WO2017199145A1 - Insectifuges - Google Patents

Insectifuges Download PDF

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Publication number
WO2017199145A1
WO2017199145A1 PCT/IB2017/052797 IB2017052797W WO2017199145A1 WO 2017199145 A1 WO2017199145 A1 WO 2017199145A1 IB 2017052797 W IB2017052797 W IB 2017052797W WO 2017199145 A1 WO2017199145 A1 WO 2017199145A1
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WIPO (PCT)
Prior art keywords
compound
insect repellent
acid
composition
repellent composition
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Application number
PCT/IB2017/052797
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English (en)
Inventor
Homa IZADI
Walter Wilhelm Focke
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University Of Pretoria
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Application filed by University Of Pretoria filed Critical University Of Pretoria
Publication of WO2017199145A1 publication Critical patent/WO2017199145A1/fr
Priority to ZA2018/08045A priority Critical patent/ZA201808045B/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/18—Vapour or smoke emitting compositions with delayed or sustained release

Definitions

  • THIS INVENTION relates to insect repellents.
  • the invention relates to an insect repellent composition, to a method of preparing an insect repellent composition and to a method of repelling insects.
  • Insect is used to refer to insecta, arachnida and myriapoda, even though the inventors believe that the invention will find typical commercial application in the field of repellency of insecta, and in particular repellency of mosquitoes.
  • Insecta have a chitinous exoskeleton, a three-part body, three pairs of jointed legs, compound eyes and one pair of antennae.
  • Repellents are expected to satisfy several basic requirements such as commercial availability, low cost, absence of malodours, classification as a non-irritant and nontoxic material, high stability, and an acceptable evaporation rate in association with an adequate repellent effect for long-lasting effectiveness. Addressing the last one, i.e. to keep the rate at which a repellent is released from a repellent formulation under control at effective levels is still a great challenge faced by the repellent industry.
  • an insect repellent composition which includes at least a first compound and a second, different compound, at least the first compound being an insect repellent, the first compound and the second compound being capable of together forming a negative pseudo-azeotrope with a vapour composition at ambient pressure and temperature in which the first compound is present in a sufficiently high concentration to provide an insect repellent effect.
  • insect repellent composition is meant a composition which shows an insect repellent effect, or an insecticidal effect, or both an insect repellent effect and an insecticidal effect.
  • an “insect repellent” may be a substance that shows an insect repellent effect, or a substance that shows an insecticidal effect, or a substance which shows both an insect repellent effect and an insecticidal effect.
  • insect repellent effect is thus intended to include an insecticidal effect, and the term “repelling insects” may also cover killing insects.
  • the second compound may be a substance that shows an insect repellent effect, or a substance that shows an insecticidal effect, or a substance which shows both an insect repellent effect and an insecticidal effect.
  • the pseudo-azeotrope formed by the first compound and the second compound thus behaves in a fashion analogous to a higher boiling classic azeotrope, i.e. a negative azeotrope.
  • the vapour pressure of the insect repellent composition is lower than that expected for the individual constituents thereof, i.e.
  • the evaporation rate of the insect repellent composition into ambient air is lower that the evaporation rates of the constituents of the insect repellent composition at the same conditions of pressure and temperature.
  • the insect repellent composition of the invention is thus a liquid mixture that will evaporate continuously into ambient air, at a slower rate than pure ingredients thereof, and, importantly, without the composition of the liquid phase changing over time as the amount of liquid diminishes as a result of evaporation.
  • a key requirement for the formation of a negative pseudo-azeotrope is that interactions between unlike molecules of the first compound and the second compound in the composition should be much stronger than interactions between like molecules of the first compound and interactions between like molecules of the second compound. This may happen for example when the pure first compound and the pure second compound cannot form hydrogen bonds between molecules of their own kind but instead strong hydrogen bonding between molecules of the first compound and molecules of the second compound takes place.
  • the azeotrope composition represents a stable node when evaporation of the liquid into ambient air is considered, so that the liquid composition will over time, as the liquid evaporates, approach the pseudo-azeotrope composition irrespective of the initial composition of the liquid mixture.
  • a negative pseudo-azeotrope provides a reduced, constant evaporation rate for the insect repellent composition.
  • both the first compound and the second compound when evaporation is equilibrium controlled, evaporate together at a constant, reduced rate as a pseudo-azeotrope insect repellent composition (constant when the insect repellent composition is at a constant temperature and pressure), when compared respectively to the evaporation rate of a pure liquid of the first compound and a pure liquid of the second compound.
  • a negative pseudo- azeotrope liquid insect repellent composition it will thus take longer for a negative pseudo- azeotrope liquid insect repellent composition to fully evaporate, providing for a longer-lasting insect repellent effect.
  • the evaporation rate should still be high enough to provide sufficient vapour to the environment to provide an insect repellent effect.
