Antiparasitic compositions of macrocyclic lactones

Abstract

The present invention provides antiparasitic compositions for treatment or prevention of a parasitic infection in a mammal comprising a combination of macrocyclic lactones, particularly ivermectin, abamectin, and doramectin. The present invention also provides methods of treating a parasitic infection in a mammal by administering to the mammal an effective amount of an antiparasitic composition comprising ivermectin, abamectin, and doramectin, as well as methods of preparing the antiparasitic compositions.

Description

ANTIPARASITIC COMPOSITIONS OF MACROCYCLIC LACTONESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is an International (PCT) patent application which claims priority to U.S. Provisional Patent Application No. 63 / 516,384, filed 28 July 2023, the entire contents of which are incorporated herein by reference.BACKGROUNDField

[0002] The present invention relates to compositions for combating external and internal parasites in mammals. More specifically, the present invention provides for compositions comprising a combination of macrocyclic lactones, particularly ivermectin, abamectin, and doramectin; methods of using these compositions, and processes for preparing these compositions.

[0003] The class of macrocyclic lactones known as avermectins are potent antiparasitic agents against a wide range of internal and external parasites in mammals. However, some strains of parasites have become resistant to antiparasitic agents administered in conventional compositions, rendering them less effective. As such, there exists a need for antiparasitic compositions that are able to treat mammals for endoparasites and ectoparasites which have become resistant to certain macrocyclic lactones. Furthermore, there is a need in the art for effective antiparasitic avermectin compositions which are effective against a wide variety of parasite species, exhibit a high degree of injectability properties, and have enhanced shelf stability over prolonged storage time even at elevated temperatures and humidity.SUMMARY OF THE INVENTION

[0004] Various aspects of the invention provide for antiparasitic compositions comprising at least one macrocyclic lactone selected from the group consisting of ivermectin, abamectin, doramectin, and combinations thereof, in a veterinarily acceptable carrier.

[0005] Further aspects of the present invention provide for antiparasitic compositions comprising a combination of ivermectin, abamectin, and doramectin in a veterinarily acceptable carrier. The various compositions of the present invention can further comprise one or more excipients.

[0006] Aspects of the present invention further include methods of preparing compositions comprising at least one macrocyclic lactone selected from the group consisting of ivermectin, abamectin, doramectin, and combinations thereof, fortreating or controlling parasites in a mammal. In a preferred aspect, the composition comprises a combination of ivermectin, abamectin, and doramectin.

[0007] Aspects of the present invention also include methods of the prevention, treatment, or control of parasites in mammals which comprises administering to the mammal in need thereof, an effective amount of a composition comprising at least one macrocyclic lactone selected from the group consisting of ivermectin, abamectin, doramectin, and combinations thereof, for treating or controlling parasites in a mammal. In a preferred aspect, the composition comprises a combination of ivermectin, abamectin, and doramectin.

[0008] Other objects and features will be in part apparent and in part pointed out hereinafter.DETAILED DESCRIPTION

[0009] The present invention generally relates to compositions for combating external and internal parasites in mammals, methods of using these compositions, and processes for preparing these compositions. Applicant has discovered that administration of an effective amount of a composition comprising a combination of macrocyclic lactones selected from the group consisting of ivermectin, abamectin, and doramectin (e.g., a three-way combination of ivermectin, abamectin, and doramectin) is effective in the treatment, control, and prevention of a wide range parasitic infections in mammals. The compositions and associated methods of use are not only convenient for the user because they combine multiple actives but may combat resistance to certain macrocyclic lactones.

[0010] Applicant has also unexpectedly discovered that compositions with enhanced stability comprising a combination of ivermectin, abamectin, and doramectin at relatively high total macrocyclic lactone concentrations can be achieved by using a unique combination of ingredients as described herein. The solubilities of ivermectin, abamectin, and doramectin in various oils such as sesame oil or castor oil are not only comparatively different but also relatively low. Thus, formulating stable compositions with a combination of these active ingredients at relatively high total macrocyclic lactone concentrations is exceptionally challenging.

[0011] Further, applicant has surprisingly found that the compositions described are even stable for prolonged storage times at elevated temperatures and relative humidities. This enhanced stability can beneficially provide for expanded use of the compositions and shelf life in geographies and environments where ambient conditions and / or storage facilities do not provide for ideal or conventional pharmaceutical storage conditions (i.e., relatively hot and / or humid environments). In addition to enhanced stability, the compositions described herein possess properties (e.g., dispensability and release properties) especially suitable for injectables.Compositions

[0012] The active ingredients contained in the compositions described herein belong to the class of avermectins and are classified structurally as macrocyclic lactones. Avermectin compounds are potent antiparasitic agents against a wide range of internal and external parasites. The compoundswhich belong to this class are either natural products or are semi-synthetic derivatives thereof. The proposed mechanism of action of avermectins is due to the potentiation of GABA-mediated neuronal inhibitory action, promoting neuronal hyperpolarization, thus inhibiting nerve transmission. In parasites, it is believed that the action of these compounds occurs in the independent GABA chlorine channels by blocking the response of the ibotenic acid, which is a specific glutamate activation gate. Consequently, there is an increase in membrane permeability to chlorine ions, with reduction of cell resistance leading to death of the parasite by hyperexcitation.

[0013] The structure of these compounds have a complex 16-membered macrocyclic lactone ring as follows:

[0014] As used herein, the term “macrocyclic lactone” is inclusive of physiologically acceptable salts thereof. Macrocyclic lactones such as avermectins according to the present invention include, but are not limited to, ivermectin, doramectin, abamectin, milbemycin, and moxidectin. Preferred macrocyclic lactones include, but are not limited to, ivermectin, doramectin, abamectin, milbemycin, and moxidectin. In a preferred embodiment, the antiparasitic composition of the present invention comprises a combination of ivermectin, abamectin, and doramectin.

[0015] As noted, the compositions described herein can contain a relatively high total concentration of macrocyclic lactones (e.g., total concentration of ivermectin, abamectin, and doramectin) is about 1 wt.% or greater, about 2 wt.% or greater, about 3 wt.% or greater, about 4 wt.% or greater, about 5 wt.% or greater, about 6 wt.% or greater, about 7.5 wt.% or greater, or about 10 wt.% or greater. In various embodiments, the total concentration of macrocyclic lactones in the composition is from about 1 wt.% to about 10 wt.%, from about 1 wt.% to about 7.5 wt.%, from about 1 wt.% to about 5 wt.%, from about 2 wt.% to about 10 wt.%, from about 2 wt.% to about 7.5 wt.%, from about 2 wt.% to about 5 wt.%, from about 3 wt.% to about 10 wt.%, from about 3 wt.% to about 7.5 wt.%, from about 3 wt.% to about 5 wt.%, from about 4 wt.% to about 10 wt.%, from about 4 wt.% to about 7.5 wt.%, or from about 4 wt.% to about 5 wt.%.

