Patent Publication Number: US-2012041042-A1

Title: Scent Ectoparasiticidal Formulation

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a U.S. National Phase Filing of PCT/US2010/024677, filed Feb. 19, 2010, which claims priority to U.S. Provisional Application No. 61/154,520, filed Feb. 23, 2009, for which the contents of both are hereby incorporated by reference as if set forth fully herein. 
    
    
     BACKGROUND OF THE INVENTION 
     Arthropod ectoparasites commonly infecting warm-blooded animals include ticks, mites, lice, fleas, blowflies, the ectoparasite  Lucilia  sp. of sheep, biting insects including keds ( Melophagus ovinus ) and migrating dipterous larvae such as  Hypoderma  sp. and  Dermatobia  in cattle,  Gastrophilus  in horses and  Cuterebra  sp. in rodents, dogs and cats. Metaflumizone, amitraz and demiditraz are useful for the prevention and control of ectoparasiticide infestations in warm-blooded animals. Topical administration is a preferred method for administration of these ingredients. 
     In order to provide topical formulations that are stable, easy to apply, spreadable and minimize run-off, existing formulations have relied on odoriferous solvents, which have given the formulations an inauspicious smell. 
     SUMMARY OF THE INVENTION 
     The present invention provides an improved-scent ectoparasiticidal formulation, which is stable, easy-to-apply, spreadable and minimizes animal-runoff. In one embodiment the present invention provides an improved-scent ectoparasiticidal composition, which comprises metaflumizone, fructone as the primary carrier solvent and optionally, amitraz or demiditraz. More particularly, the composition comprises metaflumizone, fructone, geranyl acetate as cosolvent and skin permeation enhancer and, optionally, additional carrier solvents and/or a bridging agent. More particularly, the composition comprises (on a w/v basis): about 20% to about 50% fructone; about 10% to about 30% metaflumizone; about 0% to about 20% amitraz or about 0% to about 20% demiditraz; about 5% to about 15% dimethylsulfoxide (DMSO); about 5% to about 15% N,N-diethyl-m-toluamide (DEET); about 5% to about 15% γ-hexylactone; about 5% to about 15% geranyl acetate; and about 1% to about 10% 1-methoxy-2-propyl acetate. More particularly, the composition comprises about 10% to about 20% w/v amitraz. Alternatively, the composition comprises about 10% to about 20% w/v demiditraz. 
     Another aspect of the invention provides a method for preventing or treating an ectoparasite infestation in a warm-blooded animal, comprising, topically administering to the warm-blooded animal the improved-scent ectoparasiticidal composition. 
     Another aspect of the invention provides a kit for preventing or treating an ectoparasite infestation in a warm-blooded animal comprising a topical unit dose formulation of the improved-scent ectoparasiticidal composition. 
     Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Topical veterinary compositions containing metaflumizone, amitraz and/or demiditraz as active ingredients are highly desirable due to the effective and persistent activity of metaflumizone against a variety of ectoparasites, including, but not limited to, the dog flea,  Ctenocephalides canis , and the efficacy of amitraz and demiditraz against ticks. 
     Existing “spot-on” applications of topical veterinary ectoparasiticidal compositions applied to the base of the neck of the animal aid in making the applied composition difficult for the animal to remove, but include solvents that provide less-favorable organoleptic properties. The limited solubility and stability of ectoparasiticide agents, particularly metaflumizone and amitraz, has heretofore required the inclusion of these solvents, such as cineole (eucalyptol), that give the formulation a less favorable odor. 
