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WO2025160240A1 - Formulations insectifuges et leurs procédés de fabrication et d'utilisation - Google Patents

Formulations insectifuges et leurs procédés de fabrication et d'utilisation

Info

Publication number
WO2025160240A1
WO2025160240A1 PCT/US2025/012699 US2025012699W WO2025160240A1 WO 2025160240 A1 WO2025160240 A1 WO 2025160240A1 US 2025012699 W US2025012699 W US 2025012699W WO 2025160240 A1 WO2025160240 A1 WO 2025160240A1
Authority
WO
WIPO (PCT)
Prior art keywords
emulsion
lactate
group
total weight
concentration ranging
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/012699
Other languages
English (en)
Inventor
David Aguilar
Craig MONTELL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2025160240A1 publication Critical patent/WO2025160240A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/064—Water-in-oil emulsions, e.g. Water-in-silicone emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/31—Hydrocarbons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/02—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings containing insect repellants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/21—Emulsions characterized by droplet sizes below 1 micron

Definitions

  • the disclosed invention is generally in the field of insect repellent formulations, and methods of making and using thereof.
  • the insect repellent DEET represents the gold standard for insect repellents, and has been available to the public since the 1957.
  • DEET Despite the common use of DEET as an insect repellent, DEET has limitations, including potential for eye irritation and rashes. DEET should not be ingested. Therefore, DEET should not be applied near the mouth or eyes. DEET can damage certain types of clothing (synthetics such as rayon and Spandex), and therefore should not be used underneath some types of clothing. Moreover, DEET has to be applied at high concentrations to provide adequate repellency effectiveness. For example, a 10% DEET repellent only lasts about 2 hours and 25% DEET repellent typically lasts about 5 hours (Lupi, E., Hatz, C. and Schlagenhauf, P. The efficacy of repellents against Aedes, Anopheles, Culex and Ixodes spp. - A literature review. Travel Medicine and Infectious Disease 11, 374-411 (2013)).
  • a repellent formulation is in the form of an emulsion which includes:
  • the emulsions can be microemulsions or nanoemulsions.
  • the repellent formulation can further include a cargo.
  • a repellent formulation is in the form of an emulsion and includes:
  • the repellent formulations can be prepared according to a method including the step of:
  • the repellent formulations can be used to repel arthropods, such as insects.
  • the formulations can repel arachnids.
  • a method of repelling an insect (or arachnid) includes the steps of:
  • step (a’) applying a repellent formulation, in the form of an emulsion, as described herein, to at least a portion of a skin surface of a subject; wherein following step (a’), the portion of the skin surface to which the emulsion was applied provides a complete protection time (CPT) of at least about 12 hours, and optionally provides a CPT of about 12 hours or longer.
  • CPT complete protection time
  • Figure 1 shows a non- limiting illustration of an inverted micelle, as found in a surfactant free microemulsion repellent formulation, where the micelle self-assembles from ethyl L-lactate and lauric acid and is surrounded by paraffin oil.
  • Figure 2 shows a non- limiting illustration of a slow-release mechanism of inverted micelles from paraffin oil, when the repellent formulation is applied onto a skin surface.
  • FIG. 3 shows a non- limiting illustration of an arm-in-cage method.
  • a cage contains mosquitoes at a density of about 30 mosquitoes per 30 cubic centimeters.
  • a forearm which has exposed skin that has been treated with a repellent formulation or is untreated (acting as a control), is inserted into the cage for a period of time.
  • complete protection time CPT is calculated from the time between repellent application to the exposed skin and insertion into the cage and the first confirmed mosquito bite.
  • Figure 4 shows a bar graph of percent blood fed (y-axis) as a function of weight percentage (1% - 10%) ethyl L-lactate (ELL) in the formulation applied to artificial skin and exposed to mosquitoes, where the control is 0% ELL.
  • Figure 5 shows a bar graph demonstrating repellent properties of ethyl L-lactate (ELL) and lauric acid (LA) using artificial blood feeders.
  • the y-axis is percent blood fed and the x-axis corresponds with five different tested formulations with different concentrations (wt %) of ELL and LA, individually and in combination, applied to artificial skin and exposed to mosquitoes, where the control is 0% ELL, 6% ELL alone in ethanol, 7% LA alone in ethanol, the combination of 6% ELL with 7% LA (“6% +7% LA”) in ethanol, and IR007 is 6% ELL plus 7% LA in light paraffin oil.
  • Figure 6 shows a bar graph of percent blood fed (y-axis) as a function of percentage (1% - 7%) lauric acid (LA) applied to artificial skin and exposed to mosquitoes, where the control is 0% LA.
