# Patent

## Title
Formulations containing insect repellent compounds

## Abstract

Dihydronepetalactone, a minor natural constituent of the essential oil of catmints (Nepeta spp.) such as Nepeta cataria, has been identified as an effective insect repellent compound. Synthesis of dihydronepetalactone may be achieved by hydrogenation of nepetalactone, the major constituent of catmint essential oils. This compound, and compositions thereof, which also has fragrance properties, may be used commercially for its insect repellent properties.

## Background
This application claims the benefit of U.S. Provisional Application No. 60/624,579, filed on Nov. 3, 2004, which is incorporated in its entirety as a part hereof for all purposes.


TECHNICAL FIELD
The present invention relates to the field of insect repellency, and the use of dihydronepetalactone stereoisomers generally as repellent materials.
BACKGROUND
Repellent substances generally cause insects to be driven away from, or to reject, otherwise insect-acceptable food sources or habitats. Most known repellents are only mildly toxic. A few of the known repellents, in fact, are not active poisons at all but rather prevent damage to plants/animals or articles of manufacture by making insect food sources or living conditions unattractive or offensive. Most current commercial insect repellents contain the synthetic chemical N,N-diethyl-m-toluamide (DEET) as their primary active ingredient. For instance, repellents sold under the major commercial brand names such as Off!®, Deep Woods Off!®, and Cutter® are all DEET based products and comprise 85% of insect repellent sales (Consumer Reports Buying Guide, 1994 Special Year-End Issue). Further, Consumer Reports tests indicated that products with the highest concentration of DEET lasted the longest against mosquitoes.
Despite being an effective repellent, however, this compound has certain drawbacks. Specifically, it possesses an unpleasant odor and imparts a greasy feel to the skin. Although it has recently been re-registered for use in the US by the EPA, concerns have been raised as to its safety, particularly when applied to children [Briassoulis, G.; Narlioglou, M.; Hatzis, T. (2001) Human & Experimental Toxicology 20(1), 8-14]. Studies have demonstrated that high concentrations of DEET may give rise to allergic or toxic reactions in some individuals. Other disadvantages associated with DEET include that it (1) is a synthetic chemical having a limited spectrum of activity; (2) is a powerful plasticizer and will dissolve or mar many plastics and painted surfaces; and (3) plasticizes the inert ingredients typically used in topical formulations in order to lengthen the time of effectiveness. This leads to DEET formulations with low user acceptability.
As a result of the above limitations, DEET-free products with repellent activity are finding favor with consumers, and demand for compositions containing natural products (versus synthetic chemicals such as DEET) is increasing. These DEET-free repellent compounds require a combination of excellent repellency, high residual activity and relatively little or no toxicity to humans (or pets) and the environment. In response to these consumer demands, there is an on-going need to develop new repellent compounds, which can be obtained from, or synthesized from, natural plant materials and which are pleasant to use.
Many plant species produce essential oils (aromatic oils) that are used as natural sources of insect repellent and fragrant chemicals [Hay, R. K. M., Svoboda, K. P., Botany, in “Volatile Oil Crops: their biology, chemistry and production”; Hay, R. K. M., Waterman, P. G. (eds.); Longman Group UK Limited (1993)]. Citronella oil, known for its general repellence towards insects, is obtained from the graminaceous plants Cymbopogon winterianus and C. nardus. Examples of plants used as sources of fragrant chemicals include Melissa officinalis (Melissa), Perilla frutescens (Perilla), Posostemon cablin (Patchouli) and various Lavandula spp. (Lavender). All of these examples of plants yielding oil of value to the fragrance industry are members of the Labiatae (Lamiaceae) family. Plants of the genus Nepeta (catmints) are also members of this family, and produce an essential oil, which is a minor item of commerce. This oil is very rich in a class of monoterpenoid compounds known as iridoids [Inouye, H. Iridoids. Methods in Plant Biochemistry 7:99-143 (1991)], more specifically the methylcyclopentanoid nepetalactones [Clark, L. J. et al. The Plant Journal, 11:1387-1393 (1997)] and derivatives.
Iridoid monoterpenoids have long been known to be effective repellents to a variety of insect species [Eisner, T. Science 146:1318-1320 (1964); Eisner, T. Science 148:966-968 (1965); Peterson, C. and J. Coats, Pesticide Outlook 12:154-158 (2001); and Peterson, C. et al. Abstracts of Papers American Chemical Society, (2001) 222 (1-2): AGRO73]. U.S. Pat. No. 4,663,346 discloses insect repellants with compositions containing bicyclic iridoid lactones (e.g., iridomyrmecin). Further, U.S. Pat. No. 4,869,896 discloses use of these bicyclic iridoid lactone compositions in potentiated insect repellent mixtures with DEET.
Formal studies concerning the repellency of dihydronepetalactones, a class of iridoid monoterpenoids derived from nepetalactones (shown in FIG. 1), have been much less conclusive and have failed to teach or imply that these compounds exert a repellent effect on the common insect pests of human society. For example, a study of the composition of the secretion from anal glands of the ant Iridomyrmex nitidus showed that isodihydronepetalactone was present in appreciable amounts, together with isoiridomyrmecin [Cavill, G. W. K., and D. V. Clark. J. Insect Physiol. 13:131-135 (1967)]. Although isoiridomyrmecin was known at the time to possess good ‘knockdown’ insecticidal activity, no evidence was provided in support of a similar activity for isodihydronepetalactone, and no investigation of this compound's repellent effect (as distinct from insecticidal activity) was made.
In a later publication by Cavill, G. W. K., et al. [Tetrahedron 38:1931-1938 (1982)], the presence of dihydronepetalactones in the defensive secretion of an ant was again reported, but the authors concluded that the compound iridodial, rather than a dihydronepetalactone, was the basic repellent constituent.




Most recently, Jefson, M., et al. [J. Chemical Ecology 9:159-180 (1983)] described the repellent effect of dihydronepetalactone. Initial repellency caused by the undiluted compound was measured with respect to the ant species Monomorium destructor during feeding. After 25 seconds of exposure to the pure dihydronepetalactone, approximately 50-60% of the ants ceased to feed. However, further analyses of the repellency over a longer time course were not presented, nor were analyses with anything other than the pure undiluted compound. Repellency observed over such short periods of time (seconds) with concentrated chemicals is insufficient to allow prediction of efficacy in practical applications such as in topical insect repellents.
There is consequently a continuing need for a biologically based compound having improved insect repellent properties (with respect to DEET) and which is substantially non-toxic or only mildly toxic to humans. Preferred repellents will have activity against a wide variety of insects, including biting insects, wood-boring insects, noxious insects, household pests, and the like. Applicants have found that dihydronepetalactones, and compositions thereof, perform well as a new class of effective insect repellent compounds without the disadvantageous properties characteristic of prior-art compositions.
SUMMARY
One embodiment of this invention is an insect repellent composition or article that contains a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, represented by the general formula:




Another embodiment of this invention is a process for fabricating an insect repellent composition or an insect repellent article of manufacture by providing as the composition or article, or incorporating into the composition or article, a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, as described above.
Yet another embodiment of this invention is the use of a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, as described above, or a composition thereof, as an insect repellent; and thus an embodiment in which, in a method of repelling insects, the insects are exposed to a diihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, or a composition thereof, as described above.
Yet another embodiment of this invention is a formulated inset repellent composition that includes a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, as described above and one or more of a carrier, an adjuvant and an additive.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the chemical structures of the naturally occurring iridoid (methylcyclopentanoid) nepetalactones.



DETAILED DESCRIPTION
A nepetalactone” is a compound having the general structure:




Four chiral centers are present within the methylcyclopentanoid backbone of nepetalactone at carbons 4, 4a, 7 and 7a as shown above; (7S)-nepetalactones are produced by several plants and insects. Dihydronepetalactones are known as minor constituents of the essential oils of several labiate plants of the genus Nepeta (Regnier, F. E., et al. (1967) Phytochemistry 6:1281-1289; DePooter, H. L., et al. (1988) Flavour and Fragrance Journal 3:155-159; Handjieva, N. V. and S. S. Popov (1996) J. Essential Oil Res. 8:639-643). Dihydronepetalactones are defined by Formula 1:




wherein 1, 5, 6 and 9 indicate the four chiral centers of the molecule and the structure encompasses all possible stereoisomers of dihydronepetalactone. The structures of dihydronepetalactone stereoisomers that may be derived from (7S)-nepetalactones are shown below.





