US 2011 O150822A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0150822 A1 Nouvel et al. (43) Pub. Date: Jun. 23, 2011

(54) COMPOSITIONS AND Publication Classification METHODS OF USE (51) Int. Cl. (75) Inventors: Larry Nouvel, Plano, TX (US); A6II 3L/20 (2006.01) Luis Rios, Pembroke Pines, FL A6IP 25/22 (2006.01) (US); Cuong Tu Ba, Miami, FL (US) (52) U.S. Cl...... 424/84 (73) Assignee: Sergeant's Pet Care Products, Inc., Omaha, NE (US) (21) Appl. No.: 12/974.565 (57) ABSTRACT (22) Filed: Dec. 21, 2010 Pheromone compositions based on a combination of squalene, and 1-docosanol are described. The Related U.S. Application Data compositions are useful for behavior modification in mam (60) Provisional application No. 61/288,643, filed on Dec. mals that exhibit undesirable or harmful stress-related behav 21, 2009. iors.

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O% M Marked improvement Some improvement No change Patent Application Publication Jun. 23, 2011 Sheet 1 of 2 US 2011/O150822 A1

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FIG. Patent Application Publication Jun. 23, 2011 Sheet 2 of 2 US 2011/O150822 A1

Behavior improvement

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80 a d 60 - D. Feliway diffuser S 40 a Cat Collar 2O O Yes NO Feliway diffuser 67.6 32.5 dCat Collar 87.1 12.9 US 2011/O 150822 A1 Jun. 23, 2011

PHEROMONE COMPOSITIONS AND result in harmful or annoying behaviors that are not well METHODS OF USE tolerated by the affected animal, other animals or human owners/handlers. For example, separation anxiety in dogs CROSS REFERENCE TO RELATED frequently results in Soiling, excessive chewing or licking, APPLICATION property destruction, constant barking, and hyperactivity. Pet cats under stress, for instance, from the introduction of a new 0001. This application claims the benefit of U.S. Provi cat to the household, will often spray, Scratch, claw, and make sional Application Ser. No. 61/288,643 filed on Dec. 21, other displays of aggression. Generally, a need is recognized 2009, the disclosure of which is hereby incorporated by ref for compositions and methods that can be used on any erence in its entirety. affected domestic, farm, or Zoo animal to control Such unde FIELD OF THE INVENTION sirable behaviors. 0002 This invention relates generally to the field of ani SUMMARY OF THE INVENTION mal behavior and more particularly to pheromone composi 0006. The inventors have discovered novel pheromone tions and methods of use for modifying animal behavior. compositions that are useful for modifying behavior in mam mals, and are particularly useful for modifying objectionable BACKGROUND behaviors in domestic animals that result from stress or anxi 0003. A pheromone is a chemical signaling compound ety. The compositions are based in part on the Surprising naturally produced by many animals that elicits a predictable finding that squalene-based compositions (i.e. compositions and specific behavioral response in another member of the comprising at least 30% by weight of squalene) are effective same species. Pheromone compounds and functions vary and at modifying stress- or anxiety-related behaviors in domestic are thought to include alarm , food trail phero animals. mones, reproductive pheromones, and probably many others 0007 Accordingly, in one aspect there is provided a affecting animal behavior. Although originally and most well pheromone composition for modifying behavior of a mam documented in insect species, pheromones are the Subject of mal, the composition comprising a mixture of at least 30% (% increasing study and recognition is growing of the role that w/w) squalene, at least 10% (% w/w) linoleic acid, and at least pheromones play in modifying the behavior of mammalian 1% (% w/w) 1-docosanol. species. 0008. In another aspect there is provided a pheromone 0004. In mammals pheromones are thought to be detected composition for modifying behavior of a mammal, the com by olfactory membranes or by the vomeronasal organ (VNO position comprising 30%-80% (% w/w) squalene, 10-75% or Jacobson’s organ), which is positioned between the nose (% w/w) linoleic acid, and 1%-10% (% w/w) 1-docosanol. and mouth and functions as the first stage of the accessory 0009. In another aspect there is provided a pheromone olfactory system. However, unlike regular olfactory mem Solution for modifying behavior of a mammal, the composi branes, the VMO is connected directly to the mid-brain and tion comprising about 1%-15% by volume of a mixture of thus enjoys the shortest organ-to-brain distance in mammals. 30%-35% (% w/w) squalene, 55-65% (% w/w) linoleic acid, This feature allows pheromones present in extremely small 2%-5% (% w/w) 1-docosanol, and 1%-5% (% w/w) choles quantities to very selectively trigger certain biochemical pro terol, and about 70%-90% by volume of an organic solvent. cesses in the animal. Moreover, pheromone signals go 0010. In another aspect there is provided a pheromone directly to Subconscious areas of brain without being pro Solution for modifying behavior of a mammal, the composi cessed by the conscious brain, and thus pheromone effects are tion comprising about 1%-15% by volume of a mixture of both rapid and subconscious. While the precise mechanisms 30%-35% (% w/w) squalene, 55-65% (% w/w) linoleic acid, underlying pheromone effects on the mammalian brain 2%-5% (% w/w) 1-docosanol, and 2%-10% (% w/w) of a remain to be further explored and characterized, a growing mixture of at least two fatty acids other than linoleic acid, and body of evidence indicates clear behavioral effects likely about 70%-90% by volume of an organic solvent. involving at least hormonal responses. For example, studies 0011. In another aspect there is provided a pheromone of the house mouse have revealed a complex pheromone Solution for modifying behavior of a mammal, the composi communication system for signaling inter-male aggression tion comprising about 1%-15% by