is present at a concentration of about 0.1% to about 5% (w / w) or about 1% to about 5% (w / w). It can exist.

[0152] Examples of surfactants that can be used in the composition include, but are not limited to: Mention may be made of: glyceryl monooleate, polyoxyethylene sol. Sorbitan fatty acid esters, sorbitan esters, e.g., sorbitan monooleate (Sp an® 20), polyvinyl alcohol, polysorbates, e.g., Polysorbate Polysorbate 20 and Polysorbate 80, da-Tocopherol Polyethylene Glycol 10 00 succinate (TPGS), sodium lauryl sulfate, ethylene oxide and propylene glycol copolymers of poloxamers (e.g., LUTROL® F) 87, etc.), polyethylene glycol castor oil derivatives, e.g., Polyoxyl 35 Castor Oil Oil (Cremophor® EL), Polyoxyl 40 Hydrogenated Castor Oil (Cr emophor® RH40), Polyoxyl 60 Hydrogenated Castor Oil (Crem ophor® RH60; propylene glycol monolaurate (LAURO GLYCOL®; glyceride esters, such as glycerol caprylate / Caprate (CAPMUL® MCM), polyglycolized glycerides (G ELUCIRE®, PEG 300 Caprylic / Capric Glycerides (Sof tigen® 767), PEG400 caprylic / capric glycerides (L abrasol®), PEG 300 oleic acid glyceride (Labrafil (registered trademark) M-1944CS), PEG 300 linoleic acid glyceride (Labrafi l (registered trademark) M-2125CS); polyethylene glycol stearate and polyethylene ethylene glycol hydroxystearate, e.g., polyoxyl 8 stearate (PEG 400 Monostearate), Polyoxyl 40 Stearate (PEG 1750 Monostearate rates, etc.).

[0153] Polyethylene glycol stearate (synonyms: macrogol stearate, Polyoxyl stearate, polyoxyethylene stearate, ethoxylated stearate CAS No. 9004-99-3, 9005-08-7) is a mixed polio Mixture of monostearate and distearate esters of hydroxyethylene polymers Polyethylene glycol hydroxystearate is a compound of hydroxystearic acid and It is a mixture of monoesters and diesters of polyethylene glycol. One polyethylene glycol hydroxystearate that can be used is polyethylene In another embodiment, the composition of the present invention is The surfactant polyethylene glycol 15 12-hydroxystearate (BASF Kolliphor® HS15 (manufactured by Kolliphor), 12-hydroxystearic acid and 15-hydroxystearic acid The polymer may comprise a mixture of mono- and diesters of ethylene oxide.

[0154] Furthermore, these compounds and their amounts are well known in the art.

[0155] In another embodiment of the present invention, the composition of the present invention contains, as a surfactant, Polyoxyl 35 Castor oil (Kolliphor® EL) may be included. The composition of the present invention contains polyoxyl 40 hydrogenated castor oil (Kol Contains liphor® RH40 or polyoxyl 60 hydrogenated castor oil The compositions of the present invention may further comprise a combination of surfactants.

[0156] The compositions of the present invention may contain other inactive ingredients, such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the art of such compositions. .

[0157] Antioxidants, e.g., Vitamin E, Alpha Tocopherol, Ascorbic Acid, Palmitic Acid Ascorbyl tincture, citric acid, fumaric acid, malic acid, sodium ascorbate, methicone Sodium bisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated Hydroxyanisole), BHT (butylated hydroxytoluene), BHA and citric acid , monothioglycerol, tert-butylhydroquinone (TBHQ), benzyl alcohol and the like can be added to the composition of the present invention.

[0158] Antioxidants are generally present in the compositions of the present invention in an amount of about 1000 mg / kg based on the total weight (w / w) of the composition. In particular, it is contained in an amount of about 0.01% to about 3% or about 0.01% to about 2% (w / v). In another embodiment, the composition comprises about 0.05% to about 1.0% (w / w) of an antioxidant. Contains one or a mixture of:

[0159] Preservatives such as benzyl alcohol are suitably present in the composition in amounts of from about 0.01% to about 1%. It is used in an amount ranging from about 0.0% to about 5.0%, with about 0.05% to about 5.0% being particularly preferred. The agents include parabens (methylparaben and / or propylparaben), benzal chloride Conium, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butyl Parabens, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, azole, ethylparaben, imidourea, methylparaben, phenol, phenoxyethanol alcohol, phenylethyl alcohol, phenylmercury acetate, phenylmercury borate, Phenylmercury nitrate, potassium sorbate, sodium benzoate, sodium propionate Examples include sodium, sorbic acid, and thimerosal.

[0160] Preferred ranges for these compounds include about 0.01% to about 5%.

[0161] Benzyl alcohol is preferred.

[0162] Compounds that stabilize the pH of the composition may also be present. Such compounds and methods for using these compounds are well known to those skilled in the art. Examples include acetic acid / acetate, malic acid / malate, citric acid / citrate, and tartaric acid / alcohol. Calcium carbonate, lactic acid / lactate, phosphoric acid / phosphate, glycine / glycimate e) a compound selected from the group consisting of Tris, glutamic acid / glutamate, and sodium carbonate; These include systems that are based on sodium phosphate or sodium citrate, among others.

[0163] The aqueous suspension contains the isoxazoline compound particles and moxide particles described herein. The present invention may comprise a method for preparing a suspension comprising administering to a subject a drug product containing cutin microspheres in admixture with excipients suitable for the preparation of an aqueous suspension. can.