The term “dihydronepetalactones” or “dihydronepetalactone mixtures” refers to any mixture of dihydronepetalactone stereoisomers. The molar or mass composition of each of these isomers relative to the whole dihydronepetalactone composition can be variable. Dihydronepetalactones are abbreviated as “DHN”.
A dihydronepetalactone will be understood to encompass any and all dihydronepetalactone stereoisomers and mixtures thereof, unless a particular isomer or mixture is specified. When dihydronepetalactone is prepared from a naturally occurring source of nepetalactone some variation in molar concentration of stereoisomers is expected. Preparation from a naturally occurring source is, however, a preferred method of preparation.
Dihydronepetalactones are reported in the literature as minor constituents of the essential oils of several labiate plants of the genus Nepeta [Regnier, F. E., et al., Phytochemistry 6:1281-1289 (1967); DePooter, H. L., et al., Flavour and Fragrance Journal 3:155-159 (1988); Handjieva, N. V. and S. S. Popov, J. Essential Oil Res. 8:639-643 (1996)]. Additionally, dihydronepetalactones have been identified as constituents of the defensive secretions of certain insects, including rove beetles [Jefson, M., et al., J. Chem. Ecol. 9:159-180 (1983)] and ants, specifically Iridomyrmex species [Cavill, G. W. K. and D. V. Clark. J. Insect Physiol. 13:131-135 (1967)]. In those species that possess dihydronepetalactones, it has been proposed that they are biosynthetically derived from the iridoid monoterpene iridodial.
The chemical synthesis of dihydronepetalactones and their related iridoid monoterpenoid compounds has been described and found to be conducted in a variety of ways. The following are useful references relating to synthesis:

    
    
        1) Abelman, M. M. et al. J. Am. Chem. Soc. 104 (14) :4030-2 (1982)
        2) Fleming, I. and N. K. Terrett. Tetrahedron Lett. 25(44): 5103-5104 (1984); J. Chem. Soc., Perkin Trans. 1:2645-2650 (1998).
        3) Lee, E. and C. H. Yoon. J. Chem. Soc., Chem. Commun. 4: 479-81 (1994).
        4) Nagata, H. and K. Ogasawara. Tetrahedron Lett. 40(36): 6617-6620 (1999).
        5) Nangia, A. et al. Tetrahedron Lett. 35(22): 3755-8 (1994).
        6) Tanimori, S. and M. Nakayama. Agric. Biol. Chem. 55(4): 1181-1184 (1991).
        7) Uyehara, T. et al. J. Chem. Soc., Chem. Commun. 2:113-14 (1989); Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 32: 441-6 (1990); J. Org. Chem. 57(11): 3139-3145 (1992).
        8) Wolinsky, J. and E. J. Eustace. J. Org. Chem. 37(21): 3376-8 (1972).
        9) Wolinsky, J. and D. L. Nelson. Tetrahedron 25(17): 3767-74 (1969).
    
    


Regnier et al, op.cit., discloses the preparation of DHN from nepetalactone by the catalyzed hydrogenation of nepetalactone isolated from the essential oils of plants of the genus Nepeta (catmints). One preferred and convenient method for synthesis of dihydronepetalactone is thus by hydrogenation of nepetalactone obtained in relatively pure form from the essential oils isolated by various means from plants of the genus Nepeta (catmints). Catalysts such as platinum oxide and palladium supported on strontium carbonate give dihydronepalactone in 24-90% yields (Regnier et al. op.cit.).
The preferred process for producing the dihydronepetalactones represented by Formula I in the present invention, therefore, is by hydrogenation of nepetalactones from plants with oils of defined nepetalactone stereoisomer content, an industrially advantageous approach in terms of production cost and its biological basis. Other processes are as disclosed in U.S. Ser. No. 03/225,290 (WO 03/84946), which is incorporated in its entirety as a part hereof for all purposes.
Methods for isolation or extraction of essential oils include without limitation steam distillation, organic solvent extraction, microwave-assisted organic solvent extraction, supercritical fluid extraction, mechanical extraction and enfleurage (initial cold extraction into fats followed by organic solvent extraction).
The essential oils isolated from different Nepeta species are well known to possess different proportions of each naturally occurring stereoisomer of nepetalactone (Regnier et al. op. cit.; DePooter, et al. op.cit.; Handjieva et al op.cit.). Thus DHN prepared from oil derived from any Nepeta species will necessarily be a mixture of stereoisomers thereof, the constitution of that mixture depending upon the particular species of Nepeta from which it is derived.
As discussed herein above, four chiral centers are present within the methylcyclopentanoid backbone of the nepetalactone at carbons 4, 4a, 7 and 7a as shown:




