Anti-parasitic pore-forming composition

Abstract

To provide veterinary compositions for controlling parasites in animals, to provide use of these compositions against parasites, and to provide methods for preventing or treating parasitic infections and infestations in animals.SOLUTION: Provided is a liquid veterinary pour-on or spot-on composition comprising at least one isoxazoline compound of formula (I) and a pharmaceutically acceptable carrier (comprising at least one dermal penetration enhancer comprising menthol and a solvent system comprising a pyrrolidone solvent). Also provided are methods of using and administering such preparation in the prevention and control of parasite infestations in livestock animals.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to veterinary compositions for controlling parasites in animals, the use of these compositions as parasites. Use against parasitic worms and the prevention of parasitic infections and infestations in animals The present invention provides a method for preventing or treating a bacterial infestation. [Background technology]

[0002] Several types of pests and parasites infect domestic animals such as cattle, horses, pigs, and sheep, as well as cats and dogs. These pests and parasites can infest or infect companion animals such as It's very annoying for both of them.

[0003] Ectoparasites of animals, such as ticks, mites, lice and flies, can be found on the animal. and, by themselves or by carrying vector-borne pathogens, Domestic animals such as cattle or sheep are susceptible to different parasites, e.g. ticks. Biting lice and chewing lice ), and hematophage stable flies and blow flies. can.

[0004] Particularly important ectoparasites of cattle are ticks, e.g. Rhipicephalus bovis halus microplus) (cattle tick) and Kenyan R. sanguineus (R. de coloratus and Rhipicephalus annulatus Tick ​​infestations occur on poor quality leather, wool or sheepskin, poor quality meat / tissue, body weight This has caused significant economic losses in livestock due to reduced growth and reduced milk production. obtain.

[0005] In addition, ticks are involved in the transmission and spread of many diseases worldwide. are carriers of bacterial (e.g. rickettsial), viral and protozoal diseases; This causes tick paralysis and tick toxicosis.

[0006] Sheep and other livestock are infested with lice, blowflies, ticks, head flies, and ly), infested by a wide range of ectoparasites such as sheep lice and sheep scabies. Of particular importance are sheep blow flies, e.g. Lucilia cuprina, L. serirc ata), Chrysomyia rufifacies and The larvae of the blow fly Calliphora stygia are infected Blow flies are parasites that can cause severe suffering and loss of productivity in infected sheep. During certain times of the year when they are active, adult blowflies lay eggs on sheep. These eggs hatch and The larval stage then begins feeding on the flesh of the infected sheep, causing blow fly strike (bl The disease causes what is known as sheep fly strike or sheep myiasis.

[0007] The administration of parasiticides to animals, particularly livestock such as cattle and sheep, is extremely labor intensive. It is a laborious task and causes stress and weight loss for the animals. Such frequent treatments are particularly undesirable in feedlots and pastures. do not have.

[0008] Isoxazoline-substituted benzamide derivatives are known ectoparasiticides. .

[0009] Isoxazoline-substituted benzamide derivatives are useful for veterinary insecticidal and pesticidal purposes. As potential pesticides for mite applications, WO2005 / 085216 (N was first described in the Journal of Issan Chem. Ind. and subsequently as a parasiticide. It has been further developed for use as a

[0010] On the other hand, many variants of isoxazoline pesticides have been reported, e.g. Described in: WO2007 / 079162, WO2008 / 122375, WO20 09 / 002809, WO2009 / 024541, WO2009 / 080250, WO 2010 / 070068, WO2010 / 079077, WO2011 / 075591, WO2011 / 124998, WO2012 / 155352, WO2012 / 15567 6, WO2012 / 158396, WO2015 / 048371, WO2015 / 066 277 and EP2865369.

[0011] Several isoxazoline parasiticides have been shown to be effective in preventing or treating ectoparasitic infestations. Specific references to veterinary uses in the field are given below. Examples include: Fluralaner (CAS registration number: 864731-61-3), Afoxolaner (CAS RN:1093861-60-9), Lotilaner (CAS RN:1369852-7 1-0), and sarolaner (CAS RN: 1398609-39-6).

[0012] The isoxazoline active agent is used alone or in combination with other active agents described in the above references. Although there are compositions containing the same, there are also compositions for treating livestock animals against ectoparasites. There is a need for effective veterinary compositions and methods for protecting against Thus, the present invention solves at least one general problem and several specific problems.

[0013] An optimal composition should be effective and contain active ingredients to avoid the need for frequent reapplication. It should have rapid onset and long duration of activity and be compatible with the host animal and the human subject. It should be safe for humans and have desirable bioavailability and a desirable range of applications. should also have

[0014] Additionally, an optimal composition should be sufficiently easy to apply and wash off during rainfall. should have limited propensity to become infected and should remain effective on wet animals. It should dry within a reasonable time without damaging the animal's appearance and should be gentle on the animal's coat. The skin irritation of the animal should be tolerable, and and its effectiveness on animals through their normal activities, such as exposure to sun and water. should be maintained.

[0015] In livestock animals, such as sheep, cattle, and other animals including goats, pigs, and horses To control ectoparasites, topical application of a pour-on composition containing one or more active ingredients is used. It is common practice to use

[0016] Pour-on veterinary compositions of NSAID compounds for treating systemic anti-inflammatory diseases include It is described in US2013 / 0310372.

[0017] WO2012 / 089622 and WO2013 / 039948 disclose isoxazoline Compositions for topical administration of the compounds are disclosed. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] WO2005 / 085216 [Patent Document 2] WO2007 / 079162 [Patent Document 3] WO2008 / 122375 [Patent Document 4] WO2009 / 002809 [Patent Document 5] WO2009 / 024541 [Patent Document 6] WO2009 / 080250 [Patent Document 7] WO2010 / 070068 [Patent Document 8] WO2010 / 079077 [Patent Document 9] WO2011 / 075591 [Patent Document 10] WO2011 / 124998 [Patent Document 11] WO2012 / 155352 [Patent Document 12] WO2012 / 155676 [Patent Document 13] WO2012 / 158396 [Patent Document 14] WO2015 / 048371 [Patent Document 15] WO2015 / 066277 [Patent Document 16] EP2865369 [Patent Document 17] US2013 / 0310372 [Patent Document 18] WO2012 / 089622 [Patent Document 19] WO2013 / 039948 Summary of the Invention [Problem to be solved by the invention]

[0019] Therefore, what is needed in the art is a method and apparatus that addresses one or more of the above-mentioned shortcomings. The present invention relates to a topical composition of an isoxazoline compound that avoids the above-mentioned problems. [Means for solving the problem]

[0020] 1. The present invention provides an effective amount of a compound of formula (I) [ka]

[0021] [During the ceremony, R 1 = halogen, CF3, OCF3 or CN; n=an integer from 0 to 3 inclusive; m=1 or 2; R 2 =C1-C3 haloalkyl; T=ring structure: 5- or 6-membered or bicyclic, which is substituted with one or more radicals Y may have been; Y=methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or Two adjacent radicals Y together form a chain; Q=X-NR 3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or one or more is a 5-membered N-heteroaryl ring optionally substituted with a radical; 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, alkylsulfani alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl kill, [ka]

[0022] and; Where: Z A = hydrogen, halogen, cyano or 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 methylaminocarbonylmethyl or haloethylaminocarbonylethyl. ; R 5 =H, alkyl or haloalkyl; R 6 =H, alkyl or haloalkyl; or where R 3 and R 4 Together, [ka]

[0023] forming a substituent selected from the group consisting of or a pharma- ceutically acceptable salt thereof. VETERINARY LIQUID COMPOSITION FOR USE IN THE PROTECTION AND TREATMENT OF PARASITIC INFECTION IN ANIMALS COMPRISING THE SAME - Patent application wherein the composition is administered as a pour-on or spot-on and and a pharma- ceutically acceptable carrier comprising at least one skin permeation enhancer and a solvent system, wherein the skin penetration enhancer comprises menthol and the solvent system comprises a pyrrolidone solvent. Liquid medical compositions are of interest.

[0024] In one embodiment, the solvent system comprises a volatile solvent.

[0025] In another embodiment, the composition comprises a glycerol ester.

[0026] In one embodiment, the composition is administered as a spot-on.

[0027] In another embodiment, the composition is administered as a pour-on.

[0028] In one embodiment, the present invention relates to treating livestock animals, such as bovine or ovine animals, with ectoparasites. 5. A method for protecting an animal in need of such protection from invasion by The veterinary liquid pour-on compositions or spot-on compositions described in this application are administered in effective doses. The method includes administering the composition.

[0029] In another embodiment, the present invention provides a method for treating tick, mite or louse infestations in bovine animals. The method comprises administering to an animal in need of such treatment an effective dosage of a compound according to the present application. By administering the veterinary liquid pour-on or spot-on compositions described herein, Includes.

[0030] In another embodiment, the present invention relates to a method for the treatment of a pulmonary artery disease using any of the methods described above. A method of administering the pour-on composition described herein for the treatment of a rheumatoid arthritis, comprising administering to said patient a pour-on composition comprising: The law is (a) The composition is applied through a press-in bottle application device. Incorporating the device into a fusion device; and (b) administering to an animal in need thereof an effective amount of the composition by pour-on administration to the back of the animal; Administering accordingly; [Brief description of the drawings]

[0031] [Figure 1]Figure 1 shows the therapeutic tick efficacy against Rhipicephalus microplus in cattle obtained when pour-on compositions containing 5 mg / kg body weight of fluralaner were administered to tick-infested cattle on days 1 to 22 of the study. The graph shows compositions No. 72 (T2) and No. 73 (T3) according to the invention compared to alternative pour-on compositions (Table 4 - No. 71 (T1) and No. 74 (T4)) on day 0. [Diagram 2] FIG. 2 shows the long-term tick efficacy against Rhipicephalus microplus in cattle obtained when the pour-on composition was administered to tick-infested cattle from days 23 to 115 of the study. [Diagram 3] FIG. 3 shows in one graph the information on % tick control per day obtained from FIGS. 1 and 2 above, combined with the plasma concentration of fluralaner in the blood. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The present invention provides a method for treating a subject comprising administering to a subject a therapeutically effective amount of at least one isoxazoline compound, either alone or in combination with another active agent. Veterinary liquid compositions containing the same in combination, and compositions thereof for controlling parasites in livestock animals - Patents.com Provide for the use of.

[0033] It is therefore an object of the present invention to provide a method for administering the pour-on or spot-on compositions of the present invention. Possibly by parasites, especially ectoparasites, in livestock animals, especially cattle and sheep. The present invention provides methods for preventing, treating and controlling infection or infestation.

[0034] The preferred pour-on or spot-on veterinary application is a single dose administered over an extended period of time. and preferably for a period of 21 days or more, providing effective protection to treated animals. In addition to the duration of efficacy, the technical characteristics of the pharmaceutical composition, e.g. , ease of application (applicability / viscosity), side effects (local tolerance) and in animals (especially livestock) Residues in are an important feature.

[0035] According to the present invention, the compositions of the present invention generally have one or more of such advantageous technical features: It has been found that the

[0036] In addition, a single administration of such a composition generally provides potent protection against one or more ectoparasites. and exhibiting potent activity while exhibiting rapid onset of activity, long duration of activity, and / or improved immunity to the host animal and These drugs also tend to offer a favorable safety profile for both animal handlers and caregivers. Found.

[0037] Such pour-on or spot-on compositions surprisingly have the following properties: Stable, i.e. the active ingredient does not decompose and there are no incompatibilities due to excipients Furthermore, it has been found that the composition is easy to administer to the animal.

[0038] The expression "pour-on" refers to a liquid that is dispensed in a measuring cup or squirt bottle or automated microspray device. Using suitable equipment, animals can be topically and locally Ready-to-use products that are intended to be applied se) is understood to denote a concentrate.

[0039] The pour-on composition is typically applied in one or more lines along the dorsal midline (back) or shoulder of the animal. Typically, it is applied by pouring, often in a few lines, or as a spot-on. The composition is applied by pouring along the back of the animal, following the spine.

[0040] Such pour-on administration involves applying a small amount of the composition directly onto the skin of the animal to be treated. This allows the active ingredient to protect the entire outer surface of the animal. and, if necessary, the active ingredient (depending on its molecule) ) penetrates the skin and enters the body and acts transdermally. Preferably, the effective blood level is The composition of the present invention is administered to the skin of a cow, which is particularly difficult to administer via the skin. Therefore, when the composition of the present invention is administered by pour-on or spot-on administration, It was unexpected that effective blood levels could be achieved after What has been determined is the duration of protection. Thus, in one embodiment, the composition of the present invention is administered to cattle. and is administered for more than 2 weeks, preferably more than 4 weeks, more preferably more than 6 weeks. The present invention provides protection against ectoparasites in bovine animals for a period of 1, 8 weeks, 10 weeks or more than 12 weeks.

[0041] Pour-on compositions include liquids, emulsions, foams, pastes, aerosols, ointments (oi The composition may be in the form of a liquid, salve or gel. Typically, pour-on compositions are liquids and and after administration, the drug is sufficiently attached to the animal's fur / skin to remove the drug from the animal's fur or skin. It has sufficient viscosity to prevent spillage, is easily administered, and can be used in a variety of applications, e.g. The temperature allows for precise release of the dose from the container.

[0042] Liquid dosage forms considered suitable as pour-on compositions generally include solutions, suspensions, and the like. A solution is a mixture of two or more liquids that form a single, homogeneous phase down to the molecular level. A suspension is a mixture of insoluble solid particles dispersed in a liquid medium. The solid particles account for about 0.5% to about 30% of the suspension. The liquid may be water-based, oil-based, or both. An emulsion is a heterogeneous dispersion of one immiscible liquid in another; It relies on emulsifiers for stability.

[0043] To be successfully formulated as a pour-on, a suitable solvent that is well tolerated by the animal's skin must be selected. It is necessary that the compound is active when dissolved, dispersed or emulsified in the medium.

[0044] Preferably, for bovine animals, a pour-on composition with a volume of 30 mL or less per animal. For sheep animals, a pour-on composition is administered in a volume of 10 mL or less per animal. In one embodiment, the composition contains a viscosity enhancing component. In an embodiment, the pour-on solution is a solution of the active ingredient. In one embodiment, the pour-on solution is 50% w / In another embodiment, the active ingredient of formula v is an isoxazoline compound, in particular fluralaner. In another embodiment, the concentration of the active ingredient is 40 to 50% w / v. The composition according to the present invention is free of precipitation of the active ingredient and has spot-on These have the advantage of producing effective blood levels following administration by injection or pour-on.

