Stable isoxazoline formulation for topical application to the skin

Abstract

The invention relates to a veterinary composition for topical application to the skin comprising a) an isoxazoline compound, b) optionally, a macrocyclic lactone compound, c) one or more penetration enhancers, d) optionally, one or more veterinary acceptable solvents, e) optionally, one or more veterinary acceptable cosolvents, and f) optionally, one or more antioxidants.

Description

Stable isoxazoline formulation for topical application to the skinPriorities

[0001] Priority is claimed of Slovenian patent application no. P-2024 00037 that was filed on March 15, 2024.Field of the invention

[0002] The invention relates to a veterinary composition for topical application to the skin comprising a) an isoxazoline compound, b) optionally, a macrocyclic lactone compound, c) one or more penetration enhancers, d) optionally, one or more veterinary acceptable solvents, e) optionally, one or more veterinary acceptable cosolvents, and f) optionally, one or more antioxidants.Background of the invention

[0003] A number of pests and parasites can infest or infect domestic animals such as cattle, horses, pigs, sheep and also companion animals such as cats and dogs. These pests and parasites are of great nuisance to both the animals and their owners. Ectoparasites such as ticks, mites, lice, flies and fleas irritate the animals and can cause disease, either by themselves, or by carrying vector transmitted pathogens. New economic methods and compositions for the prevention, treatment and control of parasites in warm-blooded animals are constantly being sought.

[0004] A new family of insecticide isoxazoline compounds has been described in various patent applications; for example, in US patent application US 2007 / 0066617, and international applications WO 2007 / 079162, WO 2009 / 002809, WO 2009 / 024541, WO 2009 / 003075, W02010 / 070068 and WO 2010 / 079077. Several veterinary compositions have therefore been developed that are said to be useful against parasitic infections in animals. Many of these veterinary compositions contain a combination of two or more antiparasitic ingredients.

[0005] Fluralaner and moxidectin are both well-established antiparasiticides with proven efficacy. Veterinary compositions comprising both fluralaner and moxidectin are difficult to formulate in the view of achieving stable formulation. A veterinary composition comprising a combination of fluralaner and moxidectin for spot-on application is commercially available (Bravecto® Plus, Merck Animal Health).

[0006] As these isoxazoline compounds have been originally investigated for their use in the agricultural area it is necessary to identify specific formulations that allow their veterinary use, i.e. safe administration to control parasites in animal effectively.

[0007] One known and convenient way of administering an ectoparasiticide compound to an animal is the topical localized administration, e.g. as spot-on or pour-on. Spot-on parasiticides are often well tolerated by animals and hence easier for owners to administer compared to oral medication and to products that must be applied directly to an affected area. The benefits of a spot-on parasiticides include; a broad spectrum of activity, a low rate of adverse effects and ease of use, increased owner compliance and improved protection of animals against endoparasites and ectoparasites. The topical veterinary composition according to the invention is used in treating, controlling and / or preventing of ectoparasite and endoparasite infections in warm-blooded animals.

[0008] Topical veterinary compositions usually comprise a veterinary acceptable carrier comprising at least one solvent and at least one penetration enhancer.

[0009] Several penetration enhancers have been described in the state of the art as being suitable for topical transfer of the active substance through the skin. It is well known that there is no universal penetration enhancer or vehicle that would be optimal for the delivery of all classes of topical drugs across the skin of all species. Selection of optimal vehicle for transdermal delivery of a drug requires a close match between the physical and chemical properties of the drug, vehicle and skin lipids of the particular animal.

[0010] Transcutol® is a highly purified form of diethylene glycol monoethyl ether (DEGEE). Not to be confounded with ethylene glycol ethyl ether (EGEE) or diethylene glycol methyl ether (DGME), Transcutol® has a fully established safety profile. The nonclinical data along with a long history of use as vehicle and solvent by various routes of administration provide evidence for its safety. The pharmaceutical grades are guaranteed by the manufacturer to have purities of > 99.90% (HP grade) and > 99.80% (P grade) (Osborne DW, Musakhanian J. Skin Penetration and Permeation Properties of Transcutol®-Neat or Diluted Mixtures. AAPS PharmSciTech. 2018 Nov;19(8):3512-3533).

[0011] Isopropylidene glycerol also known as Solketal® is a low- viscosity liquid (~l lcP (@25° C) at room temperature and its freezing point is far below zero (approx. -26,5° C). Even though the vapor pressure levels of Solketal® at 20° C may be 0.1 mbar, the substance can be included in the group of high boilers showing a boiling point of about 190°C. Solketal® is harmless, non-toxic, non-irritant and has - if any - only a slight but pleasant odor, due to these characteristics and to the renewable origin, it is considered an environmentally friendly substance (Solketal®: An EHS Friendly and Sustainable Solvent; IMP AG Switzerland: Zurich, Switzerland, 2017).

