WO2013026117A1 - Non-residual, pour-on veterinary compositions, use, kit, and method for treating parasitic diseases - Google Patents

Abstract

In general, the present invention relates to veterinary compositions that can be used for treating parasitic diseases in animals, particularly dairy cattle, comprising avermectins and specific excipients acceptable for veterinary purposes. The present invention also relates to uses of said compositions, kits and improved method for treating parasitic diseases in animals.

Description

 NON-RESIDUE POUR ON VETERINARY COMPOSITIONS, USE, KIT, AND METHOD OF TREATMENT OF PARASITOSES FIELD OF THE INVENTION

 The present invention generally relates to. veterinary compositions useful in the treatment of parasitic diseases comprising avermectins and specific excipients acceptable for veterinary use.

 BACKGROUND OF THE INVENTION

 Parasitosis is classified as the main cause of losses in cattle production and dairy farming, being responsible for decreased production, retarded development of the animal and early mortality.

 In particular, endoparasitic and ectoparasitic interferes with the development and yield of animals, causing severe losses throughout their productive chain.

 Among the main ectoparasites that affect dairy cattle are tick, horn fly, berne, myiasis (scab) and mange.

 The tick is the main external parasite of dairy cattle (Boophilus microplus), because in addition to sucking blood, transmits diseases such as babesiosis (Babesia bovis and Babesia bigemina) and anaplasmosis (Anaplasma marginale). In addition, it degrades the animal's skin, decreases its milk production and, in severe cases of infestation, can lead to death.

The hornet fly (Haematobia irritans) is a blood-eating insect and resembles a domestic fly but is smaller in size. The fly eats the blood of the animals through constant and painful bites, which causes great discomfort, causing the animal to eat poorly, not sleep, and, consequently, the production of milk can decrease up to 50%.

 The berne is a fly larva (Dermatobia hominis), popularly known in Brazil as blowfly that settles on the animals' leather causing irritation and discomfort. They can puncture the leather and allow other parasites and microorganisms to enter.

 Myiases are wounds that contain fly larvae of the genera Dermatobia, Cordylobia, Calitroga, Lucilia, Sarcophaga, Chrysomya, Phormya, Gasterophilus, Wohlfahrtia and Cochliomya. The fly lays eggs in wounds, from which larvae that feed on the animal's flesh are born, hampering its development. The most common symptoms of myiasis are bad smell and constant bleeding.

 Scabies in cattle can be caused by mites, among which we can highlight the species Sarcoptes scabiei bovis, Psoroptes bovis and Chorioptes bovis.

Eridoparasitas generally ^'are parasites that are located in internal parts of hosts such as gastro - intestinal nematodes, commonly known as worms. They are internal parasites that hinder the development of animals and the youngest are the most susceptible to infestations, because their immune system is not able to generate efficient responses to fight them.

 These parasites occur enzootically and are responsible for significant economic losses, such as loss of productivity in meat and milk production and high mortality rates of calves, which may lead to a significant reduction in milk production and weight of infested animals.

The severity of the worms and the intensity of the infection are directly related to the worm species, besides several factors, such as the conditions climate, soil, vegetation, type of exploitation, breed and age of the animal, type of pasture and animal condition.

 The most common clinical signs of these infestations are weight loss, dry, goose bumps, anemia, weakness, and loss of appetite. In some cases, a swelling appears under the jaw, popularly called mumps.

 In general, parasite control is performed when damage to the animal is already occurring. At this stage the treatment becomes more difficult because the number of parasites is high and the environmental conditions are usually favorable to the multiplication and development of infestations, providing a high rate of reinfestation in animals. Thus, the most effective treatment remains the preventive one.

 The preventive treatments are performed by bathing, spraying or applying pour on products, and the chosen method will only be efficient if done correctly and if the parasites are not resistant to the active ingredients used in the compositions.

 Pour on products are those that can be applied directly to the back of animals and, therefore, are those that provide greater ease of application, as well as less stress for animals and greater safety for the applicator.

However, while advantages can be readily appreciated, pour-on products have some formulation complexity. This is because the formulations must have good adhesion to the animal's loin, good spreadability, good absorption, resistance to rain, temperature and weather variations, without causing burns or compromising the animal's leather. Furthermore, while highly desirable, formulations for pour on residues (ie leaving no residues in the meat or milk of the treated animal).

 In general, the treatment of these parasites is performed with several active principles, such as cypermethrin, chlorpyrifos, piperonyl butoxide, permethrin, neomycin sulfate, zinc oxide, citronellal, avermectins, among others.

 Avermectins are chemically related macrocyclic lactones naturally produced from the fermentation of the fungus Streptomyces avermectílis.

 In the fermentation process of S. avermectílis eight types of avermectins are produced (Ala, Alb, A2a, A2b, Bia, Blb, B2a, and B2b). Compounds "A" have a carbon 5-linked methyl (CH 3) radical, while group "B" has a hydrogen (H) attached to this carbon.

 Type "1" compounds have double bonds between carbons 22 and 23, while "2" types have single bonds.