[0045] The expression "spot-on" refers to the application of a small amount of the drug using a suitable device such as a pipette or syringe. administered topically and locally to the animal. It represents a ready-to-use concentrate that is intended to be used It will be understood that, alternatively, a multi-dose applicator may be used.

[0046] The spot-on composition is typically administered in one spot along the dorsal midline (back) or shoulder of the animal. Or by administering several spots. More typically, the composition comprises: It is applied as a spot between the animal's shoulders. Preferably, for sheep animals, it is applied to one animal. For bovine animals, apply a spot-on composition in a volume of 10 mL or less per animal. The spot-on composition is administered in a volume of 30 mL or less per day. In one embodiment, the spot-on solution is a 50% w / w solution of the active ingredient. In another embodiment, the active ingredient of formula v is an isoxazoline compound, in particular fluralaner. In another embodiment, the concentration of the active ingredient is 40 to 50% w / v. The composition according to the present invention is free of precipitation of the active ingredient and has spot-on These have the advantage of producing effective blood levels following administration by injection or pour-on.

[0047] In an alternative embodiment, particularly for sheep, the active ingredient is administered in a concentration of 1-10% w / v. It is preferably applied at 2 to 8% w / v, more preferably at 2.5 to 5% w / v. do.

[0048] Such spot-on administration deposits a small amount of the composition on the surface of the skin of the animal being treated. This allows for the direct application of the active ingredient to the outer surface of the animal. The active ingredient moves (spreads) to protect the whole, and if necessary, They penetrate the skin and enter the body (depending on the molecule) and act transdermally.

[0049] Spot-on compositions include liquids, emulsions, foams, aerosols, ointments, etc. The composition may be in the form of a liquid formulation, salve or gel. Typically, the spot-on composition is a liquid, and and, after administration, adheres sufficiently to the animal's fur / skin to allow for flow-out from the animal's fur or skin. It has sufficient viscosity to prevent spillage and is easily administered, e.g. Precise amounts can be released from the container at different temperatures.

[0050] Liquid dosage forms considered suitable as spot-on compositions generally include solutions, suspensions, and the like. A solution is a suspension or emulsion. A solution is a mixture of two or more liquids that form a single homogeneous phase at the molecular level. A suspension is a mixture of the above components. A suspension consists of insoluble solid particles dispersed in a liquid medium. The solid particles account for about 0.5% to about 30% of the suspension. The liquid may be water-based, oil-based or other liquids. An emulsion is a heterogeneous dispersion of one immiscible liquid in another. ; it depends on the emulsifier for stability.

[0051] To be successfully formulated as a pour-on or spot-on, the drug must be well tolerated by the animal's skin. The compound must exhibit activity when dissolved, dispersed or emulsified in a suitable solvent that exhibits It is essential.

[0052] If transdermal activity is desired, the compound should be readily absorbable through the skin of the animal. and the composition should be sufficiently dispersed or spread throughout the animal's body as a whole. and when so spread, should have a relatively low viscosity.

[0053] Furthermore, each compound requires special consideration and may contain solvents, diluents, It has unique chemical and physical properties that limit the types of stabilizers and other excipients. It is important to recognize that.

[0054] However, one difficulty encountered when attempting to achieve a pour-on transdermal composition is It is a fact that the skin has been described as a "black box" with regard to drug delivery. This is due to a lack of knowledge about the mechanisms of drug penetration through the epidermis and its distribution to the underlying layers. So far, no boundaries have been defined for such properties; This has led to the question of what compounds can be effectively delivered transdermally. This makes it extremely difficult to predict.

[0055] Transdermal systems that are effective for delivering one compound are often ineffective for delivering another compound. In addition, systems and devices that work in one species are usually ineffective in another. Furthermore, the presence of the stratum corneum barrier allows most of the transport through the skin to occur via the permeability This is usually too slow for rapid and extensive systemic absorption. Very few commercially available transdermal products are designed for immediate drug delivery or long-term action. Most transdermal drugs that work in humans are delivered to skin that has fur. The skin of cattle is not suitable for animals that are sensitive to the skin, particularly animals of the bovine subfamily, such as cattle. Therefore, one embodiment is a bovine It may be a pour-on or spot-on composition.

[0056] The compositions according to the invention allow the isoxazoline compound to penetrate the skin and reach another part of the body, e.g. Such pour-on compositions allow or facilitate the administration of the active ingredient to a patient's entire body (e.g., the entire body). Alternatively, the spot-on composition may comprise administering the isoxazoline to a suitable veterinarily or pharma- ceutical acceptable carrier. The composition can be prepared by dissolving, suspending or emulsifying the composition in a suitable carrier.

[0057] The compositions of the present invention are suitable for use as a treatment for dry skin, as they are easily washed off by wet animals or by rainfall that occurs after treatment. Upon contact with water, the active ingredient dissolves in water-miscible solvents, thus avoiding the disadvantage of being washed away. Rapid precipitation from conventional solvent-based compositions occurs when the composition is applied to a wet animal. Or, if the animal is exposed to rain before the treatment has had a chance to dry on the animal's surface, the active ingredient may come out of solution. The solvent precipitates from the soil and accumulates along the animal's back, and the solvent is washed away by rain. This prevents or prevents percutaneous absorption (if necessary) and limits the amount of active ingredient in the whole animal. This phenomenon is particularly important in the lower regions of the animal. Under these conditions, efficacy may be reduced.

[0058] In reality, the theory is that it is designed for use on farms with cattle or sheep, especially cattle. A contemplated veterinary composition has a shelf life of at least 12 months, preferably 24 months, at 30°C. It should have a shelf life, whereby excess is not necessary to achieve that shelf life. .

[0059] A "pharmaceutical or veterinary acceptable carrier" is generally a carrier that is safe, non-toxic and biologically acceptable. and (b) providing a carrier useful in the preparation of a pharmaceutical composition which is not undesirable in any other respect or in any other respect. It means and includes any carrier that is acceptable for veterinary or pharmaceutical use.

[0060] In some embodiments, the topical veterinary composition comprises a pharma- ceutically acceptable carrier, wherein The carrier comprises at least one solvent and at least one penetration enhancer.

[0061] For purposes of use in this invention, "isoxazoline" or "isoxazoline compound" means , the compound: [ka]

[0062] Where: R 1 = halogen, CF3, OCF3 or CN; n=an integer from 0 to 3 inclusive; m=1 or 2; R 2 =C1-C3 haloalkyl; T=ring structure: 5- or 6-membered or bicyclic, which is substituted with one or more radicals Y may have been; Y=methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or Two adjacent radicals Y together form a chain; Q=X-NR 3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or one or more is a 5-membered N-heteroaryl ring optionally substituted with a radical; 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, alkylsulfani alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl kill, [ka] TIFF0007627312000006.tif149131

[0063] and; Where: Z A = hydrogen, halogen, cyano or 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 methylaminocarbonylmethyl or haloethylaminocarbonylethyl. ; R 5 =H, alkyl or haloalkyl; R 6 =H, alkyl or haloalkyl; or where R 3 and R 4 Together, [ka] TIFF0007627312000008.tif51138

[0064] The substituents are selected from the group consisting of:

[0065] In one embodiment, T is [ka] TIFF0007627312000010.tif172149

[0066] Selected from; where in T-1, T-3 and T-4, the radical Y=hydrogen, halogen, methyl, It is halomethyl, ethyl or haloethyl.

[0067] In one embodiment, Q is [ka] TIFF0007627312000012.tif53142

[0068] Selected from; Here, R 3 , R 4 , X and Z A is as defined above; and Z B = [ka]

[0069] and Z D teeth, [ka]

[0070] It is.

[0071] In one embodiment, in the isoxazoline of formula (I), (R 1 ) n , R 2 , R 3 , R 4 , T, Y, Q, Z and X are as given in Table 1. [Table 1] TIFF0007627312000016.tif103163

[0072] In one embodiment, in the isoxazoline of formula (I), (R 1 ) n , R 2 , R 3 , R 4 , T, Y, Q, Z and X are as given in Table 2. [Table 2]

[0073] In one embodiment, the isoxazoline for use in the present invention is the compound: [ka]

[0074] where R 1a , R 1b , R 1c are each independently hydrogen, Cl or CF3 be.

[0075] Preferably, R 1a and R 1c is Cl or CF3, R 1b is hydrogen; T is [ka]

[0076] where Y is methyl, bromine, Cl, F, CN or C(S)NH2; n= 1 or 2; and Q is as described above.

[0077] In one embodiment of the isoxazoline defined herein, R 3 is H, and Then, R 4 is -CH2-C(O)-NH-CH2-CF3, -CH2-C(O)-NH -CH2-CH3, -CH2-CH2-CF3 or -CH2-CF3.

[0078] In a preferred embodiment of the pharmaceutical composition according to the invention, the isoxazoline is and one or more selected from the group consisting of: Fluralaner, afoxolaner, lotilaner, sarolaner; (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4 ,5-Dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2 -Methylbenzamide (CAS RN: 928789-76-8); 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H- [Isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN:1164267-94-0) [This is WO2009 / 0080250 ]; and 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluorophenyl) 2-oxo-2-[(2,2 ,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN:1231754-09-8) [This is disclosed in WO2010 / 070068 [is being reported].

[0079] Thus, in a preferred embodiment of the pharmaceutical composition according to the invention, the isoxazoline is and one or more selected from the group consisting of: fluralaner, afoxolaner, Lotilaner and sarolaner.

[0080] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is fluralaner. In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is afoxolaner. In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is lotilaner. In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is sarolaner. .

[0081] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is (Z)-4-[5- (3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxa [(3-yl)-N-[(methoxyimino)methyl]-2-methylbenzamide (C AS RN:928789-76-8).

[0082] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is 4-[5-(3,5 -dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl 2-methyl-N-(thietan-3-yl)benzamide (CAS RN: 1164 267-94-0) [which is disclosed in WO2009 / 0080250] .

[0083] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is 5-[5-(3,5 -dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxoxy 3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl )Amino]ethyl]-2-thiophenecarboxamide (CAS RN:1231754- 09-8) [which is disclosed in WO2010 / 070068].

[0084] In a further preferred embodiment of the pharmaceutical composition according to the invention, the isoxazoline is flurazoline. Fluralaner is effective against ectoparasites in cattle and sheep after topical administration. This shows excellent efficacy and duration of parasiticidal effect. showed.

[0085] The isoxazolines for use in the present invention may be substituted or unsubstituted phenylalanines, including pharma- ceutically acceptable salts thereof, This also includes ter and / or N-oxide.

[0086] The pharma- ceutically acceptable salts of the isoxazoline compounds represented by formula (I) or (II) are , the physical properties of the salt (e.g., pharmaceutical stability at different temperatures and humidities; crystalline properties and / or desirable solubility in water, oil, or another solvent). Acid and base salts are typically prepared, for example, by a variety of methods known in the art. The compound is formed by mixing it with an acid or base, respectively, using a method such as the It is possible.

[0087] Additionally, references to isoxazoline compounds include any of their polymorphic forms or stereoisomers. also applies equally.

[0088] The isoxazoline compounds may exist in various isomeric forms. References to compounds corresponding to the intermediates and uses according to the invention always include references to compounds of such compounds. All possible isomeric forms are included.

[0089] 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. The S-enantiomer of fluralaner exists.

[0090] Isoxazolines were detected by liquid chromatography using standard equipment and procedures. It is possible to detect and quantify the

[0091] In one embodiment, the isoxazoline active agent is at a concentration of about 0.5 to about 25% (w / v). In some embodiments of the present invention, the isoxazoline active agent is present in the composition at , about 1 to about 20% (w / v), about 1 to about 10% (w / v), about 2 to about 8% (w / v), or is about 2% (w / v), about 3% (w / v), about 4% (w / v) or about 5% (w / v) is present in the composition at a concentration of

[0092] In another embodiment, the isoxazoline active agent is between about 25% w / v and about 50% w / v In another embodiment, the concentration is 20-40% (w / v) It is.

[0093] In another embodiment, the isoxazoline active agent is from about 1 to about 6% (w / v), from about 2 to about It is present in the composition at a concentration of at or about 5% (w / v).

[0094] Additional Active Ingredients In another embodiment, the composition may further comprise one or more additional active agents. In one embodiment, the composition comprises at least one macrocyclic lactone active agent, Here, examples of macrocyclic lactone active agents include, but are not limited to, avermectins. In some embodiments, the active agent is an avermectin or milbemycin. The active bemycin drugs are eprinomectin, abamectin, ivermectin, selamectin, Milbemectin, milbemycin D, milbemycin oxime or moxidectin be.

[0095] In one embodiment, the composition comprises one or more isoxazoline compounds and eprinomectin. In a particular embodiment, the composition according to the present invention comprises fluralaner and eprinomec. Including Chin.

[0096] In one embodiment, the composition comprises a combination of fluralaner and eprinomectin or fluralaner. In one embodiment, the composition comprises a combination of Afoxora and moxidectin. A combination of afoxolaner and eprinomectin or a combination of afoxolaner and moxidectin In one embodiment, the composition comprises a combination of sarolaner and eprinomectin or In one embodiment, the composition comprises a combination of sarolaner and moxidectin. combination of terpenes and eprinomectin or combination of lotilaner and moxidectin .

[0097] In another embodiment, the topical composition of the present invention comprises an isooxygenase as described in the present application. It includes a combination of a sazoline active agent and an insect growth regulator (IGR) active agent. , IGR insecticides are diflubenzuron, dicyclanil, lufenuron, novaluron, tri The compound is selected from one or more of flumuron and cyromazine.

[0098] In another embodiment, the topical composition of the present invention comprises an isooxygenase as described in the present application. Contains a combination of the Sazorin active agent with another (one or more) ectoparasiticidal compound(s). In one embodiment, such ectoparasiticidal compounds are pyrethroids. In an embodiment, the topical composition of the present invention comprises fluralaner, afoxolaner, sarolaner or a combination of Lotilaner and a pyrethroid, in particular deltamethrin or cypermethrin. in combination with flumethrin or permethrin, or in combination with lesthrin Combinations with methrin or lambda-cyhalothrin, or In certain preferred embodiments, the composition comprises a combination of fluralaner and deltamethrin. Another preferred embodiment includes afoxolaner and deltamethrin.