[0164] Such excipients include: suspending agents, such as carboxymethyl Sodium cellulose, methylcellulose, hydroxypropylmethylcellulose, Sodium glutamate, polvinylpyrrolidone ), gum tragacanth and gum acacia; dispersing or wetting agents, such as natural phosphatides , for example, lecithin, or condensation products of alkylene oxides and fatty acids, for example, polyoxyethylene Ethylene stearate or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. For example, heptadecaethyleneoxycetanol, or ethylene oxide with fatty acids and hexyl condensates of partial esters derived from sorbitol, such as polyoxyethylene sorbitol monoesters; Oleate or partial ethylene oxide derived from fatty acids and hexitol anhydrides Condensation products of esters, for example, polyethylene sorbitan monooleate.

[0165] The aqueous suspensions may further contain one or more preservatives, for example, ethyl benzoate or n-propyl benzoate. It may also contain propyl, p-hydroxybenzoic acid.

[0166] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water include: The isoxazoline compound and moxidectin microspheres are mixed with a dispersing or wetting agent, a suspending agent, The composition may be provided in a mixture with a suitable dispersing agent or a stabilizer and one or more preservatives. Wetting agents and suspending agents are exemplified by those already mentioned above.

[0167] In one embodiment, the isoxazoline compound is present in an aqueous suspension, where the liquid carrier (diluent) is water. Suspend in liquid.

[0168] In another embodiment, the liquid carrier (diluent) of the aqueous suspension comprises water and a co-solvent.

[0169] Injectable compositions of the present invention comprising an isoxazoline compound and moxidectin microspheres The co-solvents that can be used in the composition can be a single co-solvent or a blend of co-solvents. can be done.

[0170] In one embodiment, the co-solvent used in the injectable aqueous composition of the present invention is water-miscible. The term "polar solvent" includes polar solvents.

[0171] Non-limiting examples of these co-solvents include: ethanol; alcohol, isopropanol, benzyl alcohol, glycol ethers (e.g., but not limited to Although it is not a soluble fiber, diethylene glycol monoethyl ether (DGME, Transcut ol (registered trademark), butyl diglycol, dipropylene glycol n-butyl ether, Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol Propylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc.), liquid polyethylene glycol (PEG) (e.g., PEG400), propylene glycol, carbonates (e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DM I), dimethylacetamide, dimethyl sulfoxide, glycerol formal, or A mixture of at least two of these solvents.

[0172] In one embodiment, the compositions of the present invention may be prepared using polar protic solvents, including but not limited to: However, alcohols such as ethanol, isopropanol or glycol or glycol In another embodiment, the long-acting injection of the present invention comprises Possible compositions include polar aprotic solvents such as N-methylpyrrolidone, dimethylisothiazolinone, Sorbide, dimethylacetamide, dimethyl sulfoxide or propylene carbonate include.

[0173] In one embodiment, the isoxazoline compounds may exist in various isomeric forms. Reference to isoxazoline compounds always refers to all possible isomeric forms of such compounds. Contains.

[0174] Unless otherwise indicated, compound structures in which no particular conformation is shown are those in which the compound It is intended to encompass compositions of all possible conformers of the compound, as well as compositions of all possible conformers of the compound. In some embodiments, the compound The substance is a chiral compound.

[0175] Particularly preferred is the (S) enantiomer. In some embodiments, the compound is It is a chiral compound.

[0176] In one embodiment, the isoxazoline compounds of formula (I) are those described, for example, in patent application U S2007 / 0066617, WO2007 / 079162, WO2009 / 00280 9, WO2009 / 080250, WO2010 / 070068, WO2010 / 079 077, 2011 / 075591 and WO2011 / 124998 according to any of the processes or within the capabilities of a person skilled in the art who is an expert in chemical synthesis. It can be prepared according to any other process that falls within the scope of the present invention.

[0177] For the chemical preparation of the products of the present invention, the skilled artisan will be familiar with, inter alia, the "Chemical Ab The entire contents of the "Stracts" and the references cited therein may be freely used. It is thought that this will be the case.

[0178] In one embodiment, the isoxazoline compound is in suspension in the composition. In an alternative embodiment, the suspension is aqueous. In an alternative embodiment, the suspension is non-aqueous.

[0179] In one embodiment, the pharmaceutical composition is substantially free of organic solvents.

[0180] In one embodiment, the pharmaceutical composition comprises a surfactant / wetting agent. The active agent / wetting agent is a poloxamer.

[0181] Alternatives to poloxamers are other water-soluble / water-miscible nonionic surfactants, such as sorbitol. Sorbitan fatty acid ester (Span), polyoxyethylene sorbitan fatty acid ester (Poly Sorbate / Tween), polyoxyethylene castor oil derivative (Cremaphor) , polyoxyethylene stearate, lecithin and TPGS (d-α-tocopheryl polysaccharides). Contains ethylene glycol 1000 succinate.

[0182] The surfactant / wetting agent is present in the composition in an amount of about 0.01% w / v to about 0.5% w / v, Or, it is present in an amount of about 0.05% w / v to about 0.1% w / v.

[0183] Poloxamers are made up of two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). It consists of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) sandwiched between It is a nonionic triblock copolymer (see U.S. Pat. No. 3,740,421). See the reference.

[0184] Poloxamer 124 is a poly(ethylene glycol)-block-poly(propylene glycol) copolymer. (C1H)-block-poly(ethylene glycol) (CAS No. 9003-11-6) Also known as Lutrol L44 or Kollisolv P124 .