     Advantageously, the improved-scent composition of the present invention retains the desired physical characteristics over time, without loss of potency of the actives. Further, the composition of the invention exhibits sufficient viscosity to allow for the retention of the composition when applied topically to the animal&#39;s skin or hair, while facilitating the release of the ectoparasiticide(s), such as metaflumizone, amitraz and/or demiditraz, over the desired period of time. 
     In one embodiment, the improved-scent composition of the present invention comprises metaflumizone and fructone as the primary carrier component. In another embodiment, the composition further includes amitraz as an additional active. In another embodiment, the composition further includes demiditraz as an additional active. In another embodiment, the composition further comprises geranyl acetate. In another embodiment, the composition further comprises at least one of a bridging agent, skin permeation enhancer and/or a carrier solvent. Suitable carrier solvents include γ-hexylactone, N,N-diethyl-m-toluamide and 1-methoxy-2-propyl acetate. Suitable bridging agents are those such as, for example, dimethylsulfoxide. 
     In another embodiment, the improved-scent composition of the present invention comprises metaflumizone, fructone, geranyl acetate, and at least one, at least two, or at least three of γ-hexylactone, N,N-diethyl-m-toluamide, 1-methoxy-2-propyl acetate and dimethylsulfoxide, and further optionally including amitraz and/or demiditraz. 
     In another embodiment, the metaflumizone is present at about 10% to about 40% w/v, or about 10% to about 30% w/v, or about 10% to about 20% w/v, or about 15% w/v. In another embodiment, the amitraz is present at about 0% to about 20% w/v, or about 10% to about 20% w/v, or about 15% w/v. In another embodiment, the demiditraz is present at about 0% to about 20% w/v, or about 10% to about 20% w/v, or about 15% w/v. In another embodiment, the fructone is present at about 20% to about 60% w/v, or about 20% to about 50% w/v, or about 20% to about 40% w/v, or about 30% w/v. In another embodiment, the geranyl acetate is present at about 5% to about 15% w/v, or about 7.5% to about 13% w/v, or about 10% w/v. In another embodiment, γ-hexylactone is present at about 5% to about 15% w/v, N,N-diethyl-m-toluamide is present at about 5% to about 15% w/v and 1-methoxy-2-propyl acetate is present at about 0% to about 15% w/v, or about 5% to about 15% w/v, or about 1% to about 10% w/v, or about 5% w/v. In another embodiment, dimethylsulfoxide is present at about 5% to about 15% w/v, or about 10% w/v. In another embodiment, the composition comprises, on a w/v basis, about 15% amitraz, about 15% metaflumizone, about 20% to about 40% fructone and about 10% geranyl acetate. In another embodiment, the composition comprises, on a w/v basis, about 15% demiditraz, about 15% metaflumizone, about 20% to about 40% fructone and about 10% geranyl acetate. In another embodiment, the composition comprises, on a w/v basis, about 15% to about 25% metaflumizone, about 20% to about 50% fructone and about 10% geranyl acetate. In another embodiment, the composition comprises, on a w/v basis, about 10% dimethyl sulfoxide, about 10% γ-hexylactone, about 10% N,N-diethyl-m-toluamide and about 5% 1-methoxy-2-propyl acetate. 
     In another embodiment, the improved-scent composition of the present invention comprises (on a w/v basis): about 20% to about 40% fructone; about 10% to about 20% metaflumizone; about 5% to about 15% DMSO; about 5% to about 15% N,N-diethyl-m-toluamide; about 5% to about 15% γ-hexylactone; about 5% to about 15% geranyl acetate; and about 0% to about 10% 1-methoxy-2-propyl acetate. More particularly, the composition further comprises about 10% to about 20% amitraz. Alternatively, the composition further comprises about 10% to about 20% demiditraz. In another embodiment, the composition consists essentially of (on a w/v basis), about 25% to about 35% fructone, about 15% amitraz; about 15% metaflumizone, about 10% dimethylsulfoxide. about 10% N,N-diethyl-m-toluamide, about 10% γ-hexlactone, about 10% geranyl acetate and about 5% 1-methoxy-2-propyl acetate. In another embodiment, the composition consists essentially of (on a w/v basis), about 25% to about 35% fructone, about 15% demiditraz, about 15% metaflumizone, about 10% dimethylsulfoxide, about 10% N,N-diethyl-m-toluamide, about 10% γ-hexylactone, about 10% geranyl acetate and about 5% 1-methoxy-2-propyl acetate. 