[0016] The concentration of each macrocyclic lactone can be about 0.25 wt.% or greater, about 0.5 wt.% or greater, about 0.75 wt.% or greater, about 1 wt.% or greater. Also, the concentration of each macrocyclic lactone can be about 5 wt.% or less, about 4 wt.% or less, about 3 wt.% or less, about 2.5 wt.% or less, about 2 wt.% or less, about 1 .5 wt.% or less, or about 1 wt.% or less.

[0017] In various embodiments, the concentration of ivermectin is about 0.25 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, 0.75 wt.% to about 3 wt.%, or about 1 wt.% to about 2 wt.%.

[0018] In various embodiments, the concentration of abamectin is about 0.25 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, 0.75 wt.% to about 3 wt.%, or about 1 wt.% to about 2 wt.%.

[0019] In various embodiments, the concentration of doramectin is about 0.25 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, about 0.75 wt.% to about 3 wt.%, or about 1 wt.% to about 2 wt.%.

[0020] In various compositions, the weight ratio of doramectimabamectin can be from about 1 .5:1 to about 1 :1 .5 or about 1 :1. Further, the weight ratio of ivermectin:doramectin or abamectin can be from about 3:1 to about 1 .5:1 or about 2:1 . In some embodiments, the overall weight ratio of doramectin:abamectin:ivermectin is about 1 :1 :2. In some preferred compositions, the weight ratio of doramectimabamectin is about 1 :1; the ratio of ivermectin :doramectin or abamectin is about 2:1; and the overall ratio of doramectimabamectimivermectin is about 1 :1 :2.

[0021] For example, compositions can include: antiparasitic composition comprising ivermectin in an amount of about 0.25 wt.% to about 5 wt.%, abamectin in an amount of about 0.25 wt.% to about 5 wt.%, and doramectin in an amount of about 0.25 wt.% to about 5 wt.%. In an embodiment, the antiparasitic composition of the present invention comprises ivermectin in an amount of 2 wt.%, abamectin in an amount of about 1 .2 wt.%, and doramectin in an amount of about 1 wt.%. The combination veterinary compositions can be formulated according to the methods described herein.

[0022] In general, the compositions described herein comprise a carrier, particularly a carrier suitable for an injectable composition. In various embodiments, the compositions described herein comprise at least one oil. Oils include, for example, natural or modified natural oils, fats, waxes, ethoxylated oils, and hydrogenated oils. Examples of oils include various vegetable oils which are extracted from seeds, fruits and other parts of plants. Specific vegetable oils include olive oil, sunflower oil, soybean oil, sesame oil, corn oil, cottonseed oil, coconut oil, castor oil, and various modified oils thereof. In various embodiments, the compositions described herein comprise castor oil and / or sesame oil. In various embodiments, the compositions described herein comprise a combination of oils, such as castor oil and sesame oil.

[0023] Typically, the carrier (e.g., oil) constitutes a high percentage or majority of the composition. For example, the concentration of one or more oils (e.g., castor and sesame oil) in the compositions can be about 40 wt.% or greater, about 50 wt.% or greater, about 60 wt.% or greater, about 70 wt.% or greater, or even about 80 wt.% or greater.

[0024] The compositions described herein can comprise N-methylpyrrolidone (NMP). Surprisingly, NMP has been found to contribute to enhance compositional stability. Without being bound by theory, NMP is believed to solubilize macrocyclic lactone active ingredients (particularly, each of ivermectin, abamectin, and doramectin) in the composition at even at relatively high total macrocyclic lactone concentrations. The concentration of NMP in the compositions can be, for example, about 5 wt.% or greater, about 7.5 wt.% or greater, about 10 wt.% or greater, or about 15 wt.% or greater. The concentration of NMP in the compositions can be from about 5 wt.% to about 25 wt.%, from about 5 wt.% to about 20 wt.%, from about 5 wt.% to about 15 wt.%, from about 5 wt.% to about 10 wt.%, from about 7.5 wt.% to about 25 wt.%, from about 7.5 wt.% to about 20 wt.%, from about 7.5 wt.% to about 15 wt.%, from about 10 wt.% to about 25 wt.%, from about 10 wt.% to about 20 wt.%, or from about 10 wt.% to about 15 wt.%

[0025] The compositions described herein can comprise benzyl benzoate. This ingredient has been found to be particularly effective to provide a stable and injectable compositions. The concentration of benzyl benzoate in the compositions can be, for example, about 5 wt.% or greater, about 10 wt.% or greater, about 15 wt.% or greater, or about 20 wt.% or greater. The concentration of benzyl benzoate in the compositions can be from about 5 wt.% to about 30 wt.%, from about 5 wt.% to about 25 wt.%, from about 5 wt.% to about 20 wt.%, from about 10 wt.% to about 30 wt.%, from about 10 wt.% to about 25 wt.%, from about 10 wt.% to about 20 wt.%, from about 15 wt.% to about 30 wt.%, from about 15 wt.% to about 25 wt.%, from about 15 wt.% to about 20 wt.%, from about 20 wt.% to about 30 wt.%, or from about 20 wt.% to about 25 wt.%.

[0026] Optionally, the composition may contain one or more auxiliary excipients including antioxidants, preservatives and co-solvents. However, development of a parenteral composition utilizing an avermectin requires evaluating the interaction between the drug and the other carriers and excipients of the composition. Co-solvents, for example, can include esters, for example, ethyl oleate, tributyl citrate, tri butylacetyl citrate, and C8 / C10 medium chain propylene glycol diesters (e.g., Miglyol 840). Preservatives can also be used to ensure the overall stability of the composition. Depending upon whether the compositional preservative is added to control or prevent antimicrobial growth and / or as an antioxidant to control or prevent chemical reactions, the amounts of each preservative can range from about 0.01% to about 2% by weight and / or volume of the composition.Methods of Use

[0027] Various methods of combating ectoparasites and / or endoparasites in a mammal comprises administration (e.g., via subcutaneous injection) of a therapeutically effective amount of the compositions described herein to a mammal in need thereof. According to various methods described herein, an antiparasitic composition comprising ivermectin, abamectin, doramectin, andcombinations thereof, is administered to a mammal to treat or prevent a parasitic infection or infestation. In a preferred embodiment, an antiparasitic composition comprising: (a) a combination of ivermectin, abamectin, and doramectin, (b) NMP, and (c) an oil carrier is administered to a mammal in need thereof to treat or prevent a parasitic infection or infestation.