  • “Generally regarded as safe for topical application to skin,” as used herein refers to substances that are considered safe for use in cosmetic products which are applied to the skin of a mammalian subject, such as a human. Such substances are generally understood in the field of cosmetics to be safe under the conditions of their intended use. In some instances, such substances may be reviewed by the Cosmetics Ingredient Review (CIR) and deemed safe for personal skincare products and categorized as safe to use, at specified concentrations, as may be applicable. See, for example: On-Line INFOBASE - ingredients - regulations - labeling - cosmetics - personal care products. International Journal of Toxicology 17(Suppl. 1 ): 1 — 3, 199s Copyright 1998 Cosmetic Ingredient Review, 1-3 (1998).
  • CIR Cosmetics Ingredient Review
  • CPT Consumer Protection Time
  • the effectiveness of a repellent is typically measured by its ability to provide protection for a specific period and indicates how long the repellent can effectively prevent landing, biting, and/or contact by the insect species with the treated area.
  • CPT can be calculated from the time between repellent application to the exposed skin and insertion into the cage and the first confirmed mosquito bite. A mosquito bite can be confirmed when after the bite occurs a second bite occurs within 30 minutes of the first bite.
  • the first bite is not a “confirmed mosquito bite” and is dismissed and volunteer continues testing. Subsequently, if the volunteer receives another bite at any point of the testing, this subsequent bite is considered the first bite and they leave their arm in the cage for up to at least 30 minutes or until a confirmation bite is recorded (if it occurs in less than 30 minutes) to determine if the subsequent bite is confirmed. The test continues until a set time period is reached without a confirmed bite or until the first confirmed bite is achieved. See, e.g. Luker, et al. 2023. Sci Rep 13, 1705.
  • Repellency is a measurement of the ability of a repellent to repel an insect, expressed as a percentage. Repellency (R%) is calculated using the formula:
  • R(%) ( c - ) X 100% where C is the number of insect (such as mosquito) bites) on a control and T is the number of insect bites on a repellent treated equivalent of the control.
  • C the number of insect (such as mosquito) bites
  • T the number of insect bites on a repellent treated equivalent of the control.
  • C the number of insect (such as mosquito) bites
  • T the number of insect bites on a repellent treated equivalent of the control.
  • C the number of insect (such as mosquito) bites) on a control
  • T the number of insect bites on a repellent treated equivalent of the control.
  • Alkyl lactate refers to a chemical compound derived from lactic acid, which is a naturally occurring organic acid.
  • alkyl refers to a hydrocarbon chain, which can vary in length.
  • “Fatty Acid,” as used herein refers to a chemical compound that consists of a hydrocarbon chain and a carboxylic acid group (-COOH) at one end.
  • the hydrocarbon chain may be saturated (with hydrogen atoms on the hydrocarbon chain) or unsaturated (having one or more carbon-carbon double bonds in the hydrocarbon chain).
  • Hydrophilic refers to substances, molecules, and agents having an affinity for and demonstrating solubility or dispersibility in water, facilitated by interactions such as hydrogen bonding and electrostatic attractions between the molecules and water molecules.
  • Lipophilic refers to substances, molecules, and agents that have an affinity for, or a tendency to dissolve in, lipids or fats. Such substances, molecules, and agents typically exhibit little to no solubility in water due to their non-polar nature.
  • Numerical ranges disclosed in the present application include, but are not limited to, ranges of temperatures, ranges of concentrations, ranges of times, amongst other ranges disclosed below.
  • the disclosed ranges disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein.
  • disclosure of a range of concentrations is intended to disclose individually every possible value that such a range could encompass, consistent with the disclosure herein.
  • a concentration range of about 5 wt% to 10 wt% also discloses each weight concentration within the range individually (i.e., 5, 5.6, 6, 6.8, 7, 7.1 , 8, 8.4, 9, 9.9,
  • a repellent formulation is in the form of an emulsion which includes:
  • Skin impermeable refers to the skin acting as a barrier blocking the passage, absorption, or entry of the base oil through the skin entirely. Skin impermeability is understood to be maintained by the outermost layer of the skin, known as the stratum comeum, which consists of dead skin cells and lipids that form a protective barrier.
  • Substantially skin impermeable refers to the skin acting as a barrier blocking the nearly all passage, absorption, or entry of the base oil through the skin, where less than about 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less by weight of the base oil applied to a skin surface is able to pass through skin.
  • the base oil is at a concentration ranging from about 50 wt% to 95 wt% or about 70 wt% to 90 wt% of the total weight of the emulsion, or at any individual concentration values or sub-ranges contained within the aforementioned ranges.
  • the base oil can be selected from a paraffin oil, mineral oil, petroleum, and silicone oil, or a combination thereof.
  • the paraffin oil does not permeate skin, is stable and does not become rancid at standard ambient temperature and pressure (SATP) (i.e. 25 °C and 1 atm).
  • SATP standard ambient temperature and pressure
  • the paraffin oil is a light paraffin oil, a heavy paraffin oil, or a combination thereof.