     In another embodiment the composition comprising, on a w/v basis, about 25% to about 50% fructone; about 10% to about 30% metaflumizone; about 5% to about 15% DMSO; about 5% to about 15% N,N-diethyl-m-toluamide; about 5% to about 15% γ-hexylactone; about 5% to about 15% geranyl acetate; and 0% to about 10% 1-methoxy-2-propyl acetate. 
     Another aspect of the invention provides a method for preventing or treating an ectoparasite infestation in a warm-blooded animal, comprising, topically administering to the warm-blooded animal the improved-scent composition described herein. More particularly, said composition is administered in one or more spots or discrete areas on the back of the warm-blood animal. In another embodiment, the ectoparasiticide is applied to the animal in 1, 2, 3, 4, or 5 locations (spots), preferably down the back of the animal or at the base of the neck. More particularly, the warm-blooded animal is a dog. More particular still, the dog receives about 15 mg/kg to about 25 mg/kg, preferably about 20 mg/kg of each of amitraz and metaflumizone. Alternatively, the dog receives about 15 mg/kg to about 25 mg/kg, preferably about 20 mg/kg of each of demiditraz and metaflumizone. 
     Another aspect of the invention provides a method for preventing or treating an ectoparasite infestation in a warm-blooded animal, comprising administering a diluted form of the improved-scent composition as a pour-on. More particularly, the diluted form of the improved-scent composition comprises about 1% to about 95% of the improved-scent composition described herein and at least one other solvent. 
     Another aspect of the invention provides a kit for preventing or treating an ectoparasite infestation in a warm-blooded animal comprising a topical unit dose formulation of the improved-scent composition described herein. 
     In another embodiment, the warm-blooded animal is a cat. In a still further embodiment, the warm-blooded animal is a farm animal. In another embodiment, the warm-blooded animal is a horse. 
     In another embodiment, the bridging agent is selected from the group consisting of an alkyl methylsulfoxide, e.g. dimethylsulfoxide, decylmethyl sulfoxide or tetradecylmethylsulfoxide, a pyrrolidone, e.g., 2-pyrrolidone, N-methyl-2-pyrrolidone or N-(2-hydroxyethyl)pyrrolidone, a laurocapram, acetone, dimethyl acetamide, dimethylformamide, and tetrahydrofurfuryl alcohol. In another embodiment, the bridging agent is selected from the group consisting of an L-amino acid, dimethylsulfoxide (DMSO) and a fatty acid. 
     In another embodiment, the surfactant is an anionic or cationic surfactant, a non-ionic surfactant, alcohol alkoxylate, or a nonylphenol ethoxylate. 
     In another embodiment, the composition comprises a diluent, an adjuvant, an excipient, a preservative, or a vehicle with which the active (e.g. metaflumizone and/or amitraz or demiditraz) is administered. In another embodiment, the composition includes petroleum oil, animal oil, vegetable oil, peanut oil, soybean oil, mineral oil, and sesame oil. In another embodiment, the composition does not comprise eucalyptol. In another embodiment, the composition further comprises a preservative selected from the group consisting of methylparaben, propylparaben, thiomersal, and EDTA. 