[0012] Dimethyl sulfoxide (DMSO), first synthesized in 1866, is used in a number of regulated products in human and veterinary medicine. DMSO is a highly polar aprotic substance knowing to enhance topical penetration of drugs owing to its ability to displace bound water from the stratum comeum. Literature describes the penetration enhancing activities of DMSO and its effectiveness as an excellent accelerator but this effect is concentration dependent. Increases in drug penetration have been reported with DMSO concentrations as low as 15%. However, as disclosed by A.C. Williams et all, AdvancedDrug delivery Reviews 64 (2012) 128-137 and M.E. Lane, International Journal of Pharmaceutics 447 (2013) 12-21 the significant increase in permeability generally requires higher concentrations than 60%. At these relatively high concentrations DMSO can cause erythema and wheals of the stratum comeum and may denature some proteins. A further problem is the metabolite dimethyl sulfide produced from the solvent that produces a foul odor on the breath. On the other side DMSO has been shown to have bactericidal, bacteriostatic and fungistatic activity, anti-oxidative properties and it possesses mild to moderate neuroprotective effects.

[0013] WO 2012 / 089623 relates to the topical localized formulation comprising fluralaner and additionally macrocyclic lactone compound (optionally), wherein the liquid carrier vehicle comprises glycofurol as solvent and the organic cosolvent in the spot-on formulation is a mixture of at least two of acetone, ethyl-L-lactate, dimethyl sulfoxide, dimethylacetamide (DMA) and N,N-diethyl-3-methylben- zamide.

[0014] WO 2012 / 089622 discloses topical localized formulation comprising fluralaner and additionally macrocyclic lactone compound, wherein the liquid carrier vehicle comprises N,N-diethyl-3 -methylbenzamide as solvent and a cosolvent selected from the group consisting of dimethyl sulfoxide, acetone, dimethylacetamide (DMA), ethyl alcohol, eucalyptol, dipropylene glycol monomethyl ether, methylethyl ketone, glycofurol, ethyl-L-lactate, and a mixture of at least two of these cosolvents.

[0015] WO 2019 / 122324 discloses liquid veterinary composition, comprising at least one isoxazoline compound, menthol (as penetration enhancer), isopropyl alcohol, a pyrrolidone solvent and a propylene glycol dicaprylate / dicaprate.

[0016] WO 2020 / 252269 relates to the topical veterinary acceptable composition comprising fluralaner and additionally macrocyclic lactone compound (moxidectin), N-methyl-2 -pyrrolidone (NMP), 2-pyr- rolidone and a triglyceride carrier. Composition further comprises antioxidant (BHT).

[0017] WO 2019 / 048381 relates to the liquid formulation comprising fluralaner, triethyl phosphate and cosolvent.

[0018] A marketed composition (Bravecto®Plus) comprising isoxazoline compound is disclosed in WO 2012 / 089623 as composition comprising about 1-20 w / v glycofurol, about 5-25% v / v N,N-diethyl-3- methylbenzamide, about 10-50% v / v dimethylacetamide (DMA) and about 10-20% v / v acetone. N,N- diethyl-3 -methylbenzamide (DEET) is presented as a penetration enhancer. In CVMP assessment report for Bravecto for spot-on solution for dogs and cats (EMEA / V / C / 002526 / X / 0005CVMP) CVMP stated: "The excipient DEET (present in a concentration of 14% in formulation) is classified as skin irritating and therefore concluded that the formulation can cause skin irritation" . There is also some evidence that suggest DEET may act synergistically with other chemicals and that according to studies cats are more sensitive to N,N-diethyl-3 -methylbenzamide than dogs (N,N-diethyl-meta-toluamide (DEET), Risk Characterization document, September 2000, available online: https: / / www.cdpr.ca.gov / docs / risk / rcd / deet.pdf (accessed on 08.03.2024).

[0019] Both DEET and glycofurol were found to be very prone to formation of peroxides. In several samples of glycofurol and DEET, peroxide value was determined in comparison with other penetration enhancers, like DEGEE, isopropylidene glycerol and DMSO. All materials were stored according to the manufacturer’s instructions. Determined peroxide value was the highest in samples of glycofurol and DEET, regardless of previously opening the container or not, which means that the impact on stability of the formulation is in these cases is more possible. Results are presented below - see section Examples, Table 5.

[0020] In addition, prior art formulations that use suggested solvents for isoxazoline compounds have certain drawbacks. In particular, conventional formulations can cause skin irritation and noncompliance of a treated animal.

[0021] It is an object of the invention to provide veterinary compositions comprising fluralaner, preferably in combination with moxidectin, that have advantages compared to the prior art. The veterinary compositions should have excellent stability and safety. At the same time they should provide optimal applying conditions (non-skin irritating) due to less solvents used in composition. Additionally, used penetration enhancers should be environmentally friendly.