[0185] Lutrol F68 is another poly(ethylene glycol)-block-poly(propylene glycol) ethylene glycol)-block-poly(ethylene glycol), and poloxamer 188 Also known as Kolliphor P188.

[0186] In one embodiment, the pharmaceutical composition comprises a suspending agent. Carboxymethylcellulose, especially sodium carboxymethylcellulose (NaC MC).

[0187] In alternative embodiments, the suspending agent is methylcellulose or polyvinylpyrrolidone. do.

[0188] In one embodiment, the pharmaceutical composition comprises a preservative. In one embodiment, the preservative is benzyl It's alcohol.

[0189] In an alternative embodiment, the preservative is m-cresol, benzalkonium chloride, methylparaben. It is propylparaben or propylparaben.

[0190] Injectable pharmaceutical compositions are prepared by mixing the solid components together and then diluting the solid mixture. The preparation can be carried out by suspending the compound in an agent.

[0191] The method for preparing an injectable pharmaceutical composition comprises dissolving isoxazoline particles in moxidectin microspheres. and combining the solid mixture with the granular spheres to form a solid mixture, wherein the solid mixture is subsequently In step (b), the solution is reconstituted with an aqueous liquid carrier to form an injectable aqueous suspension. is formed.

[0192] In one embodiment, the aqueous liquid carrier is water.

[0193] In an alternative embodiment, the diluent is a mixture of an isoxazoline compound and moxidectin microcrystalline cellulose. An oil or solvent in which the sphere components have little or no solubility.

[0194] The pharmaceutical composition further comprises a surfactant / wetting agent.

[0195] Specific surfactants / wetting agents and surfactant / wetting agent alternatives are described herein. and discussed in the Examples.

[0196] The pharmaceutical composition may further comprise additional excipients such as suspending agents or preservatives.

[0197] Specific examples of suitable excipients and substitutes are provided herein below and in the Examples. , is being discussed.

[0198] Particle size and measurement of isoxazoline compound particles and moxidectin microspheres Injectable compositions of the present invention comprising particles of an isoxazoline compound having a defined particle size Such compositions have been found to have particularly beneficial properties.

[0199] In one embodiment, the moxidectin microspheres and isoxazoline compound particles are They have the same particle size.

[0200] Thus, in this specification, reference to "particle size of isoxazoline compound" refers to The moxidectin microspheres were measured in the same manner and in a similar manner. This includes references to:

[0201] In one embodiment, the isoxazoline compound and / or moxidectin microspheres D50 particle size of about 25 microns to about 250 microns as measured by a static light scattering device The particle size distribution is about 11 microns to about 250 microns, and about 50 microns to about 150 micron particle size, about 75 microns to about 130 microns particle size, about 90 Particle size of about 30 microns to about 100 microns It has a size.

[0202] The particle size distribution indicates the relative amounts of particles present according to size.

[0203] D10 is the particle size distribution below which 10% of the particles fall.

[0204] D50 is the particle size measurement distribution representing the size below which 50% of the particles fall.

[0205] D90 is the particle size measurement distribution representing the size below which 90% of the particles fall.

[0206] In another embodiment, the particle sizes are different.

[0207] In one embodiment, the particle size of the isoxazoline compound and moxidectin microspheres is The sizes are in the same range.

[0208] In another embodiment, the particle sizes are not within the same range.

[0209] In certain embodiments, the particle size D10 of the isoxazoline compound is greater than 10 μm. The particle size D50 is 80-120 μm, and the particle size D90 is 2 It is less than 10 μm.

[0210] In certain embodiments, for moxidectin microspheres, the particle size D10 is 5 0μm, the particle size D50 is 100-150μm, and the particle size The D90 of the lens is less than 200 μm.

[0211] In certain embodiments, the particle size D10 is about 10 μm, about 20 μm, about 30 μm, It is about 40 μm, about 50 μm, about 60 μm or about 80 μm.

[0212] In certain embodiments, the particle size D10 of the moxidectin microspheres is about 80 μm.

[0213] In certain embodiments, the particle size D50 is about 50 μm, about 75 μm, about 80 μm, Approximately 90μm, approximately 100μm, approximately 110μm, approximately 120μm, approximately 130μm, approximately 140μm Or about 150 μm.

[0214] In certain embodiments, the particle size D50 of the moxidectin microspheres is about 11 0 μm.

[0215] In certain embodiments, the particle size D90 is about 100 μm, about 130 μm, about 150 μm, or about 200 μm. μm, about 175 μm, about 200 μm or about 250 μm.

[0216] In certain embodiments, the particle size D10 of the isoxazoline compound is about 20-35 μm. m, particle size D50 is about 90-105 μm, and particle size D9 0 is approximately 155 to 175 μm.

[0217] In certain embodiments, for moxidectin microspheres, the particle size D10 is about 60-85 μm, particle size D50 is about 90-115 μm, and particle The size D90 is approximately 145 to 165 μm.

[0218] In certain embodiments, for moxidectin microspheres, the particle size D10 is about 80 μm, particle size D50 is about 110 μm, and particle size D9 0 is approximately 150 μm.

[0219] In certain embodiments, the particle size D10 is about 25-30 μm and the particle size D The particle size D50 is about 95-100 μm, and the particle size D90 is about 160-170 μm is.

[0220] In certain embodiments, the particle size D10 is about 10-20 μm and the particle size D The particle size D50 is about 85-110 μm, and the particle size D90 is about 170-185 μm is.