     Bridging agents that are suitably employed in the compositions disclosed herein include, without limitation, alkyl methyl sulfoxides (such as dimethylsulfoxide (DMSO), decylmethyl sulfoxide and tetradecylmethyl sulfoxide); pyrrolidones (such as 2-pyrrolidone, N-methyl-2-pyrrolidone and N-(2-hydroxyethyl)pyrrolidone); laurocapram; and miscellaneous solvents such as acetone, dimethyl acetamide, dimethyl formamide, and tetrahydrofurfuryl alcohol. Other bridging agents include amphiphiles such as L-amino acids, and fatty acids. Additional bridging agents are disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition (1995), on page 1583. 
     The term “carrier” refers to a diluent, adjuvant, excipient, preservative, and/or vehicle with which a compound or composition is administered. Carrier solvents that may be suitably employed in the composition of the invention include single solvents, or a mixture of two or more solvents. Preferably, the carrier solvents have minimal odor or mask odors of other agents. Due to the instability of metaflumizone and amitraz in the presence of primary alcohols, preferred solvents are non-hydroxyl-group-containing solvents. Surprisingly, the use of fructone as a carrier solvent provides optimum formulation properties while minimizing odors. In addition to fructone, γ-hexylactone (also known as γ-caprolactone; ethyl butyrolactone; γ-ethyl-n-butyrolactone; hexanolide-1, 4; 4-hydroxy hexanoic acid γ-lactone or tonkalide), δ-hexylactone, γ-butyrolactone etc., Synperonic NCA 830, can be employed. Within other embodiments, solvents such as N,N-diethyl-m-toluamide, dimethyl isosorbide, diisopropyl adipate and/or 1-methoxy-2-propyl acetate may be advantageously utilized in combination with the fructone, γ-hexylactone to comprise the carrier solvent mixture. Suitable pharmaceutical carriers are described in “Remington&#39;s Pharmaceutical Sciences” by E. W. Martin, 18 th  Edition. 
     As used in the specification and claims, the terms “about” and “approximately” designate that a value is within a statistically meaningful range. Such a range can be typically within 10%, more typically still within 5%, and even more typically within 2% of a given value or range. The allowable variation encompassed by the terms “about” and “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art. 
     As used herein, the term “w/v” designates weight of component/volume of composition, and the term “mg/kg” designates milligrams per kilogram of body weight. The term “a.i.” or “ai” designates active ingredient, and may be combined with other terms. For example “mg a.i./kg” designates milligrams of active ingredient per kilogram of body weight. 
     As used herein, the term “treating” or “treatment” of a condition, such as an ectoparasite infestation, includes inhibiting an existing condition or arresting its development; or ameliorating or causing regression of the condition. The term “preventing” or “prevention” of a condition, such as an ectoparasite infestation, includes substantially blocking or inhibiting the development or growth of a condition before it starts. Compositions that treat or prevent infestations herein will preferably exhibit at least 90% efficacy. 
     As used herein, the term “ectoparasiticide” refers to an agent that is capable of preventing, reducing or eliminating ectoparasite infestations. Preferred ectoparasiticides of the present, invention include metaflumizone, amitraz, demiditraz, fipronil, pyriprole, dinotefuran and imidacloprid. 
     As used herein, the term “organoleptic” refers to the sensory properties of a particular composition, particularly the smell, taste, colour, and feel of the composition. Improved or enhanced organoleptic properties of ectoparasiticidal compositions, as used herein, generally refers to reduced scent or a favorable scent. 
     Metaflumizone is known in the art by its chemical name: (E,Z)-2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(tri-fluoromethoxy)-phenyl]hydrazinecarboxamide and is described in U.S. Pat. No. 5,543,573. The chemical structure of metaflumizone is shown below: 
     