[0022] This object has been achieved by the subject-matter of the patent claims.Description

[0023] A first aspect of the invention relates to a veterinary composition for topical application to the skin comprising or essentially consisting of a) an isoxazoline compound, preferably according to ATCvet code [QP53BE]; more preferably fluralaner; b) optionally, a macrocyclic lactone compound, preferably according to ATCvet code [QP54A], more preferably moxidectin; c) one or more penetration enhancers, preferably comprising or essentially consisting of diethylene glycol monoethyl ether (DEGEE), isopropylidene glycerol, dimethyl sulfoxide (DMSO), and combinations thereof; d) optionally, one or more veterinary acceptable solvents, preferably comprising or essentially consisting of dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-me- thyl pyrrolidone (NMP), or combinations thereof; e) optionally, one or more veterinary acceptable cosolvents, preferably comprising or essentially consisting of acetone, ethanol, isopropanol, or combinations thereof; andf) optionally, one or more antioxidants, preferably comprising or essentially consisting of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherols, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate, or combinations thereof.

[0024] The veterinary compositions according to the invention are devoted for topical application to the skin. The compositions provide localized administration of an isoxazoline compound, preferably fluralaner, optionally in combination with a macrocyclic lactone compound, preferably moxidectin, and overcome the drawbacks of the prior art.

[0025] The veterinary compositions according to the invention exhibit excellent stability, especially of the pharmacologically active ingredient(s) against degradation, as has been shown after storage for 1 month at 50°C and 75% r.h.

[0026] The veterinary compositions according to the invention comprise a) an isoxazoline compound, preferably fluralaner; b) optionally, a macrocyclic lactone compound, preferably moxidectin; c) one or more penetration enhancers, preferably selected from diethylene glycol monoethyl ether (DEGEE), iso- propylidene glycerol, dimethyl sulfoxide (DMSO), and combinations thereof; and preferably at least one, more preferably at least two, still more preferably at least three further veterinary acceptable excipients independently from one another selected from d) solvents, e) cosolvents and d) antioxidants; preferably at least one d) solvent, at least one e) cosolvents, as well as at least one d) antioxidants.

[0027] Unless expressly stated otherwise, percentages are expressed as weight by volume percentages = w / v, i.e. calculated by dividing the mass of the solute in g by the volume of solution in ml then multiplying this by 100.

[0028] The composition according to the invention comprises an isoxazoline compound.

[0029] Isoxazoline compounds according to the invention are classified preferably under ATCvet code [QP] antiparasitic products, insecticides and repellents; more preferably [QP53] ectoparasiticides, insecticides and repellents; still more preferably [QP53B] ectoparasiticides for systemic use; yet more preferably [QP53BE] isoxazolines.

[0030] For the purpose of the description, unless expressly stated otherwise, the term "isoxazoline compound" refers to the non-salt form, veterinary acceptable salts, veterinary acceptable solvates, and / or veterinary acceptable prodrugs thereof.

[0031] Preferably, the isoxazoline compound is selected from fluralaner, afoxolaner, esafoxolaner, lo- tilaner and sarolaner; more preferably fluralaner.

[0032] Preferably, the content of the isoxazoline compound is within the range from 0.5 to 40% w / v, preferably from 5 to 35% w / v, more preferably from 20 to 35% w / v.

[0033] Optionally, the composition according to the invention comprises a macrocyclic lactone compound.

[0034] The optionally present macrocyclic lactone compound according to the invention is classified preferably under ATCvet code [QP] antiparasitic products, insecticides and repellents; more preferably [QP54] endectocides; still more preferably [QP54A] macrocyclic lactones.

[0035] For the purpose of the description, unless expressly stated otherwise, the term "macrocyclic lactone compound" refers to the non-salt form, veterinary acceptable salts, veterinary acceptable solvates, and / or veterinary acceptable prodrugs thereof.

[0036] Preferably, the macrocyclic lactone compound is selected from moxidectin, ivermectin, milbe- mycin oxime, selamectin, emamectin, eprinomectin, latidectin and lepimectin; more preferably moxidectin.

[0037] Preferably, the content of the macrocyclic lactone compound is within the range of from 0 to 20% w / v, preferably from 0. 1 to 10% w / v, more preferably from 0.5 to 5% w / v.

[0038] In preferred embodiments, the composition according to the invention additionally comprises an insect growth regulator compound, instead of the optional macrocyclic lactone compound, or in addition to the optional macrocyclic lactone compound.

[0039] Preferred insect growth regulator compounds according to the invention include chitin synthesis inhibitors and juvenoids (juvenile hormone mimics).

[0040] Preferably, the insect growth regulator compound is classified under ATCvet code [QP] antiparasitic products, insecticides and repellents; more preferably [QP53] ectoparasiticides, insecticides and repellents; still more preferably- [QP53A] ectoparasiticides for topical use, including insecticides; yet more preferably [QP53AX] other ectoparasiticides for topical use such as methoprene or pyriproxyfen; or- [QP53B] ectoparasiticides for systemic use; yet more preferably [QP53BC] chitin synthesis inhibitors, such as lufenuron or diflubenzuron.

[0041] Further insect growth regulator compounds include but are not limited to fenoxycarb, novaluron, triflumuron, fluazuron, and cyromazine.