The group "A" shows a butyl group (C4H9) bonded to carbon 25, and group "b" one isopropyl radical (C ₃ H _7).

 In this process the types that are produced in larger quantities are: A2a, Bia, and B2a.

 Bia avermectins are the most important because they have high efficacy with broad parasiticide spectrum. In industrial production, the separation of groups Bia and Blb is not possible, therefore the commercial products are mixtures of no less than 90% of group "a" and no more than 10% of group "b", being the activity of these two counterparts are almost identical.

Abamectin, also known as avermectin Bia, is a natural product obtained from the process of fermentation, serving as a starting point for the production of a semi-synthetic analogue (22, 23-dihydroavermectin B1 or ivermectin), the structure of which can be considered as a hybrid between components B1 and B2.

 Iivermectin was the first macrocyclic lactone to be commercialized and thanks to its broad spectrum of action, efficacy and clinical safety became the treatment of choice for cattle, sheep, goats, pigs and horses.

 In general, avermectins have high antiparasitic activity acting on arthropods and nematodes, presenting activity at extremely low dosages, and can be administered by various routes, such as oral, injectable and topical.

 Their mechanism of action is quite complex and not fully elucidated, but it is suggested that they cause increased permeability of chlorine ions, resulting in susceptible nematode and arthropod paralysis due to inhibition of gamma-aminobutyric acid neurotransmitter (GABA).

 This fact explains why these compounds do not act on cestodes and trematodes, since these organisms do not have GABA receptors.

 These compounds present low toxicity to mammals, as they do not cross the blood-brain barrier (BBB), and thus do not reach GABA receptors.

 Avermectins are drugs used extensively in food-producing animals, recommended worldwide for the treatment of endoparasites and ectoparasites for cattle over four months of age.

These compounds are of great importance in the prevention of pathologies in dairy herds. Critical factors to be overcome are the determination of the withdrawal time of these drugs and the monitoring of their residues in animal products intended for human consumption.

 The compounds intended for the prevention of endoparasitic and ectoparasitic mentioned leave residues in milk, which can be harmful to human health, and this persistence depends on a number of variables, including the amount of milk production at the time of treatment, the state of animal health, the type and amount of drug used, the route of administration and notably the type of vehicle used in the drug formulation.

 The presence of veterinary drug residues in milk is a public health problem that deserves special consideration as it has a number of consequences for human health.

 The consumption of milk with drug residues can cause hypersensitivity reactions / anaphylactic shock, changes in the fermentation process of lactic acid bacteria, which are more sensitive to drugs, preventing fermentation to occur satisfactorily, intestinal flora imbalance and potential teratogenic effects. .

 In addition to the direct damage to human health, the regular consumption of drug residues in milk may cause the selection of resistant bacterial strains, exerting a selective pressure on the intestinal flora of humans, favoring the growth of microorganisms with natural or acquired resistance. , or giving way to the emergence of resistance in enteropathogenic bacteria.

There are patent applications comprising veterinary formulations for treating parasitic diseases, which contain descriptions of the pour-on form, of which the following may be highlighted: GB 2,213,722, WO 9726895, PI 9607262-8, US 6,013,636, WO 0140446, NZ 336,139 and PI 9714236-0.

 In this context, the intensive production of high quality milk without antibiotic residues is extremely important, given the damage and consequences resulting from the rejection of contaminated milk above the tolerance levels, as well as the damage caused to human health.

 DESCRIPTION OF THE INVENTION

 To address the shortcomings of existing treatments, the depositor has developed improved pour-on veterinary compositions that are effective against a broad spectrum of parasitic agents in animals, particularly in dairy cattle.

 Advantageously, the compositions according to the present invention leave no residues of their constituent compounds in the milk or meat of the treated animals, as well as no symptoms of intoxication are detected.

 In addition, the veterinary compositions according to the present invention have good applicability and adhesion to the loin of the animal without causing burns or staining on the leather, especially in the applied regions, including white areas (most susceptible to staining).

Generally, as used herein, "veterinary composition" means a pour-on composition suitable for veterinary use, especially in dairy cattle, containing at least one avermectin and acceptable excipients for veterinary use. By "non-residual" is meant that the composition according to the present invention, besides being effective in the treatment of parasitic diseases, leaves substantially no residue of its constituent compounds, especially of active principle, in the milk or meat of the treated animals.

 Thus, the present invention relates to non-residual veterinary pouron compositions comprising at least one avermectin and specific veterinary acceptable excipients. The advantages observed are the result of a specific qualitative and quantitative selection of active ingredients and excipients.

 In accordance with the present invention, the active ingredients are employed as avermectins, which may be selected from one or more of the avermectins Ala, Alb, A2a, A2b, Bia, Blb, B2a, and B2b, including abamectin or semisynthetic analogues thereof. , such as dihydroavermectin or ivermectin, as well as their salts, esters, hydrates, derivatives, prodrugs or metabolites, in any polymorphic form.

 Where applicable, the actives may be used in racemic form, in pure enantiomer form, or as enantiomer derivatives.

