AU2013368970A1

AU2013368970A1 - Pharmaceutical composition containing a derivative of N-phenylpyrazole and permethrin, and use for the production of a topical veterinary medicament

Info

Publication number: AU2013368970A1
Application number: AU2013368970A
Authority: AU
Inventors: Nathalie Delhom; Bertrand Havrileck
Original assignee: Virbac SA
Current assignee: Virbac SA
Priority date: 2012-12-27
Filing date: 2013-12-20
Publication date: 2015-07-16
Also published as: FR3000393B1; EP2938361A1; FR3000393A1; BR112015015493A8; WO2014102693A1; BR112015015493B1; BR112015015493A2

Abstract

The invention relates to a topical veterinary pharmaceutical composition consisting of an N-phenylpyrazole, permethrin and a phase change inhibitor selected from ethanol, benzyl alcohol and the mixture thereof; and to the use of same in the prevention and/or the treatment of infestations of pets by external parasites.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A DERIVATIVE OF N-PHENYLPYRAZOLE AND PERMETHRIN, AND USE FOR THE PRODUCTION OF A TOPICAL VETERINARY MEDICAMENT 5 The present invention relates to a topical veterinary pharmaceutical composition combining an N-phenylpyrazole, preferably fipronil, and an ectoparasiticide, notably permethrin, for treating infestations by external parasites (flea, tick, mosquito, sand fly, mange mite, etc.). Pets are often infested by one or more hematophagic parasites such as 10 dog or cat fleas, ticks, or else mange mites (responsible for mange). Fleas are wingless insects which have a laterally compressed body and highly developed legs suitable for jumping. They are blood-sucking ectoparasites of mammals or birds. The some 2000 species listed belong to the order Siphonaptera. Two species of fleas are commonly encountered in Europe; they are the cat flea 15 (Ctenocephalidesfelis) and the dog flea (Ctenocephalides canis) which live in the fur of the animals. Flea bites cause itching in both animals and humans. The flea saliva (secreted at each bite) can also, depending on individuals, lead to immediate or delayed allergic reactions. These reactions result in various skin lesions and itching. Two types 20 of flea-related dermatosis are distinguished: pulicosis and flea allergy dermatitis. Even though in both cases the dermatosis results from a more or less substantial infestation with fleas, only in the second case is there an associated allergic phenomenon. Flea allergy dermatitis (FAD) is the most common cause of pruritus in dogs. In France, in adult dogs, it thus represents close to half of the pruritic dermatoses. Close to 80% of 25 dogs which exhibit FAD also have atopic dermatitis. At the same time, two atopic dogs out of three exhibit FAD. It is therefore probable that atopic dogs are predisposed to the development of a flea bite allergy and that infestation with the latter is a triggering factor for atopic dermatitis. This is proof of the need for a very intensive antiflea control in atopic dogs or dogs belonging to at-risk breeds. Furthermore, FAD is probably the 30 main cause of the reappearance of pruritus in desensitized atopic dogs. Fleas of the genus Ctenocephalides are moreover intermediate hosts of Dipylidium caninum, a parasitic worm of the small intestine of dogs and cats. The carnivore becomes infested by swallowing parasitized fleas. This infestation can cause anal pruritus, engorgement of the anal sacs and also dermatitis of the perineal region. 6618495 1 (GHMatters) P100275.AU LYNT For this reason it is sometimes recommended to worm animals regularly in addition to combating fleas. Similarly, ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma sp, etc.) can also cause the animal stress and be harmful to its health. They 5 can also be harmful to humans. However, the most serious problem with ticks is that they are a vector for pathogenic agents that can affect animals just as much as humans. Among the major diseases that have to be avoided, mention may be made of Borelliosis (Lyme disease caused by Borellia burgdorferi), babesiosis (pyroplasmosis caused by Babesia sp.) and rickettsiosis. Ticks can also release toxins with paralyzing and 10 inflammatory properties, which are sometimes deadly. Mange (Demodex sp., Sarcoptes sp., Otodectes sp., etc.) is particularly difficult to combat since very few effective active materials exist; frequent treatments are required. Mosquitoes (Culex sp., Aedes sp., Anopheles sp., etc.) play an 15 extremely significant role in human and animal health, since, beyond the damage they cause by their bites, they represent the largest group of vectors for pathogenic agents which can be transmitted to humans, including numerous zoonoses. They are vectors for three groups of agents which are pathogenic to humans: Plasmodium, filaria and numerous arboviruses. They are present on all the landmasses of the planet (with the 20 exception of the Antarctic) - both in forested areas and in savannah or urban areas - as soon as a freshwater or brackish water surface, even small or transient, is available. Sixty-five species are listed in metropolitan France. Sand flies (Phlebotomus sp., etc.) are hematophagic insects. The sand fly is a vector insect. If it is infected, its bite transmits leishmaniasis. 