[0042] For the purpose of the description, unless expressly stated otherwise, the term "insect growth regulator compound" refers to the non-salt form, veterinary acceptable salts, veterinary acceptable solvates, and / or veterinary acceptable prodrugs thereof.

[0043] The composition according to the invention comprises one or more penetration enhancers (skin permeation enhancers).

[0044] Preferably, the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE), isopropylidene glycerol, dimethyl sulfoxide (DMSO), or combinations thereof.

[0045] In preferred embodiments, the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE).

[0046] In preferred embodiments, the one or more penetration enhancers comprise or essentially consist of isopropylidene glycerol.

[0047] In preferred embodiments, the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO).

[0048] Preferably, the total content of the one or more penetration enhancers is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

[0049] Preferably, the content of diethylene glycol monoethyl ether (DEGEE) is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

[0050] Preferably, the content of isopropylidene glycerol is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

[0051] Preferably, the content of dimethyl sulfoxide (DMSO)is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

[0052] Preferably, the veterinary composition according to the invention additionally comprises one or more excipients independently of one another selected from d) solvents, e) cosolvents and f) antioxidants.

[0053] A solvent according to the invention can preferably be regarded as a primary solvent for a poorly-soluble compound, e.g. moxidectin and / or fluralaner. A cosolvent preferably enhances the solubility of the poorly-soluble compound. Preferably, a cosolvent is only present when a solvent is present as well, and the amount of the solvent preferably exceeds to amount of the cosolvent.

[0054] Optionally, the composition according to the invention comprises the one or more veterinary acceptable solvents.

[0055] Preferably, the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or combinations thereof.

[0056] In preferred embodiments, the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA).

[0057] In preferred embodiments, the one or more veterinary acceptable solvents comprise or essentially consist of dimethyl sulfoxide (DMSO). For the purpose of the invention, dimethyl sulfoxide (DMSO) may have dual action and thus act as both penetration enhancer and solvent.

[0058] When the composition according to the invention contains a combination of- diethylene glycol monoethyl ether (DEGEE) and / or isopropylidene glycerol with- dimethyl sulfoxide (DMSO), the dimethyl sulfoxide (DMSO) is preferably regarded as a solvent.

[0059] When the composition according to the invention contains- neither diethylene glycol monoethyl ether (DEGEE) nor isopropylidene glycerol but- dimethyl sulfoxide (DMSO), the dimethyl sulfoxide (DMSO) is preferably regarded as a penetration enhancer.

[0060] Preferably, the total content of the one or more veterinary acceptable solvents is within the range of from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v.

[0061] Preferably, the content of dimethylacetamide (DMA) is within the range of from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v. A pour-on or spot-on formulation generally can advantageously comprise dimethylacetamide (DMA) in an amount from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v.

[0062] Preferably, the content of dimethyl sulfoxide (DMSO) is within the range of from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v.

[0063] Optionally, the composition according to the invention comprises the one or more veterinary acceptable cosolvents.

[0064] Preferably, the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof; preferably acetone, isopropanol or combinations thereof.

[0065] In preferred embodiments, the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

[0066] In preferred embodiments, the one or more veterinary acceptable cosolvents comprise or essentially consist of isopropanol.

[0067] In preferred embodiments, the one or more veterinary acceptable cosolvents comprise or essentially consist of ethanol.

[0068] Preferably, the total content of the one or more veterinary acceptable cosolvents is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v, more preferably from 5% w / v to 20% w / v.

[0069] Preferably, the content of acetone is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v, more preferably from 5% w / v to 20% w / v. A pour-on or spot-on formulationgenerally can advantageously comprise acetone in an amount from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v, more preferably from 5% w / v to 20% w / v.

[0070] Preferably, the content of isopropanol is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v more preferably from 5% w / v to 20% w / v. A pour-on or spot-on formulation generally can advantageously comprise isopropanol in an amount from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v, more preferably from 5% w / v to 20% w / v.

[0071] Preferably, the content of ethanol is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v more preferably from 5% w / v to 20% w / v.

[0072] In particularly preferred embodiments of the composition according to the invention, c) one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE), isopropylidene glycerol, dimethyl sulfoxide (DMSO), or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or combinations thereof; and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof.

[0073] Preferably, c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE), isopropylidene glycerol, dimethyl sulfoxide (DMSO), or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, isopropanol, and a combination thereof.

[0074] Preferably, c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

[0075] Preferably, c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of isopropanol.

[0076] In other particularly preferred embodiments of the composition according to the invention, c) the one or more penetration enhancers comprise or essentially consist of isopropylidene glycerol, dimethyl sulfoxide (DMSO), diethylene glycol monoethyl ether (DEGEE), or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or combinationsthereof; and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof.

[0077] Preferably, c) the one or more penetration enhancers comprise or essentially consist of isoprop- ylidene glycerol, dimethyl sulfoxide (DMSO), or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, isopropanol, or a combination thereof.

[0078] Preferably, c) the one or more penetration enhancers comprise or essentially consist of isoprop- ylidene glycerol; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

[0079] In further particularly preferred embodiments of the composition according to the invention, c) one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or a combination thereof; and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof.