volume of a mixture of and dominance, mating readiness, and for signaling stress to 30%-35% (% w/w) squalene, 55-65% (% w/w) linoleic acid, the other members of the colony. All of these behaviors have 2%-5% (% w/w) 1-docosanol, 1%-5% (% w/w) cholesterol demonstrated correlations with hormonal pathways. Phero and 2%-10% (% w/w) of a mixture of at least two fatty acids mone effects may also be mediated by basic olfactory mecha other than linoleic acid, and about 70%-90% by volume of an nisms and behavioral effects associated with olfactory pro organic solvent. cessing. For example, olfactory processing is known to be 0012. In another aspect there is provided a pheromone important for newborn mammals. Newborns, including Solution for modifying behavior of a mammal, the composi humans, can identify the mother from her scent. This process tion comprising about 1%-15% by volume of a mixture of may be crucial to bonding and Survival and is thought a likely 65%-70% (% w/w) squalene, 18%–21% (% w/w) linoleic candidate for involving pheromone mechanisms in mam acid, 2%-5% (% w/w) 1-docosanol, and 7%–9% (% w/w) of mals. Thus growing evidence is consistent with an important a mixture of at least two fatty acids other than linoleic acid, role for pheromones in controlling mammalian behavior, and and about 70%-90% by volume of an organic solvent. particularly those behaviors associated with bonding, Social 0013. In another aspect there is provided a pheromone ization, aggression and stress. Solution for modifying behavior of a mammal, the composi 0005. In domestic, farm, and Zoo animals, including dogs, tion comprising about 1%-15% by volume of a mixture of cats, horses, Swine, cattle, tigers, lions, bears, elephants, etc., 65%-70% (% w/w) squalene, 18%–21% (% w/w) linoleic fear and anxiety arising from various sources frequently acid, 2%-5% (% w/w) 1-docosanol, 7%–9% (% w/w) of a US 2011/O 150822 A1 Jun. 23, 2011

mixture of at least two fatty acids other than linoleic acid and composition, and preferably contributes 2%-9% (% w/w). 1% (% w/w) cholesterol, and about 70%-90% by volume of When both cholesterol and a mixture of additional fatty acids an organic solvent. are included in the composition, the combined components 0014. In a further aspect there is provided a method of together contribute no more than about 10% (% w/w) to the modifying stress-related behavior in a mammal, the compo composition. sition comprising administering to the mammal atherapeuti 0020 Squalene is a natural organic compound originally cally effective amount of a squalene-based pheromone com obtained for commercial purposes primarily from shark liver position, the composition comprising at least 30% (% w/w) oil, but is also derived from botanical Sources, including squalene, at least 10% (% w/w) linoleic acid, and at least 1% amaranth seed, rice bran, wheat germ, and olives. As derived (% w/w) 1-docosanol. from shark liver oil, squalene is readily available from many 0015. In an additional aspect there is provided a composi commercial sources. As discussed herein, squalene com tion for modifying behavior of a mammal, the composition prises at least about 30% (% w/w), 35% (% w/w), 40% (% comprising a solid matrix into which is incorporated 10%- w/w), 45% (% w/w), 50% (% w/w), 55% (% w/w), 60% (% 20% by weight of a pheromone composition, the pheromone w/w), 65% (% w/w), 70% (% w/w), 75% (% w/w), 80% (% composition comprising 30%-80% (% w/w) squalene, w/w), or 85% (% w/w) of the formulation. For example, the 10-75% (% w/w) linoleic acid, and 1%-10% (% w/w) amount of squalene present in the formulation may range 1-docosanol. from about 30%-80% (% w/w) and preferably ranges from about 65%-70% (% w/w). In a further embodiment, the BRIEF DESCRIPTION OF THE DRAWINGS amount of squalene present in the formulation may range from about 30%-35% (% w/w). In a further embodiment, the 0016 FIG. 1 is a bar graph illustrating the behavioral amount of squalene may range from about 35%-60% (% results obtained in a study of the effects on behavior of an W/w). In still another embodiment, the amount of squalene exemplary pheromone composition on dogs exhibiting may range from about 45%-70% (% w/w). behavior problems; and 0021 Linoleic acid is an omega-6-, used in the 0017 FIG. 2 is a bar graph illustrating the behavioral biosynthesis of (AA) and some prostaglan results obtained in a clinical field trial of a pheromone com dins. It is found in the of cell membranes. It is abundant position on cats exhibiting behavior problems. in many vegetable oils, especially safflower and Sunflower oils. Similarly, linoleic acid is also available from a variety of DETAILED DESCRIPTION OF THE INVENTION commercial sources. As discussed herein, linoleic acid com 0018. The pheromone compositions provided herein are prises at least about 10% (% w/w), 15% (% w/w), 16% (% believed to mimic certain naturally occurring pheromones w/w), 17% (% w/w), 18% (% w/w), 19% (% w/w), 20% (% that have a calming effect on mammals. As such, the compo w/w), 21% (% w/w), 22% (% w/w), 23% (% w/w), 24% (% sitions are useful for controlling behavior in mammals and are w/w), 25% (% w/w), 30% (% w/w), 35% (% w/w), 40% (% especially useful for controlling stress- or anxiety-induced w/w), 45% (% w/w), 50% (% w/w), 55% (% w/w), 56% (% behavior in pets and domestic animals such as, but not limited w/w), 57% (% w/w), 58% (% w/w), 59% (% w/w), 60% (% to, dogs, cats, and horses. In particular, the pheromone com w/w), 61% (% w/w), 62% (% w/w), 63% (% w/w), 64% (% positions disclosed herein are based in part on the unexpected w/w), 65% (% w/w), 70% (% w/w), 75% (%w/w), or 80% (% finding that compositions made primarily from squalene, a w/w) of the formulation. For example, the amount of linoleic naturally occurring organic compound obtained from shark acid present in the formulation may range from about 10%- liver oil, and certain Volatile organic compounds including 75% (% w/w) and