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 / 000366. 66617, and International Patent Applications WO2005 / 085216 and WO2007 / 079 162, WO2009 / 002809, WO2009 / 024541, WO2009 / 0 No. 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, Long-acting injectable compositions comprising a molecule and at least one carrier, solvent or excipient has been disclosed.

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

[0004] WO2016 / 164487 describes at least one A sustained release injectable composition comprising an isoxazoline active agent of the formula (I), a pharma- ceutically acceptable polymer and a solvent. Possible veterinary formulations are disclosed.

[0005] U.S. Patent No. 9,609,869 is directed to a method for treating pests associated with agriculture, horticulture, livestock and companion animals. Disclosed is an insecticidal compound based on an isoxazoline derivative 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 administering to a subject a subject a compound comprising at least one isoxazo Long-acting formulations to combat parasites, including phosphorus-active drugs, 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]benzene Zuamide; Tigolanel (Tigola ) disclosed in WO2019 / 012377 ner) (CAS RN 1621436-41-6).

[0008] Moxidectin has been shown to be effective against worms, nematodes, mites and fungi, 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 products and their preparation and use are disclosed.

[0010] An advantageous injectable pharmaceutical composition for veterinary applications is one which exhibits both cytotoxicity and cytotoxicity in the plasma of the treated animal. The effective concentration levels of the active compounds (moxidectin and isoxazoline compounds) were This makes it possible to provide the drug over a long period of time with just one injection.

[0011] In addition to the duration of release for such compositions, the technical properties of the injectable veterinary formulations also vary. Characteristics such as ease of application (injectability and resuspension) and side effects (localized post-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 combination formulation A technically feasible solution that allows 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 enable the use of these new compounds in conditions where repeated administration is undesirable. The composition further comprises excipients that do not interfere with the moxidectin microspheres and are stable. The manufacturer should ensure that the product provides the correct moxidectin content. [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] US 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] Accordingly, there is provided a method for the preparation of isoxazoline compounds and moxidexamide compounds which overcome one or more of the limitations of the prior art. There is a need for injectable pharmaceutical compositions for extended release of tacrolimus. [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 and isoxazoline compounds having anti-inflammatory properties and a reduced risk of injection site irritation. 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 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=a 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 ring 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 haloethylaminocarbonylethyl, tetrahydrofuryl, Methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, proton Cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl haloethylaminocarbonylcyclopropyl, [ka]

[0018] [Here, Z A = hydrogen, halogen, cyano, halomethyl (CF3)]; R 4 = Hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, Toxomethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, Aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, di Methoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl , 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 wetting agents and / or one or more preservatives, and water. is.

[0020] A further embodiment is a method of treating or preventing a parasitic infestation in an animal, comprising: and 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 steps of: (a) preparing isoxazoline particles (preferably by crystallization); (b) Melting the fat, wax or mixture thereof and mixing it with moxidectin and optionally An antioxidant is added and the microspheres are sprayed (preferably by spinning disk atomization). moxidectin microparticles are prepared by optionally sieving. The stage of preparing the fair; (c) The moxidectin microspheres obtained in step (b) are mixed with the isocyanate microspheres obtained in step (a). placing in a first container together with the soxazoline particles; (d) dissolving excipients, including suspending agents, wetting agents and / or preservatives, in water and adding the mixture to a second container; preparing the aqueous carrier by placing (e) transferring the aqueous carrier from the second container (d) to the first container (c) and shaking to prepare a ready-to-use aqueous carrier; The solids are then recycled to form 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 microparticles a first container containing a solid mixture of cross-spheres; (b) a second formulation comprising one or more suspending agents, wetting agents and / or preservatives, and an aqueous carrier comprising water; a container; and (c) Prior to subcutaneous or intramuscular injection into animals, the moxidectin microspheres and instructions for reconstituting the soxazoline compound particles with said aqueous carrier; Includes.

[0023] Further embodiments include the use of such agents 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 administration by subcutaneous or intramuscular injection. [Brief description of the drawings]

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

[0025] The present invention has long-term efficacy against parasites, safety, and physical and chemical stability. and isoxazoline compounds and moxidexate with reduced risk of injection site irritation. The present invention provides an injectable composition comprising the chin microspheres.

[0026] The physical stability of the injectable suspension is determined by the precise amount of isoxazolamide in one general formulation. Accurate injection of a homogenous suspension containing both the Zolin compound and moxidectin This is particularly important for enabling dosing. The inventors have developed two different solid components: The densities of isoxazoline (crystalline) particles and moxidectin microspheres are different (this The problem of the difficulty of providing a uniform suspension must be overcome. Chemical stability in formulations is particularly challenging for moxidectin.

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

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

[0029] Furthermore, the injections are safe for the animals after injection and have no side effects, particularly no tolerability. It is advantageous that the injection does not cause irritation at the injection site.

[0030] The composition is administered by injection, so that the composition is administered by generally accepted 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 this class The compound is known to have excellent activity against infestations of parasitic organisms 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 death of tissue. Although irritation at the injection site may be unavoidable in some animals, veterinarians and animal owners should It is generally considered that injection site swelling exceeding 2 x 2 cm lasting more than 3 days is unacceptable. Minimal injection site irritation is defined as an injection site irritation less than 2 x 2 cm in size and lasting less than 2-3 days. This standard applies to veterinarians and is generally accepted by its clients.