[0080] Preferably, c) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, isopropanol, or a combination thereof.

[0081] Preferably, c) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

[0082] Preferably, c) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of isopropanol.

[0083] In particularly preferred embodiments, the composition according to the invention comprises(i) DEGEE, DMA, and isopropanol;(ii) DEGEE, DMA, and acetone;(iii) isopropylidene glycerol, DMA, and isopropanol;(iv) isopropylidene glycerol, DMA, and acetone;(v) DMSO, DMA and isopropanol; or(vi) DMSO, DMA and acetone.

[0084] In particularly preferred embodiments, the composition according to the invention comprises(i) DEGEE, DMSO, and isopropanol;(ii) DEGEE, DMSO, and acetone;(iii) isopropylidene glycerol, DMSO, and isopropanol;(iv) isopropylidene glycerol, DMSO, and acetone;(v) DMSO and isopropanol; or(vi) DMSO and acetone.

[0085] Optionally, the composition according to the invention additionally comprises the one or more antioxidants.

[0086] Preferably, the one or more antioxidants comprise or essentially consist of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherols, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate, or combinations thereof; preferably of not more than two.

[0087] Preferably, the one or more antioxidants comprise or essentially consist of butylated hydroxytoluene, butylated hydroxy anisole, or a combination thereof; preferably butylated hydroxytoluene.

[0088] Preferably, the total content of the one or more antioxidants is within the range of from 0 to 0.3% w / v, preferably 0.05 to 0.25% w / v, most preferably 0.05 to 0.15% w / v.

[0089] Preferably, the content of butylated hydroxytoluene (BHT) is within the range of from 0 to 0.3% w / v, preferably 0.05 to 0.25% w / v, most preferably 0.05 to 0.15% w / v.

[0090] The composition according to the invention can also include additional ingredients such as additional veterinary acceptable excipients. Veterinary acceptable excipients can be selected from stabilizers, anti-nucleating agents, crystallization inhibitors, spreading agents, systemic absorption agents and the like. A single excipient may have one or more functions.

[0091] In particularly preferred embodiments, the composition according to the invention comprises or essentially consists of a) fluralaner; b) moxidectin; c) diethylene glycol monoethyl ether (DEGEE), isopropylidene glycerol, or DMSO; d) dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); e) acetone or isopropanol; and f) butylated hydroxytoluene (BHT).

[0092] The composition according to the invention is applicable topically to the skin of an animal in the form of a liquid composition, preferably in the form of a spot-on formulation or a pour-on formulation.

[0093] In preferred embodiments, the composition according to the invention is a pour-on formulation.

[0094] In other preferred embodiments, the composition according to the invention is a spot-on formulation.

[0095] The composition according to the invention is preferably filled in containers for single dose application. Suitable containers are, for example, plastic tubes / pipettes consisting of polypropylene or plastic tubes / pipettes consisting of polypropylene and aluminum. In order to protect the formulation from moisture or evaporation, the tubes or pipettes may be sealed in secondary packaging such as aluminum sachets, PVC blister, poly chlorotrifluoroethylene PCTFE / PVC blister or aluminum blister, which may be closed by heat sealing, e.g. with aluminum foil and similar aluminum laminates.

[0096] The composition of the invention may be filled in primary packaging material and packed into secondary packaging, optionally under inert gas atmosphere.

[0097] The veterinary compositions according to the invention can be manufactured by standard procedures of pharmaceutical technology using standard equipment that is commercially available.

[0098] For example, when the veterinary composition is a spot-on solution it is preferred to firstly mix and dissolve excipients, such as antioxidant, in one solvent or mixture of solvents and thereafter to add Moxidectin and Fluralaner. After every addition, the resultant mixture is stirred until every ingredient is fully dissolved. The resultant solution may then be filtered, e.g. through a stainless steel filter. Aliquots of the solution may be filled into pipettes, e.g. made of polypropylene or polypropylene and aluminum, which may be sealed and packaged.

[0099] Another aspect of the invention relates to the veterinary composition according to the invention as described above for use in the treatment or prevention of parasitic infections in pets.

[0100] Likewise, another aspect of the invention relates to the use of an isoxazoline compound, preferably moxidectin, optionally in combination with a macrocyclic lactone compound, preferably fluralaner, for the manufacture of the veterinary composition according to the invention as described above for the treatment or prevention of parasitic infections in pets.

[0101] Likewise, another aspect of the invention relates to a method of treating or preventing parasitic infections in pets comprising applying, preferably topically to the skin, an effective amount of the veterinary composition according to the invention as described above.

[0102] The composition according to the invention is a veterinary composition that is suitable and typically also devoted for the prevention and / or the treatment of parasitic infections, particularly mixed parasitic infections, in animals, preferably in pets, more preferably in mammalian pets, most preferably in cats.

