Composition for controlling mite infestations

Abstract

The present invention relates to a parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein, and to its use as a medicine or as a parasiticide. The present invention further relates to a method for maintaining honeybee colonies and controlling mite infestations. The present invention further relates to a device comprising a parasiticidal composition according to the invention.

Description

[Technical Field]

[0001] The present invention relates to a parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein. The present invention further relates to a method for maintaining honeybee colonies and controlling mite infestations. The present invention further relates to a device comprising a parasiticidal composition according to the present invention. [Background technology]

[0002] The Western honeybee (Apis mellifera L., Hymenoptera: Apidae) is an economically, agriculturally, and environmentally important species. Recent decades have seen a significant decline in honeybee populations. One of the main reasons for this decline is due to mite infestations in honeybee colonies.

[0003] Honeybee colony boxes and hives can be suitable habitats for a variety of mites (Acari), including non-parasitic, omnivorous, pollen-feeding, and parasitic species. Among the various mite species associated with honeybees, Varroa destructor, Acarapis woodi, Varroa jacobsoni, and Tropilaelaps clareae are economically significant pests that infest honeybee colonies, potentially leading to the collapse of the beekeeping industry.

[0004] Varroa mites are currently the largest biotic stressor for bees in their parasitic capacity and by acting as vectors for viruses, including acute bee paralysis virus (ABPV), Kashmir bee virus (KBV), Israeli acute paralysis virus (IAPV), and ragged bee virus. Varroa destructor is an obligate parasite that attacks various developmental stages of A. mellifera. Varroa mites attack honeybee colonies as ectoparasites of adult and developing bees, spreading disease, affecting colony health, and shortening colony lifespan. Varroa mites, along with the viruses they vector, affect honeybee immune responses, making them more susceptible to various pathogens.

[0005] The traditional method used to control Varroa mites has been to hang plastic strips impregnated with chemical pesticides between the wax combs of beehives. However, repeated use of chemical pesticides is known to cause lethal effects on honeybee development. Furthermore, the mites are rapidly developing resistance to many commonly used treatments, prompting researchers to develop numerous alternative methods for preventing and treating Varroa mite infestations. These methods range from structural or mechanical modifications to beehive units in apiaries, the use of new pesticides, and administration methods that are beneficial and effective alternatives to standard treatments.

[0006] Amitraz (N'-(2,4-dimethylphenyl)-N-[(2,4-dimethylphenyl)iminomethyl]-N-methylmethanimidamide / CAS 33089-61-1) is a tertiary amino compound that is a 1,3,5-triazapenta-1,4-diene substituted with a methyl group at the 3-position and 2,4-dimethylphenyl groups at the 1- and 5-positions. It is one such synthetic compound with insecticidal and acaricidal properties that is used worldwide to control pests on both animals and crops. Amitraz is a formamide that exhibits both acaricidal and insecticidal activity and is frequently used by beekeepers to protect honeybee colonies from Varroa destructor mites. Therefore, there is a need to provide a parasiticidal composition that has good stability and ensures good dose reproducibility, beekeeper safety, and efficient activity.

[0007] In view of the potential value of amitraz against parasitic mites, there is a long-felt need in the art to develop formulations with enhanced and sustained release activity of the active substance, improved characteristics of the formulation in terms of stability, and efficient inhibitory activity against Vellus mites.

[0008] It is an object of the present invention to provide a stable parasiticidal composition for controlling mite infestation in honeybee colonies. It is another object of the present invention to provide a method for controlling mite infestation in honeybee colonies and a method for maintaining honeybee colonies.

[0009] Another object of the present invention is to provide the use of a stable parasiticidal composition for controlling mite infestations in honeybee colonies. Summary of the Invention

[0010] Main Aspects of the Invention In one aspect, the present invention provides a parasiticidal composition for controlling mite infestation, such as for controlling mite infestation in honey bee colonies, comprising: (a) an octopamine receptor agonist; (b) a metal oxide; The present invention relates to a parasiticidal composition comprising:

[0011] In another aspect, the present invention relates to a device adapted for use in beekeeping, comprising a parasiticidal composition according to the present invention.

[0012] In another aspect, the present invention relates to a method for controlling mite infestation in a honeybee colony comprising exposing the honeybee colony to a parasiticidal composition according to the present invention.

[0013] In another aspect, the present invention relates to the use of a parasiticidal composition according to the invention for controlling mite infestations in honeybee colonies.

[0014] In another aspect, the present invention relates to the use of metal oxides to stabilize octopamine receptor agonists.

[0015] Further aspects of the present invention In one aspect, the present invention provides a parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein, comprising: (a) an effective amount of an octopamine receptor agonist; (b) a stabilizing amount of a metal oxide; (c) optionally, one or more acceptable excipients; and The present invention relates to a parasiticidal composition comprising:

[0016] In one aspect, the present invention provides a parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) optionally one or more excipients; The present invention relates to a parasiticidal composition comprising:

[0017] In one aspect, the present invention provides a semi-solid parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein, comprising: (a) an effective amount of an octopamine receptor agonist; (b) a stabilizing amount of a metal oxide; (c) one or more excipients, for example one or more excipients suitable for obtaining a semi-solid antiparasitic composition, such as one or more excipients suitable for obtaining a gel or a paste; The present invention relates to a semi-solid parasiticidal composition comprising:

[0018] In one aspect, the present invention provides a semi-solid parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) one or more excipients suitable for obtaining a semi-solid anti-parasitic composition, such as one or more excipients suitable for obtaining a gel or a paste; The present invention relates to a semi-solid parasiticidal composition comprising:

[0019] In another aspect, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations therein, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) one or more excipients suitable for obtaining a semi-solid anti-parasitic composition, such as one or more excipients suitable for obtaining a gel or a paste; Including, The present invention relates to a parasiticidal semi-solid composition in which the % degradation of amitraz is reduced and the total amount of amitraz in the formulation remains constant after a storage period of at least 12 months at room temperature.