25 Infestations with these various parasites, and most particularly with fleas, therefore represent a considerable health problem for infested animals and therefore require suitable treatments to be made available; it thus appears advantageous to combine different active agents in order to broaden the spectrum of action of formulations being developed. 30 Within the context of its work, the Applicant has sought to develop a formulation for the skin with easy administration, combining an N-phenylpyrazole, preferably fipronil, with permethrin at a high concentration (greater than 50% by 6618495 1 (GHMatters) P100275.AU LYNT weight/volume); in this context the Applicant encountered problems with crystallization at low temperature of the formulations thus prepared. Combinations of derivatives of N-phenylpyrazole and permethrin have been known for a long time, since the overlap and complementarity of the spectra 5 of actions of the active agents makes them particularly appealing for combating parasites in agriculture and in the veterinary field, where each of the active agents is commonly used. The Applicant has observed that permethrin changes phase at low temperatures, that is to say it crystallizes when it is formulated at a high concentration 10 with another active ingredient in an excipient or in a mixture of excipients according to the prior art; storage tests at 8'C carried out on formulations combining between 51 and 75% by weight/volume of permethrin and between 0 and 10% by weight/volume of fipronil in diethylene glycol monoethyl ether demonstrate a systematic phase change of the formulation (appearance of crystals at the latest after 5 days of storage) as soon as 15 the permethrin content exceeds 65% by weight/volume; increasing the content of fipronil in the formulation lowers this permethrin concentration threshold beyond which phase change of the formulation occurs. The appearance of crystals during the storage of pharmaceutical products poses several problems; firstly one of organoleptics: the presence of crystals in 20 a liquid formulation imparts a cloudy, opalescent appearance to the formulation, which constitutes an obstacle to its use. Moreover, crystal formation characterizes physical instability and loss of homogeneity of the formulation, which are troublesome for its administration. Finally, it may also denote chemical instability and a risk of the active 25 compounds breaking down, which is highly detrimental. The Applicant set themselves the goal of providing a product for preventing and treating flea infestations in domestic animals, which product has a broad spectrum of action and is easy to administer while having a rapid and long-lasting action. 30 Another aim of the invention is the development of stable compositions, the storage of which does not require any specific precautions (such as keeping the product at a temperature above 20'C, for example). 6618495 1 (GHMatters) P100275.AU LYNT N-phenylpyrazoles are a large family of compounds with a very broad spectrum of activity, including antiparasitic activities; they are described in patent applications EP 0 295 117 and EP 0 352 944. Permethrin, or (3-phenoxyphenyl)methyl (lRS,3RSlRS,3SR)-3-(2,2 5 dichlorovinyl)-2,2-dimethylcyclopropane- 1 -carboxylate (CAS N'52645-53-1), has the following chemical structure: It is a powerful neurotoxic insecticide of the pyrethroid family. International application WO 2011/038024 describes a pesticidal 10 composition for spot-on administration, comprising low concentrations of active agents in order to limit as much as possible the adverse side effects; it proposes in particular the combination of fipronil and a pyrethroid; the active agents as a whole are present in a content of less than 20% by weight of the total composition and no problem of phase change of the active agents is described. 