[0099] In another preferred embodiment, the composition of the present invention comprises an avermectin or a milbemycin, and at least one endoparasiticide, such as thiabendazole, oxybendazole, azole, mebendazole, fenbendazole, flubendazole, oxyfendazole , albendazole, triclabendazole, delquantel, febantel, levamisole pyrantel, oxantel, emodepside, monepantel, atelocantel, moran cephalosporin, praziquantel, epsiprantel, closantel, clorsulon, and rafoxani Includes nitroxynil and nitroxynil.

[0100] Generally, the additional active agent is included in the composition in an amount of about 0.1% to about 50% w / v. More typically, the additional active agent is present in an amount of from about 0.5% to about 25% w / v, from about or about 1% to about It may be included in an amount of 10% w / v.

[0101] In another embodiment of the invention, an additional active agent (e.g., an additional active agent as described above) is The active ingredient is a compound that is formulated to deliver a dose of about 5 μg to about 50 mg per kg of animal body weight. In another embodiment, the additional active agent can be included in the composition. About 0.01 mg to about 30 mg, about 0.1 mg to about 20 mg, or about 0.1 mg to about In another embodiment, the compound may be present in an amount sufficient to deliver a dose of 10 mg. The additional active agent is about 5 μg to about 200 μg or about 0.1 mg per kg of animal body weight. In yet another embodiment of the present invention, the additional Any one of the active agents (classes) is administered at a dose of about 0.5 mg / kg to about 50 mg / kg. Included in the dosage.

[0102] The ability of an active agent to be distributed topically or transdermally following pour-on administration depends on the nature of the compound. It will be appreciated that the effectiveness of the composition will depend on both the physicochemical properties and the inactive excipients of the composition. There will be.

[0103] Examples of inactive excipients that affect transdermal distribution are skin penetration enhancers or "penetration enhancers." These are typically used in compositions designed to deliver active compounds transdermally. It is used in

[0104] Skin penetration enhancers (or penetration enhancers) are substances that help compounds pass through the skin into the bloodstream, other body fluids (lymphatic Pharmacologically acceptable compounds that facilitate absorption or penetration into the body (liquid, blood, and / or body tissues (fatty tissues) It is a carrier.

[0105] The composition according to the present invention includes menthol as a skin penetration enhancer.

[0106] Menthol is available as one of two enantiomers or as a racemate. The naturally occurring substance is the levorotatory form of (-)-menthol (or Synthetic menthol is a racemic mixture of equal amounts of (-)-menthol and (+)-menthol (or d-menthol). Preferably, levomenthol E P (European Pharmacopoeia) or l-menthol (USP) is used in the compositions of the present invention. Alternatively, other terpenoids, such as eucalyptol, camphor, d-lysine, Monene, nerolidol, 1-8 cineole and mixtures thereof are included in the composition. Alternatively, a combination of menthol and eucalyptol may be used. do.

[0107] In certain embodiments of the present invention, menthol is present in an amount of about 2 to about 20% w / v of the composition. In particular, about 5 to about 15% w / v, or in particular, about 6 to about 12% w / v, or It is present in an amount of about 10% w / v.

[0108] In one embodiment, the transdermal liquid formulation of the present invention comprises two or more skin penetration enhancers.

[0109] Penetration enhancers include dimethyl sulfoxide (DMSO), isopropyl myristate, and perylene glycol. Dipropylene glycol disodium, silicone oil, fatty esters, triglycerides , and fatty alcohols, pyrrolidones, ethanol, propylene glycol, ethyl acetate Certain solvents, such as ethyl acetate and dimethylacetamide, and substances that destroy the barrier function of the stratum corneum These compounds constitute a diverse class of compounds including those that are capable of

[0110] Non-limiting examples of suitable skin penetration enhancers include, but are not limited to, the following: Includes: terpenoids, e.g., menthol, eucalyptol, camphor, d-lysine Monene, nerolidol, 1-8 cineole and mixtures thereof, saturated or unsaturated fatty acids esters or diesters of propylene glycol or esters of glycerol, Diesters or triesters, saturated or unsaturated fatty acids, saturated or unsaturated fatty alcohols ethyl acetate, xylene, isopropyl myristate or a mixture thereof.

[0111] In particular, the skin penetration enhancer is menthol and xylene and / or d-limonene and / or minyl In one embodiment, the dermal penetration enhancer is a combination of isopropyl acrylate. In another embodiment, the dermal irritant is ethanol or eucalyptol or a combination thereof. The penetration enhancer is menthol.

[0112] Other substances have been shown to increase the flux of certain active agents through the skin as well. These include: lipophilic compounds, such as laurocapram (Azone); fatty acids or alcohols, e.g., oleic acid, oleyl alcohol, certain fatty acid esters, e.g., isopropyl myristate, methyl nonanoate, ethyl acetate, methyl caprate, etc. Mixtures of certain penetration enhancers with propylene glycol have also been used, particularly These compounds are known to enhance the delivery of certain active ingredients.

[0113] Further penetration enhancers include dimethyl isosorbide and glycol ethers, e.g., diethyl ether. Diglycol monoethyl ether (DGME, Transcutolr®), Butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol Monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol Monomethyl ether, propylene glycol monomethyl ether, propylene glycol It is monoethyl ether.

[0114] In certain embodiments of the present invention, the skin penetration enhancer comprises about 2 to about 90% w / w of the transdermal liquid formulation. and more particularly from about 5 to about 80% w / v, or more particularly from about 10 to about 70% In one embodiment, menthol is present at 10% w / v. In another embodiment, menthol is present at about 10% w / v and eucalyptus Putol is present at 10% w / v.

[0115] The optional second dermal penetration enhancer is particularly preferably present in an amount of about 2 to about 70% w / v of the transdermal liquid formulation. In particular, from about 5 to about 50% w / v, or more particularly, from about 10 to about 40% w / v. It is present in an amount v.

[0116] The pharma- ceutically acceptable carrier may be any suitable carrier or any combination thereof that is commonly used in the art of compositions. The solvent system includes a solvent, which includes a solvent or mixture of solvents.

[0117] Certain solvents suitable for topical compositions can be characterized as having good spreading properties. However, alternative solvents for topical compositions are suitable for transporting active agents through the skin barrier into the systemic circulation. They can be characterized by their ability to enhance penetration.

[0118] In certain embodiments of the present invention, the composition is provided with a spreading and / or penetration enhancing ability of the composition. It contains a mixture of enhancing solvents.

[0119] In certain compositions of the present invention, the solvent is present in an amount of about 10 to about 90% by weight of the transdermal liquid preparation. In particular, about 20 to about 80% w / v, about 25 to about 70% w / v, about 70% w / v, The amount is 60% w / v.

[0120] In one embodiment, the solvent system comprises at least one pyrrolidone solvent and at least one volatile solvents, particularly volatile alcohol solvents.

[0121] In another embodiment, the solvent system may comprise, instead of or in addition to a volatile solvent, glycerol. One or more of the following non-volatile solvents: glycerol esters, propylene glycol esters, or another non-volatile solvent. Including the above.

[0122] In another embodiment, the solvent system is glycerol esters, propylene glycol esters Contains one or more of the following:

[0123] In an embodiment of the invention, the pyrrolidone solvent is present in an amount of about 5 to about 50% w / v of the composition. In particular, about 5 to about 40% w / v, or more particularly, about 5% w / v, about 10% w / v or less. or in an amount of about 35% w / v.

[0124] In particular, the pyrrolidone solvent is 2-pyrrolidone, N-methylpyrrolidone (NMP) or the like. In one embodiment, the pyrrolidone solvent is 2-pyrrolidone. In an embodiment, the pyrrolidone solvent is NMP.

[0125] In certain embodiments of the present invention, 2-pyrrolidone or NMP comprises about 5 to about 50% of the composition. In particular, about 5 to about 40% w / v, or, in particular, about 5% w / v, In an amount of about 10% w / v or about 35% w / v.

[0126] In an embodiment of the present invention, the volatile solvent, particularly the alcoholic solvent, is present in an amount of from about 5 to about 60% of the composition. % w / v, particularly from about 5 to about 50% w / v, or particularly from about 20 to 45% w / v. % w / v, or in particular about 33-35% w / v, about 54-55% w / v or about 10% It is a w / v quantity.

[0127] In particular, the volatile solvent, in particular the alcohol solvent, is a volatile alcohol, such as ethyl alcohol. Coal, methanol or isopropyl alcohol (isopropanol) or a mixture of these In one embodiment, the alcohol solvent is isopropyl alcohol.

[0128] Volatile substances generally evaporate easily at room temperature and become vapor or gas easily. The state coalition defines volatile organic compounds as compounds that are "measured at standard atmospheric pressure of 101.3 kPa at 250°C ( The definition of volatile organic compounds is "any organic compound having an initial boiling point below 482°F."

[0129] In certain embodiments of the present invention, isopropyl alcohol comprises about 5 to about 60% of the composition. and in particular from about 5 to about 50% w / v, or in particular from about 20 to about 45% w / v. v, or in particular about 33-35% w / v, about 54-55% w / v or about 10% w / v is the amount.

[0130] In another embodiment, the solvent system comprises at least one pyrrolidone solvent and at least one The class of volatile solvents includes, in particular, alcohol solvents and additional solvents.

[0131] In another embodiment, the solvent system comprises at least one pyrrolidone solvent and at least one glycerol esters, propylene glycol esters or other non-volatile solvents include.

[0132] Non-limiting examples of suitable solvents include, but are not limited to, the following solvents: For example, water, pyrrolidone solvents such as 2-pyrrolidone, N-methyl-2-pyrrolidone and and / or mixtures thereof, as well as glycol ethers, such as ethylene glycol monohydrate, Ethyl ether, diethylene glycol monoethyl ether or dipropylene glycol Monoethyl ether, ethyl lactate, glycol ethers such as diethylene glycol Monoethyl Ether (DEGMEE), Glycerin, Dimethyl Isosorbide, Triacetate propylene glycol, glycol ether, for example, having an average molecular weight of about 200 to 10 00 polyethylene glycol (PEG), dimethyl isosorbide, carboxylic acid and dicarboxylic acid Glycerol including PEG esters of carboxylic acids and PEG esters of fatty acids, triacetin esters, caprylic / capric triglyceride (Miglyol 812 (registered glycerol ethers, including glycerol formal; dicaprylic acid / Propylene glycol dicaprylate (Miglyol 840®), lactate uril, diisopropyl adipate (DIPA, also known as "CERAPHYL 230" known), diisobutyl adipate, dimethyl isosorbide (DMI), citric acid Acetyl tributyl, oleic acid; carboxylic acid esters, including esters of diacids; keto acetone, methyl isobutyl ketone (MIK), methyl ethyl ketone, acetone trinitrile, C1-C12 alcohols, e.g., benzyl alcohol, methanol, ethyl Isopropanol, (1,2-propanediol, isopropanol isopropyl alcohol) and butanol; aromatic ethers, e.g., anisole; amides For example, dimethylacetamide, monomethylacetamide and dimethylformamide; Dimethyl sulfoxide (DMSO), ethylene glycol, propylene glycol, glycol Coal carbonates, including but not limited to propylene carbonate and bromine carbonate. ethylene carbonate; C1-C12 alkyl esters of carboxylic acids, e.g., butyl acetate or octyl acetate and benzyl acetate; C1-C12 alkyl esters of dicarboxylic acids; aryl esters, such as benzyl benzoate, ethyl benzoate, and the like; and diethyl phthalate. The diesters of dicarboxylic acids are diethyl sebacate or diisopropyl adipate. Ethylene glycol (EG), propylene glycol (PG), various grays Liquid polyoxyethylene glycol (PEG), e.g., PEG400, EG monocarbamate Caprylate or PG monocaprylate, EG caprylate or PG caprylate, EG monocaprylate Nolaurate or PG monolaurate, EG dicaprylate / dicaprate or PG dicaprylate Preprate / Dicaprate, Diethylene glycol monoethyl ether (DGME, Tr anscutol (registered trademark), butyl diglycol, dipropylene glycol n-butyl ethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl Ether, Dipropylene glycol monomethyl ether, Propylene glycol monomethyl ether, propylene glycol monoethyl ether or a combination thereof; esters or diesters, for example, but not limited to, dimethyl isosorbide; For example, but not limited to, triacetin, lauryl lactate, glycerol formate, diethyl sebacate, diisopropyl adipate, Dibutyl dipicate, PG monocaprylate, PG caprylate, PG monolaurate, P G Dicaprylate / dicaprate, isopropyl palmitate, or mixtures thereof.

[0133] In one embodiment, the composition does not include a volatile solvent. Lalanel, penetration enhancer (menthol), solvent (pyrrolidone), and glyceryl monocaprylate The solution preferably contains 20 to 80% v / v of the lysate and does not contain any volatile solvent.

[0134] The present invention includes an isoxazoline active agent in a carrier that includes a lipophilic solvent or lipophilic solvent system. The topical composition provides very good long-term efficacy against ectoparasites. It has been found that the topical composition of the present invention The non-active excipients in the formulation help trap the isoxazoline active drug within the skin for extended periods of time. required for long-term effectiveness against ectoparasites while promoting The active agent diffuses continuously into the circulatory system at a rate that results in a concentration of the active agent in the bloodstream that is It is believed that this makes it possible.

[0135] This is because the desired biological effect, e.g. This allows for a rapid anti-inflammatory effect in cases where long-term duration is undesirable with NSAIDs. These are used in typical topical compositions designed to rapidly promote the transdermal passage of compounds such as This is contrary to the approach taken.

[0136] Vegetable oils (e.g., soybean oil, peanut oil, castor oil, corn oil) may be used as vehicles or diluents. coconut oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, etc.), mineral oil (e.g., without limitation petroleum, paraffin, silicone, etc.), aliphatic hydrocarbons or cyclic Hydrocarbons (e.g., limonene, or, for example, medium chain (e.g., C8-C 12 ) Trig Lycerides, e.g., Miglyol 812 or Miglyol 840) or mixtures thereof It would be possible to use.

[0137] In one embodiment, the pour-on or spot-on isoxazoline composition comprises glyceryl monoxide. Contains nocaprylate.