[0034] As used herein, the particle size data reported are based on static light scattering (LAS) measurements. These methods are well known in the art, such as NMR diffraction (also known as IR 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 into the muscle ( This means that it can be injected intravenously (im) or subcutaneously (sc) (e.g., 18 g). J).

[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] A pharma- ceutically acceptable excipient is an inert substance that forms 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 the animal's bedding, on the animal's skin or fur, The insult referred to may be present within the animal body, e.g. within the blood or another organ. In the case of invasion into the tissue of the body, the term "invasion" is also intended to be synonymous with the term "infection." 1, in which the term "infection" is used as commonly used in the art unless otherwise indicated. As understood by the

[0039] Aqueous suspensions are mixed with an aqueous liquid, including water or a water-miscible liquid, but do not dissolve in the aqueous liquid. means a composition that includes particles that are not coated.

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

[0041] A reconstitutable (or resuspendable) formulation is one 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 animal. The contents of the vessel 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 create a solution or suspension. It is a process.

[0043] The aqueous liquid vehicle may include any number of excipients for the formulation, such as one or more aqueous diluents, These 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 which spread or act as vectors for the

[0045] Important arthropod parasites - ectoparasites (insect and acarid pests) are discussed 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. Examples of adult flies include the horn fly and the fly Tobia japonica. Haematobia irritans, horse fly ) or Tabanus spp., stable fly or Stomoxys calcitrans, blackfly (b deer fly or Simulium spp. r fly, Chrysops spp., louse fly, se fly) or Melophagus ovinus, Tsetse fly or Glossina sp. Examples of parasitic flies include the bot fly (Ophiuchus p. Oestrus ovis and Cuter spp. ebra spp.), blow fly or Pha enicia spp.), screwworm or cochliomyia Hominivorax (Cochliomyia hominivorax), the 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: ite), Dermanyssus gallinae; Ich mite or scab mite or Scab mites Mange mites (Astigmata), e.g., Acaridae spp., e.g. Sarcoptes scabiei (Sarcoptes scabiei); te), for example Psoroptidae spp., for example , Chorioptes bovis, Psoroptis ovis (Psoroptes ovis) and Demodex canis (Demodex cani s); ear mite Otodectes sinochits cynotis; chiggers, e.g. Trombiculidae species (Trib. ombiculidae spp., e.g., North American chigger Erican chigger Trombicul alfrezugesi alfreddugesi).

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

[0049] Lice include the following: 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, Ctenocephalus species alides spp.), e.g. dog flea (Ctenocephalides Ctenocephalides canis and cat fleas flea) (Ctenocephalides felis) Xenopsylla spp., e.g., Xenopsylla Oriental rat flea (Xenopsilla ceopsis) sylla cheopis); and Pulex spp., e.g. For example, the human flea (Pulex irritans) itans)).

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

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

[0053] For the avoidance of doubt, references herein to "treatment" include As used in the specification, the term "ectoparasite" includes references to curative and palliative treatments. References to "biological control" include killing, repelling, and controlling pests on animals and in the animal's environment. To prevent, expel, disable, prevent, eliminate, mitigate This includes minimizing and eradicating.

[0054] Prophylaxis is the stopping of a new or subsequent infestation or infection from becoming established.

[0055] "Control of ectoparasite infestation" means to prevent infestation or to prevent infestation 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 cestodes) and / or reducing the inhibiting, in whole or in part, the development of a parasitic infestation in or on an animal; means.

[0057] Efficacy against endoparasites was evaluated by measuring the endoparasites (especially helminths) immediately after necropsy of the host animal. It can be evaluated by counting.

[0058] Reductions in parasite numbers (especially gastrointestinal helminth parasites) may alternatively be due to the reduction of fecal eggs or characteristic In this case, the effective amount of the composition is: Reducing the number of worm eggs or larvae excreted in the faeces of treated animals before and after treatment Thus, it is confirmed.

[0059] The composition of the present invention is administered parenterally via injection. The concentration of the active ingredient in the composition is Depending on the animal being treated, the desired therapeutic or It should be sufficient to provide a prophylactically effective amount.

[0060] The compositions according to the invention can be used to treat helminth infections, for example by using a compound selected from the group consisting of: for treating an infection caused by one or more helminths selected from : Ancylostoma spp.; Anec ator spp.; Ascaridia spp.; Ascari Ascaris spp.; Brugia spp.; Bunostomum spp.; Capillar 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 spp.) s spp.); Enterobius spp.; Filaroi Filaroides spp.; Habronema spp. Haemonchus spp.; Heterakis spp. Heterakis spp.;Hyostrongylu 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. 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 there are also other animals such as ferrets and raccoons. Other animals may also become infected. The parasitic worm 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 then 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 in treating 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 from 5% to about 100% after the first dose. This means that the amount of arthropods (e.g., insects, mites) is reduced to the range of The effects of the compounds of the invention may be, for example, ovicidal, insecticidal and / or acaricidal. Larvicidal, nymphicidal and / or It may be an insecticidal, adulticidal or a combination thereof.