       
         
         
             
             
         
       
     
     ProMeris® is the trade name for the veterinary formulation of metaflumizone (plus amitraz for dogs) marketed by Fort Dodge Animal Health (Wyeth, now Pfizer). 
     Demiditraz is known in the art by its chemical name: 2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole and is described in Example 58 of U.S. Publication No. 2007/0167506. 
     To manufacture the improved-scent compositions of the present invention, metaflumizone and optionally amitraz and/or demiditraz may be dissolved in the carrier solvent or solvents and bridging agent, and the surfactant, if desired, added to the carrier solvent solution. These compositions may then be utilized for spot-on topical application or may be further diluted for alternative uses. Compositions are most suitably formulated as creams, gels, solutions, or in microspheres. 
     Improved-scent ectoparasiticidal compositions of the invention may further comprise other agents known in the art, such as preservatives (e.g., methylparaben and propylparaben), colorants, antioxidants, or the like. Generally, these agents are present in the composition in an amount up to about 2% on a weight to volume basis. Preservatives may include, for example, thiomersal, EDTA, or the like. 
     Suitable exemplary polymers (“polymeric agents”) for gelling and/or adhering that may be used in the compositions of the invention include, but are not limited to, colloidal silicone dioxide, ethyl cellulose, methyl cellulose, methacrylic esters copolymers, carboxylated vinyl acetate terpolymer, Resyn® 29-2930, and polyvinylpropylene (PVP)/Vinyl acetate copolymers. “Gantrez”® is the trade name for a family of polyvinylmethylether formulations (as solutions, creams, powders, etc.) manufactured by International Specialty Products, of Wayne, N.J. Gantrez powder formulations comprise poly(vinylmethylether/maleic anhydride). Gantrez cream formulations comprise ethyl or butyl esters of polyvinylmethylether/maleic anhydride copolymer and ethyl or butyl esters of PVM/MA copolymer. Resyn® 29-2930 is the trade name for vinyl acetate/crotanoates/vinylneodecanoate copolymer. 
     Carbopol® is the trade name of exemplary carbomers used in the formulation of certain embodiments of the presently disclosed compositions. Acrylic acid polymers other than—or in addition to—carbomers are also contemplated for use in the present invention. 
     In those embodiments in which compositions are formulated as microspheres, polymers including, but not limited to, sulfopolyester (AQ55S polymer from Eastman Chemical Co., Kingsport, Tenn., USA; typical repeating units of these polymers are disclosed in column 7 of U.S. Pat. No. 5,260,052.), and cellulose acetate butyrate (CAB), poly(lactide-co-glycolide) (PLGA) may be employed. Alternatively, microsphere formulation may employ one or more of polylactic galactide, hollow microspheres such as Expancel (Nobel Industrie), Polytrap (Dow Corning), and hollow silica microspheres (Silica Beads from Maprecos). 
     Additionally, UV-absorbing compounds, photostabilizers, viscosity modifying agents, antimicrobial agents, dyes, thickeners, antioxidants, taste enhancers or deterrents, vitamins, adherents, perfumes, deodorants, physiologically or dermatologically acceptable carriers, diluents, excipients or adjuvants may be included in the compositions and formulations of the present invention. 
     Advantageously, the ectoparasiticidal topical veterinary composition of the invention allows for administration of active ingredients and demonstrates no irritation and minimal adverse scent to the skin/hide/hair of the host animal with reduced and improved organoleptic properties. 
     When topically administered, the improved-scent ectoparasiticidal composition of the invention is effective for preventing or mitigating ectoparasitic infection and/or infestation for prolonged periods of time in Warm-blooded animals such as swine, cattle, sheep, horses, goats, camels, water buffalo, bison, donkeys, rabbits, kangaroos, fallow deer, reindeer, minks, chinchillas, raccoons, chicken, geese, turkeys, ducks, dogs, cats, or the like, preferably dogs, cats, swine, cattle, horses or sheep, and most preferably dogs. 
     Examples of topical administrations suitable for use in the method of the invention include spot-on, pour-on, dip, wash, shampoo, foam, gel, lotion, cream, microsphere-encapsulated formulation, powder, or any of the conventional means of topically applying a liquid or semi-liquid veterinary composition. The topical mode of administration will vary with the species and size of the host animal. In a preferred embodiment, the composition of the present invention is administered as a spot-on formulation to a dog. 
     Ectoparasitic infection or infestations suitable for treatment by the methods of the invention include fleas, ticks, lice, mites and flies. In particular, the methods and kits of the present invention are suitable for treating or preventing flea infestations, and even more particularly, infestations of the dog flea,  Ctenocephalides canis  and tick infestations. 
     The composition of the invention may be administered in dose rates of mg of active ingredient per kg of body weight of the host animal. As will be understood by those skilled in the art, dose rates suitable for use in the method of invention will vary depending upon the identity of the ectoparasiticide, the mode of administration, the species and health of the host animal, the target parasite, the degree of infection or infestation, the breeding habitat, the potency of the additional parasiticidal compound, or the like. 
     Typical “spot-on” applications of exemplary embodiments of the invention are applied to the base of the neck of the animal or generally along the dorsal midline in the area between the shoulder blades, so as to aid in making the applied composition difficult for the animal to remove. 
     For a more clear understanding of the invention, the following examples are set forth hereinbelow. These examples are merely illustrative and are not understood to limit the scope or underlying principles of the invention in any way. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the examples set forth hereinbelow and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. 
     Unless otherwise designated, all parts are parts by weight/volume. The term qs designates quantity sufficient to obtain a total of 100%. 
     EXAMPLES 
     Low-Scent Metaflumizone-Amitraz Solution, Suitable for Use as a Spot-on Treatment 
     Composition A: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 15% w/v Metaflumizone/ 
               