  • the evaporation of the insect repellent composition into ambient air e.g. from the skin of a user, or from a textile coated or impregnated and worn by the user, or from an container holding the insect repellent composition or from a controlled release device, will typically not be entirely equilibrium controlled, so that equilibrium is established only at a vapour-liquid interface of the insect repellent composition. Nevertheless, even under these conditions it may be that the vapour has the same composition as the evaporating insect repellent composition, depending on evaporation conditions and transport properties of the insect repellent composition. Under non-ideal conditions, the insect repellent composition of the invention is thus more accurately described as a pseudo-azeotrope, and not as a classical azeotrope.
  • the insect repellent composition is typically a liquid composition or formulation, although crystallised negative pseudo-azeotrope compositions also fall within the scope of the invention.
  • the insect repellent composition may be suitable for direct application, such as topical application as a cream or a gel or a soap, to the skin of a user.
  • the insect repellent composition may instead or in addition be suitable for indirect application, e.g. in a polymeric matrix, deposited on a fabric or incorporated in the fibres of the fabric, in a microcapsule, in a bicomponent fibre, in textiles, in microporous polymers, as liquid vaporizer, and the like.
  • the insect repellent composition may include additives to improve the physical or chemical properties of the insect repellent composition.
  • additives include colorants, odorants, softeners, and the like.
  • any additive must not act as an azeotrope breaker, or if it has the tendency to act as an azeotrope breaker, it must be present in a sufficiently low concentration that it does not break the negative pseudo- azeotrope formed between the first compound and the second compound.
  • the first compound and the second compound may be capable of hydrogen bonding with each other.
  • the first compound and/or the second compound may respectively act as either a hydrogen acceptor and/or as a hydrogen donor in hydrogen bond formation between unlike molecules of the first compound with unlike molecules of the second compounds present in the insect repellent composition.
  • the first compound and the second compound may independently be an ester or an amine or an alcohol or may independently include an amide or an imide functional group or a carboxylic acid functional group or an ester group.
  • the first compound and the second compound may independently include more than one of a particular functional group in their structure or they may include more than one kind of functional group from the selection of functional groups set out hereinbefore.
  • the first compound, which is an insect repellent, may be a hydrogen acceptor.
  • the first compound which is an insect repellent, is a compound which includes one or more amide or imide functional groups.
  • the first compound may be selected from the group consisting of DEET (N,N- diethyl-meta-toluamide), DEET analogues, icaridin (picaridin), icaridin analogues, DEPA (N,N- diethyl phenylacetamide), IR3535, N-butyl-acetanilide, MGK Repellent 264, N- Methylneodecanamide, AI3-35765, AI3-37220 (SS220), and derivatives thereof.
  • Table 1 illustrates some of these amides and imides.
  • the first compound which is an insect repellent, may instead be a compound which includes an ester group.
  • the first compound may thus be a phthalate or a phthalate derivative, a benzyl benzoate or a benzyl benzoate derivative, a lactone, such as nepetalactone or a nepetalactone derivative, indalone or an indalone derivative.
  • Table 2 illustrates some suitable ester compounds based on phthalate derivatives.
  • Table 3 illustrates additional suitable ester-containing compounds including benzyl benzoate, indalone, MGK326, nepetalactone and anthranilate derivatives.
  • able 2 Some ester-containin com ounds suitable for use as insect re ellents
  • the first compound which is an insect repellent, includes both an ester and an amide group as for example in IR3535 listed in Table 1.
  • Insect repellents acting as hydrogen donors in hydrogen bond formation typically include compounds with at least one alcohol group or at least one carboxylic acid group or containing at least one alcohol group in addition to at least one carboxylic acid group. It is understood that the first compound, which is an insect repellent, may, in addition, feature functional groups other than those mentioned hereinbefore and such compounds are therefore not excluded from use as the first compound.
  • the first compound, which is an insect repellent may thus be a carboxylic acid, preferably a C8-C12 fatty acid, including cyclohexane propionic acid. Table 4 illustrates some suitable carboxyl
  • the first compound which is an insect repellent
  • Table 5 illustrates some diols suitable for use as insect repellents.
  • first compound which is an insect repellent
  • first compound which is an insect repellent
  • first compound include thymol, eugenol, spathulenol and their derivatives.
  • Table 6 illustrates thymol, eugenol and spathulenol.
  • Table 6 Thymol, Eugenol and Spathulenol
  • the first compound which is an insect repellent, may thus be a compound which includes one or more amide or imide functional groups, or may be a compound which includes an ester, or which is a phthalate or a phthalate derivative, benzyl benzoate or a benzyl benzoate derivative, a lactone or a lactone derivative, a nepetalactone or a nepetalactone derivative, indalone or an indalone derivative, a carboxylic acid, a C8-C12 fatty acid, or a diol or a diol derivative.