[0020] In one aspect, the present invention relates to the use of a parasiticidal composition for maintaining honeybee colonies and controlling mite infestations therein, said composition comprising an effective amount of amitraz, a stabilizing amount of a metal oxide and finally one or more excipients, wherein the % degradation of the amitraz content is reduced and the total amount of amitraz in the formulation remains constant after a storage period of at least 12 months at room temperature.

[0021] In another aspect, the present invention provides a method for maintaining honeybee colonies and / or preventing or controlling mite infestations in honeybee colonies in beekeeping chambers, the method comprising applying to the vicinity of the honeybee colonies or in an artificial honeybee colony beekeeping chamber a parasiticidal composition comprising amitraz, a stabilizing amount of a metal oxide, and one or more excipients, for example one or more excipients suitable for obtaining a semi-solid parasiticidal composition, such as one or more excipients suitable for obtaining a gel or a paste.

[0022] In another aspect, the present invention provides a method of maintaining honeybee colonies and controlling mite infestations, comprising adapting a dosing gun to dispense a predetermined dose of a semi-solid parasiticidal composition comprising amitraz, a stabilizing amount of a metal oxide, and one or more excipients, wherein the dosing gun dispenses a volume in the range of 0.5 mL to 125 mL per dose from a cartridge containing the parasiticidal composition, and the predetermined dose dispensed is in the range of 0.1 mL to 10 mL per trigger actuation.

[0023] In another aspect, the present invention provides a method of maintaining honeybee colonies and controlling mite infestations, comprising adapting a dosing gun to release a predetermined dose of a semi-solid parasiticidal composition comprising amitraz, a stabilizing amount of a metal oxide, and one or more excipients, wherein the dosing gun releases an amount in the range of 0.5 mL to 125 mL per dose from a cartridge containing the parasiticidal composition, and the predetermined dose released is an amount in the range of 1 mL to 3 mL per trigger actuation. DETAILED DESCRIPTION OF THE INVENTION

[0024] The following description is provided to aid in a comprehensive understanding of exemplary embodiments of the present invention. Although the specification includes numerous specific details to aid in understanding, these should be considered as merely exemplary.

[0025] Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope of the present invention. Also, for clarity and conciseness, descriptions of well-known functions and configurations will be omitted.

[0026] The terms used in the following description and claims are not limited to their bibliographical meanings, but are merely used to enable the inventor to clearly and consistently understand the present invention. Therefore, it will be apparent to those skilled in the art that the following description of exemplary embodiments of the present disclosure is provided for illustrative purposes only and does not limit the scope of the present invention, which is defined by the appended claims and their equivalents.

[0027] For purposes of the following detailed description, it is to be understood that the present invention may contemplate various alternative modifications and sequence of steps, unless expressly specified to the contrary. Further, other than in any operating examples, or unless otherwise indicated, all numbers expressing quantities of materials / ingredients used herein, for example, should be understood as modified in all instances by the term "about."

[0028] Therefore, before describing the present invention in detail, it is to be understood that the present invention is not limited to particularly exemplified system or process parameters, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments of the invention and is not intended to limit the scope of the invention in any way. The use of examples anywhere in this specification, including examples of any term discussed herein, is illustrative only and does not limit the scope and meaning of the invention or of any exemplified term.

[0029] It should also be noted that as used herein, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. The terms "preferred" and "preferably" refer to embodiments of the invention that may offer certain benefits, under particular circumstances.

[0030] As used herein, the terms "comprising," "including," "having," "containing," "involving," and similar terms should be understood to mean without limitation, i.e., including without limitation.

[0031] definition The term "semi-solid composition" refers to a composition that is normally solid at room temperature and can flow under mechanical stress. It includes, for example, compositions such as pastes, gels, creams, ointments, etc. The consistency of a semi-solid composition allows for proper diffusion of an active ingredient, such as a parasiticidal drug substance.

[0032] The term "excipient suitable for obtaining a semi-solid composition" refers to one or more components that can provide a suitable consistency for forming a stable semi-solid composition. Those skilled in the art will select appropriate excipients for their ability to provide a suitable consistency for the semi-solid composition. Examples of excipients suitable for obtaining a semi-solid composition are listed below. waxes, including waxes of natural origin (such as carnauba wax or beeswax, (hydrogenated) vegetable oils) and synthetic waxes (petrolatum, ethylene or propylene oxide polymers, including liquid and hard paraffins and mixtures thereof); gelling or thickening agents which may have a polymeric structure comprising natural polymers (cellulose derivatives, xanthan gum, guar gum, carob gum, alginic acid derivatives, carrageenans, etc.) or synthetic polymers (styrene polymers, acrylic polymers, vinyl polymers, etc.), Insoluble compounds such as metal carbonates or oxides, which are capable of giving consistency to a liquid after homogeneous dispersion by increasing the number of solid particles in the composition.

[0033] The term "parasiticidal" refers to the ability of a substance to reduce or inhibit the growth of parasites.

[0034] Ectoparasitic infestations or infestations suitable for treatment by the methods of the present invention include fleas, ticks, lice, flies, and mites such as Vulpes vulgare.

[0035] As used herein, the term "apiary" or "bee farm" refers to colonies, hives, hive units, and other equipment assembled at one location for the purpose of beekeeping operations.