[0138] In another embodiment, the pharma- ceutically acceptable carrier is C4-C 22 Fatty acids or their esters , e.g., C6-C 20 Long chain alcohols, C1-C 12 Alcohol, C1-C4 Alcohol or esters with C3-C8 alcohols; 10 -C 18 Saturated fatty acids or their esters , e.g., C6-C 20 Long chain alcohols, C1-C 12 Alcohol, C1-C4 Alcohol or esters with C3-C8 alcohols; 10 -C 18 Unsaturated fatty acids or their esters For example, C6-C 20 Long chain alcohols, C1-C 12 Alcohol, C1-C4 Alcohol Esters with C6-C8 alcohols or C3-C8 alcohols; 16 Aliphatic carboxylic acids and dicarboxylic acids Monoesters or diesters of carboxylic diacids, e.g. For example, C6-C 20 Long chain alcohols, C1-C 12 Alcohol, C1-C4 alcohol or In another embodiment, the esters include esters with C3-C8 alcohols, or mixtures thereof. The carrier is C1-C 10 Alcohol, C1-C8 alcohol or C1-C6 alcohol or It may include esters thereof.

[0139] In another embodiment, the composition of the present invention comprises a polar solvent. In a preferred embodiment, the topical composition of the present invention comprises an aromatic alcohol or an ester thereof. The composition may include isopropyl alcohol or benzyl alcohol as a solvent. In one embodiment, the topical composition of the present invention comprises isopropyl alcohol. No volatile solvents are included in the composition, which includes glycerol esters.

[0140] In a preferred embodiment, the pour-on or spot-on isoxazoline composition comprises sebacillus acid. Diethyl phosphate, dibutyl sebacate, propylene glycol saturated or unsaturated fatty acids Monoesters and diesters, or C8-C 14 Glycerol having an alkyl chain length of Monoesters, diesters and triesters of C8-C 14 Saturated alkyl chain length unsaturated fatty acids with alkyl chain lengths of C14-C22, C8-C 14 Aruki Saturated fatty alcohols with a chain length of 100 and C 14 -C 22 Unsaturated fatty acids with alkyl chain lengths of The vehicle is selected from the group consisting of fatty alcohols.

[0141] In another preferred embodiment, the pour-on or spot-on isoxazoline composition is Saturated or unsaturated fatty acid monoesters and diesters of propylene glycol, or C 8-C 14Monoesters, diesters and triesters of glycerol having alkyl chain lengths of Stell, C8-C 14 Saturated fatty acids with alkyl chain lengths of C 14 -C 22 Alkyl chain of Unsaturated fatty acids with length C8-C 14 and a saturated fatty alcohol having an alkyl chain length of C 14 -C 22 and unsaturated fatty alcohols having an alkyl chain length of Contains vehicle.

[0142] In a preferred embodiment, the pour-on or spot-on isoxazoline composition is Propylene glycol dicaprylocaprate, glyceryl monocaprylate, This includes acetone and mixtures thereof.

[0143] In a preferred embodiment, the topical compositions of the present invention comprising an isoxazoline active agent comprise: In some embodiments of the present invention, the compound is dissolved in a pharma- ceutically acceptable carrier that includes one or more solvents. The solvent may be, but is not limited to, dimethyl isosorbide, glycofurol, glycerol, Glycerol formal (methylidinoglycerol or glycerin formal), triacetin, Liquid polyethylene glycols including PEG200 or PEG400, diisopropyl adipate isopropyl, isopropyl palmitate, silicone fluid; propylene glycol (or another aliphatic dihydric alcohol), benzyl alcohol, propylene glycol esters, e.g. For example, propylene glycol dicaprylate / dicaprate, propylene carbonate, Propylene glycol monocaprylate, propylene glycol dicaprylate, propylene propylene glycol monolaurate and propylene glycol dilaurate; dicarboxylic acids Alkyl esters, for example, diethyl sebacate, diisopropyl sebacate; and fatty These include esters or diesters of fatty acids, or combinations thereof.

[0144] In one embodiment of the present invention, the composition of the present invention may include a surfactant. The surfactant may be an anionic, cationic, nonionic or amphoteric surfactant. do.

[0145] Anionic surfactants include, but are not limited to, alkaline stearates; Calcium stearate;Triethanolamine stearate;Sodium abietic acid; Alkyl sulfates; sodium dodecylbenzenesulfonate, dioctyl sulfosuccinate sodium citrate; fatty acids, etc.

[0146] Examples of cationic surfactants include, but are not limited to, water-soluble quaternary amines of the formula: ammonium salts; including cetyltrimethylammonium bromide and octadecylamine hydrochloride nothing.

[0147] Nonionic surfactants that can be used in the composition include, but are not limited to, and polyoxyethylenated (PEGylated) esters, including but not limited to sorbitan esters and fatty acid esters; polyethylene glycol stearate, Polyoxyethylated derivatives of malt oil, polyglycerol esters, polyoxyethylene Polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, and ethylene oxide and propylene Copolymers of ethylene oxide, for example, but not limited to, ethylene oxide and propylene oxide. block copolymers of ethylene oxides, such as poloxamers (e.g., L-type copolymers from BASF) Lutrol® F grades and Lutrol® L grades, e.g. Lutrol(R) F68, Lutrol(R) F87, Lutrol(R) Lutrol® F108 and Lutrol® F127.

[0148] Further examples of surfactants include, but are not limited to, surfactants with HL of 6 and 5, respectively. CAPRYOL is an oily liquid with a hydrophilic-lipophilic balance of B TM 90 (Prop ETHYLENE GLYCOL MONOCAPRYLATE), CAPRYOL TM PGMC (Propylene Glycol Topically, they act as co-surfactants in microemulsions. As used herein, they can be used as dispersants, solubilizers / penetration enhancers, and as solubilizers / penetration enhancers. When used, HLB values ​​have the following general meaning: Compounds with an HLB value of <10 Compounds tend to be fat-soluble (water-insoluble), while solvents with HLB > 10 tend to be water-soluble. Surfactants with an HLB of 4 to 8 are typically useful as defoamers. Surfactants with an HLB between 7 and 11 can be useful as W / O (water-in-oil) emulsifiers. An HLB of 12 to 16 is typically when a surfactant is useful in oil-in-water emulsions. and an HLB of 11-14 indicates a wetting agent. An HLB of 15 is typical of detergents, and an HLB of 16-20 is typical of solubilizers or hydrides. There is significant overlap in scope / applications and those skilled in the art will appreciate that HLB values Only certain surfactants are used for certain purposes (e.g., defoamers, emulsifiers, wetting agents, solubilizers, etc.) It is well understood that it is not possible to predict whether a compound will be useful in treating a particular condition (e.g., a hydrotrope or a sedative). Therefore, in general, a suitable system of solvent, active agent, surfactant and other excipients is selected. Determining this will necessarily involve non-routine experimentation and inventive effort.

[0149] The composition may further comprise oleoyl macrogol glycerides (polyoxyl glycerides For example, LABRAFIL® M1944CS, both of which have an HLB of 4. and LABRAFIL® M2125CS). These compounds can also be used as the oil phase in emulsions and microemulsions, for example. , and can also be used as a penetration enhancer.

[0150] In another embodiment, the polyoxylglyceride is LABRASOL® (HL B14) containing polyethylene glycol caprylate / caprylic acid glyceride Topically, it is used as a surfactant in microemulsions. , and may also act as a solubility / penetration enhancer in topical compositions.

[0151] In another embodiment, the surfactant is a LAUROGLYCOL surfactant having an HLB of 5. TM 90 (propylene glycol monolaurate). This is a major component of topical compositions. Co-surfactant for microemulsions and solubilizer / solubilizer in topical compositions It may also act as a penetration enhancer. In some embodiments, the surfactant has an HLB of 6. PLUROL® OLEIQUE CC497 (Polyglyceryl oleate) It is.

[0152] In some embodiments of the present invention, the carrier comprises a solvent that exhibits both good spreading and penetration properties. In another embodiment, the present invention provides a composition comprising a carrier that exhibits good spreading properties. In yet another embodiment of the present invention, the carrier vehicle is provided with an active agent. A composition is provided that includes a solvent that enhances penetration of the agent through the skin and into the systemic circulation.

[0153] In some cases, a solvent may have both good spreading properties and good penetrating properties. Glycol dicaprylate / dicaprate (e.g., Miglyol 840) is an excellent It has both spreading and permeation properties.

[0154] In a particular embodiment of the present invention, propylene glycol dicaprylate / dicaprate is Preferably, the composition is present in an amount of about 2 to about 90% w / v, more preferably about 5 to about 80% w / v, or more preferably about 10 to about 20% w / v. In general, the range is about 10 to about 70% w / v.

[0155] It can also help lock the active agent into the skin for an extended period of time and the present invention Excipients that may be included in the composition include, but are not limited to, sucrose Mixed esters of sucrose and carboxylic acids, e.g., sucrose acetate isobutyrate (SA IB), etc.; low melt wax, hydrogenated vegetable oil, caprylic / capric glyceride; Glycerol esters, such as triacetin, glycerol monooleate, monolinoleate, Glycerol stearate, glyceryl distearate, etc.; Triglyceride Glycerides, such as caprylic, capric / myristic / stearic triglyceride thermoreversible polymers, e.g., Pluronics and Poloxamers, e.g., Lut Lutrol F127 or Lutrol F127 mixed with another poloxamer; or Includes any combination of these.

[0156] To provide a product with properties suitable for pour-on application, one or more additional solvents may be used. It may be desirable to add a solvent to modify the viscosity of the composition.

[0157] The viscosity of the pour-on composition can be measured by methods known in the art. do.

[0158] Suitable viscosity modifiers include, but are not limited to, water, ethanol, isopropanol, glycerol, propylene glycol, dimethyl isosorbide, triacetin or glycerol These are added in appropriate amounts known to those skilled in the art.

[0159] Representative examples of gelling and / or adhesion agents that can be used in the compositions of the present invention Polymers ("polymeric agents") include, but are not limited to, colloidal silicon dioxide. , ethyl cellulose, methyl cellulose, methacrylic acid ester copolymer, carboxy Polyvinyl acetate, polyvinyl propylene (PVP) / vinyl acetate copolymer, poly ... Poloxamer 124, Poloxamer 188, Polybutene, Povidone K17 and Povidone K90 The composition of the present invention contains coloring agents, antioxidants, preservatives, pH stabilizers, chelating agents and viscosity enhancers. It may contain other inactive ingredients such as viscosity modifiers.

[0160] Preservatives such as parabens (methylparaben and / or propylparaben) are suitably and is used in the composition in an amount ranging from about 0.01 to about 2.0% w / v, and from about 0.05 to about 2.0% w / v. About 1.0% w / v is particularly preferred. Alternative preservatives include benzalkonium chloride, benzalkonium chloride, Benzethonium, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetri amide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylpa Raben, imidourea, methylparaben, phenol, phenoxyethanol, phenyl ethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, sorbic acid Potassium benzoate, sodium propionate, sorbic acid, thimerosal Includes.

[0161] Representative chelating agents include, but are not limited to, edetate disodium and E Includes DTA.

[0162] Vitamin E, Alpha Tocopherol, Ascorbic Acid, Ascorbyl Palmitate, Citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, Sodium bisulfite, n-propyl gallate, BHA (butylated hydroxyanisole) ), BHT (butylated hydroxytoluene), BHA and citric acid, monothioglycerol The compositions of the present invention may contain antioxidants such as tert-butylhydroquinone (TBHQ), etc. can be added.

[0163] Antioxidants are generally present in an amount of about 0.01 to about 2.0% w / v, based on the total weight of the composition. with about 0.05 to about 1.0% w / v being particularly preferred.

[0164] In order to prevent the degradation of the active ingredient in the composition of the present invention, at least one stabilizer is added. It has been found to be advantageous to add

[0165] In one embodiment, an additional component of the composition according to the invention is a pharma- ceutically acceptable colorant, e.g. For example, a dye or pigment or a combination of different dyes or pigments. Treated animals were visually monitored by detecting the color of the dye on their backs. This can be done.

[0166] The colorants used in the present invention are colorants commonly known in the art. Suitable colouring agents should, of course, be acceptable for administration to food-producing livestock animals. The coloring agents are those permitted under the U.S. Federal Food, Drug, and Cosmetic Act (FD&C). For example, FD&C Blue n°1, FD&C Yellow n°5) or natural Food dyes (e.g., chlorophyllin (green)) or mixtures of any of the above colorants. The preferred range is about 0.01% to about 2% (w / v), and more preferably about It may contain from 0.01% to about 0.5% (w / v).

[0167] Optionally, the composition contains an antifoaming agent, such as Simethicone Emulsion 30% USP, Oligosaccharides, The composition may also contain sodium phosphate, sodium caprylate or mixtures thereof. The agent is present in a concentration sufficient to prevent foam formation when the composition of the present invention is diluted with water. In the present invention, the simethicone emulsion is present at a concentration of about 0.2% w / v to about 1% w / v. In some embodiments, the simethicone emulsion may be present at a concentration of about 0.5% w / v. It exists in.

[0168] Optionally, fragrances may be added to the compositions of the present invention.

[0169] Further aspects regarding the composition of the drug and various excipients are described, for example, in Gennaro, AR, et al., eds., Remington: The Scien. ce and Practice of Pharmacy (Lippincott Williams & Wilkins, 20th Ed., 2000) It is offered.

[0170] In one embodiment, the veterinary liquid pour-on composition comprises: (a) about 0.5% to about 15% w / v of an isoxazoline compound; (b) about 5% to about 15% w / v menthol; (c) about 10% to about 50% w / v isopropyl alcohol; (d) about 10% to about 40% w / v pyrrolidone solvent; and (e) about 2% to about 50% w / v propylene glycol dicaprylate / dicaprate ;includes.

[0171] In another embodiment, the veterinary liquid pour-on composition comprises: (a) about 0.5% to about 15% w / v of an isoxazoline compound; (b) about 5% to about 15% w / v menthol; (c) about 10% to about 40% w / v pyrrolidone solvent; and (d) about 2% to about 70% w / v propylene glycol dicaprylate / dicaprate ;includes.

[0172] In another embodiment, the veterinary liquid pour-on composition comprises: (a) about 0.5% to about 15% w / v of an isoxazoline compound; (b) about 5% to about 15% w / v menthol; (c) about 10% to about 50% w / v of glycerol esters (especially glyceryl monocaprylates) Related); (d) about 10% to about 40% w / v pyrrolidone solvent; and (e) about 2% to about 50% w / v propylene glycol dicaprylate / dicaprate ;includes.

[0173] In a preferred embodiment, the veterinary liquid pour-on composition comprises about 2 to about 5% w / v isopropyl alcohol. The carrier comprises about 10% w / v menthol, about 35 to about 5 5% w / v isopropyl alcohol, about 5 to about 35% w / v 2-pyrrolidone and / or contains approximately 10% w / v propylene glycol dicaprylate / dicaprate.