[0064] The effect can be direct (i.e., killing the parasite immediately) or after 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 invention, an effective amount is synonymous with a "pharmacologically effective amount." This is because the treated animals show no symptoms of parasitic infection or infestation and / or is a dose or amount that treats or ameliorates symptoms, or is an effective dose or amount that is effective in treating symptoms in animals and and / or to reduce the number of parasites on the animal and / or in or on the animal. 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 clinical symptoms or behavior of treated animals. and to determine the relative change in parasite numbers after such treatment. This can be easily confirmed by one skilled in the art by observation or detection.

[0066] Systemic administration of a drug means that it reaches its 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 compound for use in the present invention is Also encompassed are environmentally acceptable salts, esters and / or N-oxides. A reference to a phosphorus compound equally refers to any polymorphic form or stereoisomer thereof.

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

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

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

[0072] Examples are 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] TIFF2024170642000005.tif181151TIFF2024170642000006.tif56151

[0075] where in T-1, T-3 and T-4 the radical Y=hydrogen, halogen The aryl group may be 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, Z B = [ka]

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

[0079] In one embodiment, the isoxazolines for use in the present invention are those shown in Table 1. As stated above. [Table 1] TIFF2024170642000011.tif106170 [Table 2]

[0080] In one embodiment, the isoxazolines for use in the present invention are those shown in Table 2. As stated above. [Table 3] TIFF2024170642000014.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. It 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] TIFF2024170642000017.tif66153

[0085] where Y is methyl, bromine, Cl, F, CN or C(S)NH2; n= 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, azotidine, 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 The 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5 -Dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo -2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN-afoxolaner) 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-dihydroisox 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-dichlorophenyl)-2,4-diphenyl-2,5-dichlorophenyl] (chlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 9 28789-76-8).

[0093] In another embodiment, the compound of formula (I) is The 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 The 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5 -Dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo -2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN-afoxolaner) be.

[0095] In another embodiment, the compound of formula (I) is The 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trimethylsilyl) 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) 5-[1'-methyl-3'-(1,1,2,2,2-pentafluoropropyl) 4'-(trifluoromethyl)[1,5'-bi-1H-pyrazol]-4-yl ]benzamide; tigoranel (CAS RN 1621436-41-6). [ka]

[0097] The isoxazoline compounds may 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 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 afoquixote. It is the (S)-enantiomer of solaner (also called esafoxolaner).

[0101] One important aspect of the present invention is a method for producing a medicament comprising the steps of: Preferably, the molybdenum is dissolved in a fat, wax, or mixture thereof having a melting point above about 50° C. and in combination with stable microspheres containing xydectin in an aqueous suspension.

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

[0103] The microspheres are 1-10 mm in diameter and are composed of a polymeric wax or other protective material. It is a small spherical particle of 00 μm. Preferred stable moxidectin milidates 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 mixtures 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 different macrocyclic lactone compounds (e.g., The compounds described herein include, but are not limited to, avermectins or milbemycins. In some embodiments, such avermectins or microspheres are Rubemycin is also known as 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 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 Contains combinations 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 prior to administration to an animal. X-ray or electron beam irradiation is an effective sterilization process for eliminating microbial contaminants. do.

[0110] However, moxidectin is easily degraded 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 beam 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. of about 50% to about 99% by weight. and about 1% to 50% moxidectin and about 0.01 to 10% of a mixture thereof. Containing or consisting essentially of 10% antioxidants.

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

[0113] The present invention further relates to moxidectin and isoxazoline compounds, particularly moxidectin A method for introducing the steroids (i.e., fluralaner and fluralaner) into an animal body and measuring their blood levels in the animal body Methods for maintaining the organism for extended periods of time are also provided; as well as methods for preventing and controlling worms, 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 about 0.01 weight percent. % to about 1.0% by weight.

[0115] In a specific embodiment, the injectable composition of the 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 preferred melting point of greater than 40°C. Or, it has a melting point higher than 50°C.

[0117] As used herein, the term "wax" refers to the wax that is used in Hawley's The Cond ensed Chemical Dictionary, Eleventh Edit As described in the "Pyrolysis and Polymerization" series, it is defined as a high molecular weight, low melting point organic mixture or compound. It is solid at room temperature and 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 The waxes include thermoplastic ethers or mixtures thereof. They are classified as lipids. However, since it is not a polymeric 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; Non-toxic; and free of unpleasant odor and color. 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. 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, but "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 having 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 for use in the practice of the present invention include those that stabilize the moxidectin compound. Included are all antioxidants known in the art to be suitable for use in the preparation of oxidants.

[0125] The antioxidants of the present invention are used to retard oxidation, staling, rancidity and gum formation, respectively. Defined as an organic compound added to rubber, natural fats and oils, food, gasoline and lubricants The rubber antioxidant is 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 are sterilized using gamma radiation or electron beam. and can maintain shelf life without significant loss of biological activity. Moxidectin generally degrades easily, especially when irradiated, reducing 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 Glucoside) butylated hydroxyanisole), BHT (butylated hydroxytoluene), monothioglycerol tert-Butylhydroxyquinone, 6-ethoxy-1,2-dihydro-2,2, 4-trimethylquinoline, with butylated hydroxytoluene being the preferred antioxidant It is.

[0129] In certain embodiments, the antioxidant is generally present in an amount of about 0.01 to about 0.5% 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. The shelf life can 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 molten fat, wax or mixture thereof, and then The resulting mixture can then be dispersed in water by various techniques such as emulsifying or spraying the mixture, or by The mixture is mechanically treated with the melted fat, wax or mixture thereof, for example in a centrifuge. 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 produce a solid which can then be separated by procedures such as grinding, milling, etc. It can be processed as follows.