 In particular embodiment, the present invention contemplates a veterinary composition containing ivermectin.

 Preferably, the concentration of active ingredient ranges from about 0.5 to about 5% by weight, particularly about 1%.

The veterinary composition according to the present invention contains as excipients at least one solvent, at least one co-solvent, at least one oxidant and at least one vehicle.

 Suitable examples for pour-on formulations include stabilizers such as antioxidants, spill agents, preservatives, adhesion promoters, solvents, co-solvents, active solubilizers such as oleic acid, viscosity modifiers, ultraviolet blockers or colorants.

 Surface active agents may be included, as well as anionic, cationic, nonionic and anfolitic active agents.

 Another embodiment of such formulations may be non-aqueous liquid carriers such as vegetable oils and alcohols.

 Within a particular embodiment, the veterinary composition according to the present invention comprises:

 about 1% to about 27.5% of at least one aromatic alcohol with solvent and preservative functions, particularly about 25% benzyl alcohol;

 about 2% to about 11% of at least one ethylene glycol as co-solvent, particularly about 10% ethylene glycol monoethyl ether;

 about 0.001% to about 0.2% of at least one tocopherol as an antioxidant, particularly about 0.1% DL alpha tocopherol;

 at least one vegetable oil as a carrier, particularly corn oil (q.s.p.).

 Within another aspect, the present invention relates to the use of the veterinary compositions defined above in the manufacture of veterinary medicaments useful in the treatment of parasites.

In another aspect, the present invention relates to a kit comprising veterinary compositions as defined above in unit dose packs and instructions. of use.

 The present invention further relates to a method of treating parasitic diseases which comprises administering to a animal in need of such treatment a veterinary composition as defined above.

 EXAMPLES

 The following example is to be understood as particular embodiments of the invention without imposing any restriction of any form or nature.

 EXAMPLE 1

 FORMULATION OF VETERINARY COMPOSITION ACCORDING TO THIS INVENTION TABLE 1

 EXAMPLE 2

 EFFICIENCY TEST

 In preclinical application tests with the composition as defined in the previous example, ease of application was observed due to its good spreadability and good adhesion to the treated animal's loin.

The animals were found to have a mild tick (larvae) infestation on the udder and dewlap. After two days these larvae dried, generating control on the infestation. After application, there were no signs of burns on the animal's loin or spots on the leather, including its whiter parts, and no apparent symptoms of intoxication were detected.

 The following tests are usually used: a) end product safety test for toxicity issues, b) parasitic elimination efficacy test and c) residue depletion tests to determine zero contamination disposal for meat and milk.

 From the information provided herein, the person skilled in the art can prepare formulations and drugs not expressly described but performing the same functions to achieve results of the same nature. Such equivalent embodiments are encompassed by the claims set forth below.

Claims

 1. Non-residual POUR ON VETERINARY COMPOSITIONS, characterized in that it comprises at least one avermectin and excipients acceptable for veterinary use.  COMPOSITIONS according to claim 1, characterized in that said avermectin is selected from one or more avermectins Ala, Alb, A2a, A2b, Bia, Blb, B2a, and B2b, abamectin, dihydroavermectin or ivermectin.  COMPOSITIONS according to either claim 1 or claim 2, characterized in that said avermectin is ivermectin.  Composition according to any one of Claims 1 to 3, characterized in that the amount of said avermectin ranges from about 0.5 to about 5% by weight.  COMPOSITIONS according to claim 4, characterized in that the amount of said avermectin is about 1%.  COMPOSITIONS according to claim 1, characterized in that the veterinary acceptable excipients consist of at least one solvent, at least one co-solvent, at least one oxidant and at least one vehicle.  7. COMPOSITIONS according to claim 6, characterized in that it comprises from about 1% to about 27.5% of at least one aromatic alcohol as a solvent.  8. COMPOSITIONS according to claim 7, characterized in that it comprises about 25% benzyl alcohol as a solvent. COMPOSITIONS according to claim 6, characterized in that they comprise about 2% to about 11% of at least one ethylene glycol as co-solvent. COMPOSITIONS according to claim 9, characterized in that it comprises about 10% ethylene glycol monoethyl ether as a co-solvent.  COMPOSITIONS according to claim 6, characterized in that it comprises from about 0.001% to about 0.2% of at least one tocopherol as an antioxidant.  COMPOSITIONS according to claim 11, characterized in that it comprises about 0.1% DL alpha tocopherol.  Composition according to Claim 6, characterized in that it comprises vegetable oil as a carrier, particularly corn oil.  Use of a veterinary composition according to any one of claims 1 to 13, characterized in that it is for the manufacture of veterinary medicaments useful in the treatment of parasitic diseases.  KIT, characterized in that it comprises a veterinary composition according to any one of claims 1 to 13 contained in unit dose packages and instructions for use.  Parasitic treatment method, characterized in that it comprises administering to an animal in need of such treatment a veterinary composition according to any one of claims 1 to 13.  Method according to claim 16, characterized in that the animal is dairy cattle.