  • a “light paraffin oil” is a highly refined and purified paraffin oil having a viscosity of less than or equal to 0.86 g mL such as in the range of between about 0.83 to less than or equal to about 0.86 g mL -1 and is typically odorless.
  • a “heavy paraffin oil” is a paraffin oil having a viscosity of greater than about 0.86 g mL 1 , such as in a range of greater than about 0.86 to about 0.89 g mL -1 and typically has a slight odor.
  • the C2-C12 alkyl lactate is at a concentration ranging from about 2.5 wt% to 20 wt% or about 5 wt% to 10 wt% of the total weight of the emulsion, or at any individual concentration values or sub-ranges contained within the aforementioned ranges. In some instances, the C2-C12 alkyl lactate is at a concentration ranging from about 2.5 v% to 20 v% or about 5 v% to 10 v% of the total volume of the emulsion.
  • the C2-C12 alkyl lactate is selected from ethyl L-lactate, methyl lactate, myristyl lactate, cetyl lactate, lauryl lactate, menthyl lactate, and isopropyl lactate, or a combination thereof, optionally the C2-C12 alkyl lactate is ethyl L-lactate.
  • the Ce-Cis fatty acid is at a concentration ranging from about 2.5 wt% to 20 wt% or about 5 wt% to 15 wt% of the total weight of the emulsion, or at any individual concentration values or sub-ranges contained within the aforementioned ranges.
  • the Ce-Cis fatty acid is selected from lauric acid, oleic acid, myristic acid, and stearic acid, or combinations thereof, optionally the Ce-Cis fatty acid is lauric acid.
  • the repellent formulations are inverse emulsions (also referred to as reverse emulsions).
  • the emulsions or inverse emulsions contain micelles or droplets that have an average diameter on the nanometer scale and range from about 10 to 500 nanometers, about 10 to 450 nanometers, about 10 to 400 nanometers, about 10 to 350 nanometers, about 10 to 300 nanometers, about 10 to 250 nanometers, about 10 to 200 nanometers, about 10 to 150 nanometers, about 10 to 100 nanometers, about 10 to 75 nanometers, about 10 to 50 nanometers, or about 10 to 25 nanometers in diameter, or any individual value or sub-range contained therein.
  • Techniques for evaluating the size and diameters of micelles or droplets in an emulsion are known in the art.
  • the emulsions form a microemulsion having self-assembled inverted micelles therein (see Figure 1).
  • Microemulsions demonstrate thermodynamic stability and form spontaneously. In other words, the micelles contained therein self-assemble spontaneously.
  • the viscosity of the microemulsion is dependent on the dispersion of the micelles and the base medium in which they are dispersed in, wherein the heavier the base oil, the more viscous the microemulsion.
  • Microemulsions can be transparent, translucent, or milky in appearance depending on droplet size and concentration.
  • Microemulsions can be monodisperse or substantially monodisperse.
  • “Monodisperse,” refers to microemulsions where the micelles or droplets have a uniform size distribution and “substantially monodisperse,” refers to microemulsions where the majority (i.e., 90% or greater) of the micelles or droplets have a uniform size distribution.
  • the emulsion is a microemulsion, where the average diameter of the micelles or droplets are typically on the nanometer scale and range from about 10 to 100 nanometers, 10 to 75 nanometers, about 10 to 50 nanometers, about 10 to 25 nanometers, about 10 to 20 nanometers, or any individual value or sub-range contained therein.
  • the emulsion is a nanoemulsion.
  • nanoemulsions In contrast to microemulsions, nanoemulsions generally have higher dispersities than microemulsions and are typically not monodisperse. Nanoemulsions demonstrate kinetic stability and usually require steps, such as high shear mixing and/or sonication, for their formation. Nanoemulsions are prone to separation over time and surfactant(s) or emulsifying agent(s) can be used to stabilize them. Nanoemulsions can have a range of viscosities, from low to high, depending on composition and concentration.
  • the average diameter of the micelles or droplets contained therein can be on the nanometer scale and may range from about 20 to 400 nanometers in diameter, about 50 to 400 nm, about 100 to 400 nm, about 100 to 350 nm, about 100 to 300 nm, about 100 to 250 nm, about 100 to 200 nm, about 100 to 150 nm, or about 100 to 125 nm, or any individual value or sub-range contained therein.
  • the repellent formulations further include one or more surfactants and/or emulsifying agents that are generally regarded as safe for topical application to skin, such as human skin, therein.
  • Suitable surfactants include SPANTM 20-80 (such as SPANTM 80) and/or TWEEN® 20-80.
  • surfactants and/or emulsifying agents can include sodium lauryl sulfate (SLS), cocoamidopropyl betaine, cetearyl alcohol, ceteareth-20, sorbitan oleate, glyceryl stearate, PEG- 100 stearate, emulsifying wax NF, lecithin, beeswax, carbomer, dimethicone copolyol, and/or PEG- 8 dimethicone.