  • the first compound may thus be selected from the group consisting of DEET ( ⁇ , ⁇ -diethyl-meta-toluamide), DEET analogues, icaridin, icaridin analogues, DEPA (N,N-diethyl phenylacetamide), IR3535, N-butyl-acetanilide, MGK Repellent 264, N-Methylneodecanamide, AI3-35765, AI3-37220 (SS220), MGK Repellent 326, thymol, eugenol, spathulenol, dibutyl phthalate (DBP), dimethyl phthalate (DMP), dimethyl carbate (DMC), dioctyl phthalate, benzyl benzoate, indalone, nepetalactone, methyl anthranilate, ethyl anthranilate, cyclohexane propionic acid, a fatty acid containing between
  • the first compound may be selected from the group consisting of DEET ( ⁇ , ⁇ -diethyl-meta-toluamide), DEET analogues, icaridin, icaridin analogues, DEPA (N,N-diethyl phenylacetamide), IR3535, N-butyl-acetanilide, MGK Repellent 264, N-Methylneodecanamide, AI3-35765, AI3-37220 (SS220), MGK Repellent 326, thymol, eugenol, spathulenol, dibutyl phthalate (DBP), dimethyl phthalate (DMP), dimethyl carbate (DMC), dioctyl phthalate, benzyl benzoate, indalone, nepetalactone, methyl anthranilate, ethyl anthranilate, cyclohexane propionic acid, nonanoic acid, 2-e
  • the first compound is selected from the group consisting of IR3535, DEET and p-menthane-3,8-diol.
  • the first compound and the second compound form a negative pseudo-azeotrope.
  • an insect repellent composition in accordance with the invention is to be formulated for a specific insect repellent, e.g. DEET or IR3535 or p- menthane-3,8-diol, it is necessary to determine or select the second compound such that the first compound, which is an insect repellent, and the second compound together form a negative pseudo-azeotrope, that will evaporate into ambient air at a rate that is substantially, e.g. at least about 5% or at least about 10% or at least about 20% or at least about 30% or at least about 40% or at least about 50%, lower than the rate at which the first compound and the second compound evaporate at the same conditions.
  • important characteristics of the negative pseudo- azeotrope insect repellent composition of the invention include its potential to irritate skin, its toxicity and its pH. It would also be advantageous if the second compound possesses inherent insect repellency. It would be an additional advantage if some or all of the constituents of the insect repellent composition, and in particular the first compound and the second compound, are classified as GRAS (generally recognised as safe) by the US Food and Drug Administration.
  • the invention thus covers many insect repellent compositions, with the selection of the second compound in each instance firstly depending upon the ability of the second compound to form a negative pseudo-azeotrope with the first compound, i.e. on the ability of the molecules in the insect repellent composition to interact in such a way that they form a negative pseudo-azeotrope while retaining or enhancing insect repellent activity.
  • Selection of the second compound may also depend on the ability of the second compound to impart other desirable characteristics to the insect repellent composition depending on the intended use of the insect repellent composition.
  • the second compound must also be easily tolerated on the human skin, whereas if the insect repellent composition is to be used as a liquid vaporizer, it is probably only necessary for the second compound also not to be toxic and not to be irritating when inhaled or to have an unpleasant smell.
  • a very desirable additional property of the second compound would be if the second compound acts synergistically with the first compound by providing greater repellent or insecticidal activity for the insect repellent composition than the first compound and the second compound on their own might provide.
  • Another desirable property of the second compound would be if it provides the insect repellent composition with insecticidal effect, in combination with the first compound, even when the first compound and the second compound on their own might provide minimal insecticidal properties.
  • insecticidal effect at least in respect of mosquitoes
  • the insect repellent composition of the invention preferably, although not necessarily, shows an insecticidal effect (at least in respect of mosquitoes) in the vapour phase.
  • the second compound is an organic compound, which is a liquid under normal temperature and pressure conditions or under ambient conditions. It is possible that in one embodiment of the invention a particular compound is the first compound, which is in combination with another compound as the second compound, and that in another embodiment of the invention the same particular compound is the second compound which is then in combination with a different first compound.
  • the second compound may be a carboxylic acid, e.g. octanoic acid or nonanoic acid or decanoic acid or dodecanoic acid.
  • the second compound may be p-menthane-3,8-diol or citriodiol (trade name).
  • the second compound may be ethyl anthranilate.
  • the second compound has an insect repellent effect.
  • the first compound may thus be a primary insect repellent and the second compound may thus be a secondary insect repellent.
  • the first compound is the insect repellent IR3535 and the second compound is nonanoic acid.
  • the azeotropic molar ratio for IR3535 and nonanoic acid in the negative pseudo-azeotrope formed by these two compounds, at ambient conditions, and which is likely to be of commercial interest is about 75:25.
  • IR3535 and nonanoic acid however form a double pseudo-azeotrope, which is very rare indeed.
  • a second azeotropic molar ratio for IR3535 and nonanoic acid, at ambient conditions is about 10:90. This second azeotropic molar ratio defines a positive pseudo-azeotrope, and should thus be avoided.