[0028] Among the parasites (adult and larval) which may be controlled with the compositions described herein are gastrointestinal nematodes, ticks, and fly larvae. Gastrointestinal nematodes infections treatable by the compositions of the present invention include, but are not limited to, infections of Haemonchus contortus, Haemonchus placei, Haemonchus similis, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia pectinata, Cooperia punctata, and Oesophagostomum radiatum. The compositions described herein have been found to unexpectedly effective against Haemonchus sp. Ticks treatable by the compositions described herein include, for example, Rhipicephalus (Boophilus) microplus ticks. Fly larvae infections treatable by the compositions of the present invention include, but are not limited to, infections of Dermatobia hominis, Haemotobia irritans, Stomoxis calcitrans, and buffalo fly. Compositions described herein can be used to treat myiasis caused by Cochliomyia hominivorax larvae (hookworms) and Dermatobia hominis larvae, which cause berne.

[0029] The compositions of the invention can be administered in a way appropriate to the specific use envisaged, the particular host animal and weight of host mammal beingtreated, the parasite or parasites involved, degree of infestation, etc., according to standard veterinary practice. Preferably, the compositions of the present invention are formulated for parenteral administration, particularly subcutaneous injection. Injection of the composition can be accomplished using a suitable veterinary dosing device, such as a syringe or an injection gun of the types available from such suppliers as NJ Phillips Injector, Instrument Supplies and Simcoe. Choice of the injection device depends on a number of factors such as the viscosity of the composition, capability to deliver a unit dose of active drug in field conditions, etc., and according to standard veterinary practice.

[0030] The compositions described herein a particularly useful for treating or preventing parasitic infections in cows. The cow, can be for example, 7 months or older, 8 months or older, 9 months or older, 10 months or older, 11 months or older, or 12 months or older.

[0031] The amount of avermectins for the compositions can be measured by the amount of active agent per weight of the mammal beingtreated. In an embodiment of the invention, the amount of active agent can range from about 0.01 to about 100 mg / kg, where mg refers to the weight of the bioactive agent and kg refers to the weight of the mammal beingtreated. In an embodiment of the invention, the amount of bioactive agent ranges from about 0.05 mg / kg to about 10 mg / kg. In another embodiment of the invention, the amount of bioactive agent ranges from about 0.1 mg / kg to about 5mg / kg. In a preferred embodiment of the invention, the antiparasitic composition is administered at a dosage level of 1 ml / 50 kg of the mammal.In various embodiments, the antiparasitic composition administered comprises from about 200 to about 1200 pg of ivermectin, from about 120 to about 720 pg of abamectin, and from about 110 to about 660 pg of doramectin per kg of weight of the mammal. In certain embodiments, the antiparasitic composition administered comprises about 400 pg of ivermectin, about 240 pgof abamectin, and about 220 pg of doramectin per kg of weight of the mammal.

[0032] The antiparasitic composition according to the present invention may optionally be administered on a daily basis, twice per day, every second day, or on a weekly basis. In some embodiments, the antiparasitic composition of the present invention is administered at least once per day. The total (daily) amount of the antiparasitic composition may be administered optionally in one single dose or distributed over several doses, e.g., one dose in the morning and one dose in the evening. In other embodiments, the composition is administered once over a period of about 1 , about 2, about 3, about 4, about 5, or about 6 months.Process for Preparation

[0033] The compositions of the present invention can be prepared using dissolution and mixing procedures as described herein to provide an easily controllable dosage of the drug and an easily handled product. An exemplary composition is prepared by forming a mixture of a solvent and ivermectin; stirrin the mixture until the solvent and ivermectin dissolve; adding abamectin to the mixture; stirringthe mixture until the abamectin dissolves; adding doramectin to the mixture; stirring the mixture until the doramectin dissolves; adding a preservative to the mixture; stirringthe mixture until a homogenous solution comprising the preservative is obtained; and adding a veterinarily acceptable carrier to the mixture.

[0034] The veterinary composition for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the veterinary composition in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.Definitions

[0035] The term “mammal” refers to an individual that is a member of the taxonomic classMammalia. Non-exclusive examples of animals include dogs, cats, horses, swine, sheep, goats, and cows.

[0036] The term “effective amount” refers to the amount necessary or sufficient to elicit a desired effect. For example, an effective amount of a composition of the present invention will be the amount required to elicit a reduction of parasite in a mammal.

[0037] The term “preservative” refers to a substance or substances which are added to the compositions of the present invention to protect them from microbial action and chemical reaction. The term includes antioxidants (free radical scavengers) which protect the compositions from chemical reactions by scavenging free radicals thereby eliminating electron transferfrom one compound or substance to another.

[0038] The term “veterinarily acceptable” indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a composition, and / or the animal beingtreated therewith.

[0039] The terms “treatment”, “treating”, and the like, refer to reversing, alleviating, or preventing the disorder or condition to which such term applies. Thus, treatment can refer to administration of the composition of the present invention to an animal that is not at the time of administration afflicted with the disorder or condition.

[0040] When introducing elements of the present invention or the preferred embodiments thereof, the articles “a”, “an,” “the”, and “at least one” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0041] The words “preferred” and “preferably” refer to embodiments of the disclosure that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that otherembodiments are not useful and is not intended to exclude other embodiments from the scope of the disclosure.

[0042] By “consisting of” is meant including, and limited to, whatever follows the phrase “consisting of”. Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements may be present. By “consisting essentially of” is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, butthat other elements are optional and mayor may not be present depending on whether they materially affect the activity or action of the listed elements.

[0043] Also herein, the recitations of numerical ranges by endpoints include all numbers within that range (for example, 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0044] For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. Also, as appropriate, any combination of two or more steps may be conducted simultaneously.

[0045] Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” “various embodiments, or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure.

[0046] Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0047] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.EXAMPLES

[0048] Example 1. Formulation Preparation

[0049] The composition presented in table 1 was prepared as follows and shown in the flowchart below: a mixture of NMP and ivermectin was prepared; the mixture was stirred untilthe NMP and ivermectin dissolved; abamectin was added to the mixture; the mixture was stirred until the abamectin dissolved; doramectin was added to the mixture; the mixture was stirred until the doramectin dissolved; benzyl benzoate was added to the mixture; the mixture was stirred until a homogenous solution comprising the benzyl benzoate was obtained; and castor oil followed by sesame oil was added to composition.Table 1.