  • the repellent formulations are free or substantially free of any surfactants and/or emulsifying agents.
  • “Substantially free,” as used herein refers to a formulation having less than about 3%, 2%, 1%, 0.0%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less by weight of the total weight of the formulation.
  • the repellent formulation can further include a cargo selected from insect repellent agents (such as DEET), sun blocking agents, antibacterial agents, skin repair agents, wound repair agents, and fragrances, or a combination thereof.
  • the cargo is hydrophilic.
  • the cargo can be lipophilic and can be suspended in a continuous oil phase, such as formed by the base oil of the emulsion.
  • a repellent formulation is in the form of an emulsion and includes:
  • such a repellent formulation further includes one or more surfactants and/or emulsifying agents therein.
  • the repellent formulation is free or substantially free of any surfactants and/or emulsifying agents. “Substantially free,” as used herein refers to a formulation having less than about 3%, 2%, 1%, 0.0%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less by weight of the total weight of the formulation.
  • such a repellent formulation further includes a cargo selected from insect repellent agents, sun blocking agents, antibacterial agents, skin repair agents, wound repair agents, and fragrances, or a combination thereof.
  • the cargo can be hydrophilic.
  • the cargo can be lipophilic and can be suspended in a continuous oil phase, such as formed by the base oil of the emulsion.
  • the insect repellent agents may include or exclude DEET.
  • the base oil is selected from a paraffin oil (either heavy, light, or in its less processed state mineral oil) and ethyl L-lactate (ELL; a C2-C12 alkyl lactate) and lauric acid (LA; a Ce-Cis fatty acid) serve simultaneously as the emulsifier and the cargo.
  • a paraffin oil either heavy, light, or in its less processed state mineral oil
  • ELL ethyl L-lactate
  • LA lauric acid
  • the base oil such as paraffin oil
  • the paraffin oil can be an unscented (light) paraffin oil.
  • the alkyl lactate ELL is readily obtained from peas and red grapes (and other sources), is biodegradable, known to be FDA approved and safe for use in low concentrations with no irritation on skin.
  • the fatty acid LA can be derived from coconuts (and other sources), has been shown to have antibacterial properties, and is FDA approved and safe for use at up to 100% concentrations with no irritation on skin.
  • the repellent formulations are typically stable for at least one month, at least two months, three months, four months, five months, 6 months or longer, or at least one year, and optionally longer at a range of temperatures, such as temperatures ranging from about 10-70°C at 1 atm pressure.
  • the repellent formulations can remain stable at temperatures ranging from about 10-70 °C, such as from about 20-70 °C, from about 20-50 °C, from about 20-40 °C, or from about 20- 30 °C for time periods of at least 7 days, at least 4 weeks, or at least 6 months, or at least 1 year, optionally longer than 1 year, such as for at least 1.5 years, or at least 2 years at a temperature of about 70°C at 1 atm.
  • the micelles may separate. However, when thawed to a temperature within the temperature range at which the micelles are stable, the micelles selfassemble.
  • the formulations include one or more water-absorbing compounds to enhance stability, rheological properties, and/or overall functionality.
  • the water-absorbing compounds are alginates, chitosan derivatives, carboxymethyl cellulose (CMC), polyacrylates, or other hydrocolloids.
  • the water-absorbing compound is CMC.
  • the water absorbing compounds are incorporated into the formulation at concentrations ranging from about 0.1 wt% to 5.0 wt%, about 0.1 wt% to 4.5 wt%, about 0.1 wt% to 4.0 wt%, about 0.1 wt% to 3.5 wt%, or about 0.1 wt% to 3.0 wt%, or individual values or sub-ranges of the aforementioned ranges, in order to help absorb water and maintain structural integrity in varying humidity conditions.
  • the inclusion of one or more water-absorbing compounds, for example CMC, can reduce water mobility within the formulation, thereby mitigating phase separation and preventing viscosity shifts of about 5% - 65%, 5% - 60%, 5% - 55%, 5% - 50%, 10% - 50%, 15% - 50%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, or more, or individual values or subranges of the aforementioned ranges, from the baseline viscosity value under standard temperature and pressure (STP) conditions.
  • STP standard temperature and pressure
  • water-absorbing compounds can facilitate a uniform distribution of active components when the formulation is stored or applied under conditions involving temperature which are below about 5 °C or above about 40 °C, or humidity conditions which are below about 20% relative humidity (RH) or above about 80% RH.
  • the formulations may contain one or more stabilizers to improve the emulsion’s physical integrity and reduce phase separation.
  • the stabilizer is glycerol oleate, a safe nonionic surfactant or co-emulsifier.
  • Other suitable stabilizers are known.