[0036] The term "bee hive unit" or "beekeeping unit" or "beehive" as used herein refers to a bee hive having a beekeeping chamber located in the lower central part of the unit, with further chambers above and partly to the sides of the beekeeping chamber, separated therefrom by a frame having a series of slots, and having one chamber on each lower side of the hive and one partly below the beekeeping chamber, with a series of slots each formed in the partitions forming the walls of the chambers to allow bees free access from one part of the hive to another.

[0037] "Controlling" or "controlling" mites means inhibiting and / or suppressing the ability of mites to grow and / or reproduce, or limiting fungal-related damage or loss in crop plants, or refers to disease control and prevention. Control effects include all deviations from natural development, such as killing, delaying, or reducing disease-causing mites.

[0038] As used herein, the term "locus of infestation" is intended to refer to the vicinity of a beehive where it is desired to control ectoparasite infestation, including the vicinity of a beehive colony, beehive, or beehive unit, where mites, or specifically Vulgaris mites, have emerged, have begun to breed, or are most likely to emerge, or have not yet emerged.

[0039] As used herein, a "parasiticicidal amount" is the amount of active ingredient that causes a reverse modifying effect, including deviation from the natural development of a parasite, killing, regulating, depleting, retarding, etc.

[0040] The term "strip" according to the present invention refers to a strip made by extruding, cutting or braiding a flexible material. The flexible material may be, for example, a plastic material, rubber, fabric, resin or polyholoside fiber. The strip may have different shapes. Preferably, the strip is adapted for use in beekeeping, i.e. it is a non-circular strip, preferably a flat strip, with a size, rigidity and shape adapted to allow it to be slid between the frames of the hive. The strip can also be positioned on top of the frame or at the entrance to the hive.

[0041] Each of the above aspects may have one or more embodiments.

[0042] Each of the embodiments described below may be applied to one or all of the aspects described above. These embodiments are intended to be read as preferred features of one or all of the aspects described above. Each of the embodiments described below applies to each of the aspects individually described above.

[0043] The present inventors have successfully provided a stable antiparasitic composition comprising an octopamine receptor agonist such as amitraz, in which the percentage of degradation products of the octopamine receptor agonist is reduced and the total amount of the octopamine receptor agonist retained in the formulation remains constant after a storage period of at least 12 months at room temperature.The use of the antiparasitic composition of the present invention also dramatically reduced the percentage of bee mortality.

[0044] Thus, the inventors have unexpectedly found the most suitable amount of metal oxide, such as calcium oxide, to be added to a parasiticidal composition comprising an octopamine receptor agonist, such as amitraz, which is found to be sufficient to achieve efficient dosing results of the octopamine receptor agonist and a reduction in degradation products of the octopamine receptor agonist.

[0045] The semi-solid form of the parasiticide composition of the present invention has significant advantages over the liquid form. The semi-solid composition does not require dilution and has improved handling characteristics, thereby reducing the risks associated with handling liquid compositions of octopamine receptor agonists such as amitraz, which are corrosive and can easily spill and splash. Additionally, the use of a semi-solid composition can help reduce contact between the active ingredient and the beekeeper. Additionally, the octopamine receptor agonist in the semi-solid composition is quickly available for treating bees.

[0046] The solid form of the parasiticide composition of the present invention has a sustained release property, and therefore can reduce the number of applications required to achieve adequate mite control. By controlling the release of the octopamine receptor agonist in the parasiticide solid composition, a reduction in the mortality rate of bees is observed, and the longer exposure time of mites to the parasiticide composition ensures a higher rate of mite killing.

[0047] Parasiticidal compositions of the present invention One object of the present invention is to provide a parasiticidal composition for controlling mite infestations, such as for controlling mite infestations in honeybee colonies, comprising: (a) an octopamine receptor agonist; (b) a metal oxide; The present invention provides a parasiticidal composition comprising:

[0048] In one embodiment, the parasiticidal composition of the present invention comprises: (a) an effective amount of an octopamine receptor agonist; (b) a stabilizing amount of a metal oxide; Includes:

[0049] In some embodiments, the octopamine receptor agonist is an octopamine receptor agonist of formula (I) disclosed in WO 2021 / 116631(A1), which is incorporated herein by reference, wherein formula (I) is:

[0050] [ka] During the ceremony, A is selected from group (II) or (III),

[0051] [ka] X is NH, CH2, or CH-CH3; Y is a 5-linked heterocycle containing at least one nitrogen atom; Z1 is halogen, H, or CH3; Z2 is halogen, H, or CH3; Z3 is halogen, H, or CH3; Z4 is halogen, H, or CH3.

[0052] Advantageously, Y is the following group (IV) or (V):

[0053] [ka]

[0054] Advantageously, the compound of formula (I) is:

[0055] [ka] During the ceremony, -A is a group (II), X is NH, Y is a group (IV), Z1 is a halogen, Z2 is H and Z3 is a halogen, or -A is group (II), X is CH2 or CH-CH3, Y is group (V), Z1 is CH3, Z2 is CH3 and Z3 is H, or -A is group (III), X is NH, Y is group (IV) and Z4 is halogen.

[0056] Advantageously, the allogen is selected from F, Cl or Br.

[0057] In some embodiments, the compound of formula (I) is selected from detomidine (CAS No. 76631-46-4), medetomidine (D) (i.e., dexmedetomidine—CAS No. 113775-47-6), medetomidine (L) (i.e., levomedetomidine—CAS No. 119717-21-4), romifidine (CAS No. 65896-16-4), clonidine (CAS No. 4205-90-7), tizanidine (CAS No. 51322-75-9), or a mixture of two or more of these compounds. It can be, for example, a racemic mixture, such as the racemic form of medetomidine (CAS No. 86347-14-0).