A total of eight pairs of dihydronepetalactone enantiomers are possible after hydrogenation of nepetalactone. Of these, the naturally occurring stereoisomers described thus far are (9S)-dihydronepetalactones. Preferred repellent materials in accordance with the present invention include a mixture of any or all of the possible stereoisomers of dihydronepetalactone. More preferred repellent materials include a mixture of (9S)-dihydronepetalactones. Most preferred are (9S)-dihydronepetalactone stereoisomers derived from (7S)-nepetalactones. This includes the compounds commonly known as cis,trans-nepetalactone, cis,cis-nepetalactone, trans,cis-nepetalactone, and trans,trans-nepetalactone, as illustrated in FIG. 1. The predominant stereoisomers produced by N. cataria (cis,trans and trans,cis-) are preferred.
Upon completion of the hydrogenation reaction, the resulting mixture of isomer products may be separated by any conventional method (e.g., preparative liquid chromatography) to yield each highly purified pair of dihydronepetalactone diastereomers. This permits the use of various different diastereomers as are found to be most effective against particular insects. It is preferable to isolate a specific nepetalactone isomer from a plant to convert to its corresponding pair of diastereomers by hydrogenation.
In addition to variation in nepetalactone stereoisomer content between different Nepeta species, intra-species variation is also known to exist. Plants of a given species may produce oils with different compositions depending on the conditions of their growth or growth stage at harvest. In fact variation in oil composition independent of growth conditions or growth stage at harvest has been found in Nepeta racemosa, (Clark, L. J., et al. op.cit.). Plants of a single species exhibiting different oil compositions are termed chemotypes. In Nepeta racemosa, chemotypes exhibiting marked differences in the proportion of different nepetalactone stereoisomers exist. Thus, the preferred process for producing specific dihydronepetalactone enantiomers is hydrogenation of an oil from a Nepeta chemotype known to contain specific nepetalactone stereoisomers.
Insects include any member of a large group of invertebrate animals characterized, in the adult state (non-adult insect states include larva and pupa) by division of the body into head, thorax, and abdomen, three pairs of legs, and, often (but not always) two pairs of membranous wings. This definition therefore includes a variety of biting insects (e.g., ants, bees, black flies, chiggers, fleas, green head flies, mosquitoes, stable flies, ticks, wasps), wood-boring insects (e.g., termites), noxious insects (e.g., houseflies, cockroaches, lice, roaches, wood lice), and household pests (e.g., flour and bean beetles, dust mites, moths, silverfish, weevils).
A host is any plant or animal affected by insects. Typically, hosts are considered to be insect-acceptable food sources or insect-acceptable habitats. An insect susceptible article is any item of commerce created by man, which is affected by insects. This may include buildings, furniture, and the like. Typically, these articles of manufacture are considered to be insect-acceptable food sources or insect-acceptable habitats.
The terms “insect repellent”, “insect repellent composition” or “repellent composition” will refer to a compound or composition that deters insects from their preferred hosts or insect-suitable articles of manufacture. Most known repellents are not active poisons at all, but rather prevent damage to plants/animals or articles of manufacture by making insect food sources or living conditions unattractive or offensive. Typically, an insect repellent is a compound or composition that can be either topically applied to the host, or is a compound or composition that may be incorporated into an insect susceptible article to produce an insect repellent article that deters insects from the nearby 3-dimensional space in which the host or article exists. In either case, the effect of the insect repellent is to drive the insects away from or to reject (1) the host, thereby minimizing the frequency of insect “bites” to the host; and/or (2) the insect susceptible article, thereby protecting the article from insect damage. Repellents may be in the form of gases (olfactory), liquids, or solids (gustatory).
Some examples of well-known insect repellents include: benzil; benzyl benzoate; 2,3,4,5-bis(butyl-2-ene)tetrahydrofurfural (MGK Repellent 11); butoxypolypropylene glycol; N-butylacetanilide; normal-butyl-6,6-dimethyl-5,6-dihydro-1,4-pyrone-2-carboxylate (Indalone); dibutyl adipate; dibutyl phthalate; di-normal-butyl succinate (Tabatrex); N,N-diethyl-meta-toluamide (DEET); dimethyl carbate (endo,endo)-dimethyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate); dimethyl phthalate; 2-ethyl-2-butyl-1,3-propanediol; 2-ethyl-1,3-hexanediol (Rutgers 612); di-normal-propyl isocinchomeronate (MGK Repellent 326); 2-phenylcyclohexanol; p-methane-3,8-diol, and normal-propyl N,N-diethylsuccinamate. Standard repellents for mosquitoes, ticks, and the like are citronella oil (discussed below), dimethyl phthalate, normal-butylmesityl oxide oxalate and 2-ethyl hexanediol-1,3 (See, Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Ed., Vol. 11: 724-728; and The Condensed Chemical Dictionary, 8th Ed., p 756).
An insect repellent is any compound or composition that deters insects from a host. It will be appreciated that such usage makes no distinction among compounds that have highly ephemeral effects as compared to those that exhibit long-term beneficial effects, and/or those that require very high surface concentrations before there is an observable effect on insect behavior.
The term “insect repellent” thus indicates a compound or composition conferring on a host protection from insects when compared to no treatment at all. Protection desirably results in a statistically significant reduction in numbers of insects, and may, for example, be usefully determined by measuring mean complete protection time (“CPT”) in tests in which insect behavior toward treated animals, including humans, and treated inanimate surfaces is observed. Mean CPT refers to the mean length of time over repetitions of tests in which the time before the first landing, probing or biting (in the case of a biting insect) or crawling (in the case of a crawling insect such as a tick or chigger) on a treated surface is observed [see e.g. US EPA Office of Prevention, Pesticides and Toxic Substances product performance test guidelines OPPTS 810.3700; and Fradin, M. S., Day, J. F. (2002) New England Journal of Medicine 347, 13-18]. In one exemplary embodiment of this invention, the insect repellent composition hereof has a mean CPT that is statistically indistinguishable from that of DEET. In the test in which this condition of the respective mean CPT performances of a DHN composition and DEET are shown to be statistically indistinguisable, the test conditions (including amounts of active ingredients) utilized must of course be identical, or, if not identical, must differ only in ways that do not prevent utilization of the results for the purposes of documenting the existence of the condition described.
As noted above, DHN compares favorably in performance with DEET. Moreover, DHN is advantageously prepared from naturally occurring nepetalactone derived from plants whereas DEET, and many other insect repellents, are not prepared from natural sources—an important consumer consideration when choosing an effective repellent. Preparation from natural sources also offers the potential for low production costs.
A useful property of DHN is that it provides a considerable improvement over the odor of DEET while exhibiting effective insect repellency. The DHN compounds and compositions of this invention possess a pleasant fragrance. The fragrance notes of the DHN materials make them useful in imparting, altering, augmenting or enhancing the overall olfactory component of an insect repellent composition or article, for example, by utilizing or moderating the olfactory reaction contributed by one or more other ingredients in the composition. Specifically, the DHN compositions of the invention may be utilized to either mask or modify the odor contributed by other ingredients in the formulation of the final repellent composition or article, and/or to enhance consumer appeal of a product by imparting a characteristic perfume or aroma.
In addition to the chemical compounds and compositions as described above, a variety of effective insect repellents contain essential oils and/or active ingredients of essential oils. “Essential oils” are defined as any class of volatile oils obtained from plants possessing the odor and other characteristic properties of the plant. Examples of repellent compounds that are essential oils include: almond bitter oil, anise oil, basil oil, bay oil, caraway oil, cardamom oil, cedar oil, celery oil, chamomile oil, cinnamon oil, citronella oil, clove oil, coriander oil, cumin oil, dill oil, eucalyptus oil, fennel oil, ginger oil, grapefruit oil, lemon oil, lime oil, mint oil, parsley oil, peppermint oil, pepper oil, rose oil, spearmint oil (menthol), sweet orange oil, thyme oil, turmeric oil, and oil of wintergreen. Examples of active ingredients in essential oils are: citronellal, methyl salicylate, ethyl salicylate, propyl salicylate, citronellol, safrole, and limonene.
In contrast to an insect repellent, an insecticide is a compound or mixture that is capable of poisoning an insect via its oral ingestion, by contact with the insect cuticle, or by fumigant action through the air. Thus, an insecticide is a type of pesticide designed to control insect life that is harmful to man (i.e., directly harmful as disease vectors, or indirectly harmful by destruction of crops, food products, or textile fabrics). Several well-known insecticides include: inorganic compounds (such as arsenic, lead and copper); naturally occurring organic compounds (such as rotenone, pyrethrins, nicotine, copper naphthenate and petroleum derivatives); and synthetic organic compounds (such as DDT, dieldrin, endrin, chlordane, lindane, para-dichlorobenzene and parathion).
A potentiated insect repellent composition is a repellent composition that produces a result substantially in excess of that which reasonably could be expected or predicted from the known effect of the components either alone or additively. In the present invention, a potentiated insect repellent composition will typically include dihydronepetalactones or a mixture thereof, and at least one other insect repellent compound that is not itself dihydronepetalactone (sometimes referred to as a non-dihydronepetalactone insect repellent compound).
An insect repellent composition can be used as a component of an insect repellent article, wherein an insect repellent article is an article of manufacture possessing insect repellency that is enhanced, altered, or augmented by the presence thereon or therein of an insect repellent composition. As used herein with respect to insect repellency, the terms “alter” and “modify” in their various forms refer to a means of supplying or imparting insect repellency to a composition, or augmenting the existing insect repellency characteristics where natural repellency is deficient in some regard, or supplementing the existing insect repellency to modify its quality, or character. The term “enhance” is intended to mean the intensification (without effecting a change in kind or quality of repellency) of one or more repellency properties in an insect repellent composition or insect repellent article.
The dihydronepetalactones of the present invention possess unique properties of insect repellency and are particularly effective against a wide spectra of common insect pests, including biting insects, wood-boring insects, noxious insects, and household-pests, and other insects that interfere with human society. These insects include a variety of biting insects (e.g., ants, bees, black flies, chiggers, fleas, green head flies, mosquitoes, stable flies, ticks, wasps, horn flies), wood-boring insects (e.g., termites), noxious insects (e.g., houseflies, cockroaches, lice, roaches, wood lice), and household pests (e.g., flour and bean beetles, dust mites, moths, silverfish, weevils). In the case of mosquitoes, which convey pathogenic microbes, these repellent properties are additionally effective for preventing infection with such diseases.
One property that is important to overall insect repellency is surface activity, as most (if not all) repellents contain both polar and non-polar regions in their structure. A second property is volatility. Insect repellents form an unusual class of compounds where evaporation of the active ingredient from the host's skin surface or from the insect repellent article is necessary for effectiveness, as measured by the host's protection from insect bites or the article's protection from insect damage. In the case of a topical insect repellent, a certain minimum concentration of repellent is needed in the air space directly above the skin surface of the host in order to repel insects, and this concentration is a measure of the potency of the repellent. However, evaporation rate is also affected by the rate of skin absorption—in most cases, penetration into and through the skin is an undesirable mode of loss of compound from the skin surface. Similar considerations must be made for insect repellent articles, concerning the minimum concentration of repellent required in the three-dimensional air space surrounding the article itself.
A variety of strategies are available to researchers attempting to balance these properties of evaporation (and, optionally, penetration). First, it is possible to find a single active ingredient having the right balance of physical properties. Alternatively, the active ingredient could be formulated with polymers and inert ingredients added to the active ingredient for the purpose of modifying the persistence of the active ingredient on the host's skin surface or within the insect repellent article. However, adding inert ingredients to the active ingredient limits the number of molecules of active ingredient on the surface of the repellent film or article. Since a molecule must be on the surface in order to evaporate, the evaporation rate is lowered. This carries with it the negative consequence of diluting the concentration of active ingredient that can be applied to the host's skin surface or that is present on the surface of an insect repellent article. This, in turn, reduces the overall potency of a formulation containing inert ingredients. In a third alternative, the active ingredient can be contained in microcapsules to control rates of loss from the host's skin surface or insect repellent article. Finally, another technique of limiting the evaporation rate of active ingredient is to synthesize a precursor molecule, which slowly disintegrates on the skin surface or insect repellent article to release the active ingredient.
For example, release of the active ingredient may be, for example, by sub-micron encapsulation, in which the active ingredient is encapsulated (surrounded) within a skin nourishing protein just the way air is captured within a balloon. The protein may be used at, for example, a 20% concentration. An application of repellent contains many of these protein capsules that are suspended in either a water-based lotion, or water for spray application. After contact with skin the protein capsules begin to breakdown releasing the encapsulated dihydronepetalactone. The process continues as each microscopic capsule is depleted then replaced in succession by a new capsule that contacts the skin and releases its active ingredient. The process may take up to 24 hours for one application. Because protein's adherence to the skin is so effective, these formulas are very resistant to perspiration (sweat-off), and water. When applied they are dry and comfortable with no greasiness. This system results in very effective protection, but it is only effective when used on skin because clothing does not have the capability to release the proteins. An alternative system uses a polymer to encase the repellent, which slows down early evaporation leaving more dihydronepetalactone available for later evaporation. This system can often increase a repellent's length of effectiveness by 25% to 50% over comparable non-entrapped products, but often feels greasy because of the presence of the polymer. In another alternative, a synergist is used to keep stimulating the evaporation of the dihydronepetalactone in the composition.
Regardless of the particular strategy applied to control volatility of an insect repellent, each repellent must have a minimum effective evaporation rate (MEER) from the skin surface or insect repellent article to maintain the necessary minimum concentration of repellent in the air space directly above the skin surface/article for effective insect repellency. An evaporation rate greater than the minimum effective evaporation rate (MEER) results in a significant and undesirable mode of loss. The issue is further complicated, however, since the MEER will change as a function of conditions in the field. Both the avidity or biting tendency of an insect and the concentration of insects in the host's environment must be considered. For example, as the avidity of mosquitoes increases, a higher MEER will be required. In an environment having a low concentration of mosquitoes where those mosquitoes are not hungry, the MEER could be as low as 2, or more commonly, 5 or 6. In contrast, in an environment having a high concentration of hungry mosquitoes, the MEER might be as high as 12-15. Preferred in the present invention are insect compositions wherein the skin surface evaporation rate is at least equal to a minimum effective evaporation rate over a period of time where a preferred period of time is about 5 hours.
The effectiveness of DHN or any insect repellent depends upon the surface concentration of the active ingredient on the host surface to which it is applied. Many compounds known in the art to exhibit insect repellency do so, however, only in relatively concentrated form. See, for example, McGovern et al in U.S. Pat. No. 4,416,881, which discloses the use of repellent concentrations of 6.25-25%. In other situations representative of the art, it is often found that concentrations of DEET much below 1% require repeated application to achieve an effective surface concentration, yet concentrations above 30% result in excessive surface concentration, which is both wasteful and conducive to the production of undesirable side effects. A further advantage of this invention is consequently that DHN not only provides effective insect repellency at concentrations similar to those employed for DEET, DHN may be employed at concentrations up to and including neat DHN (i.e. the composition hereof may, if desired, contain 100% by weight DHN). The property of effective repellency in DHN provides many options for economical utilization of the DHN active ingredient over a wide range of levels of concentration.
In one embodiment of this invention, DHN is incorporated in effective amounts into a composition suitable for application to a host plant or animal, preferably to human skin. Suitable compositions include DHN and a vehicle or a carrier, preferably an alcohol such as iso-propyl alcohol, a lotion such as one of the numerous skin creams known in the art, or a silicaceous clay. Preferably the DHN is present in the insect repellent composition of the invention at a concentration of about 0.1% to 30% by weight, preferably about 0.5% to 20% by weight, and most preferably about 1% to 15% by weight.
In this invention, a variety of carriers or diluents for the above-disclosed dihydronepetalactones can be used. The carrier allows the formulation to be adjusted to an effective concentration of repellant molecules. When formulating a topical insect repellent, preferably, the repellant molecules are mixed in a dermatologically acceptable carrier. The carrier may further provide water repellency, prevent skin irritation, and/or soothe and condition skin. Factors to consider when selecting a carrier(s) for any formulation of insect repellent include commercial availability, cost, repellency, evaporation rate, odor, and stability. Some carriers can themselves have repellent properties.
For the present invention, the specific choice of a carrier, if any, to be utilized in achieving the desired intimate admixture with the final product can be any carrier conventionally used in insect repellent formulations. The carrier, moreover, should preferably also be one that will not be harmful to the environment. Accordingly, the carrier can be any one of a variety of commercially available organic and inorganic liquid, solid, or semi-solid carriers or carrier formulations usable in formulating insect repellent products. For example the carrier may include silicone, petrolatum, lanolin or many of several other well-known carrier components.
Examples of organic liquid carriers include liquid aliphatic hydrocarbons (e.g., pentane, hexane, heptane, nonane, decane and their analogs) and liquid aromatic hydrocarbons. Examples of other liquid hydrocarbons include oils produced by the distillation of coal and the distillation of various types and grades of petrochemical stocks, including kerosene oils, which are obtained by fractional distillation of petroleum. Other petroleum oils include those generally referred to as agricultural spray oils (e.g., the so-called light and medium spray oils, consisting of middle fractions in the distillation of petroleum and which are only slightly volatile). Such oils are usually highly refined and may contain only minute amounts of unsaturated compounds. Such oils, moreover, are generally paraffin oils and accordingly can be emulsified with water and an emulsifier, diluted to lower concentrations, and used as sprays. Tall oils, obtained from sulfate digestion of wood pulp, like the paraffin oils, can similarly be used. Other organic liquid carriers can include liquid terpene hydrocarbons and terpene alcohols such as alpha-pinene, dipentene, terpineol, and the like.
Other carriers include silicone, petrolatum, lanolin, liquid hydrocarbons, agricultural spray oils, paraffin oil, tall oils, liquid terpene hydrocarbons and terpene alcohols, aliphatic and aromatic alcohols, esters, aldehydes, ketones, mineral oil, higher alcohols, finely divided organic and inorganic solid materials.
Still other liquid carriers can include organic solvents such as aliphatic and aromatic alcohols, esters, aldehydes, and ketones. Aliphatic monohydric alcohols include methyl, ethyl, normal-propyl, isopropyl, normal-butyl, sec-butyl, and tert-butyl alcohols. Suitable alcohols include glycols (such as ethylene and propylene glycol) and pinacols. Suitable polyhydroxy alcohols include glycerol, arabitol, erythritol, sorbitol, and the like. Finally, suitable cyclic alcohols include cyclopentyl and cyclohexyl alcohols.
Conventional aromatic and aliphatic esters, aldehydes and ketones can be used as carriers, and occasionally are used in combination with the above-mentioned alcohols. Still other liquid carriers include relatively high-boiling petroleum products such as mineral oil and higher alcohols (such as cetyl alcohol). Additionally, conventional or so-called “stabilizers” (e.g., tert-butyl sulfinyl dimethyl dithiocarbonate) can be used in conjunction with, or as a component of, the carrier or carriers comprising the compositions of this invention.
Solid carriers, which can be used in the compositions of the present invention include finely divided organic and inorganic solid materials. Suitable finely divided solid inorganic carriers include siliceous minerals such as synthetic and natural clay, bentonite, attapulgite, fuller's earth, diatomaceous earth, kaolin, mica, talc, finely divided quartz, and the like, as well as synthetically prepared siliceous materials, such as silica aerogels and precipitated and fume silicas. Examples of finely divided solid organic materials include cellulose, sawdust, synthetic organic polymers, and the like. Examples of semi-solid or colloidal carriers include waxy solids, gels (such as petroleum jelly), lanolin, and the like, and mixtures of well-known liquid and solid substances which can provide semi-solid carrier products, for providing effective repellency within the scope of the instant invention.
Other carriers suitable for use in a composition of this invention, in addition to water, include one or more of the following:

    
    
        Acetone
        C10 ̃C18 Triglycerides
        C12 ̃C18 Acid Triglycerides
        Dipropyl, Dibutyl, Diisocetyl, Diisopropyl or Dimethyl Oxalate
        Cyclo(ethoxy)methicone
        Amyl, Methyl, Butyl, Ethyl, Ethoxyethanol, Ethoxydiglycol or Tetrahydrofurfuryl Acetate
        Ethoxydiglycol
        Kerosene
        Ethoxyethanol
        Diacetin
        Benzyl, Diacetone, Denatured ethyl, Tetrahydrofurfuryl or Oleyl Alcohol
        Benzyl Benzoate or Laurate
        Ethylene Carbonate
        Ethyl Hexanediol
        Oil of Bertholetta Excelsa Nut, Carthamus Tinctorius, Helianthus Annuus, Ricinus Communis, Aleurites Moluccana, Linum Usitatissimum, Cocos Nucifera, Zea Mays, Pinus Palustris, Sesamum Indicum, Glycine Soja, Helianthus Annuus, Prunus Amygdalus Dulcis, Olea Europaea, Elaeis Guineensis, Prunus Persica Kernel, Cucurbita Pepo, Brassica Campestris, Oryza Sativa, Oryza Saliva, Carthamus Tinctorius, Juglans Regia or Triicum Vulgare 
        Dibutyl Phthalate or Sebacate
        Furfural
        Butoxy-diglycol, -propanol or -ethanol
        Diethoxyethyl Succinate
        Diethyl Oxalate, Phthalate, Sebacate or Succinate
        n- or t-Butyl, Hexyl or Isopropyl Alcohol
        Glycofurol
        Gycol
        Butylene, Hexylene, Diethylene, Dipropylene, Pentylene, Propylene or Triethylene Glycol
        C6 ̃C20 linear, branched or cyclic alkane, alkanol or alkane polyol
        Butyloctanol
        Dihexyl, Diisobutyl, Diisodecyl, Ditridecyl, Dibutyl, Diisocetyl, Diisopropyl, Dipropyl or Diisoponyl Adipate
        Butyrolactone
        1,2,6-Hexanedol
        Caprylic, Capric, Lauric or Stearic Triglyceride
        Isoamyl, Isobutyl, Isopropy or Propyl Acetate
        Isobutoxypropanol
        Diisopropyl Sebacate
        Dimethoxydiglycol
        Isobutyl, Methyl or Stearyl Benzoate
        Isopropyl Laurate, Myristate, Palmitate or Stearate
        Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Benzoate
        Dimethyl Phthalate, Glutarate, Maleate, Adipate or Succinate
        Dimethyl Sulfone
        Dimethyl Ether
        Dimethyl Isosorbide
        Dioctyl Sebacate, Adipale, Phthalate or Succinate
        Methylethylketone
        3-Methoxybutanol
        Dipentene
        Methoxydigycol
        Diphenyl Methane
        Methoxy-ethanol, -isopropanol or -methylbutanol
        C4 ̃C400 polyethylene, polypropylene, polyethylene/ether or polypropylene/ether glycol
        perfluorodecalin
        Methylal
        Perfluorotetralin
        Pheroxyisopropanol
        Phenylpropanol
        Methyl Hexyl Ether
        Methylpropanediol
        Methyl Pyrrolidone
        Methyl Butyl Ketone
        Thiolanediol
        Toluene
        Propanediol
        Triacetin
        Tributyl Citrate
        Tributylcresylbutane
        propylene Carbonate
        Tricaprin
        Tricaprylin
        Trichloroethane
        Triheptanoin
        Trihydroxystearin
        Triisononanoin
        Tiisostearin
        Trilaurin
        Trilinolein
        Trilinolenin
        Trimethylhexanol
        Trimyristin
        Trioctanoin
        Triolein
        Tripalmitin
        Trisebacin
        Tristearin
        Triundecanoin
        Xytene
    
