EP2244579A2

EP2244579A2 - Domestic animal parasite-repellent device

Info

Publication number: EP2244579A2
Application number: EP08865601A
Authority: EP
Inventors: René Chelle
Original assignee: AB7 Industries SA
Current assignee: AB7 Innovation SAS
Priority date: 2007-10-02
Filing date: 2008-10-02
Publication date: 2010-11-03
Also published as: AU2008339883B2; US20100226952A1; FR2921541A1; CA2738403A1; WO2009080909A2; US9060520B2; FR2921541B1; AU2008339883A1; WO2009080909A3

Abstract

The present invention comprises a device for storing and releasing one or more mixed active compositions, for intensively controlling the external parasites of domestic animals, insects and other undesirable living organisms, composed of a polymer matrix comprising an ethylene/vinyl acetate copolymer blended with a polyether block amide, said polymer matrix being charged in an active composition/matrix ratio by weight of less than 0.66. A method for manufacturing such a device is also claimed.

Description

REPELLENT DEVICE AGAINST PESTS OF DOMESTIC ANIMALS

The present invention relates to a novel device for the differential storage and release of one or more mixed active compositions for the intensive control of the external parasites of domestic animals, insects and other undesirable living organisms. The device according to the invention is prepared from a matrix consisting of the mixture of ethylene / vinyl acetate copolymer (EVA) with PEBAX (Polyether Block Amide), applied on the body, so that the device object of the invention can be described as "fit-on".

Conventionally, the curative treatment of the infestation of domestic animals by external parasites or other undesirable living organisms involves the use, in one or more applications, of a pest control product formulated in the form of shampoos, powders, aerosol lotions. or in the form of a concentrated solution to apply at one point of the epidermis ("spot-on") or along a line, usually the line of the back ("for on").

Shampoos, powders or lotions are "shock" treatments but have only a low remanence, of the order of a few hours. Concentrated solutions, such as "spot on" or "for on" have, in addition to a "shock" effect, a residual effect of up to a few days.

The treatments with a concentrated solution called "spot-on" or "pour-on" consist in depositing on the skin a rather large quantity of active ingredient or active composition, that is to say a formulated composition containing several active molecules called active subtances. This active composition is formulated to promote its dissolution in sebum, the lipid layer covering the skin. The sebum ensures the diffusion of the active principles on the whole body of the animal. The sebum, and to some extent the sebaceous glands, also act as a reservoir for the persistence of the device. The diffusion in the sebum makes it possible to have to deposit the product only on a limited surface of the integument, generally on a zone that the animal can neither scratch nor lick.

Several brands of spot-on are currently available on the market such as: - Equi-Spot ™ Spot-On for control of flies for horses,

- Melaflon drops anti chips & parasites,

- Mo wgli insect repellent pipettes,

- Spot on Frontline® from Laboratoires Mérial, - Tiguvon® from Bayer Laboratories.

This mode of treatment is not without some disadvantages:

- the dose is delivered at once, which can pose a problem of toxicity; - the deposited asset is more or less rapidly degraded, the effect drops rapidly over time and the protection becomes almost zero after a few days;

a part of the active composition is lost by evaporation;

the animal can not be washed without leaching at the same time the active composition still on its body; - even if the product is inaccessible to the animal itself, there is still a significant risk for the owners - especially that the dose is placed on the most caressed part of the animal - as well as for other animals, if the treated subject lives in a group;

- By degradation and "wear" of the seborrheic film, the concentration of active gradually decreases, forcing a strong initial overdose to compensate for this loss. Logically, the product must be renewed as soon as the residual dose in the sebum becomes lower than the therapeutic dose. The period when the animal is wearing a truly adapted dose is therefore very short;

- One can obviously increase indefinitely doses delivered at once, at the risk of harming the animal and its masters. The persistence of these systems is therefore necessarily limited.

If the aforementioned products are mainly intended for curative treatment, there are devices whose purpose is to provide preventive protection against infestations. The most common devices in this category are antiparasitic collars, hereinafter referred to as "conventional pest control collars".