15 International application WO 2009/033175 describes an antiparasitic veterinary composition comprising two insect growth inhibitors (IGRs) and an "adulticidal" compound such as a synthetic pyrethroid; it is preferably formulated in aerosol form with N,N-dimethyloctanamide and diisopropyl adipate (DIPA) as recommended carriers. It is mentioned that crystallization of the packaged product 20 should be avoided so as not to reduce the efficacy of the product; however, it is not indicated whether this object is achieved, nor how it might be achieved. International application WO 2008/080542 proposes a formulation combining an N-arylpyrazole and a pyrethroid in a self-spreading formulation, the use of which does not present any risk, and in which no reduction in the effect of the N 25 arylpyrazole that might be due to the addition of one or more other active agent(s) is observed. The formulation developed in the context of this invention comprises, in addition to the active agents, an aliphatic cyclic carbonate (ethylene carbonate or propylene carbonate) and a cyclic or noncyclic aliphatic polyether (in particular, diethylene glycol monoethyl ether); it is preferably topical for spot-on administration. 30 This application makes no mention of the problem of active agent crystallization; it 6618495 1 (GHMatters) P100275.AU LYNT should, however, be noted that no composition example comprises a permethrin content greater than 45 g/100 ml. International application WO 97/12521 describes an antiparasitic composition comprising: 5 - an N-phenylpyrazole, in particular fipronil; - an inhibitor of the crystallization of the product during application thereof to the coat of the animal; it is preferably a combination of a surfactant (polysorbate 80) and of a film-forming agent (PVP, polyvinyl alcohol and vinyl acetate/vinylpyrrolidone copolymers); 10 - an organic solvent; and - an organic co-solvent. The crystallization problem addressed in said application is that of preventing solid particles of formulation from being visible on the animal's coat; it is therefore a different problem than that which the present invention proposes to solve, 15 namely avoiding crystallization of the product in its packaging. Patent application EP 1 372 622 emphasizes the advantage of formulating compositions with a high content of pyrethroids, in particular of permethrin, but it also teaches that the compositions have a tendency to crystallize at low temperature and when the pyrethroid is present at a high concentration (for instance 20 contents greater than 50% or than 65% volume/volume). It proposes a pyethroid-based formulation comprising a terpene or a terpene derivative or a mixture of an alkyl glycol ether with a terpene or terpene derivative as excipient in order to avoid or minimize the crystallization of the pyrethroid at low temperature. The Applicant has observed that this problem of crystallization, during 25 storage, of a composition combining an N-phenylpyrazole compound such as fipronil and a pyrethroid such as permethrin at a high concentration, is amplified and occurs more rapidly when the quantity of fipronil increases and hence the quantity of solvent available to the pyrethroid decreases, thus contributing to promoting the crystallization of the pyrethroid at low temperature. The research conducted by the Applicant has 30 enabled it to observe that this problem of crystallization can be solved by adding suitable quantities of ethanol and/or benzyl alcohol to the formulation and by avoiding the presence of a surfactant such as a polysorbate. 6618495 1 (GHMatters) P100275.AU LYNT Thus, the present invention relates to a topical veterinary pharmaceutical composition consisting of (hereinafter, unless otherwise indicated, the percentage ranges are expressed by weight relative to the total volume of the composition): 5 - between 2 and 10% by weight/volume of an N-phenylpyrazole, preferably 5-amino-i -[2,6-dichloro-4-(trifluoromethyl)phenyl] -4 (trifluoromethylsulfinyl)-1H-pyrazole-3-carbonitrile (fipronil); - between 51 and 70% by weight/volume of a pyrethroid, preferably permethrin; 10 - between 2 and 10% by weight/volume of a phase change inhibitor selected from ethanol, benzyl alcohol and a mixture thereof, - optionally, one or more antioxidants; - optionally, one or more other active agents in a total quantity not exceeding 10% by weight/volume ; 15 - in solution in an organic solvent selected from propylene glycol monomethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, propylene glycol, and mixtures thereof The use of the term "consists of' means that, according to a particular 20 embodiment of the invention, the composition does not comprise ingredients