  • Nonanoic acid is an insect repellent in its own right. It has been known for many years that some fatty acids, including hexanoic, heptanoic and nonanoic acids, exhibit high repellency properties. It has also been reported that acetic acid, pentanoic acid and hexanoic acid repel both biting and non-biting tsetse flies from hosts in the field. In general, the repellency effect of short chain fatty acids (CI - C9) is higher at higher concentrations, whereas longer chain fatty acids (C13 - C18) are more effective at lower concentrations In another embodiment of the invention, the first compound is the insect repellent DEET and the second compound is nonanoic acid.
  • the azeotropic molar ratio for DEET and nonanoic acid in the negative pseudo-azeotrope formed by these two compounds, at ambient conditions, is about 74:26.
  • the first compound which is an insect repellent, and/or the second compound, may initially be present in the insect repellent composition in any desired concentration.
  • the concentration of the first compound, and the concentration of the second compound will change as a result of differential evaporation rates until the insect repellent composition forms a negative pseudo-azeotrope of the first compound and the second compound.
  • the first compound and the second compound are from the beginning present in the insect repellent composition in their azeotropic molar ratio or nearly so.
  • the first compound and the second compound are preferably present in the insect repellent composition, as formulated, substantially in their azeotropic molar ratio.
  • the azeotropic molar ratio of the first compound and the second compound in the negative pseudo-azeotrope insect repellent composition of the invention may be such that the first compound is present in the insect repellent composition, when the insect repellent composition is at its azeotropic molar ratio, of at least about 40 molar % or at least about 50 molar % or at least about 60 molar % or at least about 70 molar %, e.g. about 74 - 75 molar % in the case of IR3535 or DEET as the first compound or primary insect repellent in a binary mixture with nonanoic acid as the second compound or secondary insect repellent.
  • a method of preparing an insect repellent composition including admixing at least a first compound and a second, different compound together to form an insect repellent composition, at least the first compound being an insect repellent, the first compound and the second compound being capable of together forming a negative pseudo-azeotrope with a vapour composition at ambient pressure and temperature in which the first compound is present in a sufficiently high concentration to provide an insect repellent effect.
  • the first compound which is an insect repellent
  • the second compound is a liquid additive miscible with the first compound.
  • Admixing of the first compound and the second compound thus typically comprises merely mixing two liquids together to form a homogenous miscible admixture.
  • the admixture is a liquid or gel or cream.
  • the admixture may also be in the form of a salt or homogenized solid mixture.
  • the first compound which is an insect repellent, may be as hereinbefore described.
  • the second compound may be as hereinbefore described.
  • the insect repellent composition may be as hereinbefore described.
  • the first compound and the second compound may be admixed in their azeotropic molar ratio to form a negative pseudo-azeotrope upon mixing.
  • in their azeotropic ratio is meant a ratio which is within about 20%, preferably within about 10%, more preferably within about 5%, even more preferably within about 2%, most preferably within about 1%, of their azeotropic ratio.
  • a method of repelling insects including vaporizing an insect repellent composition which includes a first compound, which is an insect repellent, and a second, different compound, the first compound and the second compound together forming a negative pseudo-azeotrope with a vapour composition at ambient pressure and temperature in which the first compound is present in a sufficiently high concentration to provide an insect repellent effect.
  • the insect repellent composition may be as hereinbefore described.
  • the first compound which is an insect repellent, may be as hereinbefore described.
  • the second compound may be as hereinbefore described.
  • the method may include applying the insect repellent composition as a liquid (or cream or gel) to the skin of a user, and allowing the insect repellent composition to evaporate over time from the skin of the user. Also within the scope of the invention is washing a user with a soap or personal care formulation which includes the insect repellent composition of the invention.
  • the method may instead, or in addition, include allowing the insect repellent composition to evaporate (or sublimate) over time from coated or impregnated textiles worn by the user, or from impregnated polymer based articles, such as bangles or anklets, worn by the user.
  • evaporating the insect repellent composition may include heating a supply of the insect repellent composition, e.g. electrically or with a flame.
  • the supply of the insect repellent composition may be a liquid supply in a container.
  • the container may be open to the atmosphere or may be provided with a wick.
  • the supply of the insect composition may be in the form of a substrate impregnated or infused with the insect repellent composition.