preferably ranges from about 15%-25% (% certain fatty acids, demonstrate calming effects on mammals. w/w). In a further embodiment, the amount of linoleic acid Accordingly, the term "squalene-based as used herein to present in the formulation may range from about 55%-65% describe the pheromone compositions refers to a composition (% w/w). In yet another embodiment, the amount of linoleic that includes at least 30% by weight of squalene. Most sur acid may range from about 18%–21% (% w/w). prisingly, such compositions were found to produce strong 0022 1-docosanol (also known as n-docosanol, docosyl calmative effects in mammals without additionally including alcohol, behenic alcohol behenyl alcohol, Cachalot BE-22, either or , two fatty acids that are Dehydag wax 22 (lanette), Emery 3304, and Loxiol VPG critical components in previously described pheromone com 1451) is a generally known for antiviral thera positions, such as in U.S. Pat. No. 6,077.867. peutic properties, and its use in the treatment of cold Sores. 0019. A basic pheromone composition includes at least Like squalene and linoleic acid, 1-docosanol is available from 30% (% w/w) squalene, at least 10% (% w/w) linoleic acid, a variety of commercial Sources. As discussed herein, and at least 1% (% w/w) 1-docosanol (behenyl alcohol or 1-docosanol comprises at least about 1% (% w/w), 2% (% docosyl alcohol). Preferably the composition includes 30%- w/w), 3% (% w/w), 4% (% w/w), 5% (% w/w), 6% (% w/w), 80% (% w/w) squalene in combination with 10%-75% (% 7% (% w/w), 8% (% w/w), 9% (% w/w), or 10% (% w/w) of w/w) linoleic acid, and 1%-10% (% w/w) 1-docosanol, with the formulation. For example, the amount of 1-docosanol the balance of the composition being made up of cholesterol present in the formulation may range from about 1%-10% (% or a mixture of additional fatty acids (in addition to the w/w) and preferably ranges from about 2%-5% (% w/w). In a linoleic acid) or both cholesterol and a mixture of additional further embodiment, the amount of 1-docosanol present in the fatty acids (in addition to the linoleic acid). The mixture of formulation may range from about 1%-7% (% w/w). additional fatty acids excludes both palmitic acid and oleic 0023 The cholesterol component of the current invention acid. Cholesterol, when included, contributes 0.1%-10% (% is generally defined as steroid found in the cell membranes w/w) to the composition, and preferably contributes 1%-5% and transported in the blood plasma of most animals. Cho (% w/w) to the composition. Similarly, a mixture of fatty lesterol is an important precursor molecule for the biosynthe acids, when included, contributes 0.1%-10% (% w/w) to the sis of bile acids, steroid hormones, and several other fat US 2011/O 150822 A1 Jun. 23, 2011

soluble vitamins. One skilled in the art will appreciate that the (other than linoleic acid) comprising approximately 1%-1. cholesterol component of the current invention is available 6% (% w/w) , 4.5%–6% (% w/w) n-pentade from a variety of commercial Sources. As discussed herein, canoic acid, and 0.1%–0.3% (% w/w) . In another cholesterol comprises at least about 0.1% (% w/w), 0.2% (% preferred embodiment of the current invention, the phero w/w), 0.3% (% w/w), 0.4% (% w/w), 0.5% (% w/w), 1% (% mone composition incorporates a mixture offatty acids (other w/w), 2% (% w/w), 3% (% w/w), 4% (% w/w), 5% (% w/w), than linoleic acid) comprising approximately 1%-1.6% (% 6% (% w/w), 7% (% w/w), 8% (% w/w), 9% (% w/w), or 10% w/w) myristic acid, 4.5%–6% (% w/w) n-pentadecanoic acid, (% w/w) of the formulation. For example, the amount of 0.1%–0.3% (% w/w) lauric acid, 0.8%-3% (% w/w) azelaic cholesterol present in the formulation may range from about acid, and 0.8%-3% (% w/w) pimelic acid. In yet another 0.1%-10% (% w/w) and preferably ranges from about 1%-5% preferred embodiment of the current invention, the phero (% w/w). mone composition incorporates a mixture offatty acids (other 0024. Any additional fatty acid included in the pheromone than linoleic acid) comprising approximately 1%-1.6% (% composition (besides linoleic acid) can be used in its pure w/w) myristic acid, 0.5%-1.6% (% w/w) n-pentadecanoic form, i.e., as a free fatty acid or in a derivative form Such as an acid, 0.1%–0.3% (% w/w) lauric acid, 4%–6% (% w/w) capric , salt, alcohol, ketone, ether or amide. Fatty acids are acid, 0.8%-3% (% w/w) azelaic acid, and 0.8%-3% (% w/w) commercially readily available from various chemical com pimelic acid. In an additional preferred embodiment of the panies, typically in Solid form. As discussed herein, addi current invention, the pheromone composition incorporates a tional fatty acids (other than linoleic acid) comprise at least mixture of fatty acids (other than linoleic acid) comprising about 0.1% (% w/w), 0.2% (% w/w), 0.3% (% w/w), 0.4% (% approximately 1%-1.6% (% w/w) myristic acid, 0.5%-1.6% w/w), 0.5% (% w/w), 1% (% w/w), 2% (% w/w), 3% (% (% w/w) n-pentadecanoic acid, and 0.1%–0.3% (% w/w) lau w/w), 4% (% w/w), 5% (% w/w), 6% (% w/w), 7% (% w/w), ric acid. 8% (% w/w), 9% (% w/w), or 10% (% w/w) of the formula 0027. Other compounds optionally included in the phero tion. For example, the amount of additional fatty acids present mone composition are amines, glycol, glycerol, and non in the formulation may range from about 0.1%-10% (% w/w) toxic lipophilic anti-oxidants such as butylated hydroxytolu and preferably ranges from about 6%-9% (% w/w). In a ene (“BHT”, also known as butylhydroxytoluene). In a further embodiment the amount of additional fatty acids preferred embodiment of the current invention, the phero present in the formulation may range from about 2%-10% (% mone composition comprises approximately 0.001%-1% (% w/w). w/w) butylated hydroxytoluene. The basic pheromone com 0025 To dissolve a fatty acid obtained in solid form, the position can be further combined with any carrier material fatty acid is typically added to a solvent under