other than those explicitly mentioned. According to particular embodiments of the invention, the composition comprises a quantity of pyrethroid of between 52% and 70% by weight/volume, between 52% and 67% by weight/volume, between 53% and 70% by 25 weight/volume, between 53% and 67% by weight/volume, between 54% and 70% by weight/volume, between 54% and 67% by weight/volume, between 52% and 58% by weight/volume, between 53% and 57% by weight/volume, between 54% and 55% by weight/volume and 54.5% by weight/volume. Preferably, the pyrethroid is permethrin. According to another particular embodiment of the invention, the 30 composition comprises between 6 and 7% by weight/volume of an N-phenylpyrazole, preferably fipronil, and, in order of preference, between 52% and 70% by weight/volume, between 52% and 67% by weight/volume, between 53% and 70% by weight/volume, between 53% and 67% by weight/volume, between 54% and 70% by 6618495 1 (GHMatters) P100275.AU LYNT weight/volume, between 54% and 67% by weight/volume, between 52% and 58% by weight/volume, between 53% and 57% by weight/volume, between 54% and 55% by weight/volume and 54.5% by weight/volume of the pyrethroid, preferably permethrin. Among said organic solvents, diethylene glycol monoethyl ether is 5 most particularly preferred. The antioxidants are advantageously selected from ethyl or propyl gallate, a-tocopherol, ascorbic acid, ascorbyl palmitate, monothioglycerol, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA); preferably, BHT or a mixture of BHT and BHA will be used as antioxidant. 10 When it (they) is (are) present, the antioxidant(s) preferably represent(s) from 0.005 to 2% by weight/volume approximately, and even more preferably from 0.01 to 0. 1% by weight/volume. According to a preferred variant, the composition according to the invention consists of: 15 - between 5 and 10% by weight/volume of an N-phenylpyrazole, preferably 5-amino-I -[2,6-dichloro-4-(trifluoromethyl)phenyl] -4-(trifluoromethyl sul finyl)-1H-pyrazole-3-carbonitrile (fipronil); - between 51 and 60% or between 54 and 67% by weight/volume of permethrin; 20 - between 2 and 5% by weight/volume of a phase change inhibitor selected from ethanol, benzyl alcohol and a mixture thereof, - between 0 and 2% by weight/volume of BHT and/or BHA; - in solution in an organic solvent as defined above. According to a preferred variant, the composition according to the 25 invention consists of: - between 5 and 10% by weight/volume of an N-phenylpyrazole, preferably 5-amino-I -[2,6-dichloro-4-(trifluoromethyl)phenyl] -4-(trifluoromethyl sul finyl)-1H-pyrazole-3-carbonitrile (fipronil); - between 51 and 60% or between 54 and 67% by weight/volume of 30 permethrin; - between 2 and 4% by weight/volume of a phase change inhibitor selected from ethanol, benzyl alcohol and a mixture thereof, - between 0.005 and 2% by weight/volume of BHT and/or BHA; 6618495 1 (GHMatters) P100275.AU LYNT - in solution in an organic solvent as defined above. According to a particular variant, the composition according to the invention consists of: Fipronil 6.1% 5 Permethrin 54.5% Benzyl alcohol 2% BHA 0.02% BHT 0.01% Diethylene glycol monoethyl ether qs 100 ml 10 (composition expressed as percentage by weight relative to the total volume of the composition). The compositions according to the invention which are active against blood-sucking parasites, and in particular against fleas, can be notably in the form of cutaneous liquid compositions or solutions for application to the skin, or "spot-on" 15 application, for very easy application, in one go, at one or more spots, topically, directly to the animal's skin, generally between the shoulder blades. The liquid compositions are then packaged in containers which enable the metering of said compositions, and the volume of which is less than or equal to 10 ml, and preferably between 0.1 and 10 ml and more preferably between 0.3 and 10 ml. 20 The compositions according to the invention may advantageously comprise, with a view to broadening or supplementing the spectra of action of the active agents already present in the compositions according to the invention, one or more additional active agents, with the proviso that the total content of this or these additional ingredient(s) does not exceed 10% by weight relative to the total volume of the composition and 25 preferably does not exceed 5% and even more preferably 3% by weight relative to the total volume of the composition. These additional active agents are preferably selected from endoparasiticides and ectoparasiticides. More specifically, by