[0133] The stable microspheres of the present invention are dispersed in a pharma- ceutical 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 preparation 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., carboxymethylcellulose) is The vehicle contains about 1 to 5% by weight of the vehicle, and inorganic salts (e.g., NaCl) are 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 a method for administering moxidectin and an isoxazoline compound (particularly fluralaner) to animals. and using the compositions herein to introduce and maintain levels in the bloodstream of Includes:

[0140] Isoxazoline compound particles having a defined particle size and moxidectin microparticles The injectable compositions of the present invention, including spheres, are capable of delivering a therapeutically effective amount of iodine while minimizing irritation at the injection site. These 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] Moreover, a single administration of such a composition generally provides for the treatment of one or more parasites (e.g., ectoparasites). While providing potent activity against living organisms, such as 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 are administered in a pharma- ceutically acceptable This involves administering an effective amount of an injectable composition together with an excipient.

[0144] Surprisingly, the compositions of the present invention described herein are substantially similar to those known in the art. Compared to other injectable compositions that have been developed, Superior broad spectrum efficacy against insects (e.g. fleas and ticks) faster and longer lasting 4. Provide a sustained, effective, and effective treatment for a sustained period of time while at the same time providing 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 pharma- ceutically acceptable excipient.

[0147] Pharmaceutically acceptable excipients include, but are not limited to, surfactants, antioxidants, 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 pharmacopoeitic 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 pharma- ceutically acceptable excipient. In another embodiment, the composition is about 5% to about 15% (w / v) or about 5% to about 1 0% (w / v) of pharma- ceutically acceptable excipients.

[0150] In yet another embodiment, the composition comprises about 7% to about 10% of a pharma- ceutically 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 about 10% (w / w) or about 5% to about 10% (w / w). The surfactant is preferably present at a concentration of about 0.1% to about 5% (w / w) or about 1% to about 5% (w / w). There may be.

[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 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., poloxamers, e.g., LUTROL® F) 87, etc.), polyethylene glycol castor oil derivatives, such as 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 glyceride) (G ELUCIRE®, PEG 300 Caprylic / Capric Glycerides (Sof tigen® 767), PEG400 Caprylic / Capric Glyceride (L abrasol®), PEG 300 oleic acid glyceride (Labrafil (R) 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) are mixed polioviruses Mixture of monostearate and distearate esters of oxyethylene polymers Polyethylene glycol hydroxystearate is a mixture of hydroxystearic acid and It is a mixture of mono- and diesters of polyethylene glycol. One type of polyethylene glycol hydroxystearate that can be used is polyethylene glycol hydroxystearate. In another embodiment, the composition of the present invention is The surfactant polyethylene glycol 15 12-hydroxystearate (BASF Kolliphor® HS15, manufactured by Kolliphor, a 12-hydroxystearic acid and 15-hydroxystearic acid The copolymer may comprise a mixture of mono- and diesters of ethylene oxide of the formula (I).

[0154] Moreover, 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 additional inactive ingredients, such as antioxidants, preservatives or pH stabilizers. These compounds are well known in the art of such compositions. .

[0157] Antioxidants, such as vitamin E, alpha tocopherol, ascorbic acid, palmitoyl Ascorbyl tartrate, citric acid, fumaric acid, malic acid, sodium ascorbate, methacryloyltransferase Sodium bisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated Hydroxyanisole), BHT (Butylated Hydroxytoluene), BHA and Citric Acid , monothioglycerol, tert-butylhydroquinone (TBHQ), benzyl alcohol Oils and the like can be added to the compositions of the present invention.

[0158] Antioxidants are generally present in the compositions of the present invention in an amount of about 100% by weight based on the total weight (w / w) of the composition. In particular, the amount is 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] A preservative, such as benzyl alcohol, is suitably present in the composition at 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 Paraben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, azole, ethylparaben, imidourea, methylparaben, phenol, phenoxyethanoate alcohol, phenylethyl alcohol, phenylmercury acetate, phenylmercury borate, Phenylmercury nitrate, potassium sorbate, sodium benzoate, sodium propionate Examples include sorbic acid, thimerosal, etc.

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

[0161] Preferred is benzyl alcohol.

[0162] Compounds that stabilize the pH of the composition may also be present. Such compounds and methods of using these compounds are well known to those skilled in the art. For example, acetic acid / acetate, malic acid / malate, citric acid / citrate, tartaric acid / alcohol Calcium carbonate, lactic acid / lactate, phosphoric acid / phosphate, glycine / glycimate e) 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 the moxide compound particles described herein. The present invention may comprise cutin microspheres in admixture with excipients suitable for the manufacture of an aqueous suspension. can.

[0164] Such excipients include: suspending agents, such as carboxymethyl Sodium cellulose, methylcellulose, hydroxypropyl methylcellulose, a 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 condensation products of partial esters derived from sorbitol, for example, polyoxyethylene sorbitol monoesters; Oleate, or partial esters derived from ethylene oxide and fatty acids and hexitol anhydrides Condensations 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 the 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 preservative. Wetting agents and suspending agents are exemplified by those already mentioned above.

[0167] In one embodiment, the isoxazoline compound is dissolved 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 that are non-polar.