Conventional anti-parasite collars are devices that deliver a small amount of active ingredients, but in a constant and prolonged manner over time. The storage capacity is important in terms of what is released daily, it is possible to obtain remanence of the order of several weeks or months.

Conventional antiparasitic collars generally consist of a PVC or EVA matrix only in which the pest control active ingredient is incorporated in a very low active composition / matrix ratio.

A very slight peak release effect can be observed on such collars devices the first days of application. This is generally considered a disadvantage because it represents a loss in active composition without actually making it possible to obtain an effect significant at the level of pest control action. Despite this unwanted release, we can not consider that there is a real shock effect, the released doses are not important enough; there is no shock therapeutic action obtained in the case of the curative treatments mentioned above. The laboratories have thus rather sought until now to limit as much as possible this phenomenon assimilated to a loss. The real effect of collars devices is obtained only several days after their placement on the animal and extends over time for several weeks.

Unexpectedly, contrary to the conventional approach of the laboratories manufacturing such pest control devices with residual effect, the present invention is based on the accentuation of the small peak effect observed naturally in order to obtain a real shock effect in the early hours of the day. use of the collar. This shock effect makes it possible to obtain a real therapeutic action that will be relayed over time by the residual diffusion of the active compositions inherent in conventional antiparasitic collars.

The present invention thus aims to provide a solution to the drawbacks of the prior art by means of a new device for storage and differential kinetic release of one or more mixed active compositions for the intensive fight against the external parasites of domestic animals. prepared with a matrix consisting of Ethylene Copolymer / Vinyl Acetate (EVA) mixed with PEBAX (Polyether Block Polyamides). By extension, it will be understood later in the present application that the action of the device object of the invention is not limited to the fight against the external parasites of domestic animals, but also concerns insects and other undesirable living organisms. The "fit-on" according to the invention has, as the concentrated liquid forms ("spot ~ on" and "pour-on"), a curative "shock" effect that do not have the conventional antiparasitic collars, as well as a preventive effect prolonged in time but without the disadvantages peculiar to concentrated liquid forms. The EVA / PEBAX mixture according to the invention makes it possible to deliver the active ingredients faster if EVA> PEBAX, and slower and longer if EVA <PEBAX.

According to a first aspect of the invention, it is proposed to provide a differential kinetic storage and release device for one or more antiparasitic active compositions, which mixtures can act according to complementary spectra and delays. Said device being made with a matrix consisting of a mixture of Ethylene Copolymer / Vinyl Acetate (EVA) and PEBAX, capable of releasing all the stored substance.

The pest control device according to the invention combines the advantages of the forms concentrates of the "spot-on" type and those of conventional antiparasitic collars, offering the capacity to store and release the dose adapted to each active composition.

The aforementioned aims are obtained through the use of a copolymer of Ethylene and Vinyl Acetate (EVA) mixed with a PEBAX, to form the matrix in which the antiparasitic principles are incorporated and stored, said matrix thus loaded. is put into a desired form by extrusion or injection molding.

More specifically, it is recommended according to the invention a device for applying antiparasitic principles, being reminded that the action of the active ingredient (s) is not only limited to parasites, comprising a polymer matrix loaded with antiparasitic principles characterized in that said antiparasitic principles are incorporated according to the following steps: a) - choose the antiparasitic principles as a function of both their individual spectrum and synergistic in the case where they are several and formulate them in antiparasitic compositions; b) - incorporate the liquid antiparasitic compositions in EVA / PEBAX granules, brought to the temperature appropriate for this purpose, in principle below 65 ° C., preferably at 63 ° C. in a weight ratio of active composition / matrix less than 0.66; c) - according to the invention, one proceeds to the preparation of the device for applying antiparasitic principles from the EVA / PEBAX granules, loaded with these antiparasitic compositions; said process consisting of an extrusion or injection molding of the granules obtained in step (b).

The final device has a shape adapted to its means of application, namely fixing to a collar or other support in order to place it in intimate contact with the animal's coat and skin, such a support being able to be made of leather, fabric or plastic; or in any other form suitable for ensuring an intimate contact between the device which is the subject of the invention and the animal's fur, such as, for example, a collar of the same shape as a conventional anti-parasitic collar.