[0174] In an alternative embodiment, the composition comprises about 2 to about 5% w / v of an isoxazoline compound. and the carrier comprises about 10% w / v menthol, about 5 to about 35% w / v 2-pyrrolidone. Lidone and / or approximately 10% w / v propylene glycol dicaprylate / dicaprate Includes.

[0175] In another preferred embodiment, the veterinary liquid pour-on composition comprises about 3-5% w / v, or , about 2% w / v, about 3% w / v, or about 5% w / v of an isoxazoline compound; and the carrier is about 35% w / v or about 55% w / v isopropyl alcohol and about 5 % w / v or about 35% w / v of 2-pyrrolidone or NMP.

[0176] In another preferred embodiment, the veterinary liquid pour-on composition comprises about 3-5% w / v, or , about 2% w / v, about 3% w / v, or about 5% w / v of an isoxazoline compound; and the carrier is about 35% w / v or about 55% w / v glyceryl monocaprylate and Contains about 5% w / v or about 35% w / v 2-pyrrolidone or NMP.

[0177] Of note are 5% w / v fluralaner, optionally 0.5% eprinomectin, pyrrolo Lidone solvent (preferably 2-pyrrolidone), L-menthol, Miglyol 840 and A composition comprising glycerol monocaprylate.

[0178] Of note are 5% w / v fluralaner, optionally 0.5% eprinomectin, pyrrolo Lidone solvent (preferably 2-pyrrolidone), L-menthol, Miglyol 840 and A composition comprising isopropyl alcohol.

[0179] In the method of preparing the composition of the present invention, the excipients and the isoxazoline compound are all Mix until all solids are dissolved. If necessary, add additional water to bring the composition to final volume. Add the additives (e.g., those listed above) to the container and The order in which the excipients, solvents and additives are added is important. isn't it.

[0180] In another embodiment, the composition of the present invention is an oil-in-water emulsion or a water-in-oil emulsion. In some embodiments, the oil phase can be in the form of a vegetable oil (e.g., olive oil). oil (e.g., liquid paraffin) or mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifiers include naturally occurring phosphatides (e.g., soy lecithin, ), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. For example, sorbitan monooleate) and the condensation products of the above partial esters with ethylene oxide. In some embodiments, the composition includes polyoxyethylene sorbitan monooleate. In some embodiments, the emulsion may also contain a preservative.

[0181] In another embodiment, the composition of the present invention is in the form of a microemulsion. Emulsions are highly suitable as liquid carrier vehicles. Microemulsions are: Typically, they are quaternary systems that include an aqueous phase, an oil phase, a surfactant and a co-surfactant. They are usually translucent, isotropic liquids. Microemulsions consist of tiny droplets of an aqueous phase in an oil phase. or conversely, a stable dispersion of minute droplets of an oil phase in an aqueous phase. The size of these microdroplets is typically less than 200 nm (emulsion The interfacial film is made up of alternating surface active (S A) molecules and co-surfactant (Co-SA) molecules, which act to reduce the interfacial tension. This allows the spontaneous formation of a microemulsion.

[0182] In one embodiment of the oil phase, the oil phase is prepared by extracting unsaturated polyglycosylated glycans from a mineral or vegetable oil. It can be formed from glycerides or triglycerides, or In one embodiment of the oil phase, the oil phase is formed from a mixture of compounds such as triglycerides, glycerol ... In another embodiment of the oil phase, the triglyceride comprises a medium chain triglyceride, e.g. For example, C5-C 10 Caprylic / capric triglyceride. The oil phase may be from about 1 to about 20% v / v; from about 2 to about 15% v / v; from about 7 to about 10% v / v; and , and about 8 to about 9% v / v microemulsion. represent.

[0183] The aqueous phase is typically, for example, water or a glycol derivative (e.g., propylene glycol). Glycols include glycols, glycol ethers, polyethylene glycols or glycerol. In one embodiment of the glycol derivative, the glycol is propylene glycol, diethylene glycol, dipropylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof Generally, the aqueous phase is selected from the group consisting of about 1 to about 10 of the microemulsion. It represents a ratio of % v / v or about 1 to about 4% v / v.

[0184] Surfactants for microemulsions are typically diethylene glycol monohydrates. Ethyl ether, dipropylene glycol monomethyl ether, polyglycolylated C8- C 10 Glyceride or polyglyceryl-6 dioleate or a combination of these surfactants In addition to these surfactants, co-surfactants include ethanol and propane. In addition, it contains short chain alcohols such as poloxamer and Pluronic F127. It can be used as a surfactant.

[0185] Some compounds are suitable for use in the three components discussed above (i.e., aqueous phase, surfactant and co-surfactant). However, different compounds are used for each component of the same composition. This is well within the skill level of an expert.

[0186] The pharma- ceutically acceptable carrier is a carrier that is capable of dissolving the active ingredient (e.g., an isoxazoline compound) in a solution containing the active ingredient. To inhibit the formation of sediment, optionally, a crystallization inhibitor, such as the crystallization inhibitors described below, may be added. It may contain a crystallization inhibitor or mixtures thereof.

[0187] Veterinarily and / or pharma- ceutically acceptable carriers are generally those in which the active agent is soluble. The carrier or diluent of a topical composition includes a diluent or vehicle that causes the active agent to precipitate out of solution. The active agent must be able to be delivered to the target location without precipitation or crystal formation. It will be apparent to one of ordinary skill in the art that the present invention may be used in combination with other compositions, including, but not limited to, the compositions. In another embodiment, the composition is In addition to the carrier or diluent, the composition may include a crystallization inhibitor component.

[0188] Crystallization inhibitors useful in the present invention include, but are not limited to, the following: May include: (a) Polyvinylpyrrolidone, polyvinyl alcohol, vinyl acetate and vinylpyrrolidone Copolymers of 2-pyrrolidone, e.g., N-methylpyrrolidone, dimethyl sulfoxide , polyethylene glycol, copolymers of polyoxyethylene and polyoxypropylene, Benzyl alcohol, mannitol, glycerol, sorbitol, or sorbitan Polyoxyethylenated esters; lecithin or sodium carboxymethylcellulose; Or acrylic derivatives, for example, polymers derived from acrylic monomers, for example poly and a polymethacrylate or polyacrylate according to the present invention, which inhibits the crystallization of the active agent. Solvents and similar compounds as described in (b) Anionic surfactants, such as alkaline stearates (e.g., stearic acid sodium, potassium or ammonium stearate); calcium stearate sodium or triethanolamine stearate; sodium abietic acid; alkyl sulfur phosphates (such as, but not limited to, sodium lauryl sulfate and sodium cetyl sulfate) sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate or fatty acids (e.g., coconut oil); (c) Cationic surfactants, such as those of the formula NR'R"R"'R""Y ~ > [In the formula, R The radicals may be the same or different and may be optionally hydroxylated hydrocarbon radicals. and Y is an anion of a strong acid, e.g., a halide anion, a sulfate anion. and a sulfonate anion; cetyl bromide; Trimethylammonium is one of the cationic surfactants that can be used. r; (d) Compounds of the formula NHR'R'R"'Y<">, where the R radicals are the same or different. and Y is a hydrocarbon radical, which may be hydroxylated, and Y is a mineral acid or is an anion of an organic acid; octadecylamine hydrochloride is It is one of the cationic surfactants that can be used; (e) Nonionic surfactants, e.g., polyoxyethylated sorbitan. Alternatively, an ester such as polysorbate 80 or a polyoxyethylenated alkyl ester may be used. esters; polyethylene glycol stearates, polyoxyethylated derivatives of castor oil For example, hydrogenated castor oil and its derivatives, polyglycerol esters, polyoxyethylene Polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, or ethylene oxide and propylene copolymers of ethylene oxide; (f) amphoteric surfactants, such as substituted lauryl compounds of betaine; or (g) At least two of the compounds described in (a)-(f) above. A mixture of.

[0189] In one embodiment of the crystallization inhibitor, a pair of crystallization inhibitors is used. Such a pair may be, for example, Examples include combinations of polymeric film formers and surfactants. The pair contains polyethylene glycol and a non-ionic surfactant. Additional crystallization inhibitors are also contemplated. These agents are described above as crystallization inhibitors. The compound can be selected from the group consisting of:

[0190] In some embodiments, the crystallization inhibitor is present in an amount of about 1 to about 30% (w / v). Typically, the crystallization inhibitor is present in an amount of about 1% to about 20% (w / v), about 1% to about 1 It can be present in a proportion of 0% (w / v), or from about 5% to about 15% (w / v). The inhibitors that are acceptable are added to the composition to suppress the growth of the plant when the composition is applied. In some embodiments, the composition is an inhibitor that inhibits the formation of crystals of the active agent. The present invention includes compounds that function as crystallization inhibitors other than those listed in the document. In these embodiments, the compatibility of the crystallization inhibitor is at least 10% (w / v). 10% (w / v) isoxazolidinium chloride in the solvents listed above with a crystallization inhibitor. When samples containing phosphorus-active drugs were placed on glass slides at 20°C for 24 hours, The crystal formation is sufficiently accelerated to result in less than 20 (preferably less than 10) crystals. This can be confirmed by testing whether the inhibitory effect is suppressed.

[0191] The pour-on composition may also (or alternatively) include one or more spreading agents. These materials distribute the active ingredient throughout the integument or skin of the animal recipient. They act as carriers to help the synthesis of the glycerol. Dipropylene glycol phosphate, silicone oil, fatty acid ester, triglyceride and / or may contain a fatty alcohol.

[0192] Various spreading oil / solvent combinations, e.g. oil-based solutions, alcoholic and isopropyl alcohol. Propanol solutions (e.g., solutions of 2-octyldodecanol or oleyl alcohol) ), esters of monocarboxylic acids (e.g., isopropyl myristate, isopropyl palmitate, Propyl, lauric acid oxalate, oleyl oleate, decyl oleate oleate, hexyl laurate, oleyl oleate, decyl oleate and 12-1 a caproic acid ester of a saturated fatty alcohol having a carbon chain of eight carbons; Esters of dicarboxylic acids (e.g., dibutyl phthalate, diisopropyl isophthalate, Diisopropyl dipic acid and di-n-butyl adipate) solution, or aliphatic Solutions of esters of acids (e.g., glycols) and the like may also be suitable. dispersants, such as pyrrolidin-2-one, N-alkylpyrrolidin-2-one, Acetone, polyethylene glycol or their ethers or esters, propylene glycol It may also be advantageous to include ethylene glycol or synthetic triglycerides.

[0193] In some embodiments of the present invention, the topical compositions of the present invention may further comprise an emollient and / or a spreading agent. and / or film formers may be added. Emollients, spreading agents and film formers may be added. It is well known in the art. In various embodiments, the topical compositions include The skin softeners, spreading agents and film-forming agents that can be used include those described above in (a) to (g). Ingredients mentioned in the above, such as polymer derivatives, for example polyvinylpyrrolidone, Polyvinyl alcohol and copolymers of vinyl acetate and vinylpyrrolidone; anionic interfaces. Active agents; Cationic surfactants; Nonionic surfactants; Amphoteric surfactants; Amine salts, and and combinations thereof. In one embodiment, the emollient comprises from about 0.1 to about 10% ( It is used at a ratio of about 0.25 to about 5% (w / v).

[0194] Topical administration of the compositions of the present invention results in effective plasma concentrations. contains the active agent in a concentration sufficient to provide good long-term efficacy against ectoparasites. The present invention provides a method for the effective delivery of the compound of the present invention to animals by transdermal injection through the skin into the systemic circulation and onto the body surface of the animal. The compositions of the present invention provide for localized distribution of the active agent on the animal's coat and into the bloodstream. In this embodiment, the topical composition comprises an isoxazoline active agent. It provides high levels of efficacy at unexpectedly low plasma concentrations of the drug.

[0195] In some embodiments of the invention, the composition maintains effective levels of the active agent in plasma for an extended period of time. and control the penetration rate of isoxazoline compounds to significantly extend the duration of efficacy. It is formulated to

[0196] The liquid preparations according to the present invention promote this superior long-term efficacy against ectoparasites. The bioavailability is determined by the amount of the drug that is absorbed into the systemic circulation. It is a measure of the degree of therapeutically active drug delivered. It is represented by the letter F. Obligate biosynthesis Bioavailability is the amount of a drug that is absorbed into the systemic circulation after non-intravenous administration (i.e., after oral, transdermal, or subcutaneous administration). The availability of the active drug in the blood is measured.

[0197] Absolute bioavailability is the dose-corrected area under the curve (AUC) for non-intravenous administration. is divided by the AUC when administered intravenously. For example, The formula for calculating F for a drug is:

number

[0198] In one embodiment, the isoxazoline compound in the composition according to the invention is administered by pour-on administration. or after spot-on administration, has an absolute systemic bioavailability of 5-10%. In an embodiment, the absolute systemic bioavailability is between 2 and 10%. In another embodiment, the absolute systemic bioavailability is 30-40%. In another embodiment, the absolute systemic bioavailability is 20-30%. , higher than 30%.

[0199] Treatment method In another aspect of the invention, an animal is administered an effective amount of at least one isoxazoline The active agent is applied in a pharma- ceutical acceptable form suitable for pour-on and / or spot-on application to the skin of an animal. The present invention relates to a method for treating parasitic infestation in an animal, comprising administering a topical composition comprising the Methods for preventing or treating an ectoparasite attack / infection are provided. It has long-lasting efficacy against insects (e.g., fleas and ticks) and in certain embodiments In some cases, they may also be active against internal parasites that infest animals.

[0200] In one embodiment of the present invention, the composition comprises an effective amount of at least one isoxazoline active agent. The method includes administering a topical composition comprising the steps of: Methods of treating or preventing parasitic infestation or infection in animals are provided. Ectoparasites against which the compositions are effective include, but are not limited to, fleas, ticks, The composition is active against internal parasites, including mites, mosquitoes, flies and lice. In certain embodiments that include one or more additional active agents, the compositions and methods of the present invention include Parasites (e.g., but not limited to, roundworms, hookworms, and nematodes of the gastrointestinal tract of animals and humans) It may also be effective against insects, reptiles and tapeworms.

[0201] External parasites to be treated include, but are not limited to, fleas, ticks, and mites. , mosquitoes, flies, lice, blowflies and combinations thereof.