    


In addition to the above-mentioned materials, such as the liquid hydrocarbons, the carrier can contain conventional emulsifying agents which can be used for causing the dihydronepetalactone compounds to be dispersed in, and diluted with, water for end-use application.
Insect repellent compositions of the present invention containing the dihydronepetalactones may also contain adjuvants known in the art of personal care product formulations, such as thickeners, buffering agents, chelating agents, preservatives, fragrances, antioxidants, gelling agents, stabilizers, surfactants, emolients, coloring agents, aloe vera, waxes, other penetration enhancers and mixtures thereof, and therapeutically or cosmetically active agents.
Additionally, the compositions of the present invention may also contain other adjuvants such as one or more therapeutically or cosmetically active ingredients. Exemplary therapeutic or cosmetically active ingredients useful in the compositions of the invention include fungicides, sunscreening agents, sunblocking agents, vitamins, tanning agents, plant extracts, anti-inflammatory agents, anti-oxidants, radical scavenging agents, retinoids, alpha-hydroxy acids, emollients, antiseptics, antibiotics, antibacterial agents or antihistamines, and may be present in an amount effective for achieving the therapeutic or cosmetic result desired.
Additionally, the compositions of this invention may contain one or more other additives such as an antioxidant, an emulsion stabilizer, a preservative, a propellant, an emollient, a sunscreen agent, a surfactant, an emulsifying agent, a solubilizing agent and/or an ultraviolet light absorber. Examples of materials that may function as such additives are set forth below.
The compositions of this invention may include one or more materials that may function as an antioxidant, such as reducing agents and free radical scavengers. Suitable materials that may function as an antioxidant include one or more of the following:

    
    
        Acetyl Cysteine
        Ascorbic Acid
        Ascorbyl Palmitate or Stearate
        t-Butyl Hydroquinone
        cysteine
        Diamylhydroquinone
        Dicetyl, Dilauryl, Dimyristyl, Distearyl or Ditridecyl Thiodipropionate
        Erythorbic Acid
        2-Ethylhexyl, Lauryl, Myristyl, Palmitoyl or Stearyl 4-methoxycinnamate
        Ethyl Ferulate
        Ferulic Acid
        Hydroquinone
        p-Hydroxyanisole
        Hydroxylamine Sulfate
        Magnesium Ascorbate
        Magnesium Ascorbyl Phosphate
        Octyl Gallate
        Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Salicylate
        Octocrylene
        Phloroglucinol
        Polyethylene glycol ether of tocopherol
        Potassium Ascorbyl Tocopheryl Phosphate
        Potassium Sulfite
        Propyl Gallate
        Rutin
        Sodium Ascorbate
        Sodium Erythorbate
        Sodium Sulfite
        Sodium Thloglycolate
        Sorbityl Furfural
        Tertiary butyl 4-methoxy phenol
        Thiodiglycol
        Thiodiglycolamide
        Thioglycolic Acid
        Thiolactic Acid
        Thiosalicylic Acid
        Tocopherol
        Tocopheryl Acetate
        Tocopheryl Linoleate
        Tocopheryl Nicotinate
        Tocopheryl Succinate
        Tris(Nonylpheny)Phosphite
    
    


The compositions of this invention may also include one or more materials that may function as an emulsion stabilizer. These materials would not act as primary emulsifiers, but would prevent or reduce the coalescence of emulsified droplets. This could be accomplished, for example, by modifying the continuous or the disperse phase of the emulsion through electrical repulsion, from changes in viscosity, or from film formation on the droplet surface. Suitable materials that may function as an emulsion stabilizer include one or more of the following:

    
    
        Cetyl Alcohol
        Montmorillonite
        Aluminum Caprylate, Stearate, Laurate, Palmitate, Lanolate or Myristate
        C15 ̃C18 Glycol
        Dodecylhexadecanol
        H(OCH2CH2),OH where n=350 to 160,000
        Pectin
        Glucose Pentaacetate
        Glycol Oleate, Palmitate, Stearate or Ricinoleate
        (Alkyl)cellulose
        Hydroxyalkyl (alkyl)cellulose
        Calcium Laurate, Myristate or Stearate
        C10 ̃C50 alcohol such as cetyl, myristyl, stearyl, tallow or lauryl alcohol
        Polyvinyl Acetate
        Lanolin
        Styrene/maleic anhydride copolymer
        Xanthan gum
    
    


The compositions of this invention may also include one or more materials that may function as a preservative, which would prevent or retard microbial growth and thus protect the composition (or products made therefrom) from spoilage or from inadvertent contamination by the consumer during use. Suitable materials that may function as a preservative include one or more of the following:

    
    
        Ammonium Benzoate or Propionate
        Chloroxy enol
        Isobutylparaben
        o, m or p-Cresol
        Isodecylparaben
        Benzoic Acid
        Isopropyl Cresol, Paraben or Sorbate
        Benzotriazole
        Benzyl Alcohol
        Magnesium Benzoate
        Benzylparaben
        Dehydroacetic Acid
        Magnesium Propionate
        5-Bromo-5-Nitro-1,3-Dioxane
        Diazolidinyl Urea
        Magnesium Salicylale
        2-Bromo-2-Nitropropane-1,3-Diol
        Dibromopropamidine Diisothionate
        Butyl Benzoate
        Dimethyl Hydroxymethyl Pyrazole
        Butylparaben
        Dimethylol Ethylene Thiourea
        Calcium Benzoate, Salicylate, Sorbate, Paraben or Propionate
        Dimethyl Oxazolidine
        Methyl Hydroxyl Hydantoin
        Methyldibromo Glutaronitrile
        Methylisothiazolinone
        Methylparaben
        Ethylparaben
        Chlorhexidine Diacetate, Digluconate or Dihydrochloride
        Formaldehyde
        Glutaral
        Glyoxal
        Chloroacetamide
        Hexamidine
        Chlorobutanol
        Hexamidine Diparaben
        Phenol
        p-Chloro-m-Cresol
        Hexamidine Paraben
        Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Salicylate
        Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Benzoate
        Octocrylene
        Phenoxyethanol
        Chlorophene
        4Hydroxybenzoic Acid
        Phenoxyethylparaben
        P-Chlorophenol
        Hydroxymethyl Dioxoazabicyclooctane
        Phenoxyisopropanol
        Chlorothymol
        Imidazolidinyl Urea
        Phenyl Benzoate
        Phenyl Mercuric Acetate, Benzoate, Borate, Bromide or Chloride
        Potassium Salicylate, Sorbate, Benzoate, Propylparaben, Butylparaben, Ethylparaben, Methylparaben, Paraben, Phenoxide, o-Phenylphenate or Propionate
        Propionic Acid
        Propyl Benzoate
        Phenylparaben
        Propylparaben
        o-Phenylphenol.
        Silver Borosilicate
        Silver Magnesium Aluminum Phosphate
        Sorbic Acid
        Sodium Hydroxymethylglycinate, Methylparaben, Paraben, Phenolsulfonate, Phenoxide, o-Phenylphenate, Propionate, Propylparaben, Pyrithione, Salicylate, Sorbate, Benzoate, Butylparaben, p-Chloro-m-Cresol, Dehydroacetate, Ethylparaben, Formate or Hydroxymethane Sulfonate
        Zinc Pyrithione
    
    


The compositions of this invention may also include one or more materials that may function as a propellant, which are chemicals used for expelling products from pressurized containers (aerosols). The functionality of a propellant depends on its vapor pressure at ambient temperature and its compressibility. Liquids or gases can be used as propellants as long as the pressure developed within the container is safely below the container's bursting pressure under normal storage and use conditions. Suitable materials that may function as a propellant include one or more of the following:

    
    
        Butane
        CH3CClF2 
        Nitrogen
        Carbon Dioxide
        CH3CF2 
        Nitrous Oxide
        Dimethyl Ether
        Isobutane
        Pentane
        Ethane
        Isopentane
        Propane
        CH3CHF2 
    
    