[0058] In some preferred embodiments, the octopamine receptor agonist is amitraz (CAS 33089-61-1).

[0059] In some embodiments, the metal oxide is selected from (i) alkali metal oxides, such as sodium oxide and potassium oxide, or (ii) alkaline earth metal oxides, such as calcium oxide, barium oxide, and magnesium oxide. Preferably, the metal oxide is calcium oxide.

[0060] In some preferred embodiments, the octopamine receptor agonist is amitraz and the metal oxide is calcium oxide.

[0061] In some embodiments, the parasiticidal compositions of the present invention are in (i) a liquid form such as an emulsion, suspension, or oil dispersion (OD), (ii) a semi-solid form such as a gel or paste, or (iii) a solid form such as an extruded composition, water dispersible granule (WDG), wettable powder (WP), or dust.

[0062] Preferably, the liquid parasiticide composition comprises one or more excipients that are suitable for obtaining a liquid composition.

[0063] Preferably, the parasiticidal semi-solid composition comprises one or more excipients suitable for obtaining a semi-solid composition, as detailed below.

[0064] Preferably, the parasiticide solid composition comprises one or more excipients suitable for obtaining a solid composition. The one or more excipients suitable for obtaining a solid composition include synthetic polymers such as ethylene vinyl acetate (EVA) or polyvinyl chloride (PVC), or natural polymers such as starch or modified starch. Preferably, the one or more excipients are suitable for obtaining a solid composition by extrusion. Extrusion requires heating the composition at high temperatures, generally above 100°C, which can decompose the octopamine receptor agonist. The inventors have shown that octopamine receptor agonists are particularly stable in solid compositions prepared by extrusion containing metal oxides, compared to solid compositions lacking metal oxides.

[0065] In some embodiments, the metal oxide is in an amount sufficient to stabilize the octopamine receptor agonist in the composition.

[0066] In some embodiments, the percentage of degradation of the octopamine receptor agonist is reduced and the total amount of octopamine receptor agonist in the composition remains constant after storage at room temperature for at least 12 months.

[0067] In some embodiments, the percentage of degradation of the octopamine receptor agonist is reduced and the total amount of octopamine receptor agonist in the composition remains constant after at least 12 months of storage at 30° C. In some other embodiments, the percentage of degradation of the octopamine receptor agonist is reduced and the total amount of octopamine receptor agonist in the composition remains constant after at least 6 months of storage at 40° C.

[0068] In some embodiments, the octopamine receptor agonist is at a concentration in the range of 0.1% to 20% w / w of the composition, for example, 0.5% to 10% w / w of the composition, for example, 1% to 5% w / w of the composition, for example, 1% to 3% w / w of the composition, for example, 2% w / w of the composition.

[0069] In some embodiments, the metal oxide is at a concentration in the range of 1% to 20% w / w of the composition, such as 5% to 15% w / w of the composition, such as 5% to 10% w / w of the composition, for example 9% w / w of the composition.

[0070] In some embodiments, the composition contains one or more excipients, e.g., -wax, gelling or thickening agents, and / or - further comprising an insoluble compound.

[0071] In some embodiments, the wax comprises (i) a naturally occurring wax such as carnauba wax or beeswax, (hydrogenated) vegetable oils, and / or (ii) a synthetic wax such as petrolatum, preferably liquid and / or hard paraffin, ethylene oxide polymers (also known as "macrogols"), propylene oxide polymers, or ethylene propylene oxide copolymers (also known as "macrogol derivatives").

[0072] In some embodiments, the gelling or thickening agent has a polymeric structure and includes (i) natural polymers such as cellulose derivatives, xanthan gum, guar gum, carob gum, alginic acid derivatives, carrageenan, etc., or (ii) synthetic polymers such as styrene polymers, acrylic polymers, vinyl polymers, etc.

[0073] In some embodiments, the insoluble compound is a metal carbonate or oxide, which can impart consistency to the liquid after homogeneous dispersion by increasing the number of solid particles in the composition.

[0074] The one or more excipients may be a food-acceptable excipient and / or a pharmaceutically acceptable excipient. Preferably, the one or more excipients are suitable for treating honeybees.

[0075] In some embodiments, the parasiticidal compositions of the present invention further comprise one or more excipients at a concentration in the range of 30% to 95% w / w of the composition, for example, 50% to 90% w / w of the composition, for example, 60% to 90% w / w of the composition, for example, 88%.

[0076] In some embodiments, the parasiticidal composition of the present invention is a semi-solid composition, such as a gel or paste, and the water content in the composition is at least <2% w / w (less than 2% w / w) of the composition, such as <1% w / w (less than 1% w / w) of the composition, for example <0.5% w / w (less than 0.5% w / w) of the composition.

[0077] In some embodiments, the parasiticidal compositions of the present invention comprise: an effective amount of amitraz in a concentration ranging from 0.1% to 20% w / w of the composition, a stabilizing amount of calcium oxide in a concentration ranging from 1% to 20% w / w of the composition, and -Excipients at a concentration ranging from 30% to 95% w / w of the composition Includes:

[0078] In some embodiments, the parasiticidal compositions of the present invention further comprise an excipient selected from the group comprising carriers, solvents, emulsifiers, penetration enhancers, preservatives, and emollients, such as antioxidants.

[0079] In some embodiments, the parasiticidal composition is an acaricidal composition, such as a varroacide-killing composition.