[0050] Example 2. StabilityTesting

[0051] Pilot scale batches of the composition of Example 1 were tested for stability under (1 ) accelerated conditions at 40°C at 75% relative humidity for 6 months and (2) extended storage conditions at 30°C at 75% relative humidityfor up to 36 months. The results of the testing show no decrease in concentration of the macrocyclic lactones outside of specification limits up to 36 months. The figures below show the concentration of each macrocyclic lactone during the extended storage conditions stability test.

[0052] Example 3. In vitro evaluation of the combination of doramectin, ivermectin, and abamectin against Haemonchus sp.

[0053] This study aimed to evaluate the in vitro synergistic effect of different combinations of macrocyclic lactones against Haemonchus sp. larvae in infective stage (L3). The in vitro test wasperformed following a matrixof combinations built for the combination of abamectin +ivermectin and doramectin using 125 experimental points, reproduced in duplicate as detailed in the Table 2 below.Table. 2 Matrix of the trial on the response surface of the different combinations of abamectin (ABA), ivermectin (IVM), and doramectin (DRM). Concentration of molecules in the combination, expressed in micromolar (pM), and ratio of molecules in the combination, expressed in percentage (%).

[0054] Two cattle subjects were chosen to be experimentally infected by oral route, with a dose of1 ,000 L3 / kg (110,000 and 150,000 L3) of a pure isolate of Haemonchus sp., previously characterizedphenotypically as resistant to ivermectin. The feces of both animals were used to perform fecal cultures (Roberts & O'Sullivan, 1950), aiming to produce L3 to be used in the in vitro test.

[0055] The in vitro effect of the combination of two or three different avermectins (abamectin, doramectin, and ivermectin) resulted in an unexpected significant synergistic effect against Haemonchus sp. obtained from cattle. The in vitro effect of the combination of two orthree avermectins showed to be higherthan the effect of non-combined molecules.

[0056] The in vitro synergistic effect of the triple combination presented higher results than the double combinations. The in vitro synergism level against gastrointestinal nematodes in cattle by the combination of different avermectins is dependent on the used molecules and proportions, and the combination in a ratio similar to a formulation containing 1 .2% ABA + 2% IVM + 1.1% DRM showed a high synergism SCORE against an ivermectin-resistant Haemonchus sp. isolate.

[0057] The inhibition of larval migration at each experimental point was used as the dependent variable, with the value being expressed as a percentage and being calculated according to the following formula: inhibition % = number of non-migrant larvae / (number of migrating larvae + number of non-migrant larvae).

[0058] The results obtained in the larval migration inhibition test (TIML) were used to build response surfaces and to determine the synergism score of the different combinations and the ratios of each combination. The online software SynergyFinderPlus (www.synergyfinder.or / ) was used to perform data analysis and to build the response surface plots. The combinations were compared to each other, according to the mixture synergy score, calculated using the Loewe additivity model (Loewe, 1953), which captures the molecular interaction relationships by compa ringthe change in the power of the dose-response curves between combined and non-combined molecules.

[0059] The synergistic effect was considered as significant if p < 0.05 (p < 5e-2) or, in case of absence of p value, the synergism was considered as significant according to what was previously established by the SynergyFinder 2.0 use manual, (synergyfinder.fimm.fi / synergy / synfin_docs / ), currently unavailable, being, accordingto the authors: antagonism = score lower than -10, additism = score between -10 and 10, and synergism = score higherthan 10.

[0060] All drugs, at their highest concentration and when not combined, showed an inhibition mean higher than 30%, and inhibitions lower than 10% were seen at the lowest concentration.

[0061] In the possible two-by-two combinations of the three avermectins, the highest mean inhibition by TIML was observed in the double combination of ABA + IVM (38.77%), followed by the double combinations of IVM + DRM (37.12%) and ABA + DRM (35.46%).

[0062] All combinations of avermectins showed a significant mean synergistic effect (p < 0.05). Among the evaluated combinations, the combination of ABA + IVM + DRM was the one that showedthe highest mean synergism score (21 .89), followed by the combinations of IVM +DRM (14.88), ABA +IVM (14.59), and ABA + DRM (13.03). & doramectin

[0063] Example 4. Acaricidal efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1.2% abamectin against the tick Rhipicephalus (Boophilus) microplus in cattle - Field test.

[0064] The study aimed to evaluate the acaricidal efficacy of an injectable composition based on 2% ivermectin, 1 .1% doramectin, and 1 .2% abamectin consistent with Example 1 against the tick Rhipicephalus (Boophilus) microplus in cattle with natural infestation by a test at field level.

[0065] The referred study was conducted with animals selected accordin to the criteria for inclusion and exclusion, with a total of 20 randomly included cattle subjects, being 1 control group (no treatment) and 1 treated group (n = 10 for each group).

[0066] In order to evaluate the results referring to the acaricidalefficacy, the arithmetic means of engorged females in the Control Group were taken as values of 50.9, 54.6, and 77.4, respectively, for days D-3, D-2, and D -1 , then obtaining a pre-treatment arithmetic mean of 60.97 engorged females. For the Treated Group, the arithmetic means of engorged females were 47.2, 58.4, and 77.7,respectively, for days D-3, D-2, and D-1 , then obtaining a pre-treatment arithmetic mean of 61 .1 engorged females.

[0067] Through the statistical analysis, it was seen that there was no significant difference between the experimental groups for the mean values of engorged females in the three days preceding the treatment (p = 1.0000).

[0068] Statistical comparisons between the posttreatment means of the Control and Treated Groups showed a significant difference (p ≤ 0.05) on days D+3, D+7, D+14, D+21 , D+28, D+35, D+42, D+49, and D+56.

[0069] The results related to the acaricidal efficacy were presented by comparing the posttreatment mean counts of engorged females present in the animals between the Control and Treated Groups. Therefore, the obtained results were the following for arithmetic efficiency: D+3 = 81 .59%; D+7 = 96.59%; D+14 = 97.95%; D+21 = 97.36%; D+28 = 97.5%; D+35 = 97.85%; D+42 = 95.82%; D+49 = 93.9%; D+56 = 79.88%; and D+63 = 35.34%.

[0070] In order to consider a product as an acaricide, the latter should present a minimum 95% efficacy in the evaluations performed 7 and 14 days after the treatment, that is, at times D+7 and D+14. Thus, the test composition presented an acaricidal efficacy against R. microplus in naturally infested cattle higher than 96% on these two dates.