[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 chlorine-based compound, diethylene glycol monoethyl ether (DGME, Transcut ol (registered trademark), butyl diglycol, dipropylene glycol n-butyl ether, Ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, diphenyl ether Propylene glycol monomethyl ether, 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, dimethylsulfoxide, glycerol formal, or A mixture of at least two of these solvents.

[0172] In one embodiment, the compositions of the present invention may be comprised of a polar protic solvent, including but not limited to a However, alcohol, e.g., ethanol, isopropanol, or glycol or glycolic acid may be used. In another embodiment, the long-acting injection of the present invention comprises Possible compositions include polar aprotic solvents, such as N-methylpyrrolidone, dimethyl isopropanol, etc. Sorbide, dimethylacetamide, dimethylsulfoxide or propylene carbonate include.

[0173] In one embodiment, the isoxazoline compounds may exist in various isomeric forms. A reference to a soxazoline compound always includes all possible isomeric forms of such a compound. Includes.

[0174] Unless otherwise indicated, compound structures in which a particular conformation is not shown are intended to represent the structure of that compound. The present invention includes compositions of all possible conformers of the compound, as well as compositions of all possible conformers of the compound. In some embodiments, the term "compound" is intended to encompass compositions that contain less than The object 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 compound of formula (I) is, for example, 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 may be prepared according to any other process falling within the scope of the present invention.

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

[0178] In one embodiment, the isoxazoline compound is in suspension in the composition. 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 polyoxyethylene stearate) 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 non-ionic triblock copolymer made of Please refer to.

[0184] Poloxamer 124 is a poly(ethylene glycol)-block-poly(propylene glycol) copolymer. (R)-block-poly(ethylene glycol) (CAS number 9003-11-6) Also known as Lutrol L44 or Kollisolv P124. .

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

[0186] In one embodiment, the pharmaceutical composition comprises a suspending agent. In one embodiment, the suspending agent is a calcination 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. Laben or propylparaben.

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

[0191] The method for preparing an injectable pharmaceutical composition comprises injecting isoxazoline particles into moxidectin microspheres. and combining the solid mixture with the granular spheres to form a solid mixture, which is then In the step of (a), the aqueous suspension is reconstituted with an aqueous liquid carrier to prepare 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 microemulsion. 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 are 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. , has been discussed.

[0198] Particle size and measurement of isoxazoline compound particles and moxidectin microspheres The injectable composition of the present invention comprises 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 have the same particle size.

[0200] Thus, in this specification, references to "particle size of the isoxazoline compound" include The moxidectin microspheres were mixed into compositions having the same particle size and measured in the same 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 from about 11 microns to about 250 microns, and from about 50 microns to about 150 micron particle size, about 75 microns to about 130 microns particle size, about 90 Particle size: microns to about 110 microns, particle size: about 30 microns to about 100 microns It has size.

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

[0203] D10 is the particle size distribution representing the size 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 a particular embodiment, 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, the particle size D50 is about 90-105 μm, and the 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, the particle size D50 is about 90-115 μm, and the 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, D50 of particle size is about 110 μm, and D9 of particle size is about 120 μm. 0 is approximately 150 μm.

[0219] In a particular embodiment, the particle size D10 is about 25-30 μm, and the particle size D D50 is about 95-100 μm, and the particle size D90 is about 160-170 μm It is.

[0220] In a particular embodiment, the particle size D10 is about 10-20 μm, and the particle size D D50 is about 85-110 μm, and the particle size D90 is about 170-185 μm It is.

[0221] In a particular embodiment, the particle size D10 is about 10-15 μm, and the particle size D D50 is about 95-105 μm, and the particle size D90 is about 175-180 μm It is.

[0222] In a particular embodiment, the particle size D10 is about 10 to 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 a particular embodiment, the particle size D10 is about 15-20 μm, and the particle size D D50 is about 45-55 μm, and particle size D90 is about 90-95 μm .

[0224] In a particular embodiment, the particle size D10 is about 30 to 50 μm, and the particle size The size D50 is approximately 70 to 130 μm.

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

[0226] In a particular embodiment, the particle size D10 is about 40 μm, and the particle size D50 is approximately 100 μm.

[0227] Volume weighted particle size is 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 a Sympatec Helos instrument.

[0229] For use in the present invention, the isoxazoline compound is preferably a final pharmaceutical composition according to the present invention. The compound is present in a pharmaceutical composition according to 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 according to 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 is present in amounts of

[0231] In one embodiment of the invention and / or embodiments of the invention, the composition comprises: (a1) a physiological (b) comprising eprinomectin as the macrocyclic lactone active against The isoxazoline compound includes fluralaner, preferably (S)-fluralaner. nothing.

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

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

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

[0235] In one embodiment of the invention and / or embodiments of the invention, the composition comprises: (a) a physiologically (b) containing eprinomectin as the active macrocyclic lactone, and The isoxazoline compound is afoxolaner, preferably (S)-afoxolaner. Includes

[0236] In one embodiment of the invention and / or embodiments of the 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 of the invention and / or embodiments of the invention, the composition comprises: (a) a physiologically (b) an isomer of the formula (I) containing selamectin as an active macrocyclic lactone; Afoxolaner, preferably (S)-afoxolaner, is used as the oxazoline compound. include.