  • the one or more stabilizers are incorporated into the formulation at concentrations ranging from about 0.1 wt% to 5.0 wt%, about 0.1 wt% to 4.5 wt%, about 0.1 wt% to 4.0 wt%, about 0. 1 wt% to 3.5 wt%, or about 0. 1 wt% to 3.0 wt%, or individual values or sub-ranges of the aforementioned ranges,.
  • the stabilizers may help form a stabilized interface between the continuous (oil) and dispersed (micellar) phases. Such stabilizers enhance the longterm shelf life of the formulation, particularly under elevated temperature or fluctuating humidity conditions.
  • the formulation may contain one or more antioxidants to reduce oxidative degradation of the formulation over time.
  • the one or more antioxidants can include tocopherols and/or butylated hydroxytoluene (BHT). Other suitable antioxidants are known.
  • the one or more antioxidants are incorporated into the formulation at concentrations ranging from about 0.05 wt% to 3.0 wt%, about 0.05 wt% to 2.5 wt%, about 0.05 wt% to 2.0 wt%, about 0.05 wt% to 1.5 wt%, or about 0.05 wt% to 1.0 wt%, or individual values or sub-ranges of the aforementioned ranges.
  • the addition of antioxidants can extend the product’s shelf life, preserve product color and/or odor, and maintain the potency of lipophilic ingredients (e.g., fatty acids and base oils).
  • the formulation contains one or more humectants to enhance user comfort by retaining moisture on the skin on which it is applied.
  • the one or more humectants can be glycerin and/or sorbitol. Other suitable humectants are known.
  • the one or more humectants are added at concentrations between about 0.5 wt% to 7.0 wt%, about 0.5 wt% to 6.5 wt%, about 0.5 wt% to 6.0 wt%, about 0.5 wt% to 5.5 wt%, about 0.5 wt% to 5.0 wt%, about 0.2 wt% to 5 wt% or about 0.1 wt% to 5 wt%, or individual values or sub-ranges of the aforementioned ranges.
  • the presence of humectants helps counteract dryness or irritation, improving the overall sensory attributes of the formulation during topical application.
  • the repellent formulations can be prepared according to a method including the step of:
  • the base oil, C2-C12 alkyl lactate and Ce-Cis fatty acid are the same as already described in Section II above.
  • the three components can be mixed in any order.
  • the C2-C12 alkyl lactate and Cs-Cis fatty acid are mixed first and then the combination may be added into the base oil.
  • the preparing step (a) is performed with heating. In some instances, heating is applied to heat the mixture to a temperature of at least about 70 °C or higher. Heating is typically applied to promote complete dissolution of all components and could also promote micelle formation.
  • Heating may be applied for any suitable amount of time needed to ensure dissolution of any solid components of the mixture, such as for a period of at least about 5 seconds to about five minutes, or longer.
  • the length of heating time can be impacted by the volume of the mixture.
  • the heating can applied for a short period of time ranging from about 30 to 60 seconds.
  • heating is not performed using a water-based heating bath to avoid or minimize exposure of the mixture to water vapor. In the event that a water bath is used, the contents can be sealed and vented to prevent or minimize exposure to water vapor.
  • the emulsion formed can further include a cargo and the method further includes adding the cargo into the mixture of the C2-C12 alkyl lactate, the Ce-Cis fatty acid, and the base oil.
  • the cargo is selected from insect repellent agents, sun blocking agents, antibacterial agents, skin repair agents, wound repair agents, and fragrances, or a combination thereof.
  • the cargo is hydrophilic.
  • the cargo can be lipophilic and can be suspended in a continuous oil phase, such as formed by the base oil of the emulsion.
  • a step (b) of sonicating and/or shaking the emulsion formed can be performed to promote formation or increase rate of the formation of micelles.
  • the method further includes a step (c) of heating the formed emulsion to promote formation or increase the rate of formation of micelles.
  • This heating may be a continuation of the heating applied for purposes of dissolution of any solid components of the mixture, where the heating may be continued to be applied to the mixture after all solid components have been dissolved.
  • heating is applied to heat the mixture to a temperature of at least about 70 C or higher. Heating may be applied for any suitable amount of time needed to promote formation or increase the rate of formation of the self-assembled micelles, such as for a period of time ranging from about 10 to 90 seconds, 20 to 60 seconds, or 30 to 60 seconds.
  • the mixture further includes at least one surfactant and/or emulsifying agent and the mixture can be sonicated, typically with cooling (such as by exposing the mixture to an ice-water bath or other cooling solution).
  • the at least one surfactant can include SPANTM 20-80 (such as SPANTM 80) and/or TWEEN® 20-80.