[0202] In another embodiment relating to treatment for ectoparasites, the ectoparasite is Boophilus rhinoceros Boophilus / Rhipicephalus, Dermacentre Genus Dermacentor, Ixodes, Boophilus ophilus, Ambylomma, Haemaphysalis maphysalis, Hyalomma ticks, especially Bohemia ticks Ticks of the genus Boophilus (Rhipicephalus), especially Microtrichia purus species (microplus) (Ixodes bovis), the Kenyan R. decoloratus and Rhipicephalus annulatus ).

[0203] Rhipicephalus microplus, Kenyan bullfinch Ixodes ricinus (R. decoloratus) and Rhipicephalus annulatus (R. annulatus) ulatus is a single-host tick, which means that it This means spending time with the same animal.

[0204] Multi-host ticks are characterized by the fact that after each stage the tick falls to the ground and reattaches to a different host. and multi-host ticks, where the host type may differ between different stages. For example, Amblyoma cajennense , Ixodes holocyclus, i.e., paralysis Mada 2: H. longicornis, Rhipicephalus appendicula Rhipicephalus appendiculatus and Ambylo Amblyoma haebraum, Dermacentor albipi Dermacentor albipictus, Ambiloma maculatum ( Amblyoma maculatum, Amblyoma andersonii a andersoni), Ixodes ricinus, Dermacentor marginatus do.

[0205] Additional examples of ectoparasites include, but are not limited to, the following: myiasis flies that cause rhesusitis, e.g. Dermatobia hominis (known as "Berne" in Brazil) and the screwworm fly (Coc hliomyia hominivorax) (blood fly); causes sheep myiasis Flies, e.g. Lucilia sericata, Sheep fly Lucilia cuprina (Australia, New Zealand and South Africa) In Brazil it is known as blowfly strike. (I).

[0206] Stable flies, i.e. flies whose adults are parasites, such as Haema tobia irritans)(horn fly), Haematobia irritans exiqua (buffalo fly) and Stomoxys calcitrans (stabl e fly).

[0207] Blood-sucking lice are parasites in that they feed on blood from their hosts and transmit pathogens. It is more important to know the chewing lice or biting lice. g lice) feed on the hair and skin, and occasionally on blood from the host. The important louse parasite is the cattle biting louse. (Bovicola bovis), longnosed cattle louse e louse) (Linognathus vituli), woolly cow louse (li ttle blue cattle louse)(Solenopotes capi) llatus), shortnosed cattle louse (H aematopinus eurysternus and cattle lice tail louse)(Haematopinus quadripertusus ), and the sheep body louse (Bovicola ovis) of sheep and goats.

[0208] Important mite parasites include, for example, the bursaphelenchus mites (Chorioptes bovi). s), Sarcoptes scabiei, and sheep lichen The mite is Psoroptes ovis.

[0209] The above list is not exhaustive and other ectoparasites may also occur in animals (especially domestic animals, In particular, it is known in the art that ruminants, more particularly cattle or sheep, are harmful. These include, for example, migratory dipteran larvae.

[0210] Surprisingly, the pour-on compositions of the present invention provide protection against one or more of these parasites. It has been found to be effective in removing

[0211] In some embodiments of the present invention, the isoxazoline compound is particularly useful in combination with another active ingredient. When used in combination with other agents, the compositions may also be used to combat endoparasites, such as, inter alia, Anaprocephalus. Anaplocephala, Ancylostoma, Ane Anecator, Ascaris, Capillaria laria, Cooperia, Dipylidium ), Dirofilaria, Echinococcus cus, Enterobius, Fasciola , Haemonchus, Oesophago stumum, Ostertagia, Toxocara ra), Strongyloides, Toxuscaris ascaris, Trichinella, Trichu ris and Trichostrongylus The compound can be used to treat a helminth selected from the group consisting of:

[0212] In another preferred embodiment, the methods and compositions of the present invention are for the treatment of parasitic necrosis in cattle or sheep. Used to treat or prevent worm infections and infestations in livestock animals (e.g. cattle or sheep). When treating Rhododendron truncatula, the methods and compositions are particularly effective against: (Rhipicephalus (Boophilus) microplus) Haematobia irritans (horn fly), St omoxys calcitrans) (stable fly), and the following: Myiasis (sheep) caused by blowflies, e.g. Luciola formosum (Luc ilia sericata)(European green blowfly), Green blowfly (Lucilia cuprina) , Australian sheep blowfly; Australia, New Zealand In India and South Africa, it is called blowfly strike. Also known as the white-banded blowfly (Chrysomya rufifacie Hairy maggot fly, Chrysomy varipes a varipes)(Small green blowfly), a type of black fly ( Calliphora stygia)(Common brown blowfly) Calliphora augur (Lesser brow n blowfly(eastern), Calliphora novisia novicia)(Lesser brown blowfly(western).

[0213] In ruminants (e.g., cattle and sheep) that can be controlled with the compositions of the present invention, The important louse species are Bovicola spp. and Linognathus spp. Linognathus spp. (e.g., Bovic ola ovis).

[0214] The terms "treating" or "treat" or "treatment" "treatment" means the eradication or elimination of parasites infesting the animals being treated. In order to reduce the number of parasites, the authors apply the method of the present invention to animals infested with parasites (especially ectoparasites). The term "application or administration" is intended to mean administering or administering the composition of the present invention. It should be noted that such a method can be used to prevent (re)infestation by such parasites. I want to be loved.

[0215] The compositions of the present invention are administered in an effective amount (parasiticidal) suitable for controlling parasites to the desired extent. Administer at .

[0216] An "effective amount" is an amount effective to eradicate an infestation in a host animal or reduce the number of parasites infesting the animal. In some embodiments, an effective amount of the composition of the present invention refers to an amount of the composition sufficient to cause an active ingredient to be effective. The drug achieves at least 70% efficacy against the target parasite.

[0217] Efficacy can be assessed by methods known in the art, for example, the WAA for ectoparasite assessment. The effective amount of the active ingredient is calculated as outlined in the VP guidelines. The drug is at least 80% effective or at least 90% effective against the target pest. Preferably, the effective amount of the active agent is at least 95% effective against the target parasite. Achieve at least 98% or 100% efficacy.

[0218] In each aspect of the invention, the compounds and compositions of the invention can be used to treat a single parasite species. It is possible to control infestations in animals with a combination of different parasite species. Cut.

[0219] The compositions of the present invention may be administered continuously to treat or prevent parasitic infection or infestation. In this manner, the compositions of the present invention can be administered in an amount effective to control the target parasite. To effectively control parasites, One or more applications of the compositions of the present invention may be necessary. Only one dose is needed to treat a worm infestation and protect the animal from reinfestation. That is it.

[0220] Generally, approximately 100 mg / kg body weight is administered as a single dose or in divided doses over 1-5 days. A dosage of 0.001 to about 100 mg is sufficient, although, of course, higher or lower dosages may be used. Dosage ranges may be given and are within the scope of the invention. Determining a specific medication regimen for a parasite is well within the routine skill of a practitioner. A single dose is preferred.

[0221] In another embodiment for treating livestock animals such as cattle or sheep, the administered isoform The dosage of the oxazoline active agent can be from about 1 to about 30 mg / kg of body weight. In the present case, the administered dose is about 1 to about 20 mg / kg or about 1 to about 15 mg / kg. Preferably, the dose of isoxazoline active agent administered to the livestock animal is about 1 to about 1 0 mg / kg body weight.

[0222] The compositions according to the invention are effective for ruminant animals such as cattle, sheep, goats, camels and llamas. Particularly useful, especially if they are livestock animals raised for their meat and milk or wool. This is particularly useful where animals are kept in captivity or as working animals.

[0223] In one embodiment, the animal is a bovine animal, such as a cow. To obtain effective blood levels of isoxazoline compounds following single-dose or spot-on administration Efficacy against parasites such as ticks in cattle is particularly challenging. , highly unexpected.

[0224] As used herein, bovine animals are ruminant mammals of the genus Bos and include, but are not limited to, This includes, but is not limited to, cattle, steers, heifers, cows (lactating and non-lactating), calves, Cattle, bulls and also buffaloes are particularly preferred. That is, bovine animals raised for meat. In another embodiment, the animal is a sheep. In another embodiment, the animal is a goat.

[0225] As used throughout this specification, "long acting" means "ng" refers to a duration of activity lasting more than 24 hours, preferably more than one week. Preferably, the duration is greater than 2 weeks. Protection of bovine animals from tick infestation is achieved by the present invention. This is a particularly preferred embodiment of the invention.

[0226] What constitutes an "effective amount" for use in the present invention is a dose of the parasite that infests such animals. to completely eradicate or at least significantly reduce the parasites that infest animals The amount of isoxazoline compound described herein required, Alternatively, this may be the therapeutic dose or quantity of the animal house or surroundings. For example, to effectively control and eliminate the presence of parasites in homes, buildings, farms, fields, etc. and / or the amount, therapeutic dose or quantity that can be reduced ) can be shown.

[0227] Effective reduction of animal infestations or effective control of parasites in their surroundings; and / or and therefore: what constitutes such an effective amount is as defined herein. Parasite counts in animals before and after administration of the isoxazoline compounds described in the literature Detection is easily determined by comparing the number of parasites in the infected area or in the surrounding area of ​​the animal. by counting the number of parasites visible to the naked eye on the surface of the animal or in its surroundings. This can be done by counting the parasites using traps or another detection device in the field. The difference in numbers obtained from such counts performed before and after treatment can be used to estimate the dose applied. To make such counts statistically reliable, certain It is necessary to monitor a minimum number of host animals or detection devices.

[0228] For use in the present invention using the isoxazoline compounds described herein The therapeutic or prophylactic effect against parasites may be, for example, ovicidal, larvicidal and / or adulticidal. The effect may be direct, i.e., immediate parasite attack. or kill the parasites after a certain time has elapsed, e.g., when molting occurs, or The time or frequency of the bite, or the amount of blood or blood that the parasite ingests in one bite The effect may be manifested by affecting the amount of body fluids. Alternatively, the effect may be manifested by, for example, Reproductive or egg-laying efficiency of insects, e.g. size, number or quality of eggs laid; hatching rate; hatched eggs larval survival; or directly by reducing the sex ratio of hatched larvae. or it could be for the number of offspring in the next generation. .

[0229] or the effect on the economic performance of the animal, e.g. daily weight gain, feed conversion or can monitor differences in milk production.

[0230] Therefore, we aim for a 100% or close to 100% reduction in parasites. A reduction of about 5% in the number of cases can already be a significant reduction. This is because such a limited reduction Even a small amount of the drug has already alleviated certain symptoms in animals affected by parasites and improved their health. The mortality rate of parasites is a good indicator of the effectiveness of the treatment. Another effect is reduced parasite reproduction, i.e. producing fewer offspring. It could be.

[0231] In a preferred embodiment, the reduction of the infestation on animals or the control and / or reduction achieved A reduction in the number of specific types of parasites by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% reduced Here, the order of preference increases with respect to:

[0232] In one embodiment, the Abbott formula is used to calculate percent control efficacy, compared to an untreated control. This provides at least 90% tick efficacy.

[0233] The treatments used in the present invention can be used on a single animal during the treatment period. More preferably, the animals are kept in a group at the same time or in a single pen, enclosure, herd, shed or farm. All animals in a study are treated simultaneously.

[0234] As used herein, the term "treatment" and similar terms, e.g. For example, "treating" or "treat" refers to The present invention relates to a method for treating a parasite infestation comprising administering an effective amount of an isoxazoline to a subject infected with one or more species of parasite. This indicates that the drug should be administered to animals suffering from a range of conditions (of varying severity).

[0235] "Protection" means that existing infestations of animals are reduced and / or eliminated; The prevention / reduction / reduction of new infestations that appear after administration of the composition according to the invention means to be treated.

[0236] The term "(parasitic) infection or infestation" refers to an infection or infestation caused by one or more (parasitic) pathogens. where symptoms include clinical symptoms (parasitic diseases) and subclinical symptoms. can be.

[0237] Subclinical symptoms typically do not directly result in clinical signs in animals infected with the parasite. Although it is not a medical condition, it is a condition that causes economic losses. Such economic losses can occur, for example, in young animals. Reduced growth and feed efficiency in animals, reduced weight gain in meat producing animals, and This may be due to reduced milk production in cattle or reduced wool production in sheep.

[0238] The term "parasitic disease" refers to any clinically evident disease associated with or resulting from infection with one or more parasites. Significant pathological symptoms and diseases, e.g., parasitism in ruminants (e.g., sheep or goats) For worm-induced gastroenteritis or anemia or colic in horses.

[0239] For purposes of this invention, "protection from reinfestation" refers to protection from reinfestation in animals that are free of live parasites. They live in an environment where the parasite is present or in close contact with animals (or humans) that are infested with the parasite. The animal is infested with parasites because of contact with them (and therefore "at risk of infestation"). It encompasses the situation of exposure to a new insult. Reinvasion is a second or subsequent insult.

[0240] This is because an animal that is (virtually) uninfested with parasites at a given time may develop an infection with an external parasite. The composition of the present invention is effective in preventing such newly emerged infections. Killing the parasite before it can establish an infestation in the animal or Reduces parasite numbers to insignificant levels, limiting irritation and injury to animals. Limited.

[0241] In one embodiment, the composition exhibits long-lasting efficacy and is effective for at least one month. , providing protection against parasites in livestock animals.

[0242] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against ticks of at least 50%.

[0243] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against ticks of at least 70%.

[0244] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against ticks of at least 90%.

[0245] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against lice of at least 50%.

[0246] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against lice of at least 70%.

[0247] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against lice of at least 90%.

[0248] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against mites of at least 50%.

[0249] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against mites of at least 70%.

[0250] In another embodiment, the compositions of the present invention can be used for at least 1 month, at least 2 months, or at least for a period of at least 3 months, at least 4 months, at least 5 months, or at least 6 months. It exhibits extremely long-lasting efficacy against mites of at least 90%.

[0251] In another embodiment, the composition is administered to combat ticks, mites, and other insects for a period of at least six weeks. or exhibits long-lasting efficacy of at least 50% against lice.

[0252] In another embodiment, the composition is administered to combat ticks, mites, and other insects for a period of at least six weeks. or exhibits at least 70% long-lasting efficacy against lice.

[0253] In another embodiment, the composition is administered to combat ticks, mites, and other insects for a period of at least six weeks. or exhibits at least 90% long-lasting efficacy against lice.