[0221] In certain embodiments, the particle size D10 is about 10-15 μm and the particle size D The particle size D50 is about 95-105 μm, and the particle size D90 is about 175-180 μm is.

[0222] In certain embodiments, the particle size D10 is about 10-25 μm and the particle size D The particle size D50 is about 40-60 μm, and the particle size D90 is about 95-100 μm. do.

[0223] In certain embodiments, the particle size D10 is about 15-20 μm and the particle size D The particle size D50 is about 45-55 μm, and the particle size D90 is about 90-95 μm. .

[0224] In certain embodiments, the particle size D10 is about 30-50 μm, and The size D50 is approximately 70 to 130 μm.

[0225] In certain embodiments, the particle size D10 is about 35-45 μm, and The size D50 is approximately 90 to 110 μm.

[0226] In certain embodiments, the particle size D10 is about 40 μm, and the particle size D50 is approximately 100 μm.

[0227] Volume weighted particle size can be determined by sieving, microscopy or laser diffraction (Malvern or It can be measured by Sympatec.

[0228] Volume-weighted particle size measurements were performed using a Malver equipped with a Hydro 2000G measuring cell. n Using a Mastersizer 2000 or a Horiba LA-910 This can be done using a laser scattering particle size distribution analyzer. Size can be measured using the Sympatec Helos instrument.

[0229] For use in the present invention, the isoxazoline compound is preferably a compound selected from the group consisting of hydroxybenzoates, ... The compound is present in the pharmaceutical composition of the present invention in an amount of about 0.1 to about 50% w / v of the composition.

[0230] The isoxazoline is present in the pharmaceutical composition of the present invention in an amount of about 10 to about 45% w / v. in an amount of about 20 to about 45% w / v; about 15 to 35% w / v, or about 25% w / v to about 3 5% w / v, or about 1% w / v to about 12% w / v, or about 3% w / v to about 9% w / v It is present in an amount of

[0231] In one embodiment and / or embodiments of the present invention, the composition comprises: (a1) a physiologically (b) a compound represented by formula (I) containing eprinomectin as the macrocyclic lactone active against The isoxazoline compound contains fluralaner, preferably (S)-fluralaner. nothing.

[0232] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) containing milbemycin oxime as the active macrocyclic lactone, and Fluralaner, preferably (S)-fluralaner, is an isoxazoline compound to be used. Includes.

[0233] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) an isomer of formula (I) containing selamectin as the active macrocyclic lactone; The oxazoline compound includes fluralaner, preferably (S)-fluralaner.

[0234] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) a compound represented by formula (I) containing moxidectin as the active macrocyclic lactone; The isoxazoline compound contains afoxolaner, preferably (S)-fluralaner. nothing.

[0235] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) a compound having the formula (I) The isoxazoline compound is afoxolaner, preferably (S)-afoxolaner. Includes

[0236] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) containing milbemycin oxime as the active macrocyclic lactone, and The isoxazoline compound to be used is afoxolaner, preferably (S)-afoxolaner. Includes Solanel.

[0237] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) an isomer of formula (I) containing selamectin as the active macrocyclic lactone; Afoxolaner, preferably (S)-afoxolaner, is used as the oxazoline compound. include.

[0238] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) containing moxidectin as the active macrocyclic lactone, and The isoxazoline compound is afoxolaner, preferably (S)-afoxolaner. Includes

[0239] In one embodiment and / or embodiments of the present invention, the composition comprises: (a) a physiologically (b) a compound having the formula (I) Isoxazoline compounds include sarolaner.

[0240] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound having the formula (I) containing milbemycin oxime as a macrocyclic lactone; Isoxazoline compounds include sarolaner.

[0241] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound having selamectin as a macrocyclic lactone and an isoxa compound represented by formula (I) Zoline compounds include sarolaner.

[0242] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound containing moxidectin as a macrocyclic lactone and an isooxygenase represented by formula (I); Sazoline compounds include sarolaner.

[0243] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound having eprinomectin as a macrocyclic lactone and an isopropyl alcohol represented by formula (I) Xazoline compounds include lotilaner.

[0244] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound having the formula (I) containing milbemycin oxime as a macrocyclic lactone; Isoxazoline compounds include lotilaner.

[0245] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound having selamectin as a macrocyclic lactone and an isoxa compound represented by formula (I) Zoline compounds include lotilaner.

[0246] In one embodiment of the present invention and / or embodiments of the present invention, the composition comprises a physiologically active (b) a compound containing moxidectin as a macrocyclic lactone and an isooxygenase represented by formula (I); Sazoline compounds include lotilaner.

[0247] Injectable compositions generally need to be sterilized before administration to an animal. In one preferred embodiment and / or preferred embodiments of the present invention, the microspheres comprise For example, it may be sterilized by gamma or electron beam irradiation.

[0248] Physiologically active macrocyclic lactones decompose upon irradiation and lose much of their biological activity. It has been reported that microspheres (a) do not adversely affect the stability of the active ingredient. It can be sterilized for injection by irradiation.

[0249] In one embodiment, the amount of isoxazoline compound in the pharmaceutical composition according to the present invention is It is approximately 30% w / v of the pharmaceutical composition according to the invention.

[0250] In one embodiment, the amount of isoxazoline compound in the pharmaceutical composition according to the present invention is It is approximately 7.5% w / v of the pharmaceutical composition according to the invention.

[0251] In one embodiment, the pharmaceutical composition must be reconstituted prior to injection. The pharmaceutical composition is reconstituted in an aqueous liquid carrier prior to injection.