               
                   
                   
                 15% w/v Amitraz Spot-On - 
               
               
                   
                   
                 Alternate Formula 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
                 1.34 mL 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 Amitraz †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 10.0 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.00 
               
               
                   
                 acetate 
               
               
                   
                 Geranyl acetate 
                 10.0 
               
               
                   
                 γ-Hexalactone 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad (31.4) 
               
               
                   
                 Density (g/mL) 
                 1.070 
               
               
                   
                   
               
               
                   
                   † Contains 2% overage. 
               
            
           
         
       
     
     In a vessel containing fructone, γ-hexylactone, followed by N,N-diethyl-m-toluamide, dimethyl sulfoxide (DMSO), 1-methoxy-2-propyl acetate, and finally geranyl acetate are added and agitated until mixed. Metaflumizone and amitraz are then added and the solution is thoroughly mixed until all solids are completely dissolved. The solution is then mixed over 4 Å activated molecular sieves, filtered and packaged. 
     The following compositions are prepared according to the general procedure described fro composition A. 
     Composition B: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 15% w/v Metaflumizone/ 
               
               
                   
                   
                 15% w/v Amitraz Spot-On - 
               
               
                   
                   
                 Alternate Formula 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
                 1.34 mL 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 Amitraz †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 10.0 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.00 
               
               
                   
                 acetate 
               
               
                   
                 Geranyl acetate 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad (42.2) 
               
               
                   
                 Density (g/mL) 
                 1.070 
               
               
                   
                   
               
               
                   
                   † Contains 2% overage. 
               
            
           
         
       
     
     Composition C: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 15% w/v Metaflumizone 
               
               
                   
                   
                 Canine Flea only Spot-On - 
               
               
                   
                   
                 Alternate Formula 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 13.8 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.00 
               
               
                   
                 acetate 
               
               
                   
                 Geranyl acetate 
                 10.0 
               
               
                   
                 γ-Hexalactone 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad (43.2) 
               
               
                   
                 Density (g/mL) 
                 1.073 
               
               
                   
                   
               
               
                   
                   † Contains 2% overage. 
               
            
           
         
       
     
     Composition D: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 25% w/v Metaflumizone 
               
               
                   
                   
                 Canine Flea only Spot-On 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone †   
                 25.50 
               
               
                   
                 (100% pure) 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 13.8 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.00 
               
               
                   
                 acetate 
               
               
                   
                 Geranyl acetate 
                 10.0 
               
               
                   
                 γ-Hexalactone 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad (35.3) 
               
               
                   
                 Density (g/mL) 
                 1.096 
               
               
                   
                   
               
               
                   
                   † Contains 2% overage. 
               