[0254] Thus, one embodiment of the present invention is a method in which the composition according to the present invention is administered monthly. .

[0255] Thus, in another embodiment of the invention, the compositions according to the invention are administered every six weeks.

[0256] Thus, in another embodiment of the invention, the compositions according to the invention are administered every two months.

[0257] Thus, in another embodiment of the invention, the compositions according to the invention are administered every three months.

[0258] In a preferred embodiment of the invention, the composition according to the invention is administered as a single treatment per season. Administer.

[0259] Surprisingly, the topical compositions of the present invention, which include an isoxazoline active agent, unexpectedly It has been found to provide excellent efficacy against ticks at extremely low plasma concentrations. In embodiments, the topical compositions of the present invention, including selected solvents and excipients, provide long-term This results in a constant low level of active agent.

[0260] In some embodiments, sufficient plasma to achieve at least 90% efficacy against ticks. The concentration of the active agent in the In another preferred embodiment, the amount of iodine required to achieve 90% efficacy against ticks is The plasma concentration of isoxazoline active drugs is approximately 100 ng / mL or less, and approximately 75 ng / mL or less. In another embodiment of the present invention, the mAb is about 50 ng / mL or less, or even about 50 ng / mL or less. Isoxazoline activity in plasma required to achieve 90% efficacy against mites The concentration of the drug is about 75 to 100 ng / mL, about 50 to 75 ng / mL, or about 30 to 5 0ng / mL.

[0261] In one embodiment, an effective dosage of the composition is administered to combat ticks, mites, and lice for at least 21 days. To protect bovine or ovine animals from infestation or re-infestation by mites and / or stable flies do.

[0262] Thus, in another embodiment of the present invention, the pour-on composition is administered every 3 weeks or every 21 days. Administer.

[0263] Without wishing to be bound by theory, it is believed that the topical compositions of the present invention achieve 90% efficacy. The low plasma concentrations required for the administration of the compound allow it to act both superficially and systemically in the animal. Thus, it may be shown to provide protection against ectoparasites.

[0264] The topical compositions of the present invention exhibit improved efficacy against these tick species at significantly lower plasma concentrations. The efficacy of the isoxazoline active agent is determined by the amount of the non-active excipients in the compositions of the present invention that are effective in preventing the isoxazoline active agent from being released into the body. Longer duration of efficacy based on the ability to slowly deliver agents from the site of administration into the bloodstream This may allow for time.

[0265] In another embodiment of the present invention, the topical composition of the present invention surprisingly has It exhibits 90% efficacy as early as 4 days after administration of the composition, and furthermore, has a long-lasting effect. In yet another embodiment of the present invention, a topical The composition takes effect as early as 3 days, or 2 days, or 1 day after administration.

[0266] The fast acting and long lasting protection provided by the compositions of the present invention is unexpected.

[0267] In another aspect of the invention, at least one isoxazoline active agent is administered by together with a physiologically acceptable carrier and a delivery device for pour-on application of the composition to an animal. A kit for treating or preventing a parasitic infestation in a mammal is provided.

[0268] The volume of the topical composition to be applied as a spot-on or pour-on should be practical. and should be shown to be safe and effective. The volume administered depends on the size and weight of the animal and the concentration of the active ingredient. However, it is important to apply a volume that will not cause the composition to run off, especially if the animal moves. is preferred.

[0269] The composition according to the present invention has a very high concentration of isoxazoline compounds in the composition. This allows for low application volumes.

[0270] When the composition is in a pour-on form, the application volume may be about 0.3 to about 100 mL. In another embodiment, the application volume of the pour-on composition is from about 1 mL to about 100 mL or about 1 In yet another embodiment, the volume can be from about 5 mL to about 50 mL. It can be 50 mL or about 10 mL to about 100 mL.

[0271] A topical, localized spot-on composition is preferably administered in an amount of about 0.01 to 1 mL per kg. or in small volumes of about 0.05 to 0.1 mL per kg, where the target species The total volume is 0.3 to 100 mL per animal depending on the animal, preferably up to about 50 Limited to mL.

[0272] In one embodiment, the application volume is 1 mL of the composition per 10 kg of animal body weight, This results in a total application volume of 50 mL for a 500 kg bovine animal, or For a sheep, this amounts to a total application volume of 8 mL. These application volumes are It's convenient.

[0273] In another embodiment, the application volume is 1 mL of the composition per 20 kg of animal body weight; This results in a total application volume of 25 mL for a 500 kg bovine animal, or 80 kg For a 100 g sheep this results in a total application volume of 4 mL.

[0274] The pour-on or spot-on compositions according to the invention can be applied by any means known per se. , e.g., applicator guns, or volumetric flasks, pipettes, syringes, roll-ons , droppers, capsules, foil packages, vials, twist tip containers, metered doses Application using aerosols or sprays, as well as other single and multi-dose containers do.

[0275] In one embodiment, the compositions of the present invention are administered to an animal in need thereof by press-in-bottle injection. press in bottle insert application Such devices allow healthcare professionals to administer the liquid The body can be easily dispensed from the stock bottle into an (oral) syringe.

[0276] To administer the composition, the professional opens the bottle and inserts the plastic adapter into the bottle. The syringe is then pushed into the opening and the oral syringe is then attached to the port on the adapter. The patient can then draw a dose of medication from the bottle and administer the dose. The cap can then be placed back on the bottle for future use.

[0277] Currently, animal pour-on products generally require larger volumes of the composition to be administered. Therefore, the above administration methods are not suitable. Such administration methods are difficult to use to precisely deliver small amounts of medication. Not very desirable.

[0278] Thus, the present method of administration using the PIBA application system is This allows for more accurate and convenient administration of pour-on liquid preparations.

[0279] In one embodiment, the present invention relates to a method of administering a composition according to the present invention, wherein the method comprises: The law is (a) placing the composition into a press-in-bottle application device; and (b) administering an effective amount of the composition to an animal in need thereof by pouring it onto the back of the animal. and administering by; Includes.

[0280] The method includes the following steps: weighing the animals and placing them in the dosing chambers of the bottles (which Use the selected indicator (calculated in kilograms of body weight) to select the correct dose. Hold the bottle upright while slowly and gently squeezing it to fill the dosing chamber. Stand the animal upright and hold it at eye level. Place the animal on the midline of its back, running from the dorsal ridge to the ridge. , pour in the measured volume.

[0281] One aspect of the present invention is to provide a multi-use container containing the topical pour-on composition of the present invention. and thereby dispense a precise single dose aliquot of the sustained release topical composition from the container. It can be administered.

[0282] The composition must be stable to repeated exposure to the external environment, especially oxygen and water. This embodiment requires administration to the animal infrequently, such as once every 1-6 months. This may be particularly useful for the extremely long acting compositions of the present invention, which do not require .

[0283] Thus, the stability of the composition depends on the possibility of the composition being exposed to oxygen and water during multiple openings and closings. This is particularly important for applications with multi-dose containers where

[0284] The compositions according to the invention are stable, which means that they can be stored unopened and even after multiple containers have been packed. This means that the active ingredient does not substantially decompose during opening and closing.

[0285] The pour-on composition can also be applied to the animal by other conventional methods, such as by For example, the method may include rubbing the impregnated material onto at least a small area of ​​the animal, or by assembling the material. The composition can be applied using a commercially available applicator or sprayed using a syringe. Alternatively, it can be applied using a spray lace.

[0286] definition Terms used herein are understood to be within the meaning of the art unless otherwise specified. have their customary meaning.

[0287] In this disclosure and claims, the words "comprises," "contains," "contains" and "contains" are used interchangeably. "containing" and "having" Terms such as "includes," "including," "including "consisting essentially of"; "consists essentially of" or "consists essentially of "essentially" is similarly open-ended and encompasses the essential characteristics of what is being recited. As long as the nature or novelty of the invention is not altered by the presence of more than what is described, The present invention allows for the existence of more than what is listed, but excludes prior art embodiments.

[0288] As used in this specification and claims, the term "about" and "approximately" means that the value is within a statistically significant range. Such ranges are typically within 20%, more typically within 10%, of a given value or range. Typically, it will be within 10%, and more typically, within 5%. The amount of acceptable variation encompassed therein will depend on the particular system under test and will be readily understood by those of skill in the art. can be easily recognized.

[0289] In accordance with this detailed description, the following abbreviations and definitions apply: where applicable, the singular forms "a," "an," and "the" shall be used where the context clearly indicates otherwise. It should be noted that unless otherwise specified, a term encompasses multiple referents.

[0290] The publications discussed herein are provided solely for their disclosure. Nothing in the specification shall be construed as an admission that such publication is antedated. In addition, any publication dates provided may differ from the actual publication dates and may not be accurate to the extent that they are provided in a timely manner. may need to be verified separately.

[0291] When a range of values ​​is given, it makes sense to include every value in between. The upper and lower limits of these smaller ranges are understood to be those specifically excluded in that stated range. Each stated range may be included within any smaller range independently, subject to any stated limit. When either or both of the limits are included, a range excluding either of those included limits is also included in the invention. Any value within the cited ranges is also contemplated.

[0292] The concentration ranges of the components of the disclosed compositions are based on the total mass of the final composition unless otherwise indicated. Expressed as weight percent per product. EXAMPLES

[0293] Working Example The present invention is further illustrated by the following non-limiting examples, which illustrate the invention. The present invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Nor should it be construed as limiting the scope of the invention.

[0294] As a non-limiting example, the isoxazoline compound fluralaner (Compound A) was administered to bovine In some compositions, the composition comprises a compound that is capable of delivering the compound to livestock animals such as cattle, cattle, and sheep. Contains Compound A (fluralaner) and eprinomectin.

[0295] A composition was prepared and found to be effective in controlling ectoparasites (e.g., ticks) in cattle. Sexuality was evaluated. [Table 3] [Table 4] [Table 5]

[0296] To prepare the example compositions, add the vehicle or a portion of the vehicle to a compounding vessel. Then, the remaining excipients and the active agent are added. The combination is mixed until all solids are removed. Mix until all ingredients are dissolved. Additives not included here (e.g., see detailed description) may be added. The additives listed above are also included in the container and mixed into the composition. The order of addition is not important. There wasn't.

[0297] Biological Example 1: Efficacy against bull ticks (Rhipicephalus microplus) The efficacy of two pour-on compositions of the present invention containing Compound A was compared with two alternative pour-on compositions. The mites were compared to the nicotinoid composition and an untreated control. croplus) was tested.

[0298] Each study group consisted of five healthy cows, aged 6 to 15 months and weighing 70 to 150 kg. Group 1 cattle were not treated (control). Group 2 cattle were treated with 5% (w / v) treated with a pour-on composition containing Compound A in oily solution at a dose of 5 mg / kg; Group 3 cattle were administered Compound A at a concentration of 5% (w / v) in volatile solution I on day 0. The subjects were treated with Poa-on composition (Poa-on 2 composition, see Table 1) at a dose of 5 mg / kg. Group 4 cattle were treated with compound A at a concentration of 5% (w / v) in volatile solution II on day 0. A pour-on composition containing A (Pour-on 3 composition, see Table 1) at 5 mg / kg and group 5 cattle were treated with 5% (w / v) concentration in oily solution on day 0. The mice were treated with a pour-on composition containing Compound A at a dose of 5 mg / kg.

[0299] Details regarding the investigational drugs tested are provided in Table 4. [Table 6]

[0300] From day -28 to day -1 before treatment, cattle were infested with approximately 3,000 bovine ticks three times a week. (Rhipicephalus microplus) larvae invade the area, causing continued invasion For the cows of groups 2, 3, 4 and 5, the required amount of the solution was measured on day 0. and insert into a disposable syringe that is labeled with a label and attached to the back of each animal from the dorsal ridge to the base of the tail. The skin was treated with each composition by spreading the material evenly along the midline of the skin.

[0301] After treatment, the plants were infested with approximately 3,000 R. microplus larvae three times a week. Group 1 (untreated control group) was challenged with the insult for 2 weeks after treatment. Continued.

[0302] Beginning one day after treatment (day 1), fully engorged female ticks were collected from each animal. Tick ​​collections from the control group (C1) were performed 1 hour after treatment and 1 hour after feeding. Treatment was terminated after the efficacy period due to the fact that the animals were only re-infested for 2 weeks.

[0303] Additionally, collected ticks were weighed as a group to assess the effect of tick weight gain on control. The effect of the treatment was measured by assessing the vitality and reproductive potential of the treated ticks.

[0304] The efficacy of IVP is discussed in Holdsworth, P.A., Kemp, D., Gr een, P., Peter, R.J., De Bruin, C., Jons son, N.N., Rehbein, S., Vercruysse, J.W. orld Association for the Advancement of Veterinary Parasitology (WAAVP) gui delines for evaluating the efficacy of a caricides against ticks (Ixodidae) on ru minants. Veterinary Parasitology, 136(20 06) 29-43” using standard ADEQ analysis methods.

[0305] To confirm the plasma pharmacokinetic profile of Compound A (fluralaner) in cattle To determine the effect of serotoninib on the survival of mice, blood samples were collected from all treatment groups before treatment and 1, 2, and 5 days after treatment. After 7, 9, 12, 14, 16 and 21 days, the animals were collected. Blood samples are collected once weekly (i.e., every 6-8 days) until the end of the study phase.

[0306] Figures 1 and 2 show the effect of treatment with R. tabacum on the survival of the ticks up to 115 days after treatment compared to the untreated control. The total tick count % efficacy of pour-on compositions against Ixodes microplus is shown.

[0307] The therapeutic daily tick control efficacy (>95%) was 3 days after treatment in group T1 and 4 days after treatment in group T2. was reached 10 days after treatment, in group T3 4 days after treatment, and in group T4 3 days after treatment. Ta.

[0308] Group T1 (5 mg fluralaner / kg body weight), sustained daily tick control efficacy (>9 The highest efficacy (100%) was observed between 9 and 55 days after treatment. The efficacy was maintained at 1 day, with the lowest efficacy (90.6) recorded at 90 days after treatment. Eliminated on the 98th.

[0309] Group T2 (5 mg fluralaner / kg body weight), sustained daily tick control efficacy (>9 The efficacy (100%) varied from 23 to 108 days after treatment. The highest efficacy (100%) was observed 35 days after treatment. The efficacy was maintained at ~42 days, with the lowest efficacy (88.54) recorded at 111 days after treatment. T2 was eliminated on the 117th day.