constant agi that preserves the bioactivity of the squalene, linoleic acid and tation and at an elevated temperature of about 37°C. to about additional fatty acids, if included. Such carrier materials 38°C. A fatty acid can also be microencapsulated and sus include, but are not limited to resins, liposomes, Vesicles, pended in water to form a water Suspension. Fatty acids carrier proteins and the like. Suitable for inclusion in the composition include propanoic 0028. The pheromone composition is typically used by acids Such as , butanoic acids such as butyric administering to the Subject animalatherapeutically effective acid, pentanoic acids such as , hexanoic acid Such amount of the pheromone composition through any method as , heptanoic acids such as , allowing delivery of the composition by inhalation by the octanoic acids such as , nonanoic acids such as animal. Such methods of administration include, for example, , decanoic acids such as , unde simply placing or distributing the composition in the environ canoic acids such as , dodecanoic acids such as ment of the animal, either by incorporating the composition lauric acid, tridecanoic acids such as , hepta into a wearable device Such as a collar, or by applying (e.g. decanoic acids such as margaric acid, octadecanoic acids spraying) the composition to surfaces in the living environ Such as , eicosanoic acids such as , ment of the animal. The term “therapeutically effective' heneicosanoic acids such as , tricosanoic describes an amount of the pheromone compound that is acids such as , tetracosanoic acids such as Sufficient to produce a noticeable modification, i.e. improve lignocericaid, pentacosanoic acids such as , ment, of animal behavior in the Subject animal, as determined hexacosanoic acids such as , heptacosanoic acids according to behavioral observations as described herein. Such as heptaosylic acid, octacosanoic acids such as montanic 0029. For example, a pheromone composition in liquid or acid, nonacosanoic acids such as nonacosylic acid, triacon Solid form can be incorporated in various ways as are gener tanoic acids such as , henatriacontanoic acids ally well known into a solid carrier material to form a collar or Such as henatriacontylic acid, dotriacontanoic acids such as tag, and the collar or tag is then worn by the mammal. The , tritriacontanoic acids such as psyllic acid, Solid carrier material is selected from among those materials, tetratriacontanoic acids such as geddic acid, pentatriacon typically polymeric compounds, generally recognized to be tanoic acids such as ceroplastic acid, hexatriacontanoic acids Suitable for release of active compounds (e.g. pesticidal com Such as hexatriacontylic acid, nonanedioic acids such as aze pounds) and set forth in further detail herein below. Alterna laic acid, tetradecanoic acids Such as myristic acid, pentade tively, the pheromone composition is combined with a solvent cyclic acids such as n-pentadecanoic acid, and heptanedioic to form a liquid pheromone solution and the liquid phero acids such as pimelic acid. Derivatives of these fatty acids mone solution be further prepared in various formulations Such as or salts can also be used in the composition. suitable for delivery to the mammal by inhalation. For 0026. It is preferred that if additional fatty acids are example, liquid solutions can be further prepared according included in the pheromone composition (other than linoleic to methods well known in the art as a spray, gel, foam, sham acid), a mixture of at least two additional fatty acids are used. poo, or spot-on formulation. In one preferred embodiment of the current invention, the 0030. In an exemplary embodiment the pheromone com pheromone composition incorporates a mixture offatty acids position is incorporated into a solid carrier material to form a US 2011/O 150822 A1 Jun. 23, 2011

matrix containing the pheromone composition. The solid car 1%-15% by volume of the solution, in a mixture of an alcohol rier material containing the pheromone composition is then and dipropylene glycol, wherein the alcohol contributes formed into a collar as is well known and amply described in about 70%-90% by volume and the dipropylene glycol con the art, for example in U.S. Pat. No. 3,852,416. Typically an tributes about 5%-10% by volume to the solution. 0033. The concentration of the aforementioned compo admixture of an active (e.g. the pheromone composition) and nents including squalene, linoleic acid, cholesterol and other a carrier material providing the matrix is formed into Strips fatty acid mixture included in the basic pheromone composi through an extrusion process, and each strip is then formed a tion, may vary within the aforementioned ranges, depending collar by including a fastening device Such as a buckle, Snap upon the intended final form and use. However, it will be or hook. The solid carrier material forming the matrix into recognized that concentrations of the components that can be which the pheromone composition is incorporated is for used are readily ascertainable and can be assayed according example a polymer or polymer mixture with Suitable release to the behavioral methods set forth herein. characteristics Such that the pheromone composition is 0034. Thus, in one embodiment, the composition com released from the collar to be inhaled by the animal. The prises 30%-80% (% w/w) squalene, 10%-75% (% w/w) pheromone composition contributes 0.1%-50% (% w/w), linoleic acid, 1%-10% (% w/w) 1-docosanol, and 0.1%-10% preferably 5%-30% (% w/w), and more preferably (% w/w) of a mixture of at least two fatty acids other than 10%-200% (% w/w) by weight of the collar. linoleic acid. In another embodiment, the basic composition 0031 Suitable polymers for forming a solid substrate for includes 30%-80% (% w/w) squalene, 10%-75% (% w/w) making collar are well known and include, but are not limited linoleic acid, 1%-10% (% w/w) 1-docosanol, and 0.1%-10% to, polyethylene, polyvinyl