[0071] Example 5. Acaricidal efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1.2% abamectin against the tick Rhipicephalus (Boophilus) microplus in cattle - Conventional and modified stable test

[0072] The study aimed to evaluate the acaricidal efficacy on the evolutionary forms already present on the animal, as well as the prophylactic action on a reinfestation of an injectable formulation based on 2% ivermectin, 1.1 % doramectin, and 1 .2% abamectin against the tick R. microplus in artificially infested cattle (Stable Test).

[0073] The referred study was conducted with animals selected accordingto the criteria for inclusion and exclusion, randomly including a total of 21 cattle subjects, being 1 control group (no treatment), 1 group treated with 2% ivermectin, 1 .1% doramectin, and 1 .2% abamectin, and 1 group treated with a product based on 4% ivermectin (n = 7 for each group).

[0074] The results were set by comparing data among the different 3 groups (Control, Treated 1 , and Treated 2). The arithmetic means of engorged females detached from the Control Group were 33.00;29.57, and 24.43, respectively, for days -3, -2, and -1 , so obtaining a mean of these 3 pretreatment days of 29.00 engorged females. Referring to Treated 1 , the arithmetic means of detached engorged females were 37.57, 30.00, and 22.71 , respectively, for days -3, -2, and -1 , so obtaining a mean of these 3 pretreatment days of 30.10 engorged females. As for Treated Group 2, the arithmetic means of detached engorged females were 41.43, 32.00, and 26.14, respectively, for days -3, -2, and -1 , so obtaining a mean of these 3 pretreatment days of 33.19 engorged females. There was no statistical difference between the experimental groups for the mean values of engorged females on days -3, -2, and 1 that preceded the treatment. Thus, the p values found were: D-3: 0.9825; D-2: 0.9661 ; D-1 : 0.7926, and for the mean of the 3 pretreatment days = 0.9751 .

[0075] After treatment, the following averages were observed for the different groups:

[0076] Control Group: D+1 : 44.57; D+2: 18.29; D+3: 40.29; D+4: 40.43; D+5: 44.43; D+6: 48.14; D+7: 78.71 ; D+8: 99.43; D+9: 74.00; D+10: 97.57; D+1 1 : 79.00; D+12: 79.43; D+13: 60.29; D+14: 49.86;D+15: 56.43; D+16: 45.29; D+17: 61.43; D+18:17.86; D+19: 47.57; D+20: 42.43; D+21 : 53.71 ; D+22: 35.43; and D+23: 37.86.

[0077] Treated Group 1 : D+1 : 8.57; D+2: 2.57; D+3: 0.57; D+4: 0.71 ; D+5:

[0078] 0.86; D+6: 0.71 ; D+7: 0.57; D+8: 0.86; D+9: 1.29; D+10: 2.71 ; D+11 : 0.71 ; D+12: 0.71 ; D+13: 1.86; D+14: 0.00; D+15: 1.29; D+16: 0.86; D+17: 1 .71 ; D+18: 0.43; D+19: 0.14; D+20: 0.00; D+21 : 0.00; D+22: 0.57; and D+23: 0.00.

[0079] Treated Group 2: D+1 : 20.00; D+2: 3.71 ; D+3: 7.86; D+4: 9.00; D+5:

[0080] 5.86; D+6: 2.86; D+7: 3.57; D+8: 15.71 ; D+9: 8.57; D+10: 10.57; D+11 : 12.29; D+12: 6.71 ;D+13: 3.86; D+14: 6.00; D+15: 8.86; D+16: 5.86; D+17: 7.00; D+18: 1.00; D+19: 6.86; D+20: 3.00; D+21 : 2.00; D+22: 1 .29; and D+23: 2.14.

[0081] The comparison between the means of the experimental groups showed that there was no statistical difference for day +1 . However, there was a difference between the Control Group and Treated Group 1 for days +2, +3, +4, +5, +6, +7, +8, +9, +10, +1 1 , +12, +13, +14, +15, +17, +18, +20, +21 , +22, and +23. It is stressed that there was no significant difference when comparing the treated groups.

[0082] The percentages of acaricidal efficacy in cattle artificially with Rhipicephalus (Boophilus) microplus treated with the formulation based on 2% ivermectin, 1 .1% doramectin, and 1.2% abamectin (Treated Group 1), administered by subcutaneous route, was effective for the treatment (experimental infestations) when compared to the Control Group (no treatment) and the Treated Group (product based on 4% ivermectin), showing mean values above 95% for the challenge 42 days after the treatment. As exposed, it is concluded that the formulation based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin (Test composition) was effective for the acaricidal treatment (experimental infestations) during 66 days after the treatment.

[0083] Example 6. Anthelmintic efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1.2% abamectin (Test composition) against artificial infections by Haemonchus placei, Cooperia pectinata, Cooperia punctata, Oesophagostomum radiatum, and Trichostrongylus axei - CONTROLLED TEST WITH NECROPSY.

[0084] The referred study aimed to evaluate the anthelmintic efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin against gastrointestinal nematodes in cattle: Haemonchus placei, Cooperia punctata, C. pectinata, and Oesophagostomum radiatum in cattle artificially infected by a controlled test.

[0085] The study was conducted with animals selected according to the criteria for inclusion and exclusion, with a total of 21 cattle subjects being randomly included, being 1 control group (no treatment), 1 group treated with 2% ivermectin, 1 .1% doramectin, and 1 .2% abamectin and 1 group treated with a product based on 4% ivermectin (n = 7 for each group). After distributing the animals across the groups, the treatments were performed on DO as shown in the table below.

[0086] EPG and fecal culture were performed on days +1, +3, +5, +7, +9, +11 , and +13 after the treatment.

[0087] The results were set by comparing the data between the different 3 groups (Control, Treated1 , and Treated 2). The results of the arithmetic and geometric mean values of EPG in the pretreatment period were the following:

[0088] Control Group: D-7: 364.3; D-5: 585.7; D-3: 492.9; and the three-day mean: 481 .0.

[0089] Treated Group 1 : D-7: 500.0; D-5: 342.9; and D-3: 378.6; and the three-day mean: 407.1.

[0090] Treated Group 2: D-7: 314.3; D-5: 607.1; and D-3: 978.6; and the three-day mean: 633.3.

[0091] It is stressed that there was no significant difference for the Day -3 means of the Control, Treated 1 and Treated 2 Groups (bilateral p = 0.9751).