[0238] In one embodiment of the invention and / or embodiments of the 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 of the invention and / or embodiments of the invention, the composition comprises: (a) a physiologically (b) containing eprinomectin as the active macrocyclic lactone, and Isoxazoline compounds include sarolaner.

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

[0241] In one embodiment of the invention and / or embodiments of the invention, the composition comprises a physiologically active (b) a macrocyclic lactone comprising selamectin, and Zoline compounds include sarolaner.

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

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

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

[0245] In one embodiment of the invention and / or embodiments of the invention, the composition comprises a physiologically active (b) a macrocyclic lactone comprising selamectin, and Zoline compounds include lotilaner.

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

[0247] Injectable compositions generally need to be sterilized prior to administration to an animal. In one preferred embodiment of 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 when irradiated and lose much of their biological activity. It has been reported that the 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 The amount 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] Administration of the additional therapeutic agent may be in the same composition or in a separate composition.

[0255] The additional therapeutic agent may 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-benzimidine dazoles (e.g., febantel, netobimin and thiophanate); benzimidazolidinates benzimidazole derivatives, such as thiazole benzimidazole derivatives (e.g. thiabendazole and campendazole), carbamate benzimidazole derivatives (e.g., fenben Albendazole, Albendazole (oxide), Mebendazole, Oxfendazole, Pa Rubendazole, oxibendazole, flubendazole and triclabendazole); Imidazothiazoles (e.g., levamisole and tetramisole); tetrahydropyri amides (morantel and pyrantel), salicylanilides (e.g., closantel, o cyclozanide, rafoxanide 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, bamazine and phenothiazines; dichlorophene, arsenicals (e.g., thiacetaramide, Melorsamine and arsenamide; Cyclooctadepsipep parahedramides (e.g., derquantel); and amino-acetonitrile compounds (e.g., monepantel, AAD1566); Compounds such as amidine and tribendimidine (these are all pharma- ceutical approved compounds).

[0043] The present invention includes any acceptable form thereof, such as a salt, solvate or 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 animals experience minimal injection site irritation.

[0259] As noted above, minimal injection site irritation lasted for less than 2-3 days. Mean injection site irritation 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 isoxygen used. The sazolin compound, the animal species 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 1 kg of animal body weight. About 0.01 to 200 mg per gram (in one embodiment, about 0.1 to 1 kg of animal body weight) 00 mg / kg of animal body weight, or 0.5 to 50 mg / kg of animal body weight The total dose may be administered in a single dose or in divided doses (1-30 mg / kg). The drug is administered at the prescribed dose.

[0263] Generally, good results are achieved with moxidectin at about 0.01 to 10 mg per 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] Injectable pharmaceutical compositions 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 dosing every six months.

[0267] Furthermore, administration every 12 months is also preferred. This allows the animal to be free of ectoparasites ( In particular, fleas and ticks) and internal parasites (in particular, filaria and / or gastrointestinal worms). 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, etc.) 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 a moxide The particle size D50 of cutin microspheres is about 75 microns to about 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 pharma- ceutically acceptable excipient capable of forming a suspension with the compound of (a); a vehicle containing the agent; and (c) Pre-injection of a solid crystalline isoxazoline compound with moxidectin microspheres. 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) according to claims 1, 8, 9, 10, 11, 12, 17 and 18; Particles of an isoxazoline compound and the moxidectin microspheres according to claims 1 to 12 a first container containing a solid mixture of A; (b) a second formulation comprising one or more suspending agents, wetting agents and / or preservatives, and an aqueous carrier comprising 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 of formula (I) as 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 (by injection) administering the compound to an animal (especially 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 a static light scattering instrument. It has a volume weighted particle size distribution D50 of about 250 microns.

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

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

[0278] Another aspect of the invention is a method of producing an injectable veterinary composition according to the invention, comprising the steps of: 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 mixing it with moxidectin and optionally Antioxidants were added and the 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 isocyanate microspheres obtained in step (a). placing in a first container together with the soxazoline particles; (d) dissolving excipients, including suspending agents, wetting agents and / or preservatives, in water and adding the mixture to a second container; preparing the aqueous carrier by placing (e) transferring the aqueous carrier from the second container (d) to the first container (c) and shaking to form a reconstituting said solid by forming

[0279] The rotating disc controls key process parameters such as melt temperature, flow rate and disc speed. To produce uniform spherical particles with a narrow particle size distribution span by controlling It is recognized as a manufacturing technique.

[0280] Spinning disk atomization uses mechanical energy to compress a 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 is then processed into microspheres by various techniques such as those shown above. The microspheres may be considered as microspheres prepared by forming them in a surgical procedure.

[0284] Alternatively, a mixture of the physiologically active macrocyclic lactone and, optionally, other excipients is cooled and A solid can be obtained by subjecting the solid to treatment, 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 of the invention and / or embodiments of the invention, the mixture in the first container A method for treating or preventing a parasitic infestation in an animal comprising administering to said animal an effective amount of any one of claims 1 to 14. 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 are and / or an isoxazoline compound represented by the formula ( II).

[0287] In one embodiment of the invention and / or embodiments of the 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 to animals a parasitic infestation for an extended period of time, such as 6 months or 12 months. and 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 is administered to an animal in need thereof. This involves administering the drug to the body via injection as directed.