The compositions of this invention may also include one or more materials that may function as an emollient, which is a cosmetic ingredient that maintains the soft, smooth, and pliable appearance of skin. The purpose of an emollient is to remain on the skin surface or in the stratum corneum to act as a lubricant, to reduce flaking, and to improve the skin's appearance. Suitable materials that may function as an emollient include one or more of the following:

    
    
        Acetylated Lanolin or Lanolin Alcohol
        Bisphenylhexamethicone
        Bertholetta Excelsa Nut Oil
        Caprylic/Capric Glycerides
        Butoxyethyl Stearate
        Caprylic/Capric/Succinic Triglyceride
        Acetylated Sucrose Distearate
        Acetyl Trihexyl Citrate
        Butyl Isostearate, Myristate, Oleate or Stearate
        caprylyl Glycol
        Acetyl Trioctyl Citrate
        Cetearyl Octanoate or Palmitate
        Prunus Armenlaca Kernel Oil
        Cetyl Acetate, Caprylate, Lactate, Laurate, Octanoate or Oleate
        Arachidyl Propionate
        C14 ̃C15 Alcohols
        Cetylarachidol
        Argania Spinosa Oil
        C12 ̃C28 Alkyl Acetate, Benzoate or Lactate or Octanoate
        Persea Gratissima Oil
        Orbignya Olelfera Oil
        Melissa Officinalis Seed Oil
        C24 ̃C28 Alkyl Methicone
        C12 ̃C13 Alkyl Octanoate
        Cetyl Glycol, Glycol Isostearate or Glycol Palmitate
        Benzyl Laurate
        Bis-Diglyceryl Polyacyladipate-1 or -2
        Camellia Kissi Oil
        Isostearyl, Myristyl, Lauryl, Isocetyl, Pentadecyl, Oleyl, Tridecyl or Undecyl Alcohol
        Isostearyl Glyceryl Ether
        Isostearyl Benzoate, Lactate, Neopentanoate, Octanoate, Palmitate or Myristate
        Methyl Stearate
        Rosa Moschata Seed Oil
        Hydroxycetylisostearate
        Isatis Tinctoria Oil
        Isoamyl Laurate
        Isobutyl Myristate, Palmitate, Pelargonate or Stearate
        Isopropyl Laurate, Myristate, Palmitate or Stearate
        Isotridecyl Isononanoate
        Myristyl Isostearate, Lactate, Neopentanoate, Octanoate or Propionate
        Actinidia Chinensis Seed Oil
        Isocetyl Isodecanoate, Palmitate or Stearate
        Lanolin
        Lanolin Oil or Wax
        Isodecyl Citrate, Hydroxystearate, Laurate, Myristate, Neopentanoate, Palmitate or Stearate
        Neopentyl Glycol Dicaprylate, Dicaprate, Dilaurate or Dioctanoate
        Nonyl Acetate
        Lauryl Glycol
        Octyl Acetoxystearate
        Lauryl Isostearate or Lactate
        Octyldecanol
        Octyldodecanol
        Octyldodecyl Benzoate, Lactate, Neopentanoate or Octanoate
        Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Benzoate Isohexadecane
        Methyl Benzoate, Caproate, Caprylate, Caprate or Glucose Dioleate
        Isohexyl Neopentanoate, Palmitate or Laurate
        Octyl Hydroxystearate, Laurate, Isopalmitate, Isostearate, Myristate, Neopentanoate, Oleate, Palmitate or Stearate
        Methyl Glucose Isostearate, Laurate, Sesquicaprylate, Sesquicaprate, Sesquilaurate or Sesquistearate
        Isopropyl Hydroxycetyl Ether
        Isopropyl Hydroxystearate, Isostearate, Lanolate, Laurate, Linoleate, Myristate or Oleate
        2-Oleamido-1,3-Octadecanediol
        Oleyl Acetate, Lactate or Oleate
        Methyl Hydroxystearate, Laurate, Isostearate, Myristate, Oleate, Palmitate or Pelargonate
        Isopropyl Palmitate, Isopropyl or Stearate
        Isosorbide Laurate
        Passiflora Eduls Oil
        Polyethyelene Glycol Glycerides
        Polyglyceryl Myristate, Oleate, Pentastearate or Ricinoleate
        Polyglyceryl Oleyl Ether
        Polyethylene Glycol Tricapryl Citrate, Tricetyl Citrate, Trilauryl Citrate, Trimyristyl Citrate or Tristearyl Citrate
        Polyethylene Glycol Castor Oil
        Pentaerythrityl Dioleate, Distearate, Stearate, Tetrabenzoate or Trioleate
        Polyglyceryl Sesquioleate, Stearate, Tetraoleate, Tetrastearate, Caprate, Caprylate, Decalinoleate, Laurate or Isopalmitate
        Propylene Glycol Hydroxystearate Stearate, Laurate, Linoleate, Myristate, Ricinoleate, Stearte, Oleate, Soyate or Caprylate
        Propylene Glycol Myristyl Ether or Myristyl Ether Acetate
        Sucrose Polyoleate, Polypalmate, Polystearate, Ricinoleate, Stearate, Triacetate, Polylaurate, Polylinoleate, Myristate, Oleate, Laurate or Palmitate
        Polypropylene Glycol Lauryl, Cetyl, Stearyl, Oleyl or Pentaerythrityl Ether
        Tridecyl Neopentanoate, Octanoate, Stearate or Isononanoate
        Stearyl Acetate, Benzoate or Lactate
        Stearyl Glycol Isostearate or Citrate
        Polypropylene Glycol/Polyethylene Glycol
        Trimethylolpropane or Propene
        Trioctyl Trimellitate
        Tris(Tributoxysiloxy)Methylsilane
    
    


The compositions of this invention may also include one or more materials that may function as a sunscreen agent. Under 58 Fed. Reg. 28194 (May 12, 1993), a sunscreen active ingredient is defined as an “ingredient that absorbs at least 85 percent of the radiation in the UV range at wavelengths from 290 to 320 nanometers, but may or may not transmit radiation at wavelengths longer than 320 nanometers.” Suitable materials that may function as a sunscreen agent include one or more of the following:

    
    
        Aminobenzoic Acid (“PABA”)
        Glyceryl Aminobenzoate (Glyceryl PABA)
        Oxybenzone (Benzophenone-3)
        Cinoxate
        Homosalate
        Octyl Dimethyl PABA
        Diethanolamine Methoxycinnamate
        2-Ethylhexyl, Lauryl, Myristyl, Palmitoyl, or Stearyl 4-methoxycinnamate
        Lawsone with Dihydroxyacetone
        Phenylbenzimidazole Sulfonic Acid
        Menthyl Anthranilate
        Red Petrolatum
        Digalloyl Trioleate
        Octocrylene
        Sulisobenzone (Benzophenone-4)
        Dioxybenzone (Benzophenone-8)
        Octyl Methoxycinnamate
        Titanium Dioxide
        Ethyl 4-[bis(Hydroxypropyl)]Aminobenzoate(Ethyl Dihydroxypropyl PABA)
        Octyl Salicylate
        Trolamine Salicylate
    
    


The compositions of this invention may also include one or more materials that may function as a surfactant, an emulsifying agent or a solubilizing agent. Such a material may be used to reduce surface tension, to form complex films on the surface of emulsified droplets, to create a repulsive barrier on emulsified droplets to prevent their coalescence, to retard physical changes in emulsions throughout during shelf-life or to cause a solute to become part of a micelle formed by a surfactant. Suitable materials that may function as a surfactant, an emulsifying agent or a solubilizing agent include one or more of the following:

    
    