In this device, the antiparasitic principles are dispersed organic phase using a vegetable oil - such as evening primrose oil, macadamia oil, sweet almond oil, coconut oil, etc. as an intra-matrix diffusion vector of the antiparasite principles.

The oil, well chosen, is a softener also intended to prevent possible irritation of the skin. It is also an emollient that allows the passage of the dermal barrier and transfer to the adipose system that supports the active ingredients, without the se- bum is bothersome and without any other permeation agent. The operation of the device is thus realized in passive diffusion which obeys the law of Fick:

U ^ (Km x Dm / E) x S x AC]

with J: asset flow (μg / cm ² Ih),

AC: concentration difference on both sides of the membrane, Km: stratum corneum / vehicle partition coefficient, Dm: diffusion coefficient (cm ² / S), S: application area (cm ² ) and

E: thickness of the horny layer (μm).

The transfer rate of the anti-parasitic compositions depends on several factors which are:

the nature of the components of the anti-parasitic principles, the volume of anti-parasite principles relative to the volume of the matrix, the conditions for obtaining the final device, the nature of the components of the matrix,

the thickness of the final device, the dissolution rate of the active agent in the sebum.

The dissolution in the sebum is of the same nature as in the case of concentrated liquid formulations of the spot-on type seen previously.

The sebum ensures the diffusion of the asset on all the surface of the skin. Sebum and sebaceous glands also provide an asset storage function which is not essential to the operation of the device, as opposed to concentrated liquid forms. This storage in the sebum and sebaceous glands is however interesting in that it has a regulatory role of the asset flows.

The operation of the device which is the subject of the invention is characterized in that it takes place in two distinct phases: a first phase of important release of the antiparasitic principles which can last up to three days, making it possible to reach the sebum therapeutic concentration (expressed in mg / m2) of the active ingredient, without however reaching the extreme concentrations observed when using conventional concentrated liquid formulas, thanks to an active composition / matrix weight ratio of less than 0.66, up to three times higher than for a conventional pest control collar. This higher ratio determines the actual functioning of the object: o Indeed, the higher the ratio, the greater the internal pressure; o This pressure will itself determine the strength and speed of release of the active ingredients; o The nature of the matrix significantly influences the release rate. In a particular embodiment of the invention, the EVA and / θtt the PEBAX which constitute the matrix are polymers plasticized at "low temperature" and without plasticizer, between 95 and 120 ⁰ C, which thus makes it possible to keep in good condition the porous micro-array of the favorable matrix fast transfer of the active principle from the core of the matrix to the surface where it is made available. This phenomenon is, by way of comparison, different in the case of a PVC collar which is necessarily plasticized with "high temperature" plasticizers, between 140 and 170 ^° C., which compromises the quality of the porous network and slows the migration. active ingredient. To accelerate the migration in this case, it is necessary to add to the formulation a transfer agent that is compatible with the active ingredients incorporated. The collars made of EVA only do not make it possible to obtain the double effect, both shock and remanent, claimed in the present application. Only a shock effect is observed with this type of collar, no diffusion extended over time takes over after the rapid release of the active compositions. There can be no synergy of action; o The small thickness of the object of the invention, ie 2 to 10 mm, shortens the path of the active ingredient towards the release surface, which represents a significant transfer time gain, therefore a flow of active principles also more important and more regular; o The release of the active ingredients by the subject of the invention will be stronger and its speed greater than in the case of a conventional pest control collar for example; The amount of active ingredients released in a short time by the present invention will be greater than that released at the same time by a conventional pest control collar.

After the release of a large quantity of active ingredients by the device of the invention, the internal pressure drops considerably, reducing the rate of availability and the flow of said active ingredients to lead to a second phase of moderate release. decreasing antiparasitic principles of at least seven days, making it possible to compensate for the loss due to the wear of the lipid film and the degradation of the active ingredient in the body of the animal.

The device according to the invention therefore makes it possible to rapidly reach the therapeutic dose and to maintain it over a much longer period than conventional systems, but using a lesser total amount of active ingredients. Moreover, the active composition stored in the matrix according to the invention is not mobilized and therefore does not present a toxic risk for the animal and its masters. It is also protected from damage (oxidation) that can occur when using a concentrated solution deposited directly on the skin of the animal, which further extends its duration of action.