[0103] For cats suffering from or at risk of mixed parasitic infections, exemplified mixed parasitic infections that can be treated or prevented with the veterinary composition according to the invention include but are not limited to:• flea infestation (Ctenocephalides felis) and tick (Ixodes ricinus);• ear mite infestation (Otodectes cynotis);• notoedric mange (Notoedres cati);• infections with lungworm Eucoleus aerophilus (syn. Capillaria aerophila) (adults);• lungworm disease (L3 / L4 larvae of Aelurostrongylus abstrusus);• infections with lungworm Aelurostrongylus abstrusus (adults);• infections with eye worm Thelazia callipaeda (adults);• heartworm disease (L3 and L4 larvae of Dirofilaria immitis);• infections with gastrointestinal nematodes (L4 larvae, immature adults and adults of Toxocara cati and Ancylostoma tubaeforme);• infections with intestinal roundworm (4th stage larvae, immature adults and adults;• Toxocara cati;• infections with intestinal hookworm (4th stage larvae, immature adults and adults of Ancylostoma tubaeforme); or• heartworm disease caused by Dirofilaria immitis.

[0104] The veterinary composition according to the invention is preferably used as part of a treatment strategy for treatment or prevention of:• flea infestation (Ctenocephalides felis) and and tick (Ixodes ricinus);• flea allergy dermatitis (FAD);• infestations with ear mites (Otodectes cynotis);• infections with intestinal roundworm (4th stage larvae, immature adults and adults);• Toxocara cati;• infections with intestinal hookworm (4th stage larvae, immature adults and adults of Ancylostoma tubaeforme); or• heartworm disease caused by Dirofilaria immitis.

[0105] Preferably, the veterinary composition according to the invention is applied topically to the skin, preferably to undamaged skin.

[0106] Preferably, the veterinary composition according to the invention is applied topically to the skin, i.e. cutaneously, by applying it in form of a spot-on formulation, preferably spot-on solution to the skin. Depending upon the size and weight of the cat to be treated, the spot-on formulation is to be applied, e.g. pipetted, up to 6,25 kg body weight in one spot at the base of the skull and in 2 spots at the base of the skull on cats greater than 6.25 kg body weight.

[0107] Preferably, the veterinary composition according to the invention is administered at least once.

[0108] In a preferred embodiment, an effective amount of the veterinary composition according to the invention is administered a single time and then treatment is terminated.

[0109] In another preferred embodiment, a first effective amount of the veterinary composition according to the invention is administered, i.e. applied to the skin, and after 12 weeks, a second effective amount of the veterinary composition according to the invention is administered, i.e. applied to the skin. After administration of the second effective amount, treatment may be terminated.

[0110] Alternatively, after administration of the second effective amount, treatment may be continued, i.e. after 12 weeks, a third effective amount of the veterinary composition according to the invention is administered, i.e. applied to the skin. After administration of the third effective amount, treatment may be terminated or continued.

[0111] When treatment involves repeated administration, every administered subsequent effective amount of the veterinary composition according to the invention preferably essentially corresponds to every administered preceding effective amount of the veterinary composition according to the invention (i.e. first effective dose ~ second effective dose ~ third effective dose and so on).Examples:

[0112] Preferred specific embodiments of the invention are described in the following examples. It is, however, to be understood that the invention is not limited to these examples.

[0113] Examples 1-17 were prepared according to the following process:(i) dissolving an antioxidant in a solvent or mixture of solvent(s), cosolvent(s) and / or penetration enhancer(s) until clear solution is obtained;(ii) adding a pharmaceutical ingredient (API) to the mixture under stirring until clear solution is obtained;(iii) adding another pharmaceutical ingredient (API) to the mixture under stirring until clear solution is obtained;(iv) adding solvent(s), cosolvent(s) and / or penetration enhancer(s) to the mixture under stirring up to the final volume;(v) filtering the final solution to assure removal of particles;(vi) filling of solution into glass vials and;(vii) closing the glass vials.

[0114] The following veterinary compositions were prepared:Table 1 : Veterinary compositions of isoxazoline compound part 1q.s. = ad 1 mlTable 2: Veterinary compositions of isoxazoline compound part 2q.s. = ad 1 ml

[0115] The drop in the content of antioxidant BHT and related substances of moxidectin were evaluated after stress stability testing for 1 month 50° / 75% RH on presented veterinary compositions in Table 3.

[0116] Content of BHT was analyzed by HPLC. Separation was achieved on a Kinetex XB-C18 (250 x 4.6 mm; 5 pm) column, using a mobile phase consisting of water and mixture of water and acetonitrile, in a dual-mode gradient for 17 minutes. The column was maintained at 20 °C and detection was carried out at 280 nm by using a UV detector.

[0117] Related substances of moxidectin were analyzed by HPLC. Separation was achieved on a Kinetex XB-C18 (150 x 4.6 mm; 2.6 pm) column, using a mixture of ammonium acetate buffer pH 4.8 and acetonitrile as mobile phase. The column was maintained at 50 °C and detection was carried out at 242 nm by using a diode-array detector.Table 3: The drop in the content of BHT and related substances of moxidectin on presented veterinary compositions, using isoxazoline compound

[0118] Furthermore, the physicochemical properties such as surface tension, contact angle and spreading diameter were evaluated and are presented in Table 4.