[0080] In some embodiments, the parasiticidal compositions of the present invention comprise: (a) amitraz at a concentration of about 2.0% w / w of the composition; (b) calcium oxide at a concentration of about 9.5% w / w of the composition, and (c) petrolatum, preferably paraffin, at a concentration of about 88.5% w / w of the composition Includes:

[0081] In a preferred embodiment, the calcium oxide has CAS number 1305-78-8 and / or the paraffin has CAS number 8009-03-8.

[0082] The following objects also define the parasiticidal composition according to the present invention.

[0083] The present invention provides a parasiticidal composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) optionally one or more excipients; The present invention provides a parasiticidal composition comprising:

[0084] In one embodiment, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) optionally, one or more excipients; The present invention provides a semi-solid parasiticidal composition comprising:

[0085] In some embodiments, the semi-solid composition is a paste or a gel.

[0086] In one embodiment, the parasiticidal composition of the present invention comprises amitraz at a concentration ranging from 0.1% to 20% w / w of the composition.

[0087] In another embodiment, the parasiticidal composition of the present invention comprises amitraz at a concentration ranging from 0.5% to 10% w / w of the composition.

[0088] In yet another embodiment, the parasiticidal composition of the present invention comprises amitraz at a concentration ranging from 1% to 5% w / w of the composition.

[0089] In a preferred embodiment, the parasiticidal composition of the present invention comprises amitraz at a concentration in the range of 1% to 3% w / w of the composition.

[0090] In a preferred embodiment, the parasiticidal composition of the present invention comprises amitraz at a concentration of 2% w / w of the composition.

[0091] In one embodiment, the parasiticidal composition of the present invention comprises a metal oxide selected from oxides of alkali metals or alkaline earth metals.

[0092] In one embodiment, the metal oxide is an oxide of an alkali metal selected from the group including sodium and potassium.

[0093] In one embodiment, the metal oxide is an oxide of an alkaline earth metal selected from the group including calcium, barium, aluminum, and magnesium. In a preferred embodiment, the metal oxide is calcium oxide.

[0094] In one embodiment, the parasiticidal composition comprises a metal oxide at a concentration in the range of 1% to 20% w / w of the composition.

[0095] In one embodiment, the parasiticidal composition comprises a metal oxide at a concentration in the range of 5% to 15% w / w of the composition.

[0096] In one embodiment, the parasiticidal composition comprises calcium oxide at a concentration in the range of 1% to 20% w / w of the composition.

[0097] In one embodiment, the parasiticidal composition comprises calcium oxide at a concentration in the range of 5% to 15% w / w of the composition.

[0098] In one embodiment, the parasiticidal composition comprises calcium oxide at a concentration in the range of 5% to 10% w / w of the composition.

[0099] In one embodiment, the parasiticidal composition comprises calcium oxide at a concentration of 9% w / w of the composition.

[0100] In one embodiment, the parasiticidal composition comprises one or more excipients, preferably one or more excipients designated as Generally Recognized As Safe (GRAS).

[0101] In one embodiment, the one or more excipients comprise petrolatum, such as petrolatum selected from the group comprising liquid paraffin and / or solid paraffin.

[0102] In one embodiment, the one or more excipients are at a concentration ranging from 30% to 95% w / w of the composition.

[0103] In one embodiment, the one or more excipients are at a concentration ranging from 50% to 90% w / w of the composition.

[0104] In one embodiment, the one or more excipients are at a concentration ranging from 60% to 90% w / w of the composition.

[0105] In one embodiment, the one or more excipients are at a concentration of 88% w / w of the composition.

[0106] In one embodiment, the one or more excipients are suitable for obtaining a semi-solid composition, such as a gel or a paste.

[0107] In one embodiment, the present invention provides a semi-solid parasiticidal composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz in a concentration ranging from 0.1% to 20% w / w; (b) a stabilizing amount of calcium oxide in a concentration ranging from 1% to 20% w / w; (c) one or more excipients at a concentration ranging from 30% to 95% w / w; wherein each component is by weight of the total composition.

[0108] In one embodiment, the present invention provides a semi-solid parasiticidal composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz in a concentration ranging from 1% to 5% w / w; (b) a stabilizing amount of calcium oxide in a concentration ranging from 5% to 10% w / w; (c) petrolatum as an excipient at a concentration ranging from 50% to 90% w / w; wherein each component is by weight of the total composition.

[0109] In some embodiments, the semi-solid antiparasitic composition is a paste or a gel, for example the water content in the gel composition is at least <2% w / w (less than 2% w / w), such as at least <1% w / w, for example at least <0.5% w / w.

[0110] In one embodiment, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) one or more acceptable excipients suitable for obtaining a semi-solid composition; and The present invention provides a semi-solid parasitic killing composition comprising:

[0111] In one embodiment, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of a metal oxide; (c) one or more acceptable excipients suitable for obtaining a semi-solid composition; and wherein degradation of amitraz is reduced and the total amount of amitraz in the formulation remains constant after a storage period of at least 12 months at room temperature.

[0112] In one embodiment, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz; (b) a stabilizing amount of calcium oxide; (c) Vaseline; wherein degradation of amitraz is reduced and the total amount of amitraz in the composition remains constant after a storage period of at least 12 months at room temperature.

[0113] In one embodiment, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz in a concentration ranging from 0.1% to 20% w / w; (b) a stabilizing amount of calcium oxide in a concentration ranging from 1% to 20% w / w; (c) petrolatum in a concentration ranging from 30% to 95% w / w; each component being by weight of the composition; To provide a parasiticidal semi-solid composition in which the degradation of amitraz is reduced and the total amount of amitraz in the composition remains constant after a storage period of at least 12 months at room temperature.