  • surfactants and/or emulsifying agents include, without limitation, sodium lauryl sulfate (SLS), cocoamidopropyl betaine, cetearyl alcohol, ceteareth-20, sorbitan oleate, glyceryl stearate, PEG- 100 stearate, emulsifying wax NF, lecithin, beeswax, carbomer, dimethicone copolyol, and/or PEG- 8 dimethicone.
  • SLS sodium lauryl sulfate
  • cocoamidopropyl betaine cetearyl alcohol
  • ceteareth-20 ceteareth-20
  • sorbitan oleate glyceryl stearate
  • PEG- 100 stearate PEG- 100 stearate
  • emulsifying wax NF emulsifying wax NF
  • lecithin beeswax
  • beeswax carbomer
  • the surfactant and/or emulsifying agent may be present at weight concentrations in a range from about 0.01 wt% to 30 wt% based on the total weight of the mixture, as well as any individual weight percentage or sub-range contained within.
  • the sonication can be performed with an ultrasonic probe, where the probe tip is placed in the mixture.
  • sonication is not applied by means of an ultrasonic water bath.
  • the ultrasonic probe is typically pulsed and each pulse can have an amplitude of about 40% and/or the ultrasonic probe is pulsed with a plurality of pulses having about 3 seconds of sonication time and about 3 seconds of no sonication time per pulse. Other amplitudes and pulse times are possible.
  • the amplitude can be in a range from about 15 to 50% or 20 to 40% and the pulse time may range from about 1 to 5 seconds or 2 to 4 seconds, as well as individual values or sub-ranges contained within the aforementioned ranges.
  • the repellent formulations can be used to repel arthropods, such as insects.
  • the formulations can repel arachnids.
  • the repellent formulations can be used to repel one or more types of insects, such as fleas, ticks, mites, mosquitoes, flies, lice, blowflies, bed bugs, stable flies, hom flies, or black flies, and combinations thereof.
  • arachnid is a spider.
  • the mosquito is a blood- feeding species from any of the known Aedes or Anopheles subspecies, or may be from other species including, without limitation, Culex and Culiseta, and their respective subspecies.
  • the mosquito is an Aedes aegypti or Anopheles stephensi mosquito.
  • a method of repelling an insect includes the steps of:
  • step (a’) applying a repellent formulation, in the form of an emulsion, as described in Section II above, to at least a portion of a skin surface of a subject; wherein following step (a’), the portion of the skin surface to which the emulsion was applied provides a complete protection time (CPT) of at least about 12 hours, and optionally provides a CPT of at least about 12 hours.
  • CPT complete protection time
  • the subject can be any mammal.
  • the subject is a human.
  • the mammal is a livestock or farm animal (such as a cow, horse, etc.) or can be a domesticated animal (such as a dog, cat, etc.).
  • the complete protection time (CPT) is provided for at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours, or longer.
  • the complete protection time (CPT) is provided for a period of time ranging from at least about 12 to 24 hours, or individual time values or sub-ranges contained within the aforementioned range.
  • the arm-in-cage method involves step 1 , where a cage containing mosquitoes, such as at a density of about 30 mosquitoes per 30 cubic centimeters; followed by step 2, inserting a forearm, which has exposed skin that has been treated with the repellent formulation to be tested, or is untreated (acting as a control), into the cage for a period of time.
  • the complete protection time is calculated from the time between repellent application to the exposed skin and insertion into the cage and the first confirmed mosquito bite.
  • a mosquito bite can be confirmed when after the bite occurs a second bite occurs within 30 minutes of the first bite. If a second bite does not occur within 30 minutes of the first bite, the first bite is not a “confirmed mosquito bite” and is dismissed and volunteer continues testing. Subsequently, if the volunteer receives another bite at any point of the testing, this subsequent bite is considered the first bite and they leave their arm in the cage for up to at least 30 minutes or until a confirmation bite is recorded (if it occurs in less than 30 minutes) to determine if the subsequent bite is confirmed. The test continues until a set time period is reached without a confirmed bite or until the first confirmed bite is achieved. See, e.g. Luker et al. 2023. Sci Rep 13, 1705.
  • the repellent formulations demonstrate a Repellency (7?%) of at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or up to 100%. In some instances, the repellency ranges from about 25 to 100%, 50 to 100%, or 75 to 100%, or any individual percentage value or sub-range contained within the aforementioned ranges.
  • the repellent formulations can be stored inside a container that blocks out or substantially blocks ambient light from reaching the formulation. “Substantially blocks,” refers to blocking out at least about 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% of ambient light present outside of the container.
  • An emulsion comprising:
  • the base oil is selected from the group consisting of paraffin oil, mineral oil, petroleum, and silicone oil, and a combination thereof.
  • the base oil is paraffin oil, and wherein the paraffin oil is a light paraffin oil, a heavy paraffin oil, and a combination thereof.
  • microemulsion of paragraph 9 wherein the microemulsion is an inverse microemulsion.