[0092] The results of the mean fecal exams (EPG) for the times after treatment were the following:

[0093] Group control, D+1 = 464.3; D+3 = 821.4; D+5 = 500.0; D+7 = 507.1 ; D+9 = 578.6; D+11 = 385.7; and D+13 = 664.3;

[0094] Treated Group 1, D+1 = 328.6; D+3 = 264.3; D+5 = 114.3; D+7 = 85.7; D+9 = 14.3; D+11 = 21 .4; and D+13 = 21.4;

[0095] Treated Group 2, D+1 = 500.0; D+3 = 657.1; D+5 = 85.7; D+7 = 214.3; D+9 = 57.1; D+11 = 21.4; and D+13 = 35.7.

[0096] The statistical comparisons between the posttreatment means of Control and Treated Groups 1 presented a significant difference (p < 0.05) on days D+5, D+7, D+9, D+11 , and D+13. Referring to the comparison of means between the Control and Treated Groups 2, it was seen that there was a significant difference (p £ 0.05) on days D+5, D+11 , and D+13. It is stressed that there was no statistical difference when comparing the means of Treated 1 and Treated 2Groups.

[0097] The study showed that the test product, an association based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin (Test composition), administered by the subcutaneous route, at a dose of 1 mL per 50 kg of body weight, based on the arithmetic mean, was highly effective in removingH. place! (98.1 %), T. axei (100%), O. radiatum (99.3%), C. pectinata (95.3%), and C. punctata (91 .6%) in the experimental conditions of the present study.

[0098] Example 7. Anthelminthic efficacy of an injectable formulation based on 2% ivermectin,I.1% doramectin, and 1.2% abamectin (Test composition) against natural infections by gastrointestinal helminths in cattle (field test).

[0099] The present study aimed to evaluate the anthelmintic efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin against natural infections by gastrointestinal helminths in cattle, by an EPG reduction test at field level.

[0100] The study was conducted with animals selected according to the criteria for inclusion and exclusion, with a total of 20 cattle subjects being randomly included, 1 control group (no treatment), 1 group treated with 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin and 1 controlgroup (no treatment).

[0101] After distributing the animals across the groups, the treatments were performed on DO according to the table below.

[0102] EPG and fecal culture exams were performed on days +1 , +14, +21 , +28, +35, and +42 after the treatment.

[0103] The results were set by comparing data between the groups (Control and Treated). The results of the arithmetic and geometric mean values of total EPG counts in the pretreatment period were the following:

[0104] Control Group: D-7 = 315.0 and D-2 = 250.0, and the mean of D-7 and D-2 was 282.5

[0105] Treated Group: D-7 = 210.0 and D-2 = 335.0 and the mean of D-7 and D-2 was 272.5.

[0106] It is stressed that there was no significant difference between the means of days D-7 and -2 of the Control and Treated Groups (two-tailed p = 0.9699), which demonstrates that the animal ranking allowed for homogeneity in the mean EPG values per animal, with both groups being balanced in terms of parasite load.

[0107]

[0108] The results of the mean fecal examinations (EPG) for the times after treatment were as follows:

[0109] Control Group: D+7 = 340.0; D+14 = 415.0; D+21 = 470.0; D+28 = 175.0; D+35 = 370.0; and D+42 = 260.0.

[0110] Treated Group: D+7 = 70.0; D+14 = 20.0; D+21 = 35.0; D+28 = 25.0; D+35 = 40.0; and D+42 = 170.0.

[0111] The statistical comparisons between the posttreatment means of the Control and Treated Groups showed a significant difference (p < 0.05) on days D+7, D+14, D+21 , D+28, and D+35.

[0112] The results related to the anthelmintic efficacy in the field were presented by comparing the mean posttreatment EPG counts of the animals between the Control and Treated Groups. Thus, the results obtained for efficacywere the following: D+7 = 79.41%; D+14 = 95.18%; D+21 = 92.55%; D+28 = 85.71 %; D+35 = 89.19%; and D+42 = 34.62%.

[0113] The study obtained values higher than the minimum required on days +14, +21 , +28, and +35 after the treatment. Thus, the test product proved to be effective as an anthelmintic when used in cattle, in a field test, under the conditions of the present study.

[0114] Example 8. Evaluation of the boticidal efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1.2% abamectin (Test composition), against Dermatobia hominis (bot) larvae in cattle - Field Test.

[0115] The study aimed to evaluate the boticidal efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin against Dermatobia hominis larvae in cattle with natural infestation, by a test at the level of field.

[0116] The referred study was conducted with animals selected accordin to the criteria for inclusion and exclusion, with a total of 20 randomly included cattle subjects, being 1 control group (no treatment) and 1 treated group (n = 10 for each group). Once the animals were distributed across the groups, the treatments were performed on DO, as shown in the table below.

[0117] Counts of live larvae were performed on the entire animal on days D+7, D+14, D+21 , D+28, D+35, D+42, and D+56 after the treatment.

[0118] The results were set by comparing data between the 2 groups (Control and Treated 1).Referring to the results of the total counts of bots found on the animals after the randomization, the arithmetic mean of such bots found on day D-2 forthe Control Group was 40.0 and forthe Treated Group 38.5. It is stressed that there was no significant difference between the means of the Control and Treated Groups (double-tailed p = 0.8585).

[0119] Referringto the posttreatment evaluations, the results of the arithmetic means of bots found in the animals were the following:

[0120] Group control: D+7 = 45.9; D+14 = 48.3; D+21 = 43.4; D+28 = 42.1 ; D+35 = 40.9; D+42 = 34.8; D+49 = 31 .9; and D+56 = 29.5.

[0121] Treated Group: D+7 = 3.2; D+14 = 1 .3; D+21 = 0.3; D+28 = 0.3; D+35 = 1 .6; D+42 = 3.2; D+49 = 6.5; and D+56 = 7.7.

[0122] The statistical comparisons between the posttreatment means of the Control and Treated Groups showed a significant difference (p < 0.05) on days D+7, D+14, D+21 , D+28, D+35, D+42, D+49, and D+56.

[0123] Boticidal efficacy should be attested with results above 90% within 7 days. The referred study showed values higher than the minimum required on days +7, +14, +21 , +28, +35, and +42 after the treatment, and so the formulation based on 2% ivermectin, 1.1 % doramectin, and 1.2% abamectin (Test composition), proved to be efficient as a boticide for42 days, when used in cattle, in a field test.