acetate, ethylene acid copoly (% w/w) cholesterol. In an additional embodiment, the basic mers, ethylene acrylates, polyurethanes, styrene-butadiene, composition includes 30%-80% (% w/w) squalene, 10%- polyvinyl butyral, polyvinyl chloride (PVC), polyolefin, 75% (% w/w) linoleic acid, 1%-10% (% w/w) 1-docosanol, and 0.1%-10% (% w/w) of a mixture of cholesterol and at polyacrylate, and polymethacrylate esters, and silicon poly least two fatty acids other than linoleic acid. The composition mer. The polymers can contribute 0.1-99% by weight of the optionally further includes a small amount of a lipophilic collar, and typically will contribute 90%-95% by weight of antioxidant such as BHT, at least about 0.005% (% w/w), no the collar. Plasticizers can be incorporated into the mixture to more than about 0.1% (% w/w), and most typically about render the polymer resin more flexible. Suitable such plasti 0.01% (% w/w). cizers include phosphoric acid esters (e.g. tricresyl phos 0035. In another embodiment, the composition comprises phate) or phthalic acid esters (such as dioctyl phthalate). The 65%-7.5% (% w/w) squalene, 18%–21% (% w/w) linoleic collar may also include other additives such as stabilizers, for acid, 2%-5% (% w/w) 1-docosanol, and 0.1%-10% (% w/w) example antioxidants to protect the collar material from deg of a mixture of cholesterol and at least two fatty acids other radation by UV light and other oxidizing factors. Lubricants, than linoleic acid. colorants, and fillers may also be included. 0036. In another embodiment, the composition comprises 0032. The pheromone composition is generally solid in 30%-35% (% w/w) squalene, 55%-65% (% w/w) linoleic nature, but it can also be dissolved or diluted in a nonaqueous acid, 2%-5% (% w/w) 1-docosanol, and 0.1%-10% (% w/w) organic solvent or solvent mixture to form a pheromone solu of a mixture of cholesterol and at least two fatty acids other tion. Suitable solvents are generally known within the art and than linoleic acid. are recognized to include lipophilic organic diluents, alco 0037. In another embodiment, the composition comprises hols, ethylene glycol, propylene glycol, dipropylene glycol, 30%–80% (% w/w) squalene, 10%-75% (% w/w) linoleic ether, chloroform, benzene, carbon disulfide, oils including acid, 1%-10% (% w/w) 1-docosanol, and 0.1%-10% (% w/w) non-volatile and volatile oils, and combinations thereof. In an of a mixture of at least two fatty acids other than linoleic acid, exemplary embodiment, the pheromone composition is com wherein the composition is in Solution wherein the composi bined with an organic solvent or solvents and diluents to form tion contributes about 1%-15% by volume of the solution in a a pheromone solution in one of various liquid or liquid-based mixture of an alcohol and dipropylene glycol, wherein the forms such as sprays, aerosols, gels, dips, shampoos, spot alcohol contributes about 70%-90% by volume and the dipro treatments, microencapsulated products and so on. For pylene glycol contributes about 5%-10% by volume to the example, the basic composition can be dissolved in a Suitable Solution. alcohol and Supplied in a liquid form Such as a spray or foruse 0038. In another embodiment, the composition comprises in a plug-in diffuser. Suitable alcohols include ethanol, pro 30%–80% (% w/w) squalene, 10%-75% (% w/w) linoleic panol, isopropanol, butanol, pentanol, hexanol, heptanol, acid, 1%-10% (% w/w) 1-docosanol, and 0.1%-10% (% w/w) octanol, and phenyl ethyl alcohol. In a preferred embodiment, cholesterol, and the composition is in Solution wherein the the alcohols comprise ethanol, isopropanol, butanol, and phe composition contributes about 1%-15% by volume of the nyl ethyl alcohol. An alcohol solvent can be combined with a Solution in a mixture of an alcohol and dipropylene glycol, lipophilic organic diluent or carrier Such as ethylene glycol, wherein the alcohol contributes about 70%-90% by volume propylene glycol, dipropylene glycol, dipropylene glycol and the dipropylene glycol contributes about 5%-10% by monoethyl ether, dipropylene glycol methyl ether, or Dow Volume to the solution. Corning R. Q7-9180 silicone liquid. In a preferred embodi 0039. In one exemplary embodiment the composition ment, the solvent is a combination of dipropylene glycol and includes 30%-35% (% w/w) squalene, 55-65% (% w/w) an alcohol selected from the group consisting of ethanol, linoleic acid, 2%-5% (% w/w) 1-docosanol, and 1%-5% (% isopropanol, and butanol. In an exemplary embodiment, the w/w) cholesterol. Solvent comprises a combination of dipropylene glycol and 0040. In another exemplary embodiment the composition isopropanol. The basic pheromone composition is diluted to includes 30%-35% (% w/w) squalene, 55-65% (% w/w) form a solution wherein the composition contributes about linoleic acid, 2%-5% (% w/w) 1-docosanol, and 2%-10% (% 0.5%-57% by volume, preferably 1%-40% by volume, more w/w) of a mixture of at least two fatty acids other than linoleic preferably 1%-30% by volume, and even more preferably acid. US 2011/O 150822 A1 Jun. 23, 2011