[0114] In one embodiment, the present invention provides a parasiticidal semi-solid composition for maintaining honeybee colonies and controlling mite infestations, comprising: (a) an effective amount of amitraz in a concentration ranging from 1% to 5% w / w; (b) a stabilizing amount of calcium oxide in a concentration ranging from 5% to 10% w / w; (c) petrolatum in a concentration ranging from 50% to 90% w / w; each component being by weight of the composition; To provide a parasiticidal semi-solid composition in which the degradation of amitraz is reduced and the total amount of amitraz in the composition remains constant after a storage period of at least 12 months at room temperature.

[0115] Medical Uses of the Parasiticidal Compositions of the Invention Another object of the present invention is to provide a composition according to the present invention as described above for use as a medicine, for example the present invention provides a composition according to the present invention for use as a parasiticide.

[0116] The parasiticidal compositions of the present invention can also be extended for use as topical administration in veterinary applications. Examples of topical administrations suitable for use in the present invention include dripping, pouring, dipping, spraying, rinsing, shampooing, foaming, gels, lotions, powders, or any of the conventional means of topically applying a liquid veterinary composition. The topical mode or administration will vary depending on the species and size of the host animal (e.g., bee, dog, etc.).

[0117] Devices containing the parasiticidal compositions of the present invention Another object of the present invention is a device adapted for use in beekeeping, comprising a parasiticidal composition according to the invention. The device may be a strip, a beekeeping chamber, a hive, a dosing gun or a kit of parts.

[0118] According to one embodiment, the various components of the stable antiparasitic composition of the present invention may be used individually or may already be partially or completely mixed together to prepare the composition. It is also possible for the components to be packaged separately and used as components in a kit of parts.

[0119] In one embodiment, the kit can include one or more of the components used to prepare the composition according to the present invention.For example, the kit can include an octopamine receptor agonist, a metal oxide, and finally an excipient, as defined above.One or more of the components can be already combined together or can be pre-formulated.

[0120] According to an embodiment of the present disclosure, there is provided a kit comprising a stable parasiticidal gel formulation, the kit comprising multiple components including at least one of the components of the stable parasiticidal composition of the present disclosure.

[0121] In one embodiment of the present disclosure, the kit includes at least one or all of the components necessary to prepare a stable antiparasitic composition. For example, the kit may include amitraz, a metal oxide, and an excipient.

[0122] One or more of the components may be already combined together or pre-formulated. In those embodiments in which more than two components are provided in the kit, the components may already be combined and thus packaged in a single container, such as a vial, bottle, can, pouch, bag, and / or canister.

[0123] In a preferred embodiment, the device comprises a ready-to-use parasiticidal composition according to the present invention.

[0124] In some embodiments, the device is selected from a putty, a paste, a plastic porous strip, an extruded strip, other strip material, a pad, a powder, or the like.

[0125] In some embodiments, the device is a porous support, such as a cellulosic porous support (eg, cellulose) or a wood support, impregnated with a composition of the invention in liquid or semi-solid form.

[0126] Methods and Uses of Compositions According to the Invention Another object of the present invention is a method for controlling mite infestation in honeybee colonies, comprising exposing the colonies to a parasiticidal composition according to the invention.

[0127] Another object of the invention is the use of the parasiticidal composition according to the invention for controlling mite infestations in honeybee colonies.

[0128] In some embodiments, the parasiticidal composition reduces or prevents mite infestation.

[0129] In some embodiments, the mite is of the genus Vellus.

[0130] In some embodiments, the parasiticidal composition is applied to the hive, preferably the composition is applied to the beekeeping chamber.

[0131] In some embodiments, the composition is applied in an amount of 0.1 mL to 30 mL.

[0132] In one embodiment, the present invention provides a method for controlling mite infestation in the beekeeping chamber of a honeybee colony, comprising applying a parasiticidal composition onto a separate support introduced into the beekeeping chamber.

[0133] In one embodiment, the separate support is a wooden support.

[0134] In one embodiment, the present invention provides a method for controlling mite infestation in broodless honeybee colonies or in beekeeping chambers when brood is present.

[0135] In one embodiment, the present invention provides a method for controlling mite infestation in beekeeping chambers, the method comprising adapting a dosing gun to release a predetermined dose of a semi-solid parasiticidal composition comprising amitraz, the predetermined dose released being in the range of 0.1 mL to 10 mL per actuation of the trigger.

[0136] In one embodiment, the present invention provides a method for controlling mite infestation in beekeeping chambers, the method comprising adapting a dosing gun to release a predetermined dose of a parasiticidal composition, the predetermined dose released being in the range of 0.1 mL to 6 mL per actuation of the trigger.

[0137] In one embodiment, the present invention provides a method of controlling mite infestation in beekeeping chambers, comprising adapting a dosing gun to release a predetermined dose of the parasiticidal composition of the present invention, preferably wherein the predetermined dose released is in the range of 0.1 mL to 30 mL per actuation of the trigger.

[0138] In one embodiment, the present invention provides a method for controlling mite infestation in beekeeping chambers, the method comprising adapting a dosing gun to release a predetermined dose of the parasiticidal composition of the present invention, the predetermined dose released being in the range of 0.1 mL to 10 mL per actuation of the trigger.

[0139] In another embodiment, the present invention provides a method for controlling mite infestation in beekeeping chambers, the method comprising adapting a dosing gun to release a predetermined dose of the parasiticidal composition of the present invention, the predetermined dose released being a volume of 3 mL per actuation of the trigger.

[0140] In one embodiment, the predetermined dose of the parasiticidal composition ranges from 0.5 mL to 30 mL.