[0119] Compositions were tested using the following procedures:

[0120] Surface tension was measured at 25 °C using Wilhelmy plate method on KSV Instruments Sigma tenziometer. Result is an average of 10 dips, and the volume of the sample was 40 ml.

[0121] Contact angle was measured using Kruss DSA 30 goniometer at 25 °C. Drop volume of 2 pl was deposited on the flat silicon surface. The result is an average of 10 measurements.

[0122] Spreadability of the drop was measured using 60 pl of sample, deposited on the flat silicon surface at 25 °C. The diameter of the drop was determined using image analysis. Resulting diameter is an average of 10 drops.Table 4: Physicochemical parameters of veterinary compositions of isoxazoline compound

[0123] Peroxide value:

[0124] Content of peroxide was performed on HPLC system. Separation was achieved on a XBridge C18 (150 x 4.6 mm; 3.5 pm) column. Mobile phase A contains sodium dihydrogen phosphate and sodium octanesulfonate in solution, pH 4.6. Mobile phase B contains acetonitrile. Gradient elution is 22minutes long. The column was maintained at 40 °C and detection was carried out at 224 nm by using a UV detector.

[0125] Peroxide value on DEET was determined by method described in Ph. Eur 2.5.5., method A.Table 5 : Peroxide value (ppm) in used materials*tested according to Ph. Eur 2.5.5., method A

[0126] Examples 18-34 were prepared according to the following process:(i) preparing a mixture of solvent(s), cosolvent(s) and / or penetration enhancer(s)(ii) adding a pharmaceutical ingredient (API) to the mixture under stirring until clear solution is obtained;(iii) adding solvent(s), cosolvent(s) and / or penetration enhancer(s) to the mixture under stirring up to the final volume;(iv) filtering the final solution to assure removal of particles;(v) filling of solution into glass vials and;(vi) closing the glass vials.

[0127] The following veterinary compositions were prepared:Table 6: Veterinary compositions of isoxazoline compound part 3q.s. = ad 1 mlTable 7: Veterinary compositions of isoxazoline compound part 4q.s. = ad 1 ml

Claims

Patent claims:

1. A veterinary composition for topical application to the skin comprising or essentially consisting of a) an isoxazoline compound; b) optionally, a macrocyclic lactone compound; c) one or more penetration enhancers; d) optionally, one or more veterinary acceptable solvents; e) optionally, one or more veterinary acceptable cosolvents; and f) optionally, one or more antioxidants.

2. The composition according to claim 1, wherein the isoxazoline compound is selected from flu- ralaner, afoxolaner, esafoxolaner and sarolaner; preferably fluralaner.

3. The composition according to claim 1 or 2, wherein the content of the isoxazoline compound is within the range from 0.5 to 40% w / v, preferably from 5 to 35% w / v, more preferably from 20 to 35% w / v.

4. The composition according to any of the preceding claims, which comprises the macrocyclic lactone compound.

5. The composition according to claim 4, wherein the macrocyclic lactone compound is moxidectin.

6. The composition according to claim 4 or 5, wherein the content of the macrocyclic lactone compound is within the range of from 0 to 20% w / v, preferably from 0.1 to 10% w / v, more preferably from 0.5 to 5% w / v.

7. The composition according to any of the preceding claims, wherein the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE), iso- propylidene glycerol, dimethyl sulfoxide (DMSO), or combinations thereof.

8. The composition according to any of the preceding claims, wherein the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE).

9. The composition according to any of the preceding claims, wherein the one or more penetration enhancers comprise or essentially consist of isopropylidene glycerol.

10. The composition according to any of the preceding claims, wherein the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO).

11. The composition according to any of the proceeding claims, wherein the total content of the one or more penetration enhancers is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

12. The composition according to any of the proceeding claims, wherein the content of diethylene glycol monoethyl ether (DEGEE) is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

13. The composition according to any of the proceeding claims, wherein the content of isopropylidene glycerol is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

14. The composition according to any of the proceeding claims, wherein the content of dimethyl sulfoxide (DMSO)is within the range of from 10 to 60% w / v, preferably 15 to 55% w / v, more preferably in an amount of 20 to 50% w / v.

15. The composition according to any of the preceding claims, which comprises the one or more veterinary acceptable solvents.

16. The composition according to claim 15, wherein the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or combinations thereof.

17. The composition according to claim 15 or 16, wherein the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA).

18. The composition according to claim 15 or 17, wherein the one or more veterinary acceptable solvents comprise or essentially consist of dimethyl sulfoxide (DMSO).

19. The composition according to any of claims 15 to 18, wherein the total content of the one or more veterinary acceptable solvents is within the range of from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v.

20. The composition according to any of claims 15 to 19, wherein the content of dimethylacetamide (DMA) is within the range of from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v.