0041. In another exemplary embodiment the composition behaviors is readily ascertainable (e.g. noticeable reduction includes 30%-35% (% w/w) squalene, 55-65% (% w/w) in aggressive displays, barking or chewing) and can be linoleic acid, 2%-5% (% w/w) 1-docosanol, 1%-5% (% w/w) Supplemented by observing other physical indicators of stress cholesterol and 2%-10% (% w/w) of a mixture of at least two Such heart rate, weight changes, and secretion of stress hor fatty acids other than linoleic acid. mones such as cortisol. 0042. In another exemplary embodiment the composition 0046. In use, the pheromone composition can be imple includes 65%-70% (% w/w) squalene, 18%–21% (% w/w) mented in a number of different ways depending in part on the linoleic acid, 2%-5% (% w/w) 1-docosanol, and 6%-9% (% targeted mammal(s) and behavior desired to be modified. A w/w) of a mixture of at least two fatty acids other than linoleic liquid solution containing the composition can simply be acid. applied directly to the coat or skin of a mammal, or sprayed on 0043. In another exemplary embodiment the composition Surfaces or objects in the mammal’s environment, or diffused includes 65%-70% (% w/w) squalene, 18%–21% (% w/w) or sprayed into the air in the mammal’s environment. For linoleic acid, 2%-5% (% w/w) 1-docosanol, 6%-9% (% w/w) example, an exemplary liquid spray formulation containing of a mixture of at least two fatty acids other than linoleic acid 1%-40% by volume of the pheromone composition (dis and 1% (% w/w) cholesterol. Solved in a Suitable solvent) can be sprayed, for example, on 0044. In another aspect the present disclosure encom floors, walls or animal toys about once a week, or once or passes a method of modifying stress-related behavior in a several times daily, as needed, to obtain the desired behavioral mammal by exposing the mammal to a therapeutically effec modification. Alternatively, for example, a liquid formulation tive amount of a squalene-based pheromone composition, containing 1%-15% by volume of the pheromone composi wherein the composition comprises at least 30% (% w/w) tion can delivered by a diffuser such as a plug-in diffuser squalene, at least 10% (% w/w) linoleic acid, and at least 1% commercially available from as Central Life Sciences/Far (% w/w) 1-docosanol. The mammal can be exposed to the nam Companies Inc. (Phoenix, Ariz.) as the Comfort Zone(R) composition by any method allowing inhalation by the mam Diffuser (sold with Feliway(R) or DAPR) (Dog Appeasing mal over a period of time sufficient to effect a modification of Pheromone)). Alternatively, the composition in liquid or solid the target behavior, as determined according to behavioral form can be incorporated in a plasticized material Such as observations. Typically the exposure will be over a period of PVC or the like that can then be formed into a tag, or in strips at least several minutes to a few hours, but can be overa period to form a collar. of days or weeks as may be needed to achieve a satisfactory 0047. As used herein, the word “mammal’ is interchange behavioral effect, and can be continued over a period of able with the word “animal’ and encompasses any group of weeks, months or longer depending on the particular mammal Vertebrates the females of which have milk-secreting glands, and situation. For example, a mammal Suffering from a tem including man. Examples of mammals include, but are not porarily induced anxiety, for example a petanxious over a trip limited to, domestic mammals such as cats and dogs; Small to a veterinary office, may require a brief exposure to the mammals, such as hamsters, rabbits, ferrets, rats, mice, and pheromone composition before, during or after the trip to guinea pigs; commercial mammals, such as horses, sheep, relieve the anxiety and associated behavior. In contrast, a cattle, and Swine; and mammals in captivity, such as apes, mammal exposed to a stressful stimulus for a longer and chimpanzees, tigers, lions, bears, elephants, Zebras, and the continual period, such as a pet exposed to a new pet in the like. household, may benefit from regular exposure to the phero 0048. As various changes could be made in the above mone composition. formulations, products and methods without departing from 0045. Following preparation, the pheromone composi the scope of the invention, it is intended that all matter con tions and liquid pheromone solutions thereof can be readily tained in the above description and in the examples given tested for efficacy for stress-relief in mammalian species. below, shall be interpreted as illustrative and not in a limiting Commonly recognized sources of stress in mammals include SS. for example weaning, transportation especially in motorized EXAMPLES vehicles, boredom, lack of exercise, separation anxiety, loud noises, introduction to new people or animals and visits to a Example 1 veterinary office. Mammals that are stressed by exposure to such events or conditions will typically exhibit highly unde Pheromone Compositions sirable stress-related behavioral symptoms. Such stress 0049 Table 1 lists the formulations of five exemplary behaviors are commonly recognized and include for example pheromone compositions (A, B, C, D, and E) prepared fearful behavior Such as cowering or shaking; excessive according to the present teachings. Allamounts are presented chewing or barking; hyperactivity; aggressive behavior as % w/w of the composition. toward people or other animals such as growling, Snappish ness orbiting; property destruction; and frequent urination or TABLE 1 Soiling. The efficacy of the pheromone composition can be tested for example by having Subject mammals wear a collar FORMULATION (90 W/w) incorporating the pheromone composition, or by applying the composition in the form of a liquid spray, liquid diffuser or the COMPONENT A. B C D E like in a physical area associated with the stress-inducing Linoleic Acid 59.69 2O 2O 60 61.19 Myristic Acid 1.5 1.5 1 1 conditions for any given animal. In either case, the phero n-Pentadecanoic acid 4.5 5.5 1.5 O.S mone composition is sufficiently volatile for the mammal to () inhale and thus be exposed to a sufficient amount of the Cholesterol 1 1 5 1 pheromone composition to produce a noticeable behavioral Lauric Acid O.3 O.3 O.3 O.3 effect. For example, a reduction in stress-related outward US 2011/O 150822 A1 Jun. 23, 2011