        C50 ̃C650 linear or branched dihydroxy polyoxyethylene/polyoxypropylene block copolymer
        C50 ̃C650 branched polyhydroxy polyoxyethylene/polyoxypropylene block copolymer of ethylene diamine
        C12 ̃C330 ethoxylated alkyl phenol
        C16 ̃C140 polyethylene glycol ether of C12 ̃C60 alcohols
        Carboxylic acid esters of C12 ̃C330 ethoxylated alkyl phenol
        Ester of C12 ̃C40 Carboxlic Acid and C8 ̃C40 Polyethylene Glycol
        Ester of Caprylic or Capric Triglyceride and C8 ̃C40 Polyethylene Glycol
        Phosphoric acid esters of C12 ̃C330 ethoxylated alkyl phenol
        Phosphoric acid esters and diesters of C16 ̃C140 polyethylene glycol ether of C12 ̃C60 alcohols
        Abietic Acid
        Calcium Stearoyl Lactylate
        Cetethyl Morpholinium Ethosutfate
        Cetrimonium Bromide, Chloride, Methosulfate or Tosylate
        Cetyl Alcohol
        cetyl Dimethicone Copolyol
        Cetyl Glyceryl Ether/Glycerin Copolymer
        Cetyl Phosphate
        Cetearyl Glucoside
        Dextrin Behenate, Laurate, Myristate, Palmitate or Stearate
        Dicetyl Phosphate
        Diethytaminoethyl Laurate or Stearate
        Dimethyl Octynediol
        Dimyristyl Phosphate
        Glyceryl Arachidate, Behenate, Caprylate, Caprate, Cocoate, Erucate, Hydrogenated Rosinate, Hydroxystearate, Isopalmitate, Isostearate, Isotridecanoate/Stearate/Adipate, Lanolate, Laurate, Oleate, Linoleate, Linolenate, Oleate, Montanate, Myristate, Palmitate, Stearate, Palmitoleate, Ricinoleate or Uridecylenate
        Glycol Octanoate
        Hydrogenated Lecithin
        Hydrogenated Palm Glyceride
        Hydroxycetyl Phosphate
        Hydroxyethyl Glyceryl Oleate and/or Stearate
        Lanolin
        Laurtrimonium Chloride
        Lauryl Phosphate
        Lecithin
        Mannitan Laurate or Oleate
        Myristoyl Methylalanine
        Palmitic Acid
        Octoxyglyceryl Behenate or Palmitate
        Pelargonic Acid
        Pentaerythrityl Stearate
        Phosphatidylcholine
        Potassium Laurate, Myristate, Oleate, Lauryl Hydroxypropyl Sulfonate, Cetyl Phosphate, Lauryl Sulfate, Palmate, Palmitate, Ricinoleate or Stearate
        Sodium Palmate, Palmitate, Phthalate Stearyl Amide, Ricinoleate, Stearate, Stearyl Sulfate, Trideceth Sulfate, Tridecyl Sulfate, Undecylenate, Lauroyl Lactylate, Lauryl Phosphate, Myristate, Oleate, Oleoyl Lactylate, Behenoyl Lactylate, Caproyl Lactylate, Caprylate, Isostearoyl Lactylate or Laurate
        Propylene Glycol Behenate, Caprylate, Hydroxystearate, Isostearate, Laurate, Linoleate, Unolenate, Myristate, Oleate, Ricinoleate or Stearate
        Sorbitan Caprylate, Diisostearate, Dioleate, Distearate, Isostearate, Laurate, Oleate, Palmitate, Sesquiisostearate, Sesquioleate, Sesquistearate, Stearate, Triisostearate, Trioleate or Tristearate
        Raffinose Oleate
        Stearic Acid
        Stearoyl Lactylic Acid
        Stearyl Alcohol
        Sucrose Dilaurate, Distearate, Laurate, Myristate, Oleate, Palmitate, Polylaurate, Polylinoleate, Polyoleate, Polypalmate or Polystearate
        C32 ̃C82 polyethylene glycol ether of behenyl alcohol
        C20 ̃C106 polyethylene glycol ether of cetyl alcohol
        C28 ̃C80 polyethylene glycol ether of cetyl or oleyl alcohol
        C20 ̃C70 polyethylene glycol ether of cetyl and/or stearyl alcohol
        C20 ̃C80 polyethylene glycol ether of cholesterol
        C16 ̃C24 polyethylene glycol ether of decyl alcohol
        C40 ̃C80 polyethylene glycol ether of dihydrocholesterol
        C20 ̃C60 polyethylene glycol ether of isocetyl alcohol
        C18 ̃C30 polyethylene glycol ether of isodecyl alcohol
        C18 ̃C40 polyethylene glycol ether of isolauryl alcohol
        C20 ̃C120 polyethylene glycol ether of isostearyl alcohol
        C12 ̃C120 polyethylene glycol ether of glyceril caprate, caprylate, laurate, myristate, oleate, palmitate or stearate
        C14 ̃C100 polyethylene glycol ether of lauryl alcohol
        C16 ̃C24 polyethylene glycol ether of myristyl alcohol
        C20 ̃C70 polyethylene glycol ether of oleyl alcohol
        C10 ̃C100 polyethylene/polypropylene glycol ether of butyl alcohol
        C20 ̃C106 polyethylene/polypropylene glycol ether of cetyl alcohol
        C20 ̃C100 polyethylene/polypropylene glycol ether of decyl alcohol
        C14 ̃C100 polyethylene/polypropylene glycol ether of lauryl alcohol
        carboxylic acid ester of C20 ̃C120 polyethylene glycol ether of isostearyl alcohol
        Carboxylic acid esters of C14 ̃C100 polyethylene glycol ether of lauryl alcohol
        Carboxylic acid ester of C16 ̃C24 polyethylene glycol ether of myristyl alcohol
        Citric acid diesters of C14 ̃C100 polyethylene glycol ether of lauryl alcohol
        Isopropyl Laurate, Myristate, Palmitate or Stearate
        Lauric acid ester of C30 ̃C120 polyethylene glycol ether of sorbitol
        Octyl, Lauryl, Myristyl, Palmitoyl or Stearyl Salicylate
        Phosphoric acid ester of C20 ̃C106 polyethylene glycol ether of cetyl alcohol
        Phosphoric acid ester of C20 ̃C120 polyethylene glycol ether of isostearyl alcohol
        Phosphoric acid diesters of C14 ̃C100 polyethylene glycol ether of lauryl alcohol
        Phosphoric acid esters and/or diesters of C20 ̃C70 polyethylene glycol ether of oleyl alcohol
        Stearic acid ester of C15 ̃C30 polyethylene glycol ether of glycerin
        Stearic acid ester of C20 ̃C60 polyethylene glycol ether of isocetyl alcohol
        Stearic acid ester of C20 ̃C120 polyethylene glycol ether of isostearyl alcohol
        Diethanolamine salt of phosphoric acid ester of C20 ̃C106 polyethylene glycol ether of cetyl alcohol
        Diethanolamine salt of phosphoric acid ester of C20 ̃C70 polyethylene glycol ether of cetyl and/or stearyl alcohol
        Diethanolamine salt of Phosphoric acid ester of C20 ̃C70 polyethylene glycol ether of oleyl alcohol
        Disodium salt of citric acid ester of C14 ̃C100 polyethylene glycol ether of lauryl alcohol
        Disodium salt of phosphoric acid ester of C14 ̃C100 polyethylene glycol ether of lauryl alcohol
        Disodium salt of phosphoric acid ester of C20 ̃C70 polyethylene glycol ether of oleyl alcohol
        Monoethanolamine salt of phosphoric acid ester of C20 ̃C70 polyethylene glycol ether of cetyl and/or stearyl alcohol
        C12 ̃C120 polyethylene glycol diester of behenic, capric, caprylic, lauric, oleic, octanoic, palmitic or stearic acid
        Polyesters of C6 ̃C40 polyglycerin and behenic, capric, caprylic, lauric, oleic, octanoic, palmitic or stearic acid.
    
    


The compositions of this invention may also include one or more materials that may function as an ultraviolet light absorber to protect a product made from the composition from chemical or physical deterioration induced by ultraviolet light. UV absorbers, like sunscreen agents, have the ability to convert incident ultraviolet radiation into less damaging infrared radiation (heat). Suitable materials that may function as an ultraviolet light absorber include one or more of the following:

    
    
        Acetaminosalol
        3-Benzylidene Camphor
        Stilbenedisulfonate
        Allantoin PABA
        Disodium Distyrylbiphenyl Disulfonate
        Benzalphthalide
        Sulfonamide
        Drometrizole
        Benzophenone
        Benzylidene Camphor Sulfonic Acid
        Ethyl Dihydroxypropyl PABA
        Benzophenone substituted with one or more groups selected from hydroxyl, alkoxy, alkyl, halogen and sulfonate
        Benzyl Salicylate
        Ethyl Diisopropylcinnamate, Methoxycinnamate or Urocanate
        Bumetrizole
        Ethyl PABA
        Butyl Methoxydibenzoylmethane
        Butyl PABA
        Etocrylene
        Cinoxate
        Ferulic Acid
        Glyceryl Octanoate Dimethoxycinnamate
        Di-t-Butyl Hydroxybenzylidene Camphor
        Glyceryl PABA
        Digalloyl Trioleate
        Glycol Salicylate
        Diisopropyl Methyl Cinnamate
        Isoamyl p-Methoxycinnamate
        Disodium Bisethylphenyl Triaminotriazine
        Isopropylbenzyl Salicylate
        Isopropyl Dibenzoylmethane
        Octyl Triazone
        Sodium Urocanate
        Isopropyl Methoxycinnamate
        PABA
        Menthyl Anthranilate or Salicylate
        pentyl Dimethyl PABA
        Terephthaylidene Dicamphor Sulfonic Acid
        4-Methylbenzylidene Camphor
        Phenylbenzimidazole Sulfonic Acid
        Titanium Dioxide
        Octocrylene
        Polyacrylamidomethyl Benzylidene Camphor
        TriPABA Panthenol
        Octrizole
        Potassium Methoxycinnamate
        Urocanic Acid
        Octyl Dimethyl PABA
        Potassium Phenylbenzimidazole Sulfonate
        Octyl Methoxycinnamate or Salicylate
        Sodium Phenylbenzimidazole Sulfonate
    
    