[0310] Group T3 (5 mg fluralaner / kg body weight), sustained daily tick control efficacy (>9 The efficacy (100%) varied from 4 to 104 days after treatment. The lowest efficacy (65.27) was observed at 110 days after treatment. Group T3 was eliminated on day 117.

[0311] Group T4 (5 mg fluralaner / kg body weight), sustained daily tick control efficacy (>9 The efficacy (100%) varied from 3 to 72 days after treatment. The highest efficacy (100%) was observed 12 to 4 days after treatment. The efficacy was maintained at 2 days, and the lowest efficacy (65.25) was recorded at 77 days after treatment. , and was eliminated on the 84th day.

[0312] As shown in Figures 1 and 2, the pour-on compositions of the present invention provide, over an extended period of time, Excellent efficacy against bull ticks (Rhipicephalus microplus) to provide.

[0313] Pore-on for bull ticks (Rhipicephalus microplus) The long-lasting efficacy of the composition is greater than 90% compared to pour-on compositions known in the art. This is comparatively more noticeable.

[0314] The individual pharmacokinetic parameters of the compositions according to the present invention (i.e., C max and AUC) The pharmacokinetic and efficacy results of this study are summarized in one graph in Table 5 below. is doing. [Table 7]

[0315] Biological Example 2: Haematobia irritans exiciqua in cattle Efficacy of pour-on compositions against .itans exiqua. Paddock on a commercial farm near Topaz, North Queensland, Australia A paddock pen study was conducted. The purpose of the study was to Buffalo fly (Haematobia irritans) Four experimental applications of fluralaner to natural populations of Bombyx mori (L.) The purpose of the study was to determine the therapeutic and residual efficacy of the drug product. The commercial cattle were kept in the field and had been exposed to macrocyclic lactones, organophosphates, and other No external treatments with acid esters, synthetic pyrethroids or insect growth regulators have been performed. Details of the treatment groups are shown below.

[0316] The animals were selected into their groups on day 0. Before treatment began, the animals in untreated group 1 were Treatment groups 2 to 5 were then transferred to their own separate paddocks. They are kept in small pens in the yard until they are allowed to join the races. Groups 3 and 5 (IVP2 and IVP4) were maintained separately in the same study. (See Table 1 Nos. 14-82 and 14-86). Groups 1 and 4 (IV P1 and IVP3) were comparative pour-on formulations. Details of their compositions are given in the table below. 6. [Table 8]

[0317] Each animal was restrained in a head crush during treatment. The animals were treated according to their individual body weights, which were recorded before the treatment. Treatment began approximately 10 cm in front of the scapula. via a 20 mL plastic syringe onto the animal's dorsal line ending at the base of the tail. It was administered topically.

[0318] Each assessment consisted of counting the number of flies across each side of all animals in each group separately. To determine treatment allocation, buffalo fries were Counts were performed at treatment administration (day 0), followed by 1, 3, 7, and 1 day after treatment. Fly counts were performed after 4, 21, 28 and 35 days.

[0319] The number of buffalo flies in the pre-treatment groups was uniform among groups, providing adequate challenge. The total number ranged from 208.3 to 239.2 flies (arithmetic mean) for the five treatment groups. The average number of buffalo flies per animal was 10.1–10.5% during the first 3 days after treatment. In untreated control cattle, the number of flies was relatively constant, ranging from an average of 233.3 to 278.3. Between 21 and 35 days after treatment, the fly population increased to an average of 526.7. .

[0320] The total number indicated that fly infestation on the farm was sufficient for the duration of the study.

[0321] On the first day after treatment, all four IVP groups had significantly lower mean fly counts compared to the untreated control group. was significantly decreased.

[0322] IVP2, group 3, had statistically higher numbers than the remaining treatment groups; however, the control The efficacy of the remaining IVP was 97. An efficacy of greater than 7% was achieved.

[0323] Group 4 was treated with IVP3 Fluralaner + Eprinomectin pour-on - IV P3 achieved 100% control on days 3 and 14; however, these evaluations There was no statistical difference in the mean number of flies between Group 4, Group 2 and Group 3 at any time point. Group 4 The efficacy of the drug was 99.0% or higher up to the 21st day. On the 28th and 35th days, Moderate levels of efficacy were still evident with 93.3% and 80.9% control, respectively.

[0324] The remaining formulations maintained high efficacy levels of over 93.9% through day 21. The efficacy of the drugs declined to intermediate levels on days 28 and 35. On day 35, all drugs Cows treated with the agent had significantly lower arithmetic mean fly counts than the UTC group.

[0325] Among the IVP groups, efficacy ranged from 76.3% in group 5 to 80.9% in group 4. There was no difference.

[0326] The IVP formulation, when administered as a pour-on treatment, inhibited the natural population of buffalo fly It provided a high level of efficacy for the group.

[0327] The invention is further described by the following numbered paragraphs:

[0328] 1. An effective amount of a compound of formula (I) [ka]

[0329] [During the ceremony, R 1 = halogen, CF3, OCF3 or CN; n=an integer from 0 to 3 inclusive; m=1 or 2; R 2 =C1-C3 haloalkyl; T=ring structure: 5- or 6-membered or bicyclic, which is substituted with one or more radicals Y may have been; Y=methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or Two adjacent radicals Y together form a chain; Q=X-NR 3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or one or more is a 5-membered N-heteroaryl ring optionally substituted with a radical; 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, alkylsulfani alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl kill, [ka]

[0330] and; Where: Z A= hydrogen, halogen, cyano or 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 methylaminocarbonylmethyl or haloethylaminocarbonylethyl. ; R 5 =H, alkyl or haloalkyl; R 6 =H, alkyl or haloalkyl; or where R 3 and R 4 Together, [ka]

[0331] forming a substituent selected from the group consisting of or a pharma- ceutically acceptable salt thereof. VETERINARY LIQUID COMPOSITION FOR USE IN THE PROTECTION AND TREATMENT OF PARASITIC INFECTION IN ANIMALS COMPRISING THE SAME - Patent application wherein the composition is administered as a pour-on and is administered by at least one skin a dermal penetration enhancer and a pharma- ceutically acceptable carrier comprising a solvent system, wherein the dermal penetration enhancer said veterinary liquid composition comprising menthol and said solvent system comprising a pyrrolidone solvent. .

[0332] 2. T is [ka] TIFF0007627312000031.tif99145

[0333] Selected from; where in T-1, T-3 and T-4, the radical Y=hydrogen, halogen, methyl, halomethyl, ethyl or haloethyl; and Here, Q is [ka]

[0334] Selected from; Here, R 3 , R 4 , X and Z A is as defined above; and Z B = [ka]

[0335] and Z D = [ka]

[0336] is; 2. The veterinary liquid composition of paragraph 1.

[0337] 3. The veterinary liquid composition of paragraph 1 or 2, wherein the solvent system comprises a volatile solvent.

[0338] 4. The method according to paragraph 1 or 2, wherein the composition comprises about 2 to about 20% w / v of the volatile solvent. 2. A veterinary liquid composition.

[0339] 5. The veterinary medicine of any of paragraphs 1 to 3, wherein the volatile solvent is an alcohol solvent. chemical liquid composition.

[0340] 6. The composition according to paragraph 1, wherein the composition comprises about 5 to about 60% w / v of the alcohol solvent. 5. Any of the veterinary liquid compositions according to 1 to 4.

[0341] 7. Any of paragraphs 1 to 5, wherein the alcohol solvent is isopropyl alcohol. Any veterinary liquid composition.

[0342] 8. The veterinary fluid of paragraph 1 or 2, wherein the composition comprises a glycerol ester. Body composition.

[0343] 9. The glycerol ester is a saturated or unsaturated fatty acid ester of propylene glycol. Acid monoesters and diesters, or C8-C 14 Glycerol having an alkyl chain length of Monoesters, diesters and triesters of C8-C 14 having an alkyl chain length of Saturated fatty acids, unsaturated fatty acids with alkyl chain lengths of C14-C22, C8-C 14 Al Saturated fatty alcohols with chain lengths of 1 and C 14 -C 22 Unsaturated alkyl chain length 3. The veterinary fluid of paragraph 1 or 2, selected from the group consisting of fatty alcohols and mixtures thereof. Body composition.

[0344] 10. The glycerol ester is propylene glycol dicapryocaprate, glyceryl monocaprylate and mixtures thereof. 8. Veterinary liquid composition.

[0345] 11. The composition according to claim 1, wherein the composition comprises about 5 to about 70% w / v glycerol ester. A veterinary liquid composition of any of Rough 8 to 10.

[0346] 12. The method according to claim 1, wherein the glycerol ester is glyceryl monocaprylate. Any of the veterinary liquid compositions according to F8 to F11.

[0347] 13. The method of claim 1 to 12, wherein the isoxazoline compound is fluralaner. Any veterinary liquid composition.

[0348] 14. The composition comprises about 1 to about 20% (w / v) of an isoxazoline compound. 14. The veterinary liquid composition of any of paragraphs 1 to 13.

[0349] 15. The composition contains about 20 to about 50% (w / v) of an isoxazoline compound. 15. The veterinary liquid composition of any of paragraphs 1 to 14.

[0350] 16. The method of claim 1, wherein the composition comprises about 2 to about 20% w / v menthol. 5. Any of the veterinary liquid compositions of 5.

[0351] 17. The pyrrolidone solvent is 2-pyrrolidone, N-methyl-2-pyrrolidone and / or 17. The veterinary liquid composition of any of paragraphs 1 to 16, which is a liquid veterinary composition comprising the compound of formula (I) or a mixture thereof.

[0352] 18. The composition of paragraph 1, wherein the composition comprises about 5 to about 50% w / v of pyrrolidone solvent. Any of 17 veterinary liquid compositions.

[0353] 19. In addition, Paragraph 19 contains propylene glycol dicaprylate / dicaprate. Any veterinary liquid composition of RAF 1 to 18.

[0354] 20. The composition comprises about 5 to about 80% w / v propylene glycol dicaprylate. / Any veterinary liquid composition of paragraphs 1 to 19, comprising Zikaplate.

[0355] 21. The composition comprises about 5 to about 50% w / v pyrrolidone solvent and about 5 to about 80% w / v / v propylene glycol dicaprylate / dicaprate, paragraphs 1 to 20 2. Any of the veterinary liquid compositions.

[0356] twenty two. (a) about 0.5% to about 15% w / v of at least one isoxazoline compound; (b) about 5% to about 15% w / v menthol; (c) about 10% to about 50% w / v isopropyl alcohol; (d) about 10% to about 40% w / v pyrrolidone solvent; and (e) propylene glycol dicaprylate / dicaprate, about 5% to about 80% w / v 1 to 7. A veterinary liquid composition comprising:

[0357] 23. The composition comprises about 2 to about 5% of an isoxazoline compound and a carrier. about 10% w / v menthol, about 35 to about 55% w / v isopropyl alcohol, About 5 to about 35% w / v 2-pyrrolidone and / or about 10% w / v propylene glycol 23. The veterinary liquid composition of paragraph 22, comprising ludicaprylate / dicaprate.

[0358] 24. The composition comprises about 2% w / v, about 3% w / v, or about 5% w / v of isoxazoline. and the carrier is about 35% w / v or about 55% w / v isopropyl Paragraph 1, comprising alcohol and about 5% w / v or about 35% w / v 2-pyrrolidone. 10. The veterinary liquid composition of any one of claims 1 to 7.

[0359] 25. The composition comprises about 20 to about 50% of an isoxazoline compound; and The carrier is about 5 to about 15% w / v menthol, about 35 to about 55% w / v isopropyl alcohol, alcohol, about 5% to about 40% w / v 2-pyrrolidone and / or about 10% to 70% w / v Veterinary medicines in paragraphs 1-7, including propylene glycol dicaprylate / dicaprate liquid composition.

[0360] 26. The composition comprises about 2% w / v, about 3% w / v, or about 5% w / v of isoxazoline. and the carrier is about 35% w / v or about 55% w / v isopropyl Paragraph 1, comprising alcohol and about 5% w / v or about 35% w / v 2-pyrrolidone. ~7. A veterinary liquid composition.

[0361] 27. The isoxazoline compound is fluralaner, afoxolaner, or lotilane. 27. The veterinary medicine according to any one of paragraphs 1 to 26, wherein the veterinary medicine is selected from the group consisting of sarolaner and sarolaner. chemical liquid composition.

[0362] 28. Paragraphs 1 to 4 for use in the manufacture of a drug for controlling parasites. 27. The veterinary liquid composition of any one of claims 1 to 27, wherein the animal is a bovine animal or The composition is an ovine animal.

[0363] 29. The infestation by ectoparasites is an infestation by ticks and / or lice. 29. The veterinary liquid composition of any one of paragraphs 1 to 28.

[0364] 30. A method for protecting bovine animals from infestation by ectoparasites, comprising the steps of: 27. A veterinary liquid composition according to any one of paragraphs 1 to 27 in an effective dose for an animal in need thereof. The method further comprises administering

[0365] 31. Protecting cattle from infestation by ectoparasites, preferably by ticks or lice and / or to prevent infestation by ectoparasites, preferably ticks or lice. 27. A veterinary liquid according to any one of paragraphs 1 to 27 in the manufacture of a medicament for treating Use of the composition.

[0366] 32. Protect sheep from infestation by ectoparasites, preferably blowfly strike. and / or to prevent infestation by ectoparasites, preferably blowfly strike. 27. A veterinary liquid according to any one of paragraphs 1 to 27 in the manufacture of a medicament for treating Use of the composition.

Claims

1. (a) 0.5% to 15% w / v of an isoxazoline compound selected from the group consisting of fluralaner, afoxolaner, lotilaner, and sarolaner, or a pharma- ceutically acceptable salt thereof; (b) menthol, between 5% and 15% w / v; (c) an alcoholic solvent of 10% to 50% w / v; (d) 10% to 40% w / v pyrrolidone solvent; and (e) 5% to 80% w / v propylene glycol dicaprylate / dicaprate; A liquid bovine pour-on composition for use in the protection and treatment of parasitic infestations in bovine animals.

2. 2. The liquid bovine pour-on composition of claim 1, wherein the composition comprises 2% w / v, 3% w / v or 5% w / v of an isoxazoline compound; and 35% w / v of isopropyl alcohol and 35% w / v of 2-pyrrolidone as carriers.

3. 3. A liquid cattle pour-on composition according to claim 1 or 2, wherein said parasitic infestation is a tick and / or louse infestation.

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