  • the emulsion further comprises (iv) a cargo, wherein the cargo is hydrophilic and is selected from the group consisting of insect repellent agents, sun blocking agents, antibacterial agents, skin repair agents, wound repair agents, and fragrances, or a combination thereof.
  • emulsion of any one of paragraphs 1-14 wherein the emulsion further comprises one or more water- absorbing compounds optionally selected from the group consisting of carboxymethyl cellulose (CMC), alginate, chitosan, polyacrylates, and combinations thereof.
  • CMC carboxymethyl cellulose
  • alginate alginate
  • chitosan alginate
  • polyacrylates polyacrylates
  • emulsion of any one of paragraphs 1-16 wherein the emulsion further comprises at least one stabilizer optionally selected from the group consisting of glycerol oleate, sorbitan oleate, and combinations thereof.
  • the at least one stabilizer is present at a concentration ranging from about 0.1 wt% to 5.0 wt%, about 0.1 wt% to 4.5 wt%, about 0.1 wt% to 4.0 wt%, about 0.1 wt% to 3.5 wt%, or about 0.1 wt% to 3.0 wt% of the total weight of the emulsion.
  • An emulsion comprising: a base oil which is a paraffin oil; a C2-C12 alkyl lactate at a concentration ranging from about 5 wt% to 10 wt% of the total weight of the emulsion or about 5 v% to 10 v% of the total volume of the emulsion; and a Ce-Cis fatty acid at a concentration ranging from about 5 wt% to 15 wt% of the total weight of the emulsion, wherein the emulsion is an inverse microemulsion.
  • paraffin oil comprises a light, a heavy paraffin oil, or a combination thereof.
  • C2-C12 alkyl lactate is selected from the group consisting of methyl lactate, myristyl lactate, cetyl lactate, lauryl lactate, menthyl lactate, and isopropyl lactate, or a combination thereof.
  • the emulsion further comprises a cargo, wherein the cargo is hydrophilic and is selected from the group consisting of insect repellent agents, sun blocking agents, antibacterial agents, skin repair agents, wound repair agents, and fragrances, or a combination thereof.
  • the at least one surfactant is selected from the group consisting of SPANTM 80, sodium lauryl sulfate (SLS), cocoamidopropyl betaine, cetearyl alcohol, ceteareth-20, sorbitan oleate, glyceryl stearate, PEG- 100 stearate, emulsifying wax NF, lecithin, beeswax, carbomer, dimethicone copolyol, PEG-8 dimethicone, and combinations thereof.
  • SLS sodium lauryl sulfate
  • cocoamidopropyl betaine cetearyl alcohol
  • ceteareth-20 ceteareth-20
  • sorbitan oleate glyceryl stearate
  • PEG- 100 stearate emulsifying wax NF
  • lecithin beeswax
  • beeswax carbomer
  • dimethicone copolyol PEG-8 dimethicone
  • a method of repelling an insect or an arachnid comprising the steps of: (a’) applying the emulsion of any one of paragraphs 1-28 to at least a portion of a skin surface of a subject; wherein following step (a’), the portion of the skin surface to which the emulsion was applied provides a complete protection time of at least about 9 hours, optionally at least about 10 hours.
  • insect or arachnid is selected from the group consisting of a mosquito, tick, spider, bed bug, stable fly, horn fly, and black fly, and combinations thereof.
  • the mixture was heated to 70 °C on a hotplate for 5 minutes.
  • FIG. 3 shows an schematic of the arm-in-cage method.
  • CPT Complete Protection Time
  • the 6% ELL / 7% LA unscented paraffin oil (light) repellent formulation did not require any surfactants to create micelles. Instead, in this formulation ELL acts as a solvent; ELL is slightly amphiphilic, and is stable at high temperatures. Without being bound by theory, it is believed that the non-polar ends of ELL and LA can interact while the polar ends of ELL congregate forming micelles. The self-assembled micelles were then slowly introduced into the paraffin oil to provide a microemulsion which is stable in a wide range of temperatures, such as ranging from about 20°C until about 70°C, at 1 atm. Due to its self-assembling nature, even if the solution is destabilized through freezing, it can reform itself into a stable microemulsion once it reaches its stable temperature range.
  • Nanoemulsions can be prepared with the ingredients of Table 1 above and a surfactant. An exemplary method of preparation is described below.
  • Nanoemulsions 10 mL 6 wt% ELL / 7% LA nanoemulsions were prepared from SPANTM 80 (Sigma Aldrich in liquid form) and the ingredients listed in Table 1 using the following steps:
  • the vial was placed in the cold water bath and the ultrasonic probe was positioned in the vial.