            
           
         
       
     
     Composition E: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 15% w/v Metaflumizone/ 
               
               
                   
                   
                 15% w/v Amitraz Spot-On - 
               
               
                   
                   
                 Alternate Formula 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
                 1.34 mL 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 Amitraz †   
                 15.3 
               
               
                   
                 (100% pure) 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 10.0 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.0 
               
               
                   
                 acetate 
               
               
                   
                 Orange Flower Ether 
                 10.0 
               
               
                   
                 γ-Hexalactone 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad (31.4) 
               
               
                   
                 Density (g/mL) 
                 1.070 
               
               
                   
                   
               
               
                   
                   † Contains 2% overage. 
               
            
           
         
       
     
     Composition M: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 15% w/v Metaflumizone/15% w/v 
               
               
                   
                   
                 Demiditraz Spot-On Formula 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
                 1.34 mL 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone 
                 15 
               
               
                   
                 (100% pure) 
               
               
                   
                 Demiditraz 
                 15 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 10.0 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.0 
               
               
                   
                 acetate 
               
               
                   
                 Orange Flower Ether 
                 10.0 
               
               
                   
                 γ-Hexalactone 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad 
               
               
                   
                   
               
            
           
         
       
     
     Composition N: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 20% w/v Metaflumizone Spot-On 
               
               
                   
                   
                 Formula 
               
               
                   
                   
               
               
                   
                 Volume to be applied per 
                 1.34 mL 
               
               
                   
                 10 kg body weight 
               
               
                   
                   
               
               
                   
                 INGREDIENTS 
                 Quantities (% w/v) 
               
               
                   
                   
               
               
                   
                 Metaflumizone 
                 20 
               
               
                   
                 (100% pure) 
               
               
                   
                 N,N-Diethyl-m-toluamide 
                 10.0 
               
               
                   
                 Dimethyl sulfoxide 
                 10.0 
               
               
                   
                 1-Methoxy-2-propyl 
                 5.0 
               
               
                   
                 acetate 
               
               
                   
                 Orange Flower Ether 
                 10.0 
               
               
                   
                 γ-Hexalactone 
                 10.0 
               
               
                   
                 Fructone 
                 q.s. ad 
               
               
                   
                   
               
            
           
         
       
     
     Organoleptic Studies: 
     The organoleptic studies were performed on different compositions to determine the acceptability of the formulation&#39;s perceived odor in comparison to that of the original ProMeris® for dog spot-on. 
     Organoleptic Test 1: Total number of people=40 
     
       
         
           
               
               
               
            
               
                   
                   
               
               
                   
                   
                 Original 
               
               
                   
                   
                 ProMeris ® 
               
               
                   
                 Prototype Alternate Formulations 
                 for Dogs 
               
            
           
           
               
               
            
               
                   
                 Composition 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 F 
                 G 
                 H 
                 I 
                 C5 
               
               
                   
                 % w/v 
                 % w/v 
                 % w/v 
                 % w/v 
                 % w/v 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Metaflumizone †   
                 15.3 
                 15.3 
                 15.3 
                 15.3 
                 15.3 
               
               
                 (100% pure) 
               
               
                 Amitraz †   
                 15.3 
                 15.3 
                 15.3 
                 15.3 
                 15.3 
               
               
                 (100% pure) 
               
               
                 Dimethyl sulfoxide 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10 
               
               
                 N,N-Diethyl-m- 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10 
               
               
                 toluamide 
               
               
                 Eucalyptol 
                   
                   
                   
                   
                 10 
               
               
                 FRUCTONE 
                 46.0 
                 56.5 
                 37.0 
                 37.0 
               
               
                 g-Hexalactone 
                 10.0 
                   
                   
                 10.0 
                 24 
               
               
                 1-Methoxy-2-propyl 
                   
                   
                 20.0 
                 10.0 
                 20 
               
               
                 acetate 
               
               
                 Total scores 
                 215 
                 248 
                 119 
                 141 
                 67 
               
               
                 # of People rated 
                 10 
                 19 
                 1 
                 0 
                 1 
               
               
                 formulation as best 
               
               
                 smelling 
               
               
                 # of People rated 
                 0 
                 0 
                 6 
                 1 
                 28 
               
               
                 formulation as worst 
               
               
                 smelling 
               
               
                   
               
               
                   † Contains 2% overage. 
               