Figure 1 shows the device of the invention, a fit-on, used in the tests presented below, alone (1) and mounted on a collar (2) for in vivo tests. Figure 2 shows the comparative curves of operation under in vitro conditions of compounds composed of an EVA matrix, impregnated with two different active compositions, GIN2 and GIN3, the compositions of which are defined below: GIN2: β-citronellol, nerol, geraniol, tetrahydrogeraniol, coconut and castor oil; GIN3: geraniol, 1-terpinen-4-ol, γ-terpinene, α-terpinene, α-terpinolene, 1,8-cineole, α-pinene, α-terpineol, symene, aromadendrin and d-limonene.

FIG. 3 represents the different kinetic curves of the in vivo functioning of an object comprising an EVA matrix, with respect to another PVC matrix incorporating the same active composition, of GIN3.

FIG. 4 represents the kinetic curve of release of GIN3 by an object comprising an EVA matrix applied to a "German Shepherd" dog.

FIG. 5 represents the release curve of GIN3 of an object comprising an EVA matrix, placed in an oven at 38 ° C.

FIG. 6 represents the comparative curves of the kinetics of release at 38 ^° C. of a pest control collar made of PVC and of an object comprising an EVA matrix, both loaded with GIN3.

FIG. 7 represents the compared curves of kinetics of release of GIN3 and DIAZINON incorporated into an EVA matrix.

FIG. 8 represents the compared curves of the release kinetics of GIN3 incorporated in an EVA matrix and another in PEBAX for the purpose of the invention. FIG. 9 represents the compared curves of the release kinetics of delta-methrine used as an active composition incorporated into an EVA / PEBAX matrix and a PVC matrix.

FIG. 10 represents the compared curves of the release kinetics of a matrix according to the invention in EVA / PEBAX loaded with a complex active composition such as GIN5 and a PVC matrix loaded with another complex active composition, GIN4. .

FIG. 11 represents the compared curves of the release kinetics of linalool in a matrix according to the invention in EVA / PEBAX and a PVC matrix.

In a particular embodiment of the invention, the carrier polymer used is preferably a copolymer of ethylene and vinyl acetate (EVA) having a vinyl acetate (VA) content of between 15 and 33% by weight. weight, preferably from 20% by weight, based on the weight of copolymer of ethylene and vinyl acetate, having a glass transition temperature (Tg) between 50 and 7O ⁰ C, preferably 58 ° C and a melting point at 80 ^° C., to the advantage of the invention. This copolymer is associated with a PEBAX, or Polyether Block Amide (PEBA) consisting of a linear and regular sequence of polyether segments (PE) and soft polyamide segments (PA) of PEBAX grade MX 1717 of the type marketed by ARKEMA, with a Point Vicat at 6O ⁰ C. In comparison, the polyvinyl chloride (PVC) used in flexible form is the LACOVYL ^® SK 70 marketed by ARKEMA and whose glass transition temperature (Tg) is 85 ° C and the melting temperature at 130 ^° C. The PVC is decomposes at 180 ⁰ C in 2 minutes and already at 100 ⁰ C in 1 h. For this, it requires a lot of technological additives to prevent and avoid both its toxicity and its instability by thermal decomposition. The use of plasticizers such as phthalates is required for its shaping by injection or extrusion.

Among the natural antiparasitic principles which are used according to the invention, mention may be made of GIN preparations comprising a synergistic mixture of terpene alcohols, essential oils and non-active oil [Patent Application No. 06/08554 of 29/09/2006], those based on plant extracts still authorized by the European directive on biocides 98/8 / EC.

Other so-called synthetic anti-parasites have been used according to the invention, namely: chlorpyrifos, diazinon, pyrethrinoids such as deltamethrin, etc. The incorporation of an active ingredient into a polymer matrix so that it can release the said active ingredient in time and under certain conditions makes the said matrix an active polymer. According to the invention, the active polymer is composed of an EVA / PEBAX matrix, in which an antiparasite is incorporated which is delivered by the matrix onto the skin or the coat in a specific manner.