[0252] In another embodiment, the pharmaceutical composition is a ready-to-use composition ready for injection.

[0253] In one embodiment, the pharmaceutical composition is administered in combination with an additional therapeutic agent.

[0254] The administration of the additional therapeutic agent may be in the same composition or in a separate composition.

[0255] The additional therapeutic agent can be a parasiticide or a vaccine.

[0256] In another embodiment, the additional therapeutic agent is another parasiticide. isoxazoline compounds, macrocyclic lactones, Abel Mectins (e.g., ivermectin, selamectin, doramectin, abamectin, and Eprinomectin; Milbemycins (milbemycin oxime); Pro-benzimidazole dazoles (e.g., febantel, netobimin, and thiophanate); benzimidazolidin benzimidazole derivatives, such as thiazole benzimidazole derivatives (e.g., thiabendazole and cambindazole), carbamate benzimidazole derivatives (e.g., fenben Albendazole, albendazole (oxide), mebendazole, oxfendazole, paclitaxel Rubendazole, oxibendazole, flubendazole and triclabendazole); Imidazothiazoles (e.g., levamisole and tetramisole); tetrahydropyri amides (morantel and pyrantel), salicylanilides (e.g., closantel, o cyclozanide, lafoxanide and niclosamide); nitrophenol compounds (e.g. , nitroxynil and nitroscanate; benzenedis sulfonamides (e.g., clorsulon); pyrazinoisoquinolines (e.g., praziconazole); anthracene and epsiprantel); heterocyclic compounds (e.g., piperazine, diethylcarbamate, bamadine and phenothiazines; dichlorophen, arsenicals (e.g., thiacetalamide, Melorsamine and arsenamide; cyclooctadepsipep parahedramides (e.g., derquantel); and and amino-acetonitrile compounds (e.g., monepantel, AAD1566); compounds (e.g., amidantel and tribendimidine) (these are all pharmaceutically acceptable

[0039] The compound may be in any form acceptable to the present invention, such as a salt, a solvate, or an N-oxide.

[0257] One embodiment of the present invention is a method of treating or preventing a parasitic infestation in an animal, comprising: wherein the method comprises administering to an animal in need of such treatment or prevention an effective amount of any of the above-described Administering an injectable pharmaceutical composition.

[0258] In one embodiment, the animal experiences minimal injection site irritation.

[0259] As noted above, minimal injection site irritation lasts for less than 2-3 days. Mean injection site irritation of less than cm.

[0260] In one embodiment, the animal is a companion animal. In one embodiment, the companion animal is a dog or a cat. It is Ko.

[0261] The optimum effective amount to be used for best results will, of course, depend on the particular isopropyl alcohol used. The sazolin compounds, the species of animal to be treated and the type and severity of parasitic infection or infestation Depends.

[0262] Generally, good results are obtained by administering an isoxazoline compound of formula (I) to animals weighing 1 kg or more. Approximately 0.01 to 200 mg per gram (in one embodiment, 0.1 to 1 kg of animal body weight) 00mg or 0.5-50mg per kg of animal body weight or The total dose can be obtained by administering a single dose (1-30 mg / kg) or divided doses. It is administered at the prescribed dose.

[0263] Generally, good results are achieved with moxidectin at a dose of about 0.01 to 10 mg / kg of animal body weight. g (in one embodiment, 0.1 to 5 mg per kg of animal body weight) Such total dose may be administered in single or divided doses.

[0264] Injectable pharmaceutical compositions may be administered daily, weekly, monthly, semi-annually, or annually. It can be administered once.

[0265] The injectable pharmaceutical composition may be administered monthly, every two months, every three months, every four months, every five months, Every 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months Every month, every 13 months, every 14 months, every 15 months, every 16 months, every 17 months or can be administered every 18 months.

[0266] Particularly preferred is administration every six months.

[0267] Furthermore, administration every 12 months is also preferred. This allows the animal to be free of ectoparasites ( both parasites (especially fleas and ticks) and endoparasites (especially heartworms and / or gastrointestinal helminths) Particularly preferred is the long-term protection against filariasis. be.

[0268] Advantageously, the injectable compositions of the present invention can be used to treat infectious diseases (e.g., distemper, influenza, annual vaccines against influenza, rabies, and other vaccines using conventional antigens The possibility of applying them together.

[0269] In one embodiment of the injectable pharmaceutical composition, an isoxazoline compound and / or moxide The particle size D50 of the cutin microspheres is approximately 75 microns to approximately 130 microns. The particle size D10 is about 30 microns to about 100 microns.

[0270] One embodiment of the present invention is a kit for treating or preventing a parasitic infestation in an animal. wherein the kit comprises two or more containers: (a) solid crystalline isoxazoline compound and moxidectin microspheres; (b) a pharmaceutically acceptable excipient capable of forming a suspension with the compound of (a). a vehicle containing the agent; and (c) A solid crystalline isoxazoline compound and moxidectin microspheres prior to injection. instructions for combining the gel with an aqueous liquid vehicle; Wherein, in the case of solid crystalline isoxazoline compounds and moxidectin microspheres, The particle size D50 is about 75 microns to about 130 microns, and the particle size D10 is about 30 microns to about 50 microns.

[0271] In another embodiment, the isoxazoline compound is fluralaner.