[0289] Parasites, as previously described, 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, 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 represented (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 / kg, more preferably about 0.5 to about 50 mg / kg, particularly about 0.5 to about 50 mg / kg The total dosage is administered at about 1 to about 30 mg per kg of body weight. It may be administered in divided doses.

[0293] In a preferred embodiment of the present invention and / or preferred embodiments of the present invention, The active macrocyclic lactone (preferably moxidectin) is present at about 0.05 mg / kg of animal body weight. The dose is from about 0.01 to about 10 mg per kg of animal body weight, preferably from 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 chronic conditions, the treated animals experience minimal injection site irritation. I found out.

[0295] As noted above, minimal injection site irritation lasted for less than 2-3 days. Mean injection site irritation 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 to a subject in need of such treatment and / or prevention a therapeutically effective The method comprises administering to the subject a quantity 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, what has been described above 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, any combination of the features described above is clearly part of the invention. is considered to be. EXAMPLES

[0300] Working Example Example 1: Preparation of 10% moxidectin microspheres 10% moxidectin in glyceryl tristearate (GTS) microspheres The following recipe was prepared by spinning disk. [Table 4]

[0301] Briefly, 180 g of glyceryl tristearate was melted in a container and stirred. The mixture was heated to a temperature of 180° C. with 20 g of moxidectin and 0.06 g of butylated Hydroxytoluene was added and stirred until dissolved. The resulting molten solution was cooled to about 80° C. and pumped over 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 - 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. Then, place the container in a container for sterilization. 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. 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 non-irradiated assay It has been reported as: [Table 5] TIFF2024170642000021.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 heat and add cold distilled water for injection. In Example 3B and Example 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 the container.

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

[0307] Samples 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 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 milibu The microspheres and crystalline Fluralaner particles are then added and the container is shaken 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, 25 kGy); B. 15% Fluralaner + 0.17% Moxidectin Microspheres (not sieved) , GTS, 15 kGy); 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 water for injection; 2. Add a suspending agent (sodium carboxymethylcellulose (NaCMC)) Mix with an overhead mixer for approximately 5 minutes; 3. The mixture was further mixed with the homogenizer until no agglomerates were present; 4. Add the wetting agent (Poloxamer 124) and mix with an overhead mixer until uniform. Mixed with; 5. Add preservative (benzyl alcohol (BA)) and mix overhead until uniform. 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. (for 5 minutes); 8. Adjust the pH of the mixture to pH 7.0-7.4 by adding HCl and stir until homogenous. 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 until homogenous. Mix gently with a bar head mixer (5 min); 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 on a cycle.

[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 radiation.

[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. The range was ~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 0.17 mg moxidectin / kg BW) was administered subcutaneously in a single dose.

[0318] The local tolerance of the above formulations was evaluated for at least 21 days after administration.

[0319] Blood samples for measuring moxidectin and total fluralaner plasma concentrations were collected pretreatment. , 8 hours after treatment, and 1 day, 3 days, 5 days, 7 days, 10 days, 14 days, 21 days, and 2 days after treatment. 8th, 35th, 42nd, 49th, 56th, 70th, 84th, 98th, 112th, 126th , 140th, 154th, 168th and 182nd 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 comprising: (a) from about 50% by weight to about 99% by weight of a fat, wax, or mixture thereof, and 0.01% by weight of moxidectin microspheres comprising from about 10% to about 10% by weight of an antioxidant; and (b) Formula (I) [Formula 1] [During the ceremony, R １ = halogen, CF ３ , O.C.F. ３ , C.N.; n=an integer from 0 to 3, preferably 1, 2 or 3; R ２ = C １ -C ３ -haloalkyl, preferably CF ３ Or CF ２ Cl; T=a 5-12 membered monocyclic or bicyclic ring system optionally substituted with one or more radicals Y ; Y = methyl, halomethyl, halogen, CN, NO ２ , N.H. ２ -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=CH ２ , CH(CH ３ ), 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, haloethyl haloethylaminocarbonylethyl, tetrahydrofuryl, Methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, pro Cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl haloethylaminocarbonylcyclopropyl, [Case 2] [Here, Z Ａ = Hydrogen, halogen, cyano, halomethyl (CF ３ ) ]; R ４ = Hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl Toxomethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, Aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, di Methoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl haloethylaminocarbonylethyl; Or, R ３ and R ４ Together, [C3] forming a substituent selected from the group consisting of Particles of an isoxazoline compound represented by the formula: wherein the moxidectin microspheres and the isoxazoline compound particles comprise In an aqueous carrier containing the above suspending agent, one or more wetting agents and / or one or more preservatives, and water The injectable veterinary composition is suspended in

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

3. The moxidectin microspheres are from about 75% to about 95% by weight of the fat, wax, 3. An injectable veterinary composition according to claim 1 or 2, comprising:

4. 4. The method according to claim 1, wherein the fat, wax or mixture thereof comprises a fatty acid ester.

10. An injectable veterinary composition according to claim 1.

5. The fatty acid ester is a triglyceryl ester of a fatty acid, each of which is 5. The injectable veterinary composition of claim 4, wherein said alkyl group contains from 12 to 22 carbon atoms.

6. 6. The injectable composition of claim 5, wherein the fatty acid ester is glyceryl tristearate. A veterinary composition capable of

7. The moxidectin microspheres contain moxidectin in an amount of about 9-12% by weight and 8 7. The composition according to claim 1, further comprising glyceryl tristearate in an amount of from 7 to 92% by weight.