[0124] Example 9. Evaluation of the larvicidal efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1.2% abamectin in cattle infested with Cochliomyia hominivorax larvae

[0125] The study aimed to evaluate the efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin in eliminating C. hominivorax larvae in artificially induced wounds in cattle.

[0126] The study was conducted with animals selected according to the criteria for inclusion and exclusion, with a total of 30 randomly included cattle subjects on day D-14, being 1 control group (no treatment), 1 group treated with 2% ivermectin, 1 .1% doramectin, and 1 .2% abamectin, and 1 group treated with a product based on 4% ivermectin (n = 10 for each group).

[0127] The treatments were performed according to the dose described in the table below for the animals belonging to the 2 treated groups on day DO.

[0128] The results were set by comparing data among the 3 groups (Control, Treated 1 and Treated 2).

[0129] The results were evaluated forthe presence of positive animals and the number of larvae recovered from control and treated animals among the days DO, D+1 , and D+2.

[0130] The Group I (control) presented a mean body weight of 306.9 ± 65.06 kg, the Group II (treated with the formulation based on 2% ivermectin, 1.1 % doramectin, and 1.2% abamectin) presented a mean body weight of 309.2 ± 56.54 kg, while the Group III (formulation based on 4% ivermectin) presented a mean body weight of 306.2 ± 66.72 kg. The performed statistical analysis did not detect a significant difference (p > 0.05) among the mean values of the three groups, so evidencing the homogeneous randomization of the animals in terms of body weight (double-tailed p = 0.9949).

[0131] The results showed that the test product obtained curative efficacy for C. hominivorax larvae and 90.9% (arithmetic efficacy) 48 h after the treatment.

[0132] Example 10. Evaluation of the preventive efficacy for Cochliomyia hominivorax larvae of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1.2% abamectin in artificially infested cattle

[0133]

[0134] The study aimed to evaluate the efficacy of an injectable formulation based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin in eliminating C. hominivorax larvae in wounds in cattle.

[0135] This study was conducted with animals selected accordin to the criteria for inclusion and exclusion, including a total of 30 randomly chosen cattle subjects, being 1 control group (without treatment), 1 group treated with the injectable formulation product based on 2% ivermectin, 1.1% doramectin, and 1 .2% abamectin on day -14, and 1 group treated with an injectable formulation based on 2% ivermectin, 1.1 % doramectin, and 1 .2% abamectin (n = 10 for each group).

[0136] All animals were evaluated forthe presence of live larvae and active screwworms in the wounds on days +1 , +2, and +3.

[0137] The results were set by comparing data among the 3 groups (Control, Treated 1, and Treated 2).

[0138] The Group I (control) presented a mean body weight of 363.5 ± 72.62 kgon day-14 and the Group II (treated on D -14) presented a mean body weight of 356.2 ± 65.26 kg on day -14, while the Group III (treated on D -7) presented a mean body weight of 361.6 ± 73.12 kg on day-14 and of 363.6 ± 73.12 on day -7. The statistical analysis performed did not detect a significant difference (p > 0.05)among the mean values of the three groups, so evidencing the homogeneous randomization of the animals in terms of body weight (double-tailed p = 0.9932). The results showed that the product formulation presented an efficacy of 100% in terms of prevention for 14 and 7 days after the treatment. The WAAVP guide for evaluating products intended for prophylactic and / or curative effect in screwworms sets a minimum efficacy of 90% for the indication to be accepted for this purpose. Therefore, based on the methodology employed and on the WAAVP Guide, the formulation based on 2% ivermectin, 1.1 % doramectin, and 1 .2% abamectin (Test composition) showed to be 100% effective in preventin the installation of infestations by C. homnivorax larvae for a 14-day period in wounds made in cattle.

Claims

WHAT IS CLAIMED:

1. An antiparasitic composition comprising a combination of macrocyclic lactones comprising ivermectin, abamectin, and doramectin.

2. The antiparasitic composition of claim 1 , wherein the total concentration of macrocyclic lactones is about 1 wt.% or greater, about 2 wt.% or greater, about 3 wt.% or greater, about 4wt.% or greater, about 5 wt.% or greater, about 6 wt.% or greater, about 7.5 wt.% or greater, or about 10 wt.% or greater.

3. The antiparasitic composition of claim 1 , wherein the total concentration of macrocyclic lactones is from about 1 wt.% to about 10 wt.%, from about 1 wt.% to about 7.5 wt.%, from about 1 wt.% to about 5 wt.%, from about 2 wt.% to about 10 wt.%, from about 2 wt.% to about 7.5 wt.%, from about 2 wt.% to about 5 wt.%, from about 3 wt.% to about 10 wt.%, from about 3 wt.% to about 7.5 wt.%, from about 3 wt.% to about 5 wt.%, from about 4 wt.% to about 10 wt.%, from about 4 wt.% to about 7.5 wt.%, or from about 4 wt.% to about 5 wt.%.

4. The antiparasitic composition of anyone of claims 1 to 3, wherein the concentration of each macrocyclic lactone is about 0.25 wt.% or greater, about 0.5 wt.% or greater, about 0.75 wt.% or greater, about 1 wt.% or greater.

5. The antiparasitic composition of anyone of claims 1 to 4, wherein the concentration of each macrocyclic lactone is about 5 wt.% or less, about 4 wt.% or less, about 3 wt.% or less, about 2.5 wt.% or less, about 2 wt.% or less, about 1 .5 wt.% or less, or about 1 wt.% or less.

6. The antiparasitic composition of anyone of claims 1 to 5, wherein the concentration of ivermectin is about 0.25 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, 0.75 wt.% to about 3 wt.%, or about 1 wt.% to about 2 wt.%.

7. The antiparasitic composition of anyone of claims 1 to 6, wherein the concentration of abamectin is about 0.25 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, 0.75 wt.% to about 3 wt.%, or about 1 wt.% to about 2 wt.%.

8. The antiparasitic composition of anyone of claims 1 to 7, wherein the concentration of doramectin is about 0.25 wt.% to about 5 wt.%, about 0.5 wt.% to about 4 wt.%, about 0.75 wt.% to about 3 wt.%, or about 1 wt.% to about 2 wt.%.

9. The antiparasitic composition of anyone of claims 1 to 8, wherein the weight ratio ofdoramectin:abamectin is from about 1 .5:1 to about 1 :1.5 or about 1 :1 .

10. The antiparasitic composition of anyone of claims 1 to 9, wherein the weight ratio of ivermectin:doramectin or abamectin is from about 3:1 to about 1 .5:1 or about 2:1 .