[0272] One embodiment of the present invention is a kit, wherein the kit comprises: (a) a compound represented by formula (I) as defined in claims 1, 8, 9, 10, 11, 12, 17 and 18; Particles of an isoxazoline compound and moxidectin microspheres according to claims 1 to 12 a first container containing a solid mixture of A; (b) a second emulsion containing one or more suspending agents, wetting agents, and / or preservatives and an aqueous carrier containing water; a container; and (c) Mix the moxidectin microspheres with isopropyl alcohol before subcutaneous or intramuscular injection into the animals. Instructions for reconstituting the xazoline compound particles with an aqueous carrier.

[0273] In one embodiment, the first container contains a composition sufficient to treat and / or prevent a parasitic infestation in an animal. a sufficiently effective amount of moxidectin and an isoxazoline compound of formula (I) described above Contains compounds.

[0274] In one embodiment, the kit further comprises a step of reconstituting a mixture of the compositions from the first and second containers. and a device for parenterally administering the compound to an animal (by injection), in particular a syringe (e.g., using 18 gauge).

[0275] In one embodiment, the first container comprises an isoxazoline compound of formula (I) and Moxidectin microspheres have a mass of approximately 25 microns as measured by static light scattering equipment. It has a volume weighted particle size distribution D50 of about 250 microns.

[0276] In another embodiment in the first container, the particle size of the isoxazoline compound is D10 is about 20-35 μm, and the particle size D50 is about 90-105 μm, and The particle size D90 is approximately 155 to 175 μm.

[0277] Another aspect of the invention is a method of treating or preventing a parasitic infestation in an animal, wherein The method comprises administering to an animal in need of such treatment or prevention an injectable veterinary composition. This includes administering.

[0278] Another aspect of the present invention is a method of making an injectable veterinary composition according to the present invention, comprising: wherein the method comprises the steps of: (a) preparing particles of an isoxazoline compound by crystallization; (b) Melting the fat, wax or mixture thereof and adding moxidectin and optionally An antioxidant was added, and microspheres were prepared by spinning disk atomization. and preparing moxidectin microspheres by sieving; (c) The moxidectin microspheres obtained in step (b) are mixed with the ibuprofen obtained in step (a). placing the mixture in a first container together with the isoxazoline particles; (d) dissolving excipients, including suspending agents, wetting agents and / or preservatives, in water and adding the mixture to a second container; preparing an aqueous carrier by placing in; (e) Transfer the aqueous carrier from the second container (d) to the first container (c) and shake to form a. Reconstituting said solid by forming a

[0279] The rotating disc controls critical process parameters such as melt temperature, flow rate and disc speed. By controlling the particle size distribution span, uniform spherical particles with a narrow span can be produced. It is recognized as a manufacturing technology.

[0280] Spinning disk atomization uses mechanical energy to compress the liquid film or form droplets. It is an encapsulation technique that increases the kinetic energy of the particles to allow them to disintegrate at high speed.

[0281] Alternatively, moxidectin may be homogeneously incorporated into a fat, wax, or mixture thereof. To do this, other methods such as hot melt extrusion, hot melt granulation, thin film evaporation, etc. are used. The resulting mixture can be milled or atomized to reach the desired particle size. It is possible.

[0282] If necessary, the material may be sieved to prepare a batch with a defined particle size. It can be done.

[0283] In other words, the microspheres (a) incorporate physiologically active macrocyclic lactones. The resulting mixture can then be processed into microspheres by various techniques, such as those indicated above. These can be considered microspheres prepared by forming them surgically.

[0284] Alternatively, a mixture of the physiologically active macrocyclic lactone and optionally other excipients is cooled and A solid can be obtained by the addition of hydroxybenzoates, which can then be treated by procedures such as grinding or milling. It is possible.

[0285] In general, solvent evaporation, spinning disk atomization, spray drying, and sieving are known to those skilled in the art. This is a method.

[0286] In one embodiment and / or embodiments of the present invention, the mixture in the first container an effective amount of any of claims 1 to 14 sufficient to treat or prevent a parasitic infestation in an animal; The microspheres according to any one of claims 1 to 14 and the compound of formula (I) according to any one of claims 1 to 14 and / or an isoxazoline compound represented by the formula (I) according to any one of claims 1 to 14. II).

[0287] In one embodiment and / or embodiments of the present invention, the kit further comprises a first and The mixture of compositions from the second container is reconstituted and prepared for parenteral administration to an animal. This includes devices (especially syringes).

[0288] Another embodiment involves administering a parasitic infestation in an animal over an extended period of 6 or 12 months. a method for treating and / or preventing a disease, wherein the method comprises the steps of: the reconstituted solution prepared when using the kit described above to an animal in need thereof. This involves administering the drug by injection as directed.

[0289] Parasites, as previously mentioned, are ectoparasites and endoparasites.

[0290] Preferred target animals are companion animals such as cats or dogs, especially dogs.

[0291] The optimum effective amount to use for best results will, of course, depend on the particular isoxazone being used. Zoline compounds and physiologically active macrocyclic lactones, the animal species and parasites to be treated It depends on the type and severity of the infection or infestation.

[0292] In one preferred embodiment of the present invention and / or preferred embodiments of the present invention, The isoxazoline compound (preferably fluralaner) is administered at a dose of 100 mg / kg of animal body weight. about 0.01 to about 200 mg per kg of animal body weight, preferably about 0.1 to about 10 mg per kg of animal body weight 0 mg, more preferably about 0.5 to about 50 mg per kg of animal body weight, particularly The total dose is administered in a single dose of about 1 to about 30 mg per kg of body weight. It may be administered in divided doses.