A formulated mixture of one or more carriers, adjuvants and/or additives may be selected from the members of the groups thereof contained in the lists set forth above. They may also be selected from a subgroup of the members of the foregoing lists formed by omitting any one or more members from the whole groups as set forth in the above lists. As a result, a mixture of carriers, adjuvants and/or additives may in such instance not only be made from one or more members selected from any subgroup of any size that may be formed by all the various different combinations of individual members from the whole groups as set forth in the above lists, but may also be made in the absence of members that have been omitted from the whole groups to form the subgroup. The subgroup formed by omitting various members from the whole group in the list above may, moreover, be an individual member of a whole group such that a carrier, adjuvant and/or additive is provided in the absence of all other members of the whole groups except the selected individual member.
Dihydronepetalactones may be utilized in the present invention individually or combined in any proportion. As is conventional in the art, the desired amount of an insect repellent composition to be added to a given insect susceptible article with properties of insect repellency is determined by the nature of the product and other factors. These factors include both considerations of cost and the nature of the other ingredients in the insect repellent composition or repellent article, their amounts, and the desired repellency effect. In general, the composition of the repellent should contain sufficient amounts of active insect repellant material to be efficacious in repelling the insect from the host over a prolonged period of time (preferably, for a period of at least several hours).
The amount of each dihydronepetalactone of Formula I or mixtures thereof in an insect repellent composition or repellent article that contains one or more of the carriers, adjuvants and/or additives as described above will generally not exceed about 80% by weight based on the weight of the final product, however, greater amounts may be utilized in certain applications and this amount is not limiting. More preferably, a suitable amount of dihydronepetalactone will be at least about 0.001% by weight and preferably about 0.01% up to about 50% by weight; and more preferably, from about 0.01% to about 20% weight percent, based on the weight of the composition or article. Specific compositions will depend on the intended use.
The dihydronepetalactone repellent compositions of the present invention can be formulated without a carrier and be effective. More often, however, the insect repellent composition will include a carrier and contain about 0.001-50% weight of the disclosed compounds, and such compound is usually in intimate mixture with the carrier to bring the active material into position for repelling common insect pests, such as biting insects, wood-boring insects, noxious insects, household pests, and the like.
The compositions of the invention may be formulated and packaged so as to deliver the product in a variety of forms including as a solution, suspension, cream, ointment, gel, film or spray, depending on the preferred method of use. The carrier may be an aerosol composition adapted to disperse the dihydronepetalactone into the atmosphere by means of a compressed gas.
Desirable properties of a topical insect repellent article include low toxicity, resistance to loss by water immersion or sweating, low or no odor or at least. a pleasant odor, ease of application, and rapid formation of a dry tack-free surface film on the host's skin. In order to obtain these properties, the formulation for a topical insect repellent article should permit insect-infested animals (e.g., dogs with fleas, poultry with lice, cows with ticks, and humans) to be treated with an insect repellent composition of the present invention by contacting the skin, fur or feathers of such an animal with an effective amount of the repellent article for repelling the insect from the animal host. Thus, dispersing the article into the air or dispersing the composition as a liquid mist or fine dust will permit the repellent composition to fall on the desired host surfaces. Likewise, directly spreading of the liquid/semi-solid/solid repellent article on the host is an effective method of contacting the surface of the host with an effective amount of the repellent composition.
Embodiments of the present invention which may be used as a topical insect repellent articles, include (but are not limited to): colognes, lotions, sprays, creams, gels, ointments, bath and shower gels, foam products (e.g., shaving foams), makeup, deodorants, shampoo, hair lacquers/hair rinses, and personal soap compositions (e.g., hand soaps and bath/shower soaps).
This invention also relates to the use of dihydronepetalactone mixtures as insect repellents in a variety of articles, which are susceptible to attack by insects. These outdoor consumable products will generally, but not necessarily, comprise an insect repellent composition of the invention, but will contain an effective amount of dihydronepetalactone. Typical articles that can be improved by the use of dihydronepetalactones and mixtures thereof include, but are not limited to: air fresheners, candles, other scented articles, fibers, sheets, cloth [e.g., for clothing, nettings (mosquito netting), and other fabrics], paper, paint, ink, clay, woods, furniture (e.g., for patios and decks), carpets, sanitary goods, plastics, polymers, and the like.
The dihydronepetalactone compositions of this invention may be blended with polymers, which may also involve a controlled release systems. Compatible polymers may or may not be biodegradable. Exemplary polymers are high-density polyethylene or low-density polyethylene, biodegradable thermoplastic polyurethanes, biodegradable ethylene polymers, and poly(epsilon caprolactone) homopolymers and compositions containing the same as disclosed in U.S. Pat. Nos. 4,496,467, 4,469,613 and 4,548,764.
Dihydronepetalactones are particularly advantageous for use as repellent materials in preparations of the present invention for a variety of reasons.
First, the compounds are cost effective to produce, an important consumer consideration when choosing an effective repellent. Many commercially available repellent products are only effective in relatively concentrated form, including as much as 5-30% (or more) repellent in a carrier, based on total weight. U.S. Pat. No. 4,416, 881 to McGovern et al., for example, discloses repellent concentrations of 6.25-25% repellent in a carrier.
Secondly, the compounds are known natural compounds, thus overcoming concerns raised against synthetic chemicals such as DEET as the primary active ingredient in repellent compositions.
Finally, in addition to the natural repellent properties of the dihydronepetalactone mixtures thus prepared, the compositions also possess a unique and pleasant fragrance. The fragrance notes of the subject compounds make them useful in imparting, altering, augmenting or enhancing the overall olfactory component of an insect repellent composition or article, for example, by utilizing or moderating the olfactory reaction contributed by one or more other ingredients in the composition. Specifically, the dihydronepetalactones of the invention or mixtures thereof may be utilized to either mask or modify the odor contributed by other ingredients in the formulation of the final repellent composition or article, and/ or to enhance consumer appeal of a product by imparting a characteristic perfume or aroma. It is expected that the pleasant fragrance of dihydronepetalactones will possess much greater appeal to consumers than other insect repellent compounds, particularly DEET.
Dihydronepetalactones and their uses are also described in U.S. Ser. No. 10/349,865, filed Jan. 23, 2003, which is incorporated in its entirety as a part hereof for all purposes.
Where the composition of this invention is stated or described as comprising, including, containing, having, being composed of or being constituted by certain components, it is to be understood, unless the statement or description explicitly provides to the contrary, that one or more components in addition to those explicitly stated or described may be present in the composition. In an alternative embodiment, however, the composition of this invention may be stated or described as consisting essentially of certain components, in which embodiment components that would materially alter the principle of operation or the distinguishing characteristics of the composition are not present therein. In a further alternative embodiment, the composition of this invention may be stated or described as consisting of certain components, in which embodiment components other than impurities are not present therein.
Where the indefinite article “a” or “an” is used with respect to a statement or description of the presence of a component in the composition of this invention, it is to be understood, unless the statement or description explicitly provides to the contrary, that the use of such indefinite article does not limit the presence of the component in the composition to one in number.

## Claims

1. A sprayable insect repellent composition comprising a component (a) that comprises a dihydronepetalactone, or a mixture of dihydronepetalactone stereoisomers, as set forth by the formula:



a component (b) that comprises an aliphatic alcohol;
a component (c) that comprises a mixture of
(i) one or more members of the group consisting of (AI) cyclo(ethoxy) methicone, (BI) bisphenyl hexamethicone, (CI) C24 ̃C28 alkyl methicone, and (DI) cetyl dimethicone polyol;
(ii) one or more members of the group consisting of (AII) glycol ricinoleate, (BII) polyglyceryl ricinoleate, (CII) propylene glycol ricinoleate, and (DII) glyceryl ricinoleate; and
(iii) octyldodecanol;

a component (d) that comprises a C50 ̃C650 branched polyhydroxy polyoxyethylene/polyoxypropylene block copolymer of ethylene diamine;
a component (e) that comprises
(i) a mixture of butylene glycol, propylene glycol and methyl propanediol, and/or
(ii) a mixture of glycerol, methyl propanediol and isostearyl neopentanoate; and

a component (f) that comprises one or more members of the group consisting of aminobenzoic acid, glyceryl aminobenzoic acid, oxybenzone, sulisobenzone, dioxybenzone and titanium dioxide.

2. The composition according to claim 1 wherein component (b) is selected from one or more members of the group consisting of methyl, ethyl, normal-propyl, isopropyl, normal-butyl, sec-butyl, and tert-butyl alcohol.

3. The composition according to claim 1 wherein component (c)(i) comprises cyclo(ethoxy) methicone.

4. The composition according to claim 1 wherein component (c)(i) comprises cetyl dimethicone polyol.

5. The composition according to claim 1 wherein component (c)(ii) comprises polyglyceryl ricinoleate.

6. The composition according to claim 1 wherein component (c)(ii) comprises propylene glycol ricinoleate.

7. The composition according to claim 1 wherein component (e) comprises both components (e)(i) and (e)(ii).

8. The composition according to claim 1 formulated as a liquid.

9. The composition according to claim 1 formulated as an aerosol.