4. An injectable veterinary composition as defined in claim 1.

8. The moxidectin microspheres and / or isoxazoline compound particles are subjected to static light having a volume weighted particle size distribution D50 of about 25 μm to about 250 μm as measured by a scattering device; An injectable veterinary composition according to any one of claims 1 to 7,

9. The particle size distribution of the moxidectin microspheres and / or isoxazoline compound 9. The injectable veterinary composition of claim 8, wherein the fabric D50 is from about 75 μm to about 150 μm. Composition.

10. The isoxazoline compound particles have a diameter of 10 μm or less as measured by a scanning electron microscope. Having a thickness of at most less than 100 μm (preferably greater than 20 μm and less than 90 μm) An injectable veterinary composition according to any one of claims 1 to 9.

11. The isoxazoline compound particles have a thickness of more than 30 μm and less than 80 μm.

11. The injectable veterinary composition of claim 10.

12. The amount of moxidectin microspheres and / or isopropyl alcohol measured by a static light scattering device The volume weighted particle size D10 of the xazoline compound particles is about 20 to 35 μm, and the particle size The particle size D50 is about 90 to 105 μm, and the particle size D90 is about 155 to 1 An injectable veterinary composition according to any one of claims 1 to 11, which is 75 μm.

13. The suspending agent is sodium carboxymethylcellulose, polyvinylpyrrolidone and The injectable veterinary agent according to any one of claims 1 to 12, selected from methylcellulose. Medical composition.

14. The composition according to claim 1, wherein the composition comprises from about 0.5% to about 15% by weight of the composition of a suspending agent.

14. An injectable veterinary composition according to any one of claims 13.

15. The injectable composition according to any one of claims 1 to 14, wherein the wetting agent is a poloxamer. Veterinary compositions.

16. 10. The composition of claim 1, wherein the composition comprises from about 0.01% to about 1.0% by weight of the composition of a humectant.

16. An injectable veterinary composition according to any one of claims 1 to 15.

17. The isoxazoline compound is fluralaner, afoxolaner, sarolaner or loxolaner. The injectable veterinary composition according to any one of claims 1 to 16, wherein the injectable veterinary composition is selected from Tiranel. Composition.

18. The method according to any one of claims 1 to 17, wherein the isoxazoline compound represented by formula (I) is fluralaner. An injectable veterinary composition according to any one of claims 1 to 4.

19. A kit, comprising: (a) a compound represented by formula (I) according to claims 1, 8, 9, 10, 11, 12, 17 and 18; Particles of an isoxazoline compound and the moxidectin microspheres according to claims 1 to 12 a first container containing a solid mixture of A; (b) a second formulation comprising one or more suspending agents, wetting agents and / or preservatives, and an aqueous carrier comprising water; a container for (c) Mix the moxidectin microspheres and the injectate prior to subcutaneous or intramuscular injection into the animals. instructions for reconstituting the soxazoline compound particles with said aqueous carrier; The kit comprising:

20. The first container contains an effective amount of moxa sufficient to treat or prevent a parasitic infestation in an animal. Cydectin and an isothiocyanate of formula (I) according to claim 1, 17 or 18.

20. The kit of claim 19 comprising a xazoline compound.

21. The kit further comprises reconstituting a mixture of compositions from the first and second containers to administer to an animal.

21. The kit of claim 19 or 20, comprising a device for parenteral administration to

22. The kit of claim 21 , wherein the device comprises a syringe.

23. In the first container, an isoxazoline compound represented by formula (I) and / or moxazoline compound represented by formula (I) The cydectin microspheres have a diameter of approximately 25 microns as measured by a static light scattering instrument.

23. Any of claims 19 to 22 having a volume weighted particle size distribution D50 of about 250 microns. The kit according to any one of claims 1 to 5.

24. In the first container, the particle size D10 of the isoxazoline compound is about 20 to 30 5 μm, the D50 of the particle size is about 90-105 μm, and The kit according to any one of claims 19 to 23, wherein the D90 is about 155 to 175 μm. .

25. A method for treating or preventing a parasitic infestation in an animal, comprising the steps of: administering to an animal in need thereof an injectable veterinary composition according to claims 1 to 18. The method.

26. A method for producing an injectable veterinary composition according to any one of claims 1 to 18. So, (a) preparing isoxazoline particles; (b) Melting a fat, wax or mixture thereof and mixing it with moxidectin and, optionally, Antioxidants were added and the microspheres were prepared by spinning disk atomization. preparing moxidectin microspheres by sieving; (c) The moxidectin microspheres obtained in step (b) are mixed with the isocyanate microspheres obtained in step (a). placing in a first container together with the soxazoline particles; (d) dissolving excipients, including suspending agents, wetting agents and / or preservatives, in water and adding the mixture to a second container; preparing the aqueous carrier by placing (e) transferring the aqueous carrier from the second container (d) to the first container (c) and shaking to prepare a ready-to-use aqueous carrier; reconstituting said solid by forming a usable suspension; The method comprising:

27. The reconstituted suspension obtained by the process of claim 26 is administered subcutaneously or intravenously to an animal. The method of treating or preventing a parasitic infestation in an animal includes administering the compound by intramuscular injection. Use of the kit according to any one of claims 19 to 24 for the purpose of

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