way of additional active agents mention may be 30 made of the isoxazolines, macrocyclic lactones, neonicotinoids, and insect growth regulators. Mention will particularly be made of compounds which mimic juvenile hormones, notably azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin, or else chitin synthesis inhibitors, notably chlorfluazuron, novaluron, 6618495 1 (GHMatters) P100275.AU LYNT cyromazine, diflubenzuron, fluazuron, flucycloxuron, lufenuron or teflubenzuron. Mention may also be made of compounds such as amitraz, pyriprole, metaflumizone, praziquantel, emodepside, ivermectin, moxidectin, milbemycin or selamectin or else dinotefuran, nitenpyram, imidacloprid, indoxacarb or spinetoram. 5 Pyriproxyfen is particularly preferred, in a quantity of between 1 and 10% by weight relative to the total volume of the composition, preferably between 1 and 5% by weight relative to the total volume of the composition and even more preferably at 2% by weight relative to the total volume of the composition. According to a particular variant, the composition according to the 10 invention consists of: Fipronil 6.1% Permethrin 54.5% Pyriproxyfen 2% Benzyl alcohol 2% 15 BHA 0.02% BHT 0.01% Diethylene glycol monoethyl ether qs 100 ml (composition expressed as percentage by weight relative to the total volume of the composition). 20 The pharmaceutical composition according to the invention is preferably packaged in single-dose pipettes. The pipettes can consist of one or more films, the constituent material of which can be selected from polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride, cyclic olefin copolymer (COC), polychlorotrifluoroethylene (PCTFE), or 25 derivatives thereof, taken alone or as mixtures. Preferably, the film is the PolybarTM sold by the company Alcan PackagingTM, which consists of a film of cyclic olefin copolymer (COC) co-extruded between two layers of polypropylene (PP). The Polybar is then backed or laminated with a BarexTM film. Other films of different nature can be used alone or in combination with the previous films in order to form the pipette. The material thereof can be 30 selected from polyethylene terephthalate (PET), polyamide, aluminum or the polyacrylonitrile sold by the company BP ChemicalsTM under the brand name Barex T M , or derivatives thereof, taken alone or in combination. 6618495 1 (GHMatters) P100275.AU LYNT The volume of the composition according to the invention contained in the pipettes may be 0.44 ml, 1.1 ml, 2.2 ml, 4.4 ml or 6.6ml. Generally, the volume may be between 0.1 and 10 ml, preferably between 0.3 and 6.6 ml and even more preferably between 0.44 and 6.6 ml. 5 Another subject of the present application relates to a liquid pharmaceutical composition as previously described, as an antiparasitic veterinary medicament for topical application, for use in the prevention (protection against) and/or treatment of infestations by external parasites, such as fleas, ticks, mosquitoes, sand flies and mange mites, in domestic animals, in particular in dogs (what is referred to as 10 "spot-on" application). According to this use, said medicament is intended to be applied by direct application to the skin of the animal, at the shoulder blades or along a dorsal line starting from the base of the tail and going up to the neck. The quantity of medicament to be administered can range from 15 approximately 0.3 to 6.6 ml in dogs, depending on the weight of the animal under consideration, and on the dosage to be adjusted according to the frequency of the treatment. Aside from the preceding provisions, the invention also comprises other provisions which will emerge from the following description which refers to an 20 example of preparation of a pharmaceutical composition in accordance with the invention, and also to examples which demonstrate the stability of said composition during storage thereof. Nonetheless, it should be clearly understood that these examples are given solely by way of illustration of the subject of the invention, of which they in no 25 way constitute a limitation. Examples The objective of the developments carried out is the development of a formulation such that the active agents do not crystallize during storage thereof, despite a high concentration of active agents, in particular of permethrin. 