TABLE 1-continued TABLE 2-continued FORMULATION (90 W/w) Dog Type of Behavior Dog ID Name Dog Type Age Disorder COMPONENT A. B C D E 6 Tyson American 8 year Soiling. Very Smelly 1-Docosanol (Behenyl 2 2 2 4.99 2 Mastiff old dog. alcohol or Docosyl 7 Murphy Cocker 1 year Very hyperactive and Alcohol) Spaniel old Soilingsmelly. Squalene (Shark 31 67.69 68.19 30 34 8 & 9 Buster Border Both 2 Destructive house Origin) and Terriers years old Capric Acid 4 Barney AZelaic Acid 1.5 1 O Diesel Collie cross 7 months Very Snappy with BHT O.O1 O.O1 O.O1 O.O1 O.O1 with Belgian old owners, did not like Pimelic Acid 1.5 1 Sheppard to be fussed with or (Heptanedioic acid) touched. 1 Artimakay Deerhound 5 months Constantly barking at TOTAL 1OO 1OO 100 1OO 100 old owner for attention 2 Herby Wirehaired 3 years Soiling Toileting Dachshund old when left alone. 3 Millie Terrier 2 years Very nervous of Example 2 old people and big dogs. 4 Benji Yorkshire 1/3 Did not like men and Terrier years old was nervous of other Behavior Modification in Dogs dogs. 5 Bailey Chocolate 1 Nervous of people he 0050. The primary objective of this study was to assess the Labrador months did not know and efficacy of apheromone collar comprising the formulation of old Some dogs. the present invention in controlling stress related behaviors in 6 Bigun German 9 years Easily stressed dogs. The collar was formed from an extrusion process using Sheppard old leading to COSS hyperactivity PVC into which a composition according to formula C from Retriever Example 1 was incorporated at 6% by weight (of the collar). 7 Mutley Cross breed 15 year Senile barking (deaf All of the dogs enrolled in the study were client-owned dogs old and nearly blind) presented to a veterinary practice for behavior-related prob 8 Piglet Terrier cross 4 years Easily stressed and old suffers from lems. Owners were invited to participate in the study if the polydipsia (over dog exhibited one or more of the following symptoms: ner drinking) and vousness or fear of noise; timidity/fear of other dogs or polyuria (urinating people; excessive chewing; excessive barking; aggressive excessively) displays toward other dogs or the owner; Soiling when left 19 Dobbie Cross breed 9 year Some instances of alone; and/or hyperactivity. old aggressive behavior 0051. The testing period lasted anywhere from one to three months. Animal Subjects acted as their own controls. All 0053 As illustrated in FIG.1, 77% (or 13/17) of all animals animals were treated with a plasticized collar in which the for which data was analyzed showed a positive behavior composition of formula C was incorporated. Nineteen dogs response to the dog pheromone collar. were enrolled in the study. Two animals were excluded from Example 3 the final data analysis, leaving data from a total of seventeen Behavior Modification in Cats animals. The two excluded animals shared a household and 0054. A clinical field trial was conducted in 119 cats pre each managed to detach the other's collar shortly after the sented for one or more of the following behavior problems: collars were applied. urination, Scratching, aggressiveness, and/or excessive timid 0052 Behavioral characteristics of all subject dogs are set ity. Animals that presented one or more of these conditions forth in Table 2 below. were enrolled in the study and divided into one of two treat ment groups. Animals from the first group wore a pheromone TABLE 2 collar for a period of two months. The collar was formed from an extrusion process using PVC into which was incorporated Dog Type of Behavior a composition according to formula C from Example 1 at 9% Dog ID Name Dog Type Age Disorder by weight (of the collar). Animals from the second group 1 Neelko Rottweiler 9 months Nervous of noises, were treated using a commercial plug-in cat pheromone dif Border Collie old timid with other dogs fuser (Comfort Zone(R) diffuser sold with Feliway(R) for a Cross and people. period of two months. The study was conducted under a blind 2 Riddick Rottweiler 2 year Nervous of noises old and hyperactive in condition so that the human owners did not know the identity the house. of the brand name, manufacturer name and composition dur 3 Rosie Staffe 2/3 Barked at everything ing the course of the study. Owners were asked to answer year old through the window simply “Yes” or “No” as to whether the owner noticed any and was hyperactive. behavior improvement during the course of the two month 4 Rufus Staffe 2 year Very nervous and old timid and shied away treatment period. from other dogs. 0055 FIG. 2 is a bar graph summarizing the results of the 5 Dixie Staffie cross 1 year Very hyperactive, study and illustrating that the majority of cat owners reported old over the top playful noticeable behavior improvement using the composition of and chewed a lot. the present invention both in the collar and in the diffuser. Results were statistically significant at 1%. US 2011/O 150822 A1 Jun. 23, 2011

Example 4 closed by preferred embodiments and optional features, Liquid Compositions modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such 0056 Table 3 lists three liquid formulations (F, G, and H) modifications and variations are considered to be within the of the pheromone composition according to the present teach Scope of this invention as defined by the appended claims. ings. AS is shown, each liquid formulation consists of a phero mone “concentrate' composition consisting primarily of What is claimed is: squalene and linoleic acid, plus 1-docosanol, cholesterol, 1. A pheromone composition for modifying behavior of an additional fatty acids and BHT. The pheromone composition animal, the composition comprising a mixture of at least 30% contributed 15.1% by volume to the final volume of each (% w/w) squalene, at least 10% (% w/w) linoleic acid, and at liquid formulation, after the mostly solid pheromone “con least 1% (% w/w) 1-docosanol. centrate' was dissolved in a mixture of dipropylene glycol 2. A pheromone composition for modifying behavior of an and an alcohol (ethanol 190 proof (90%), isopropanol, or animal comprising 30%-80% (% w/w) squalene, 10-75% (% butanol). All amounts listed below are presented as % V/v. w/w) linoleic acid, and 1%-10% (% w/w) 1-docosanol. 3. The pheromone composition of claim 2 further compris TABLE 3 ing 0.1%-10% (% w/w) cholesterol. 