  • the nanoemulsions include a surfactant and a formed using sonication. Such nanoemulsions can also be evaluated for their ability to repel Aedes aegypti mosquitoes using arm-in-cage studies, such as those discussed in Example 1A, and using an arm-in-cage method (Figure 3). Testing under such conditions, the nanoemulsions would be expected to provide CPT times similar to the microemulsions, such as IR007. CPT times would be expected to remain consistent since the active components, such as ethyl L-lactate (ELL) and lauric acid (LA), are the same.
  • active components such as ethyl L-lactate (ELL) and lauric acid (LA) are the same.
  • Example 2 Evaluation of Ethyl L-Iactate (ELL) alone, Lactic acid (LA) alone, combinations of ELL and LA (in ethanol or oil) tested on Artificial Skin
  • Tests were conducted on artificial skin, which was integrated into a blood feeder system.
  • Artificial skin is a membrane made of a dessicated chitosan mixture that absorbs hydrophilic compounds when rehydrated. This apparatus holds approximately 2 mL of blood, maintaining it at a temperature of 36°C to mimic human conditions. Due to the risk of coagulation, tests were limited to a maximum of 20 minutes.
  • the following five formulations were tested: The Control was ethanol (alone) (containing 0% ELL); 6% ELL alone in ethanol; 7% LA alone in ethanol; 6% ELL and 7% LA in light paraffin oil (referred to as “IR700”); and the combination of 6% ELL and 7% LA in ethanol. Ethanol was chosen as a solvent based on its ability to solubilize LA.
  • Figure 5 shows a bar graph demonstrating repellent properties of ethyl L-lactate (ELL) and lauric acid (LA) using artificial blood feeders.
  • the y-axis is percent blood fed and the x-axis corresponds with the 5 different tested formulations described above.
  • Tests were conducted on artificial skin, which was integrated into a blood feeder system.
  • Artificial skin is a membrane made of a dessicated chitosan mixture that absorbs hydrophilic compounds when rehydrated. This apparatus holds approximately 2 mL of blood, maintaining it at a temperature of 36°C to mimic human conditions. Due to the risk of coagulation, tests were limited to a maximum of 20 minutes.
  • ELL formulations were prepared and applied directly to the artificial skin. A control having no ELL was also prepared.
  • the artificial skin treated with the above samples was exposed to Aedes aegypti mosquitoes and the percent blood fed was evaluated.
  • Ethyl laurate was tested as a substitute for lauric acid in a paraffin oil base combined with ethyl lactate.
  • Formulations containing about 5-10 wt% ethyl laurate, 5-10 wt% ethyl lactate, and 80-90 wt% paraffin oil were prepared and evaluated via artificial feeders and arm-in-cage assays. Although initial findings with artificial blood feeders were promising, this ethyl laurate- based emulsion proved ineffective in arm-in-cage assays.
  • the first mosquito bites occurred within approximately 3 minutes of introducing the treated arm into a cage of Aedes aegypti mosquitoes.

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Abstract

L'invention concerne des compositions répulsives et leurs procédés de fabrication et d'utilisation. Par exemple, de telles compositions répulsives peuvent être formées à partir d'une combinaison d'un lactate d'alkyle, d'un acide gras et d'une huile de base qui forment une émulsion pouvant être utilisée, par exemple, pour repousser divers insectes, tels que des moustiques.
PCT/US2025/012699 2024-01-23 2025-01-23 Formulations insectifuges et leurs procédés de fabrication et d'utilisation Pending WO2025160240A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130296284A1 (en) * 2004-08-31 2013-11-07 Stiefel Research Australia Pty Ltd Microemulsion & sub-micron emulsion process & compositions
US20140037747A1 (en) * 2011-02-23 2014-02-06 The Board Of Trustees Of The University Of Illinoi S Amphiphilic dendron-coils, micelles thereof and uses
US20170181970A1 (en) * 2007-12-07 2017-06-29 Foamix Pharmaceuticals Ltd. Oil foamable carriers and formulations
US20200230036A1 (en) * 2017-08-31 2020-07-23 Shiseido Company, Ltd. Water-in-oil emulsion cosmetic
US20230052833A1 (en) * 2019-12-27 2023-02-16 Shiseido Company, Ltd. Oil-based particles and external composition

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130296284A1 (en) * 2004-08-31 2013-11-07 Stiefel Research Australia Pty Ltd Microemulsion & sub-micron emulsion process & compositions
US20170181970A1 (en) * 2007-12-07 2017-06-29 Foamix Pharmaceuticals Ltd. Oil foamable carriers and formulations
US20140037747A1 (en) * 2011-02-23 2014-02-06 The Board Of Trustees Of The University Of Illinoi S Amphiphilic dendron-coils, micelles thereof and uses
US20200230036A1 (en) * 2017-08-31 2020-07-23 Shiseido Company, Ltd. Water-in-oil emulsion cosmetic
US20230052833A1 (en) * 2019-12-27 2023-02-16 Shiseido Company, Ltd. Oil-based particles and external composition

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