  • Figure 1 shows graphs of (a) the time dependence of the released weight fraction of a liquid phase comprising IR3535 and nonanoic acid and (b) the mole fraction of IR3535 remaining in the liquid phase as a function of the weight fraction of mixture released, where the indicated concentrations refer to the initial IR3535 content of the liquid phase;
  • Figure 2 shows a graph of thermogravimetric analysis mass loss rates for IR3535- nonanoic acid binary mixtures compared with those of pure IR3535 and pure nonanoic acid measured at 50°C;
  • Figure 3 shows graphs of the partial radial distribution functions of (a) either nitrogen or oxygen with methyl groups in IR3535, and (b) the carbonyl oxygen atom in the nonanoic acid molecule;
  • Figure 4 shows graphs of the partial radial distribution functions of H-0 (OH) in the nonanoic acid molecule at various initial concentrations of IR3535 in a liquid phase, where structures (a) and (b) are two typical conformations containing nonanoic acid;
  • Figure 5 shows graphs of the partial radial distribution functions involving nitrogen at various initial concentrations of IR3535 in a liquid phase
  • Figure 6 shows graphs of the mosquito protection provided by a negative pseudo azeotrope containing 75 mole % IR3535 and 25 mole % nonanoic acid, pure IR3535 and pure DEET tested 3 to 360 minutes after application;
  • Figure 7 shows a graph comparing the measured density of IR3535 and the calculated density in an AUA model
  • Figure 8 shows a graph comparing the reported density of ⁇ , ⁇ -dimethylacetamide and the calculated density in MedeA-GIBBS with an AUA model and the calculated density in MedeA-LAMMPS with a pcff+ model;
  • Figure 9 shows a flowchart used for the single phase properties of mixtures containing nonanoic acid and IR3535 during Monte-Carlo simulations performed by the MedeA-GIBBS software suit;
  • Figure 10 shows a graph of non-isothermal thermogravimetric analysis mass loss rates for DEET-nonanoic acid binary mixtures compared with those of pure DEET and pure nonanoic acid measured at 50°C;
  • Figures 11.1 - 11.27 show Derivative Weight-Temperature curves of experimental binary compositions and of their parent compounds; and Figures 12.1 - 12.8 show Derivative Weight-Temperature curves of selected experimental binary compositions, with their compositions altered towards their suspected negative azeotropic compositions, and of their parent compounds.
  • Experimental study 1 shows Derivative Weight-Temperature curves of selected experimental binary compositions, with their compositions altered towards their suspected negative azeotropic compositions, and of their parent compounds.
  • IR3535 is an effective and safe repellent. It comprises an ester and a tertiary amide functional group, both acting as hydrogen bond acceptors. IR3535 was thus selected as a suitable first compound, which is an insect repellent.
  • IR3535 A range of carboxylic acids as molecules capable of forming strong interactions with IR3535 were reviewed. Considering safety, pH value and as a consequence the potential to cause skin irritation, and inherent repellency effect, nonanoic acid was selected as a potential second compound. IR3535 was supplied by Merck Chemicals. Nonanoic acid was supplied by Sigma Aldrich. The reagents were used as received without further purification.
  • a typical characteristic of a classical azeotropic mixture is the constant composition during equilibrium distillation.
  • the typical process involved in the application of an insect repellent is open evaporation at temperatures well below the boiling point and not distillation.
  • a constant composition during open evaporation must thus be substantiated.
  • evolved gas analysis such as TG-FTIR can be used to investigate the evaporation mechanism of liquids, due to the low volatility of the insect repellent mixtures investigated, the small amount of vapour released at experimental conditions could not be sensed by a thermogravimetric analyser coupled to a Fourier-transform infrared spectrometer.
  • Table 7 Initial compositions of binary insect repellent compositions used in the oven test
  • the samples were transferred into evaporation dishes.
  • the volume of the mixture in each evaporation dish was 13.5 ⁇ 0. 1 mL.
  • the mass loss over time of the mixtures from the evaporation dishes were measured, using an electronic balance (XPS360 model with O.OOlg accuracy).
  • 10 ⁇ of each mixture was taken to prepare as a FTIR sample.
  • the mass after the FTIR measurement was measured again to correct for the portion of the sample lost during the FTIR spectroscopy.
  • the insect repellent compositions or mixtures in the evaporation dishes were thus evaporated continuously and samples for FTIR spectroscopy were removed periodically.
  • the liquid phase FTIR spectra were recorded at room temperature in the wavenumber range 4000 to 600 cm -1 at a resolution of 1 cm -1 .
  • the tests were carried out within 785 hours.
  • the measured FTIR were used to determine the composition of the samples in the evaporation dishes over time.
  • An inverse identification method was adopted to determine the composition of the unknown compositions from their known FTIR spectra.
  • test variable matrix of the training set comprised 24 different known mixtures of IR3535 and nonanoic acid in such a way that the mixtures were representatively distributed from 0 mole % to 100 mole % IR3535 as shown in Table 8.
  • Table 8 Compositions used for constructing the training set for inverse mapping
  • a cross validation test was adopted, in which one out of 24 training points is taken out of the training set. This is referred to as the validation point.
  • the PLSR is constructed with the rest of the 23 training points to estimate the composition of the validation point by introducing the spectrum of the validation point. This process was repeated in turn for the 24 training points and the average of the errors, for the PLSR constructed with 1 to 15 PLSR directions was computed.