[0141] In one embodiment, the predetermined dose of the parasiticidal composition ranges from 0.5 mL to 20 mL.

[0142] In one embodiment, the predetermined dose of the parasiticidal composition ranges from 0.5 mL to 10 mL.

[0143] In one embodiment, the predetermined dose of the parasiticidal composition ranges from 0.5 mL to 6 mL.

[0144] In one embodiment, the predetermined dose of the parasiticidal composition is in the range of 1 mL to 5 mL.

[0145] In one embodiment, the predetermined dose of the composition is 3 mL.

[0146] In one embodiment the invention provides a method of controlling mite infestation in a colony of honey bees in a beekeeping chamber, the method comprising adapting a dosing gun to release a predetermined dose of a semi-solid parasiticidal composition comprising amitraz in an amount in the range of 10 mg to 110 mg per 3 mL of composition in the beekeeping chamber, for example in an amount in the range of 40 mg to 60 mg per 3 mL of composition in the beekeeping chamber.

[0147] In one embodiment, the present invention provides a method for controlling mite infestation in a colony of honeybees in a beekeeping chamber, the method comprising using a dosing gun adapted to release a predetermined dose of a semi-solid parasiticidal composition comprising amitraz in an amount of 55 mg per 3 mL of parasiticidal gel composition in the beekeeping chamber.

[0148] In one embodiment, the semi-solid composition may be applied directly using a dosing gun, a caulking gun.

[0149] The semi-solid composition can be applied to additional supports within the hive. This treatment is most effective when carried out over the entire beekeeping cycle. The semi-solid composition of the present invention is effective for at least 7 days.

[0150] Stabilization of octopamine receptor agonists Another object of the present invention is the use of metal oxides to stabilize octopamine receptor agonists.

[0151] In some embodiments, the octopamine receptor agonist is one or more selected from the group consisting of amitraz or an octopamine receptor agonist of formula (I), as described above. Preferably, the octopamine receptor agonist is amitraz.

[0152] In some embodiments, the metal oxide is selected from (i) alkali metal oxides, such as sodium oxide and potassium oxide, or (ii) alkaline earth metal oxides, such as calcium oxide, barium oxide, and magnesium oxide. Preferably, the metal oxide is calcium oxide.

[0153] In some embodiments, the octopamine receptor agonist is amitraz and the metal oxide is calcium oxide.

[0154] In some embodiments, the metal oxide is in an amount sufficient to stabilize the octopamine receptor agonist in the composition.

[0155] In some embodiments, metal oxides are used to stabilize the octopamine receptor agonist at elevated temperatures, such as temperatures up to 100° C., e.g., temperatures up to 140° C. This is particularly useful during extrusion processes where the temperature is elevated above the melting point of the composition being extruded.

[0156] In some embodiments, the percentage of degradation of the octopamine receptor agonist is reduced and the total amount of octopamine receptor agonist in the composition remains constant after at least 12 months of storage at room temperature.

[0157] All features described herein may be combined with any of the above aspects in any combination. In order that the present disclosure may be more readily understood, reference is now made to the following description by way of example. However, the scope of the present disclosure is not limited by the examples. Those skilled in the art will understand that the present disclosure includes the foregoing examples and can be further modified and varied within the scope of the present disclosure. It will be understood that all listed tests and physical properties are determined at atmospheric pressure and room temperature (i.e., 25° C.) unless otherwise specified herein or in the referenced test methods and procedures.

[0158] It will be understood that the specification and examples are illustrative and not limiting of the disclosure, and that other embodiments within the spirit and scope of the disclosure will be suggested to those skilled in the art. Other embodiments can be made that are also within the scope of the disclosure. The following examples illustrate the invention, but are not intended to limit the scope of the claims in any way. [Brief explanation of the drawings]

[0159] [Figure 1] 1 illustrates the loading of a dosing gun and its use in administering the parasiticidal composition of the present invention to a honeybee colony box unit. [Example]

[0160] Example 1: Preparation of a semi-solid composition according to the present invention

[0161] [Table 1]

[0162] Preparation method: Using a water bath, the paraffin was heated to 60°C. Then, the mixture was stirred using a blade mixer. After the paraffin mixture was melted and homogenized, the amitraz was added under strong stirring. Then, calcium oxide was stirred and mixed until completely dissolved and homogenized. The mixture was then heated at 45°C for 30 minutes before being packaged.

[0163] Example 2: Stability of semi-solid compositions according to the present invention

[0164] [Table 2]

[0165] Note: Composition B consists of amitraz, paraffin, and calcium oxide. A semi-solid composition according to the present invention. Composition A is a semi-solid composition containing amitraz and paraffin.

[0166] [Table 3]

[0167] The above observations were made at 40°C / 75% HR, the term T refers to the time interval at which the readings were taken, the suffixes refer to the duration in months, i.e., 1.5 months, 3 months, and 6 months during storage. The term CV refers to the coefficient of variation between different doses achieved in one interval.

[0168] From Table 3 above, it was observed that the composition of the present invention, designated as Composition B, had the least amount of % degradation of amitraz compared to Composition A which did not have the presence of calcium oxide.

[0169] Example 3: Device according to the invention and its use in a hive Loading the medication gun The parasiticidal composition of Example 1 was loaded into the dosing gun [shown as 1, 2, and 3 in Figure 1] and secured. The syringe cap was removed [shown as 4 in Figure 1]. The trigger was lightly and briefly pressed several times [shown as 5 in Figure 1] to prepare the tool ready to apply the product to the hive. Each pull of the trigger delivered a standard 3 mL dose of product. Thus, two 3 mL doses were applied per beekeeping chamber.