4. The pheromone composition of claim 3 comprising FORMULATION (90 viv) 1%-5% (% w/w) cholesterol. COMPONENT F G H 5. The pheromone composition of claim 2 further compris Dipropylene Glycol 7.178 7.178 7.178 ing 0.1%-10% (% w/w) of a mixture offatty acids wherein the Ethanol 190 proof (90%) 77.600 mixture of fatty acids comprises at least two fatty acids Isopropanol 77.600 selected from the group consisting of capric acid, lauric acid, Butanol 77.600 aZelaic acid, myristic acid, n-pentadecanoic acid, pimelic Linoleic Acid 9.362 9.362 9.362 Myristic Acid O.151 O.151 O.151 acid, and . n-Pentadecanoic acid (Pentadecylic 0.0755 0.0755 0.0755 6. The pheromone composition of claim 2 further compris Acid) ing cholesterol and a mixture of fatty acids wherein together Cholesterol O.151 O.151 O.151 Lauric Acid O.O453 O.0453 O.0453 the cholesterol and mixture offatty acids contribute no more 1-Docosanol (Behenyl alcohol or O.302 O.302 O.302 than about 10% (% w/w) to the composition. Docosyl Alcohol) 7. The pheromone composition of claim 2 comprising Squalene (Shark Origin) S.134 S.134 S.134 Capric Acid 30%-35% (% w/w) squalene, 55-65% (% w/w) linoleic acid, AZelaic Acid and 2%-5% (% w/w) 1-docosanol. BHT O.OO151 O.OO151 O.OO151 8. The pheromone composition of claim 7 further compris Pimelic Acid (Heptanedioic acid) ing 1%-5% (% w/w) cholesterol. 9. The pheromone composition of claim 7 further compris TOTAL 1OO 1OO 1OO ing 2%-10% (% w/w) of a mixture of at least two fatty acids other than linoleic acid. 0057. One skilled in the art would readily appreciate that 10. The pheromone composition of claim 7 further com the methods and compositions described herein are represen prising 1%-5% (% w/w) cholesterol and 2%-10% (% w/w) of tative of exemplary embodiments, and not intended as limi a mixture of at least two fatty acids other than linoleic acid. tations on the scope of the invention. It will be readily appar 11. The pheromone composition of claim 2 comprising ent to one skilled in the art that varying Substitutions and modifications may be made to the present disclosure dis 65%-70% (% w/w) squalene, 18%–21% (% w/w) linoleic closed herein without departing from the scope and spirit of acid, and 2%-5% (% w/w) 1-docosanol. the invention. 12. The pheromone composition of claim 2, wherein the 0058 All patents and publications mentioned in the speci composition is dissolved in a solvent to form a pheromone fication are indicative of the levels of those skilled in the art to Solution. which the present disclosure pertains. All patents and publi 13. A pheromone solution for modifying behavior of an cations are herein incorporated by reference to the same animal comprising: extent as if each individual publication was specifically and a. about 0.5%-40% by volume of a pheromone composi individually indicated as incorporated by reference. tion comprising 30%-35% (% w/w) squalene, 55-65% 0059. The present disclosure illustratively described (% w/w) linoleic acid, and 2%-5% (% w/w) herein suitably may be practiced in the absence of any ele 1-docosanol; and ment or elements, limitation or limitations that are not spe b. about 70%-90% by volume of an organic solvent. cifically disclosed herein. Thus, for example, in each instance 14. The pheromone solution of claim 13, wherein the sol herein any of the terms "comprising.” “consisting essentially vent is selected from the group consisting of ethanol, butanol, of” and “consisting of may be replaced with either of the propanol, phenyl ethyl alcohol, ethylene glycol, propylene other two terms. The terms and expressions which have been glycol, dipropylene glycol methyl ether, dipropylene glycol employed are used as terms of description and not of limita monoethyl ether, ether, isopropyl palmitate, chloroform, ben tion, and there is no intention that in the use of Such terms and Zene, carbon disulfide, Dow Corning R. Q7-9180 silicone expressions of excluding any equivalents of the features fluid, oils including non-volatile and Volatile oils, and com shown and described or portions thereof, but it is recognized binations thereof. that various modifications are possible within the scope of the 15. The pheromone solution of claim 13 wherein the com present disclosure claimed. Thus, it should be understood that position contributes about 0.5%-15% by volume to the phero although the present disclosure has been specifically dis mone solution. US 2011/O 150822 A1 Jun. 23, 2011

16. The pheromone solution of claim 13, wherein the com 20. A method of modifying stress-related behavior in a position further comprises 1%-5% (% w/w) cholesterol. mammal comprising administering to the mammal a thera 17. The pheromone solution of claim 13, wherein the com peutically effective amount of the pheromone composition of position further comprises 2%-10% (% w/w) of a mixture of claim 1. at least two fatty acids other than linoleic acid. 21. The method of claim 21 wherein the composition com 18. The pheromone solution of claim 13, wherein the mix prises 30%-80% (% w/w) squalene, 10-75% (% w/w) linoleic ture further comprises 1%-5% (% w/w) cholesterol and acid, and 1%-10% (% w/w) 1-docosanol. 2%-10% (% w/w) of a mixture of at least two fatty acids other 22. The method of claim 21 wherein the pheromone com than linoleic acid. position further comprises 0.1%-10% (% w/w) cholesterol. 19. A pheromone composition for modifying behavior of 23. The method of claim 21 wherein the pheromone com an animal comprising: position further comprises 0.1%-10% (% w/w) of a mixture a. about 10%-30% by volume of a mixture of 65%-70% (% offatty acids. w/w) squalene, 15%-25% (% w/w) linoleic acid, 2%-5% 24. The method of claim 21 wherein the pheromone com (% w/w) 1-docosanol, 6%-9% (% w/w) of a mixture of position further comprises 1%-5% (% w/w) cholesterol and at least two fatty acids other than linoleic acid and 1% (% 0.1%-10% (% w/w) of a mixture of fatty acids. w/w) cholesterol; and b. about 70%-90% by volume of an organic solvent. c c c c c