  • the optimum number of the PLSR directions to result in the least estimated error was found to be 3.
  • thermogravimetric measurements were performed using a Perkin-Elmer TGA 4000 thermogravimetric analyser. A 180 ⁇ open aluminium pan was partially filled with 85 ⁇ 5 ⁇ g of sample. The sample was kept isothermal at 50°C for the duration of the test period. The high test temperature of 50°C was selected to maximise volatility and because it corresponds to the highest temperature at which insect repellents are expected to function during typical commercial use. The data was collected under nitrogen at a flow rate of 50 mL min-1 to prevent oxidation.
  • AUA force field An anisotropic united-atom (AUA) force field was used to describe intermolecular forces and intermolecular potential energy. Due to the lack of proper potentials in AUA for tertiary amides, parameters were added to the force field and the modified AUA force field was used after validating it against a set of tertiary amides as well as against the understudy molecule, i.e. I R3535. The added parameters are shown in Table 9 below and the validation graphs are presented in Figures 7 and 8.
  • Anopheles arabiensis mosquitoes were collected from a stock population cage in which both sexes have been maintained. The mosquitoes were maintained at 27°C, 70% relative humidity under a 12/12 hour light/dark photo period. Adults were provided with a 10% sucrose solution and were periodically blood fed on restrained pigs.
  • Repellency assays were performed with 3-5 day old female An. arabiensis that had been starved for 6 hours but previously fed on a 10% sucrose solution. Repellent activity was assessed by topical application of the test substance to a human's arm skin, and subsequent exposure of the treated area to unfed female mosquitoes. The number of landings relative to an untreated negative control was recorded, and the protection determined.
  • Paper cups 500 ml were modified by replacing the base of each cup with mosquito netting held in place with a rubber band and covering the mouth of the cup with transparent plastic film.
  • IR3535 mole fraction in the remaining liquid against the released mass fraction is depicted in Figure 1 (b). It is clear that the rate of release of a mixture with an initial composition of 10 mole % IR3535 is the highest while the rate of release of a mixture with an initial composition of 75 mole % IR3535 is the lowest.
  • the composition of the residual liquid was determined by an inverse analysis technique.
  • the IR3535 mole fraction in the remaining liquid was then plotted against mole fraction released as shown in Figure 1 (b).
  • Figure 1 (b) shows that most of the mole fractions of IR3535 in the remaining liquid initially either increases or decreases but then stabilises at a plateau value around the composition of 75 mole % IR3535. Convergence of the compositions around the same value for all mixtures irrespective of their initial concentration is a typical sign for a negative pseudo- azeotrope. It is also clear from Figure 1 (b) that the initial composition around 10 mole % IR3535 is stable and the composition is almost fixed during the test. Other mixture compositions however diverge around this plateau value. This observation indicates formation of a lower boiling pseudo-azeotrope mixture at this concentration.
  • thermogravimetric measurements of the IR3535-nonanoic acid binary mixtures compared with those of pure IR3535 and pure nonanoic acid evaporating into nitrogen at 50°C are shown in Figure 2.
  • Figure 1 clearly shows that evaporation was fastest for the mixture with the initial composition of 10 mole % IR3535 and the slowest for the mixture with the initial composition of 75 mole % IR3535. Almost 45% of the nonanoic acid evaporated in 120 hours, whereas only 23% of the IR3535 had evaporated over the same period of time.
  • the slower evaporation of IR3535 is not surprising since the reported vapour pressure of IR3535 is almost 10% of the vapour pressure of nonanoic acid at 20°C.
  • DEET-25 mole % nonanoic acid is depicted in Figure 10. This shows that the rate of mass loss of the 75 mole % DEET-25 mole % nonanoic acid mixture is lower than that of the pure components. In other words a binary composition of 75 mole % DEET and 25 mole % nonanoic also forms a negative pseudo-azeotrope.
  • the TGA scan for DEET-nonanoic acid binary mixtures was done from 30°C to 250°C at 2°C/min with a temperature gradient of 2°Cmin "1 .
  • RDFs Radial distribution functions involving the interaction sites in pure IR3535 and nonanoic acid are presented in Figure 3(a) and Figure 3 (b) respectively.
  • RDFs involving the hydroxyl hydrogen and oxygen in the nonanoic acid molecule and RDFs involving nitrogens in IR3535 in a series of mixtures with different concentrations of IR3535 are presented in Figure 4 and Figure 5.
  • Structures (a) and (b) are two typical conformations containing nonanoic acid, collected from the understudy ensemble, causing peaks at 3.7 and 3.9 A respectively.
  • the indicated concentrations refer to the initial IR3535 content of the liquid phase.
  • RDF Radial distribution functions
  • Figure 6 depicts that during the first two hours of exposure time, DEET shows better protection than IR3535. However after the third hour the protection of DEET suddenly drops, whereas the protection provided by IR3535 reduces at a lower rate. After four hours post application DEET does not show any protection and IR3535 was found to be only 62% as effective as the negative control.