21. The composition according to any of claims 15 to 20, wherein the content of dimethylsulfoxide (DMSO) is within the range of from 0% w / v to 60% w / v, preferably from 5% w / v to 55% w / v, more preferably from 10% w / v to 50% w / v.

22. The composition according to any of the preceding claims, which comprises the one or more veterinary acceptable cosolvents.

23. The composition according to claim 22, wherein the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof; preferably acetone, isopropanol or combinations thereof.

24. The composition according to claim 22 or 23, wherein the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

25. The composition according to any of claims 22 to 24, wherein the one or more veterinary acceptable cosolvents comprise or essentially consist of isopropanol.

26. The composition according to any of claims 22 to 25, wherein the one or more veterinary acceptable cosolvents comprise or essentially consist of ethanol.

27. The composition according to any of claims 22 to 26, wherein the total content of the one or more veterinary acceptable cosolvents is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v, more preferably from 5% w / v to 20% w / v.

28. The composition according to any of claims 22 to 27, wherein the content of acetone is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v, more preferably from 5% w / v to 20% w / v.

29. The composition according to any of claims 22 to 28, wherein the content of isopropanol is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v more preferably from 5% w / v to 20% w / v.

30. The composition according to any of claims 22 to 29, wherein the content of ethanol is within the range of from 0% w / v to 50% w / v, preferably from 1% w / v to 30% w / v more preferably from 5% w / v to 20% w / v.

31. The composition according to any of the proceeding claims, which additionally comprises the one or more antioxidants.

32. The composition according to claim 31, wherein the one or more antioxidants comprise or essentially consist of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherols, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate, or combinations thereof; preferably of not more than two.

33. The composition according to claim 31 or 32, wherein the one or more antioxidants comprise or essentially consist of butylated hydroxytoluene, butylated hydroxy anisole, or a combination thereof; preferably butylated hydroxytoluene.

34. The composition according to any of claims 31 to 33, wherein the total content of the one or more antioxidants is within the range of from 0 to 0.3% w / v, preferably 0.05 to 0.25% w / v, most preferably 0.05 to 0.15% w / v.

35. The composition according to any of claims 31 to 34, wherein the content of butylated hydroxytoluene (BHT) is within the range of from 0 to 0.3% w / v, preferably 0.05 to 0.25% w / v, most preferably 0.05 to 0.15% w / v.

36. The composition according to any of the preceding claims, wherein c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE), dimethyl sulfoxide (DMSO), isopropylidene glycerol, or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or combinations thereof; and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof.

37. The composition according to claim 36, wherein c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE), dimethyl sulfoxide (DMSO), or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, isopropanol, and a combination thereof.

38. The composition according to claim 36 or 37, wherein c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

39. The composition according to any of claims 36 to 38, wherein c) the one or more penetration enhancers comprise or essentially consist of diethylene glycol monoethyl ether (DEGEE); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); ande) the one or more veterinary acceptable cosolvents comprise or essentially consist of isopropanol.

40. The composition according to any of the preceding claims, wherein c) the one or more penetration enhancers comprise or essentially consist of isopropylidene glycerol, dimethyl sulfoxide (DMSO), and a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or combinations thereof; and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof.

41. The composition according to claim 40, wherein c) the one or more penetration enhancers comprise or essentially consist of isopropylidene glycerol, dimethyl sulfoxide (DMSO), or a combination thereof; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, isopropanol, or a combination thereof.

42. The composition according to claim 40 or 41, wherein c) the one or more penetration enhancers comprise or essentially consist of isopropylidene glycerol; d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

43. The composition according to any of the preceding claims, wherein c) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA), benzyl alcohol, ethyl lactate, ethyl acetate, dimethyl isosorbide, glycerol formal, dipropylene glycol monomethyl ether, N-methyl pyrrolidone (NMP), or a combination thereof; and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, ethanol, isopropanol, or combinations thereof.

44. The composition according to claim 43, whereinc) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone, isopropanol, or a combination thereof.

45. The composition according to claim 43 or 44, wherein c) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of acetone.

46. The composition according to any of claims 43 to 45, wherein c) the one or more penetration enhancers comprise or essentially consist of dimethyl sulfoxide (DMSO); d) the one or more veterinary acceptable solvents comprise or essentially consist of dimethylacetamide (DMA); and e) the one or more veterinary acceptable cosolvents comprise or essentially consist of isopropanol.

47. The composition according to any of the preceding claims, which comprises or essentially consists of fluralaner; moxidectin; diethylene glycol monoethyl ether (DEGEE), isopropylidene glycerol, or DMSO; a mixture of dimethylacetamide (DMA) and acetone, or a mixture of dimethylacetamide (DMA) and isopropanol; and butylated hydroxytoluene (BHT).

48. The composition according to any of the preceding claims which is a pour-on formulation.

49. The composition according to any of the preceding claims which is a spot-on formulation.

50. The composition according to any of the preceding claims for use in the treatment or prevention of parasitic infections in pets.

51. The composition for use according to claim 50, wherein the pets are cats.

52. The composition for use according to claim 50 or 51, wherein the veterinary composition is applied topically to the skin.