[0293] In one preferred embodiment of the present invention and / or preferred embodiments of the present invention, physiological The active macrocyclic lactone (preferably moxidectin) is administered at a dose of about 0.05 mg / kg of animal body weight. The dose is 0.01 to about 10 mg per kg of animal body weight, preferably about 0.1 to about 5 mg per kg of animal body weight. Such total dose may be administered in single or divided doses.

[0294] The injectable veterinary compositions of the present invention are used to treat and / or prevent parasitic infestations in animals. When used in the treatment of rheumatoid arthritis, the treated animals experience minimal injection site irritation. I found out.

[0295] As noted above, minimal injection site irritation lasts for less than 2-3 days. Mean injection site irritation of less than cm.

[0296] Another aspect of the invention is a method for treating and / or preventing a parasitic infestation in an animal. wherein the method comprises administering a therapeutically effective amount of a compound to a subject in need of such treatment and / or prevention. a dose of an injectable veterinary composition according to the invention or a kit according to the invention nothing.

[0297] Again, as far as injectable veterinary compositions and kits are concerned, all that has been described above is The same applies to parasites and parasitic infestations.

[0298] The features of the present invention are described in the embodiments of this application; however, for the sake of brevity, However, not all combinations of these features are literally described.

[0299] However, it is clear that any combination of the features described above is part of the invention. is considered to be. [Example]

[0300] Example Example 1: Preparation of 10% moxidectin microspheres 10% moxidectin in glyceryl tristearate (GTS) microspheres The following recipe was prepared by rotating a disc: [Table 4]

[0301] Briefly, 180g of glyceryl tristearate was melted in a container and stirred. The mixture was heated to a temperature of 180°C while stirring. 20g of moxidectin and 0.06g of butylated Hydroxytoluene was added and stirred until dissolved. The resulting molten solution was cooled to about 80°C. and pumped onto a 4-inch disk at 3000 RPM heated to approximately 90°C. The resulting microspheres were sieved and screened for further characterization and testing. Submicron material was collected.

[0302] Example 2 Sterilization of 10% moxidectin in GTS microspheres - by irradiation of the microspheres Stability against The microsphere composition described below was placed in multiple 20 mL serum vials. Two of the vials are flushed with dry nitrogen gas to remove oxygen. Close with an elastomeric septum and a crimped aluminum cap. The microspheres were then subjected to both gamma irradiation and electron beam irradiation at doses of 15, 20, and 25 kGy. The microspheres were extracted in acetonitrile / water (1:1) and 23- (O-methyloxime)-F28249a analyzed by high performance liquid chromatography The results of this experiment are summarized in Table 2 below. GTS microspheres The samples were sterilized at either low or room temperature, with or without a nitrogen overlay.

[0303] Samples were evaluated for changes during the assay. % assay is % of the non-irradiated assay. It has been reported as. [Table 5] TIFF0007769070000021.tif43170

[0304] Example 3: Preparation of a liquid aqueous vehicle Approximately 50% of the distilled water for injection is charged into a container, heated to approximately 70-80°C, and suspending agent NaCM Add C, hypromellose E50 or PVP and homogenize until dissolved. Remove from heat and add cold distilled water for injection. In Examples 3B and 3D, the volume was increased to 10 liters by adding HCl. The pH was adjusted to 4.5-5.5.

[0305] Each vehicle was sterilized by autoclaving, and the vehicle solution was stored in a sterile container. Stored in a container.

[0306] Product Dose Uniformity - Ready-to-Use Injectable Suspension Moxidectin microspheres and fluralaner particles exhibit similar particle sizes, but Therefore, to find a suitable vehicle for uniform resuspension and dosing, To this end, a number of different vehicles were tested.

[0307] Sampling containing 15% Fluralaner and 1.7% Moxidectin GTS Microspheres The pellets were shaken by hand for approximately 30 seconds until visibly dispersed within each vehicle.

[0308] The following vehicles were investigated:

[0309] Example formulation of a viscous aqueous vehicle for reconstitution / resuspension: [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0310] Six 1 mL samples were then taken and subjected to moxidectin and fluralaner assays. The results are shown in Table 4 below. [Table 11]

[0311] Example 4: Preparation and Use of Final Formulation When used, the vehicle prepared in Example 3 was mixed with the moxidectin mixture prepared in Example 1. Add the microspheres and crystalline fluralaner particles and shake the container to The spheres and fluralaner particles were dispersed in a liquid vehicle. The formulation was then administered as a treatment. The dose designated for the subject dog's weight was drawn into a syringe and injected subcutaneously.

[0312] Example 5 Pharmacokinetics of an injectable formulation containing GTS moxidectin microspheres and fluralaner particles. evaluation formulation: A. 15% Fluralaner + 0.17% Moxidectin Microspheres (unsieved) , GTS, 25kGy); B. 15% Fluralaner + 0.17% Moxidectin Microspheres (Unsieved) , GTS, 15kGy); C. 15% Fluralaner + 0.17% Moxidectin Microspheres (D50 = 75 μm, GTS, 25 kGy); D. 15% Fluralaner + 0.17% Moxidectin Microspheres (D50 = 15 0 μm, GTS, 25 kGy).