30 6618495 1 (GHMatters) P100275.AU LYNT 1. Examples of compositions according to the invention Composition % w/v % w/v Fipronil 6.1% 6.1% Permethrin 54.5% 54.5% Benzyl alcohol 0% 2% Butylhydroxytoluene (BHT) 0.01% 0.01% Butylhydroxyanisole (BHA) 0.02% 0.02% Diethylene glycol monoethyl ether qs 100 ml qs 100 ml Preparation process 5 Introduce the diethylene glycol monoethyl ether then the benzyl alcohol into a container. Mix. Next add the permethrin (fluidized beforehand), mix until completely solubilized. Introduce the fipronil, mix until the fipronil is completely solubilized. Check the appearance: clear solution with no particles. 10 Successively introduce the butylhydroxytoluene (BHT) and the butylhydroxyanisole (BHA). Mix until solubilized. Check the appearance: clear solution with no particles. 2. Stability tests of the composition according to the invention The compositions detailed in tables I, II and III below were stored in 15 transparent, colorless 10 ml glass bottles at 8'C. Any appearance of crystals was observed with the naked eye. 6618495 1 (GHMatters) P100275.AU LYNT Composition % w/v % w/v % w/v Fipronil 2.96% 2.96% 2.96% Permethrin 66.80% 66.80% 66.80% Polysorbate 80 1% Ethanol 1% Benzyl alcohol 1% Butylhydroxytoluene (BHT) 0.01% 0.01% 0.01% Butylhydroxyanisole (BHA) 0.02% 0.02% 0.02% Diethylene glycol monoethyl qs 100 ml qs 100 ml qs 100 ml ether Storage time before observation lday solution solution solution 2 days solution solution solution 5 days solution crystallization solution 6 days solution crystallization crystallization 7 days crystallization- 8 days crystallization 12 days Table I 5 6618495 1 (GHMatters) P100275.AU LYNT Composition % w/v % w/v % w/v Fipronil 2.96% 2.96% 2.96% Permethrin 66.80% 66.80% 66.80% Polysorbate 80 2% Ethanol 2% Benzyl alcohol 2% Butylhydroxytoluene (BHT) 0.01% 0.01% 0.01% Butylhydroxyanisole (BHA) 0.02% 0.02% 0.02% Diethylene glycol monoethyl qs 100 ml qs 100 ml qs 100 ml ether Storage time before observation 1 day solution solution solution 2 days solution solution solution 5 days crystallization solution solution 6 days solution solution 7 days solution solution 8 days solution solution 12 days solution solution Table II 5 6618495 1 (GHMatters) P100275.AU LYNT Composition % w/v % w/v % w/v Fipronil 2.96% 2.96% 2.96% Permethrin 66.80% 66.80% 66.80% Polysorbate 80 1% 1% 2% Ethanol 2% 1% Benzyl alcohol 2% Butylhydroxytoluene (BHT) 0.01% 0.01% 0.01% Butylhydroxyanisole (BHA) 0.02% 0.02% 0.02% Diethylene glycol monoethyl qs 100 ml qs 100 ml qs 100 ml ether Store time before observation 1 day solution solution solution 2 days solution solution solution 5 days solution solution crystallization 6 days solution Start of crystallization 7 days solution crystallization 8 days solution crystallization 12 days crystallization Table III The Applicant had observed during preliminary tests that combining fipronil (at a content of between 2.50 and 6.1% by weight/volume) and permethrin formulated in diethylene glycol monoethyl ether always leads to rapid crystallization (5 5 days or less) when the permethrin concentration is between 54.5 and 75% by weight/volume. The same formulation additionally comprising polysorbate 80, ethanol and/or benzyl alcohol was also tested; these tests demonstrate that no crystallization is observed after 12 days for a formulation of this kind comprising permethrin in a 10 proportion of 66.8%, as long as this composition comprises 2% of ethanol or benzyl alcohol; this is not the case with polysorbate alone, or when the content of each of these solvents is reduced to 1% or else if it is 2% but the composition also comprises 1% polysorbate 80. These results therefore demonstrate that, although ethanol and benzyl 15 alcohol at 2% by weight act effectively to inhibit crystallization, when polysorbate 80 is 6618495 1 (GHMatters) P100275.AU LYNT introduced on its own this leads to worse crystallization results and cancels out the beneficial crystallization-inhibiting effect resulting from the presence of ethanol and benzyl alcohol. Composition % w/v % w/v Fipronil 6.1% 6.1% Permethrin 54.5% 54.5% Benzyl alcohol 0% 2% Butylhydroxytoluene (BHT) 0.01% 0.01% Butylhydroxyanisole (BHA) 0.02% 0.02% Diethylene glycol monoethyl ether qs 100 ml qs 100 ml Observation tilue D5 day at 8'C crystallization solution D5 days at 8'C crystallization solution D8 days at 8'C crystallization solution Table IV 5 The results presented in table IV compare the same formulation, comprising or not comprising benzyl alcohol; these tests demonstrate that no crystallization is observed after 8 hours for a formulation of this kind comprising permethrin in a proportion of 54.5%, as long as this composition comprises 2% of benzyl alcohol. 10 These results therefore demonstrate that benzyl alcohol at 2% by weight acts effectively to inhibit crystallization. 6618495 1 (GHMatters) P100275.AU LYNT