  • the insect repellent solution prepared in accordance with the invention and containing 75 mole % IR3535 and 25 mole % nonanoic acid showed better, longer lasting repellency during the whole time lag study since it can provide full protection for four hours.
  • IR3535 and nonanoic acid also showed a lower boiling pseudo- azeotrope at 10 mole % IR3535 and 90 mole % nonanoic acid. Occurrence of this rare phenomenon of double pseudo-azeotropy is attributed to two different rearrangements of 0 molecular structures at different molar ratios of IR3535 and nonanoic acid.
  • a range of known insect repellent compounds were selected on the basis of their 5 chemical structures. The structure, boiling point and commercial sources of selected repellents are presented in Table 10. All the compounds were used as received, without further purification.
  • a set of fatty acids were selected on the basis of safety, intrinsic pH as a proxy for skin irritation potential and inherent insect repellence effect.
  • the structure and boiling point of selected fatty acids are presented in 11.
  • Table 12 Composition of the binary mixtures of repellents
  • HI-PT8 IR3535 Nonanoic acid 60% IR3535-40% C9 HI-PT9 IR3535 Citriodiol 61% IR3535- 39% Citriodiol
  • Citriodiol lcaridin 60% Citriodiol-40% lcaridin
  • Citriodiol HI-PT25 Citriodiol Dodecanoic acid 75% Citriodiol-25% C12
  • thermogravimetric analyzer TGA 4000 thermogravimetric analyzer.
  • a 180 ⁇ open alumina pan was partially filled with 100 ⁇ 1 ⁇ of sample.
  • the sample was heated from 20°C to 250°C, at a heating rate of 5°C min 1 .
  • the data was collected under N 2 at a flow rate of 50 mL min "1 to prevent oxidation.
  • the Derivative Weight-Temperature curves of binary mixtures and their parent compounds were compared.
  • the Derivative Weight-Temperature curves for all of the test binary mixtures, other than HI-PT19 and HI-PT20, are presented in Figures 11.1 - 11.27. Comparing the volatility of the mixture with the parent compounds provides an approach to estimate the pseudo-azeotrope compositions. Thus, where the curve of the binary mixture is above those of the parent compounds, negative pseudo-azeotropy may be suspected.
  • the pseudo-azeotropic status of the mixtures is presented in Table 13.
  • HI-PT16 60% Ethyl anthranilate-40% C8 Pseudo-azeotropy was not observed.
  • HI-PT17 58% Ethyl anthranilate-42% C9 Pseudo-azeotropy was not observed.
  • the eight samples were divided into two groups. Four samples were tested in the morning and four samples were tested in the afternoon. The tests were conducted based on the aforementioned WHO-2009 protocol. Full ethical approval was obtained from the Health Ethics Committee of the South African Medical Research Council (Record No: 26/2016). The volunteers filled an informed consent form. The repellency of formulations was tested for two hours.
  • One mL of the 20% ethanolic DEET solution on one arm of a volunteer was compared with the same amount of the candidate repellent on the other arm of the volunteer.
  • one mL of the candidate repellent was applied to one arm, and one mL of the DEET standard solution was applied to the other arm.
  • C w is the circumference of the wrist in cm
  • C e is the elbow- cubital fossa circumference in cm
  • D we is the distance in cm between C e and C w .
  • CPT Complete protection time
  • the WHO test set-up was modified as follows: Repellency was assessed for topical application of the test substance on a human's arm skin followed by subsequent exposure of the treated area to unfed female mosquitoes. Seven human volunteers were recruited. The number of landings relative to the untreated negative control was recorded, and the repellency percentage was determined. This was done over extended periods of time following the initial topical application.
  • Paper cups 500 mL was modified by replacing the base of the cup with mosquito netting held in place with a rubber band and covering the mouth of the cup with transparent plastic film. Twenty-five, unfed 5-day old, active host-seeking female An. arabiensis were selected from the test mosquitoes using an aspirator and introduced to the cup. The test area of the volunteers' skin was washed with scent-free soap and rinsed with water. An aliquot of 0.1 mL of the test formulation (for the test hand) was applied evenly to a 10 cm 2 length of the forearm skin and allowed to dry. Initially, the readiness of mosquitoes to probe was assessed by keeping an untreated arm in contact with the cup for 30 seconds. Mosquito activity can be observed through the transparent plastic film.
  • the cup was placed in contact with the treated forearm of volunteers.
  • the number of mosquitoes probing (attempting to feed on the volunteers, through the netting) was recorded.
  • the repellence effect was determined hourly for up to six hours post application for the test samples with promising results.
  • a new batch of mosquitoes was introduced to the same cup. The old mosquitoes were inserted into a new cup for further mortality study.