[0313] The formulations were prepared as follows: A. Vehicle 1. Add approximately 80% of the total volume of distilled water for injection; 2. Add a suspending agent (sodium carboxymethylcellulose (NaCMC)) Mixed with an overhead mixer for approximately 5 minutes; 3. The mixture was further mixed with a homogenizer until no agglomerates remained; 4. Add the wetting agent (Poloxamer 124) and mix with an overhead mixer until uniform. Mixed with; 5. Add the preservative (benzyl alcohol (BA)) and mix until homogenous. Mixed in a mixer; 6. Sodium phosphate was added and mixed with an overhead mixer until uniform. ; 7. Gently mix the antifoaming agent (simethicone) with an overhead mixer until uniform. (5 minutes); 8. Adjust the pH of the mixture to pH 7.0-7.4 by adding HCl and stir until homogeneous. Mix gently with an overhead mixer (5 min); 9. Add sufficient water to bring the final weight for injection to the desired volume, then mix thoroughly until homogeneous. Mix gently with a bar-head mixer (5 minutes); 10. The resulting formulation was placed into an injectable vial and sealed with a stopper; 11. The vials were autoclaved at 121°C for 15 minutes.

[0314] B. Active ingredients 1. Solid Fluralaner and Moxidectin GTS Microspheres (Prepared as Above) (prepared by centrifugation) was added to the vial and sealed; 2. The vials were terminally sterilized by gamma irradiation.

[0315] C. Formation of a Reconstituted Injectable Formulation 1. The vehicle from vial A was added to the active ingredient vial B and shaken; 2. The resulting suspension was ready for injection.

[0316] Similar procedures were used to prepare the formulations of Examples 5B-H. The batch size was 50 mL. It was in the range of ~1000mL. [Table 12]

[0317] Samples of formulation A, formulation B, formulation C, or formulation D were administered to eight beagle dogs. Different groups received 0.1 mL / kg BW (i.e., 15 mg fluralaner / kg BW, 0 The dose was 0.17 mg moxidectin / kg BW, administered subcutaneously in a single dose.

[0318] Local tolerance of the formulations was assessed for at least 21 days after administration.

[0319] Blood samples for measuring moxidectin and total fluralaner plasma concentrations were collected before treatment. , 8 hours after treatment, and 1 day, 3 days, 5 days, 7 days, 10 days, 14 days, 21 days after treatment, 2 8th, 35th, 42nd, 49th, 56th, 70th, 84th, 98th, 112th, 126th , 140 days, 154 days, 168 days, and 182 days.

[0320] A study demonstrating long-term plasma levels of moxidectin and fluralaner in dogs after subcutaneous administration Favorable pharmacokinetic profiles were obtained for all test formulations.

[0321] There were no significant injection reactions during evaluation of the formulation of Example 5.

Claims

1. 1. An injectable veterinary composition for use in the treatment or control of ectoparasitic infections in animals, comprising: (a) moxidectin microspheres comprising about 50% to about 99% by weight of a fat, a wax, or a mixture thereof and 0.01% to 10% by weight of an antioxidant; and (b) particles of an isoxazoline compound that is fluralaner; wherein the moxidectin microspheres and isoxazoline compound particles are suspended in an aqueous carrier comprising one or more suspending agents, one or more wetting agents and / or one or more preservatives, and water; wherein the moxidectin microspheres and / or isoxazoline compound particles have a volume weighted particle size distribution D50 of 75 μm to 150 μm as measured by a static light scattering device; The injectable veterinary composition.

2. 10. The injectable veterinary composition of claim 1, wherein said fat, wax or mixture thereof has a melting point above about 40°C.

3. 3. An injectable veterinary composition according to claim 1 or 2, wherein the fat, wax or mixture thereof comprises a fatty acid ester.

4. 4. The injectable veterinary composition of claim 3, wherein said fatty acid ester is glyceryl tristearate.

5. 5. An injectable veterinary composition according to any one of claims 1 to 4, wherein the isoxazoline compound particles have a thickness of more than 10 μm and less than 100 μm as measured by scanning electron microscopy.

6. 6. The injectable veterinary composition of any one of claims 1 to 5, wherein the moxidectin microspheres and / or isoxazoline compound particles have a volume weighted particle size D10 of about 20-35 μm, a particle size D50 of about 90-105 μm, and a particle size D90 of 155-175 μm.

7. An injectable veterinary composition according to any one of claims 1 to 6, wherein the suspending agent is selected from sodium carboxymethylcellulose, polyvinylpyrrolidone and methylcellulose.

8. An injectable veterinary composition according to any one of claims 1 to 7, wherein said wetting agent is a poloxamer.

9. A kit for preparing an injectable veterinary composition according to any one of claims 1 to 8, comprising: (a) a first container containing a solid mixture of particles of the isoxazoline compound and moxidectin microspheres; (b) a second container containing one or more suspending agents, wetting agents and / or preservatives and an aqueous carrier comprising water; and (c) instructions for reconstituting the moxidectin microspheres and isoxazoline compound particles with said aqueous carrier prior to subcutaneous or intramuscular injection into an animal; The kit comprises:

10. 10. The kit of claim 9, wherein the kit further comprises a device for reconstituting and parenterally administering the mixture of compositions from the first and second containers to a non-human animal.

11. A method for producing an injectable veterinary composition according to any one of claims 1 to 8, comprising the steps of: (a) preparing isoxazoline particles; (b) preparing moxidectin microspheres by melting a fat, wax or mixture thereof and adding moxidectin and optionally an antioxidant and preparing the microspheres by spinning disk atomization and sieving; (c) placing the moxidectin microspheres obtained in step (b) together with the isoxazoline particles obtained in step (a) into a first container; (d) preparing an aqueous carrier by dissolving excipients, including suspending agents, wetting agents, and / or preservatives, in water and placing the resulting mixture in a second container; (e) transferring the aqueous carrier from the second container (d) into the first container (c) and reconstituting the solid by shaking to form a ready-to-use suspension; The method comprising:

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