Claims

1. A topical veterinary pharmaceutical composition consisting of: - between 2 and 10% by weight/volume of an N-phenylpyrazole; - between 51 and 70% by weight/volume of permethrin; 5 - between 2 and 10% by weight/volume of a phase change inhibitor selected from ethanol, benzyl alcohol and a mixture thereof, - optionally, one or more antioxidants; - optionally, one or more other active agents in a total quantity not exceeding 10% by weight/volume; 10 - in solution in an organic solvent selected from propylene glycol monomethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, propylene glycol, and mixtures thereof

2. The topical veterinary pharmaceutical composition as claimed in 15 claim 1, characterized in that it contains 54.5% by weight/volume of permethrin.

3. The topical veterinary pharmaceutical composition as claimed in claim 1 or claim 2, characterized in that the antioxidant(s) is (are) selected from ethyl or propyl gallate, a-tocopherol, ascorbic acid, ascorbyl palmitate, monothioglycerol, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). 20

4. The topical veterinary pharmaceutical composition as claimed in claim 1 or claim 3, characterized in that it consists of: - between 5 and 10% by weight/volume of an N-phenylpyrazole; - between 54 and 67% by weight/volume of permethrin; - between 2 and 4% by weight/volume of a phase change inhibitor 25 selected from ethanol, benzyl alcohol and a mixture thereof, - between 0.005 and 2% by weight/volume of BHT and/or BHA; - in solution in an organic solvent selected from propylene glycol monomethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, propylene glycol, 30 and mixtures thereof

5. The topical veterinary pharmaceutical composition as claimed in any one of the preceding claims, characterized in that said N-phenylpyrazole is 6618495 1 (GHMatters) P100275.AU LYNT 5-amino-i -[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)- 1H pyrazole-3-carbonitrile (fipronil).

6. The topical veterinary pharmaceutical composition as claimed in any one of the preceding claims, characterized in that said organic solvent is diethylene 5 glycol monoethyl ether.

7. The topical veterinary pharmaceutical composition as claimed in any one of the preceding claims, characterized in that it consists of. Fipronil 6.1% Permethrin 54.5% 10 Benzyl alcohol 2% BHA 0.02% BHT 0.01% Diethylene glycol monoethyl ether qs 100 ml as percentage by weight relative to the total volume of the composition. 15

8. The topical veterinary pharmaceutical composition as claimed in claim 1, characterized in that it consists of. Fipronil 6.1% Permethrin 54.5% Pyriproxyfen 2% 20 Benzyl alcohol 2% BHA 0.02% BHT 0.01% Diethylene glycol monoethyl ether qs 100 ml (composition expressed as percentage by weight relative to the total volume of the 25 composition).

9. The topical veterinary pharmaceutical composition as claimed in any one of the preceding claims, characterized in that it is packaged in a single-dose pipette.

10. The topical veterinary pharmaceutical composition as claimed in 30 any one of the preceding claims, for use in the prevention and/or treatment of infestations by external parasites in domestic animals. 6618495 1 (GHMatters) P100275.AU LYNT

11. The topical veterinary pharmaceutical composition as claimed in any one of claims 1 to 10, for use as claimed in claim 10, characterized in that it is administered by "spot-on" application. 6618495 1 (GHMatters) P100275.AU LYNT