            
           
         
       
     
     A small volume (1.0 ml) of each composition was placed on a filter paper in a petri dish. 40 persons employed by Wyeth volunteered to take part in the organoleptic test. Each volunteer smelled the sample and then rated the odor from 1 to 7, with a score of 7 being the best. The rating was such that the higher the score, the more acceptable the perceived odor was. Results indicated that composition G scored the highest aggregate of 248, which means it had the most acceptable odor. Also, zero people out of 40 scored it as the worst smelling formulation. Composition G contained high levels of fructone, which was observed to have a fruity odor. 
     Organoleptic Test 2: Total number of people=36 
     Organoleptic test was performed on different variations of the preferred composition (G) from test 1, with geranyl acetate and orange flower ether evaluated as possible partial replacements for 1-Methoxy-2-propyl acetate. 36 persons employed by Wyeth volunteered to take part in organoleptic test 2. 
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Composition 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 J 
                 K 
                 L 
                 A 
                 E 
               
               
                   
                 % w/v 
                 % w/v 
                 % w/v 
                 % w/v 
                 % w/v 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Metaflumizone †   
                 15.3 
                 15.3 
                 15.3 
                 15.3 
                 15.3 
               
               
                 (100% pure) 
               
               
                 Amitraz †  (100% pure) 
                 15.3 
                 15.3 
                 15.3 
                 15.3 
                 15.3 
               
               
                 Dimethyl sulfoxide 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
               
               
                 N,N-Diethyl-m- 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
               
               
                 toluamide 
               
               
                 FRUCTONE 
                 q.s. ad 
                 q.s. ad 
                 q.s. ad 
                 q.s. ad 
                 q.s. ad 
               
               
                   
                 (36.4) 
                 (31.4) 
                 (26.4) 
                 (31.4) 
                 (31.4) 
               
               
                 g-Hexalactone 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
                 10.0 
               
               
                 Geranyl acetate 
                   
                   
                   
                 10.0 
               
               
                 Orange flower ether 
                   
                   
                   
                   
                 10.0 
               
               
                 1-Methoxy-2-propyl 
                 10.0 
                 15.0 
                 20.0 
                 5.0 
                 5.0 
               
               
                 acetate 
               
               
                 Total scores 
                 121 
                 117 
                 142 
                 158 
                 113 
               
               
                 # of People rated 
                 4 
                 4 
                 7 
                 13 
                 7 
               
               
                 formulation as best 
               
               
                 smelling 
               
               
                 # of People rated 
                 6 
                 5 
                 1 
                 1 
                 12 
               
               
                 formulation as worst 
               
               
                 smelling 
               
               
                   
               
               
                   † Contains 2% overage. 
               
            
           
         
       
     
     Results show that composition A scored a highest aggregate of 158. 
     Efficacy Study: 
     Compositions A and B were tested for efficacy to determine if the new spot-on formulations are as efficacious as ProMeris® for controlling existing infestation and weekly challenges of flea and tick infestations on mixed breed dogs. Results showed that all dogs presented normal health and behavior throughout the course of study. Flea counts indicated that efficacy rates against infestation for Compositions A, B, and ProMeris® for Dogs, were not statistically different and ≧98.8% on all time points evaluated after treatment up to Day 42. In regards to tick counts, geometric means were not statistically different between Compositions A, B, and ProMeris® for Dogs and ≧97.3% on all times evaluated after treatment up to Day 28. On study day 35, efficacy rate for Composition B dropped below 90% and was significantly lower than Composition A and ProMeris® for Dogs. 
     It will be apparent to those skilled in the art that various modifications and variation can be made to the compositions and methods described herein and as provided in the examples above without departing from the spirit or scope of the compositions and methods. 
     All cited patents and publications referred to in this application are herein incorporated by reference in their entirety.