[0170] How to apply The parasiticide composition was applied to colonies without brood and when brood was present. The frames of the beekeeping chambers were scraped to remove all wax and propolis that could prevent bees from contacting the gel. The upper feeder, the upper bar of the beekeeping chamber, or, in the case of double-chamber hives, the underside of the frame for the upper beekeeping chamber were cleaned. Two wooden supports were included for each beekeeping chamber, on the upper bar of the frame in the center of the growing area or the center of the swarm. For better distribution of the active ingredient in the colony, at least one frame without the composition was left between two frames with the composition.

[0171] Two 3 mL doses of the parasiticidal composition were applied by using a dosing gun to apply a line of the composition onto each substrate. For dual beehive chamber hives, the total dose was two lines of 3 mL each in each beehive chamber, i.e., a total of 12 mL of composition was applied in the dual beehive chamber hives.

[0172] Benefits of parasiticidal compositions applied in cancer The parasiticidal composition reduces the load of pheagant mites by rapid knockdown action.

[0173] The composition can be used whenever honey supers are not present and when bees are active in the hive (avoiding winter treatments).

[0174] Given its rapid action, the composition can be used several times during the year to control mite infestations.

[0175] Example 4: Stability of extruded strips The following example demonstrates the improved stability of amitraz through the use of calcium oxide in a plastic extrusion process. Using this extrusion process, specific non-circular strips were designed for use in nest boxes. Plastic polymer, amitraz, and different excipients were mixed together and then extruded by heating to specific temperature conditions (up to 140°C), followed by cooling to obtain the strip shape.

[0176] [Table 4]

[0177] [Table 5]

[0178] The stability of amitraz after extrusion was dramatically improved by the use of calcium oxide (D19131) after 1 month of storage at 40°C and 75% HR compared to other compositions without calcium oxide.

Claims

1. 1. A parasiticidal composition for controlling tick infestations, comprising: (a) an octopamine receptor agonist; and (b) a metal oxide; and 1. A parasiticidal composition comprising:

2. the octopamine receptor agonist is amitraz or an octopamine receptor agonist of formula (I), 【Chemistry 1】 (In the formula, A is selected from group (II) or (III), 【Chemistry 2】 X is NH, CH2, or CH—CH3; Y is a 5-linked heterocycle containing at least one nitrogen atom; Z1 is halogen, H, or CH3; Z2 is halogen, H, or CH3; Z3 is halogen, H, or CH3; Z4 is halogen, H, or CH3; 2. The parasiticidal composition of claim 1, wherein the octopamine receptor agonist of formula (I) is preferably detomidine (CAS No.: 76631-46-4), medetomidine (D) (i.e. dexmedetomidine - CAS No.: 113775-47-6), medetomidine (L) (i.e. levomedetomidine - CAS No.: 119717-21-4), romifidine (CAS No.: 65896-16-4), clonidine (CAS No.: 4205-90-7), tizanidine (CAS No.: 51322-75-9), or a mixture of two or more of these compounds.

3. 3. A parasiticidal composition according to claim 1 or 2, wherein the metal oxide is selected from (i) oxides of alkali metals such as sodium oxide and potassium oxide, or (ii) oxides of alkaline earth metals such as calcium oxide, barium oxide, and magnesium oxide.

4. A parasiticidal composition according to any one of claims 1 to 3, wherein said metal oxide is calcium oxide.

5. A parasiticidal composition according to any one of claims 1 to 4, wherein the octopamine receptor agonist is amitraz and the metal oxide is calcium oxide.

6. the octopamine receptor agonist is at a concentration in the range of 0.1% to 20% w / w of the composition, such as 0.5% to 10% w / w of the composition, such as 1% to 5% w / w of the composition, such as 1% to 3% w / w of the composition, for example 2% w / w of the composition; and / or - said metal oxide is at a concentration in the range of 1% to 20% w / w of said composition, such as 5% to 15% w / w of said composition, for example 5% to 10% w / w of said composition, for example 9% w / w of said composition, A parasiticidal composition according to any one of claims 1 to 5.

7. A parasiticidal composition according to any one of claims 1 to 6, wherein said composition further comprises one or more excipients.

8. The parasiticidal composition of any one of claims 1 to 7, wherein the parasiticidal composition of the present invention is in (i) liquid form, (ii) semi-solid form, or (iii) solid form.

9. an effective amount of amitraz in a concentration ranging from 0.1% to 20% w / w of the composition, for example about 2.0% w / w of the composition; a stabilizing amount of calcium oxide in the range of 1% to 20% w / w of the composition, for example at a concentration of about 9.5% w / w of the composition; one or more excipients, such as paraffin, at a concentration ranging from 30% to 95% w / w of the composition, for example petrolatum, at a concentration of about 88.5% w / w of the composition; A parasiticidal composition according to any one of claims 1 to 8, comprising:

10. A composition according to any one of claims 1 to 9 for use as a medicament.

11. A composition according to any one of claims 1 to 9 for use as a parasiticide.

12. A device adapted for use in beekeeping, preferably a strip, a beekeeping chamber, a hive, a dosing gun, comprising a parasiticidal composition according to any one of claims 1 to 9.

13. 10. A method for controlling mite infestation in honeybee colonies, comprising exposing said honeybee colonies to a parasiticidal composition according to any one of claims 1 to 9.

14. Use of a parasiticidal composition according to any one of claims 1 to 9 for controlling mite infestations in honeybee colonies.

15. 1. Use of a metal oxide for stabilizing an octopamine receptor agonist, wherein preferably the octopamine receptor agonist is amitraz and the metal oxide is calcium oxide.

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