11. The antiparasitic composition of anyone of claims 1 to 10, wherein the overall weight ratio of doramectin:abamectin:ivermectin is about 1 :1 :2.

12. The antiparasitic composition of anyone of claims 1 to 11 , wherein the weight ratio of doramectiN:abamectin is about 1 :1 ; the ratio of ivermectin :doramectin or abamectin is about 2:1; and the overall ratio of doramectin:abamectin:ivermectin is about 1 :1 :2.

13. The antiparasitic composition of anyone of claims 1 to 12, further comprising N- methylpyrrolidone (NMP).

14. The antiparasitic composition of claim 13, wherein the concentration of NMP in the compositions is about 5 wt.% or greater, about 7.5 wt.% or greater, about 10wt.% or greater, or about 15 wt.% or greater.

15. The antiparasitic composition of claim 13, wherein the concentration of NMP in the compositions is from about 5 wt.% to about 25 wt.%, from about 5 wt.% to about 20 wt.%, from about 5 wt.% to about 15 wt.%, from about 5 wt.% to about 10 wt.%, from about 7.5 wt.% to about 25 wt.%, from about 7.5 wt.% to about 20 wt.%, from about 7.5 wt.% to about 15 wt.%, from about 10 wt.% to about 25 wt.%, from about 10 wt.% to about 20 wt.%, or from about 10 wt.% to about 15 wt.%.

16. The antiparasitic composition of anyone of claims 1 to 15, further comprising benzyl benzoate .

17. The antiparasitic composition of claim 16, wherein the concentration of benzyl benzoate in the composition is about 5 wt.% or greater, about 10 wt.% or greater, about 15 wt.% or greater, or about 20 wt.% or greater.

18. The antiparasitic composition of claim 16, wherein the concentration of benzyl benzoate in the composition is from about 5 wt.% to about 30 wt.%, from about 5 wt.% to about 25 wt.%, from about 5 wt.% to about 20 wt.%, from about 10 wt.% to about 30 wt.%, from about 10 wt.% to about 25 wt.%, from about 10 wt.% to about 20 wt.%, from about 15 wt.% to about 30 wt.%, from about 15 wt.% to about 25 wt.%, from about 15 wt.% to about 20 wt.%, from about 20 wt.% to about 30wt.%, or from about 20 wt.% to about 25 wt.%.

19. The antiparasitic composition of anyone of claims 1 to 18, further comprising a carrier.

20. The antiparasitic composition of claim 19, wherein the carrier comprises an oil.

21. The antiparasitic composition of claim 20, wherein the oil is selected from the group consisting of sesame oil, castor oil, and combinations thereof.

22. The antiparasitic composition of claim 20 or 21 , wherein the concentration of the oil in the composition is about 40 wt.% or greater, about 50wt.% or greater, about 60 wt.% or greater, about 70 wt.% or greater, or even about 80 wt.% or greater.

23. The antiparasitic composition of anyone of claims 1 to 22, wherein the composition comprises sesame oil and castor oil.

24. The antiparasitic composition of anyone of claims 1 to 23, wherein the antiparasitic composition is formulated for subcutaneous injection.

25. The antiparasitic composition of anyone of claims 1 to 24, wherein the antiparasitic composition comprises ivermectin in an amount of about 0.25 wt.% to about 5 wt.%, abamectin in an amount of about 0.25 wt.% to about 5 wt.%, and doramectin in an amount of about 0.25 wt.% to about 5 wt.%.

26. The antiparasitic composition of anyone of claims 1 to 25, wherein the antiparasitic composition comprises ivermectin in an amount of 2 wt.%, abamectin in an amount of about 1.2 wt.%, and doramectin in an amount of about 1 wt.%.

27. A method of treating or preventing a parasitic infection or infestation in a mammal by administering to the mammal an effective amount of the antiparasitic composition of anyone of claims 1 to 26.

28. The method of claim 27, wherein the administering is via subcutaneous injection.The method of claim 27 or 28, wherein the antiparasitic composition is administered at a dosage level of 1 ml / 50 kg of the mammal.

29. The method of any one of claims 27 to 29, wherein the antiparasitic composition administered comprises from about 200 to about 1200 pg of ivermectin, from about 120 to about720 g of abamectin, and from about 110 to about 660 pg of doramectin per kg of weight of the mammal.

30. The method of any one of claims 27 to 30, wherein the antiparasitic composition comprises 400 pg of ivermectin, 240 pg of abamectin, and 220 pg of doramectin per kg of weight of the mammal.

31. The method of any one of claims 27 to 30, wherein the mammal is a cow.

32. The method of anyone of claims 27 to 31 , wherein the parasitic infection or infestation originates from a gastrointestinal nematode, a tick, or fly larvae.

33. The method of any one of claims 27 to 32, wherein the parasitic infection or infestation originates from a gastrointestinal nematode or a gastrointestinal nematode comprising Haemonchus sp.

34. The method of claim 32 or 33, wherein the gastrointestinal nematode is selected from the group consisting of Haemonchus contortus, Haemonchus placei, Haemonchus similis, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia pectinata, Cooperia punctata, and Oesophagostomum radiatum.

35. The method of any one of claims 27 to 34, wherein the parasitic infection or infestation originates from a fly larva.

36. The method of claim 34, wherein the fly larva is selected from the group consisting of Dermatobia hominis, Haemotobia irritans, Stomoxis calcitrans, and buffalo fly.

37. The method of any one of claims 27 to 36, wherein the parasitic infection or infestation originates from Cochliomyia hominivorax (screw worm).

38. The method of any one of claims 27 to 37, wherein the parasitic infection or infestation originates from a tick.

39. The method of claim 38, wherein the comprises Rhipicephalus (Boophilus) microplus ticks.

40. The method of any one of claims 27 to 39, wherein the method treats myiasis caused by Cochliomyia hominivorax larvae (hookworms) and Dermatobia hominis larvae, which cause berne.

41. A method of preparing an antiparasitic composition comprising:a) preparing a mixture of N-methylpyrrolidone (NMP) and ivermectin; b) stirring the mixture until the N-methylpyrrolidone (NMP) and ivermectin dissolve; c) adding abamectin to the mixture; d) stirring the mixture until the abamectin dissolves; e) adding doramectin to the mixture; f) stirring the mixture until the doramectin dissolves; g) adding benzyl benzoate to the mixture; h) stirring the mixture until a homogenous solution comprising the benzyl benzoate is obtained; i) adding castor oil to the mixture; and j) adding sesame oil to the mixture.

Images