  • Table shows the repellent activity of the trial mixtures. All eight repellent mixtures provided full protection over six hours. HI-PT34 did not show repellency in the quick screen, while it showed full protection in the detailed study. Probably, the test sample was inadvertently washed from the hand of the volunteer during the quick screen of repellency.
  • Table 16 The repellency study of negative pseudo azeotrope mixtures.
  • control arm results are the number of total bites over the total number of mosquitoes in each cup on an untreated arm. All test samples provided full protection.
  • Table 1 shows the mortality of each test mixture. After putting the cup on the treated arm, the number of dead mosquitoes was counted. In the case of significant mortality, all mosquitoes were transferred to spare cups for further study. Samples HI-PT31, HI-PT14, Hl- PT15 and HI-PT32 caused high levels of mortality since the beginning of the test. This trend continued till the end of the test. Samples HI-PT29 and HI-PT35 did not show mortality in the beginning of the test, however after five to six hours after application to arm skin, their toxicity effect was activated. Sample HI-PT38 was not a strong killer. Sample HI-PT34 did not show any mortality, at least during the first six hours.
  • Table 17 The mortality study of negative pseudo azeotrope mixtures.
  • At least eight additional negative pseudo-azeotrope mixtures were thus identified on the basis of non-isothermal TGA methods. Quick screens showed promising repellency and mortality results for the mixtures. More detailed studies revealed that all identified insect repellent binary mixtures or compositions provide full protection against mosquitoes for at least six hours. Moreover, most identified insect repellent binary mixtures or compositions showed a significant mosquito mortality effect.
  • test formulations formed crystallised negative pseudo-azeotropes.
  • Ethyl anthranilate and lauric acid is one example of this category.
  • DEET and IR3535 also formed crystallised negative pseudo-azeotrope mixtures with long chain fatty acids (C14-C22). This class of azeotropic mixtures are particularly useful for inclusion in polymers, or to formulate solid soap, and the like.
  • negative pseudo-azeotrope mixtures which include an insect repellent or insecticide, as illustrated, can provide controlled-release insect repellent and/or insecticide formulations. Understanding the interactions between an insect repellent/insecticide and a potential compound for forming a pseudo-azeotrope with the insect repellent/insecticide provides one through careful selection of materials with a simple but effective means to provide a negative pseudo-azeotrope insect repellent/insecticide composition, e.g. by fundamental rearrangement in the structure of the repellents/insecticides by creating new hydrogen bonds or by breaking the structure.
  • IR3535 and nonanoic acid provide an example of such careful selection of materials since they can form a negative pseudo-azeotrope mixture at about 74- 75 mole % IR3535 and about 25-26 mole % nonanoic acid.
  • the illustrated IR3535-nonanoic acid synergistic insect repellent composition of the invention is significantly more effective in terms of repellency than the pure insect repellent compound (whether IR3535 or nonanoic acid), has a longer lasting effect than the pure insect repellent compound and also has an unexpected and very advantageous knockdown effect.
  • At least a negative pseudo-azeotrope insect repellent composition of IR3535 and nonanoic acid is also significantly more effective in terms of repellency than pure DEET, with other negative pseudo-azeotrope insect repellent compositions identified showing promise to also outperform pure DEET, and even to function as insecticidal compositions.

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Abstract

L'invention concerne une composition insectifuge qui comprend au moins un premier composé et un second composé différent. Au moins le premier composé est un insectifuge. Le premier composé et le second composé sont capables de former ensemble un pseudo-azéotrope négatif avec une composition de vapeur à pression et température ambiantes, le premier composé étant présent dans une concentration suffisamment élevée pour fournir un effet insectifuge. Dans certains modes de réalisation, la composition insectifuge peut également servir de composition insecticide.
PCT/IB2017/052797 2016-05-16 2017-05-12 Insectifuges WO2017199145A1 (fr)

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FR3079716A1 (fr) * 2018-04-05 2019-10-11 Evergreen Land Limited Composition insectifuge comprenant un acide gras insectifuge presentant entre 9 et 21 atomes de carbone
EP3763212A1 (fr) 2019-07-11 2021-01-13 SanderStrothmann GmbH Composition répulsive pour arthropodes

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3079716A1 (fr) * 2018-04-05 2019-10-11 Evergreen Land Limited Composition insectifuge comprenant un acide gras insectifuge presentant entre 9 et 21 atomes de carbone
EP3772952A4 (fr) * 2018-04-05 2022-03-02 Evergreen Land Limited Composition insectifuge comprenant un ou plusieurs acide(s) gras insectifuge presentant entre 9 et 21 atomes de carbone
EP3763212A1 (fr) 2019-07-11 2021-01-13 SanderStrothmann GmbH Composition répulsive pour arthropodes
WO2021005206A1 (fr) 2019-07-11 2021-01-14 Sanderstrothmann Gmbh Composition répulsive d'arthropodes
US11503831B2 (en) 2019-07-11 2022-11-22 Sanderstrothmann Gmbh Arthropoda repellent composition

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