The examples given here to illustrate the invention are not exhaustive and in no way limit the scope of the present application and the alternative applications that result therefrom.

Example 1: Manufacture of a Particular Device Comprising an EVA Matrix

The shaping of the subject of the invention goes through several steps already listed in the patent application No. 06/04455 of May 18, 2006, also allowing to obtain a matrix in EVA only, namely For this example, we chose to work with an ethylene-vinyl acetate (EVA) copolymer matrix. Two grades of EVA were chosen: EVA ALCUDIA ^® PA-541 having 20% vinyl acetate and PA-440 having 28% vinyl acetate, REPSOL YPF, in a ratio of 57 / 43;

the antiparasite composition chosen is GIN3 produced by AB7 Industries (composed of tea tree essential oil, geraniol, vandalin essential oil, grapefruit, mint, castor oil, coconut oil, trisodium citrate solution); firstly, GIN3 is incorporated into the EVA granules using a rapid mixer [Patent Application No. 06/04457 of 18/05/2006] at the rate of 30% GIN3 for 70% EVA;

the granules thus loaded are treated in an ARBOURG 221M350-75 injection press of 1.35 T, according to the following temperature diagram: 70 ^° C. - 80 ^° C. - 90 ^° C. -120 ^° C. and program the mold at 40 ⁰ C;

the "fit-on" objects obtained according to the invention (FIG. 1) are 0 mm medallions, 2.5 mm thick, weighing 3 grams, are divided into three batches: a batch intended for testing in vitro o a batch intended for in vivo tests o a batch intended for the kinetic study

Example 2: diffusion test of several actives in an EVA matrix

Purpose of the test and general principles:

It is established that in active polymers, the stored active composition migrates to the surface of the polymer. Once on the surface, in actual use, either the active ingredients (or a part of them) evaporate or they dissolve in the cutaneous sebum (case of use in necklace or patch).

It has also been found that an accumulation of active principle on the surface considerably disrupts the migration of this active agent from the core of the matrix to the surface.

Assuming that only the active ingredient migrates, the kinetics of the general release of the active ingredient is therefore the component of the migration rate of the active agent in the matrix and its elimination, by evaporation and / or by solubilization, of the surface of the object. The resulting kinetics is, at a given moment, limited by the slowest of these phenomena. The test below proposes to study the kinetics by limiting the elimination of the active ingredient to its solubilization in a lipid. For this purpose, the experimental device is designed to limit the evaporation phenomena.

Experience equipment:

a) samples It is necessary that the samples have a comparable weight and area. We propose to use molded samples in the "medal" mold producing 35 mm disks 0 and 2.5 mm thick (Figure 1). This mold has on one face of the initials MI etched hollow. The mold also has a 2.5 mm hole of 0 at the periphery. It is agreed that these samples will always be used face engraved (conventionally the front side) upwards. b) supports

The samples will be placed in a petri dish, against a layer of absorbent material impregnated with a fatty substance (olive oil). The absorbent material consists of a nonwoven layer or a filter paper type absorbent paper. This solution is adopted so that the sample rests on a solid support allowing a permanent contact of the surface (face verso) with the oil without all the sample being bathed there. The active composition which is fat-soluble, at the end of its surface migration, is dissolved in the oil, thus simulating the ooze of the animal. The amount of fat introduced is identical from one box to another.

Protocol:

The tested samples consist of an EVA PA-541 (57%) and PA-440 (43%) matrix in which two different active ingredients are incorporated as appropriate: GIN2 sample composed of β-citronellol, nerol, geraniol, tetrahydrogeraniol, copra and castor oil; and GIN3 sample composed of geraniol, 1-terpinene-4-ol, γ-terpinene, α-terpinene, α-terpinolene, 1,8-cineole, α-pinene, α-terpineol, symene, aromadendrin and d-limonene. The active compositions are each present in the two respective matrices at a level of 15%.

The samples from each pair GIN2 / Matrix and GIN3 / Matrix are weighed exactly and then each placed in a test box that is covered with a lid.

Samples are taken every 24 hours, wiped with a paper towel, and weighed to determine the amounts of active ingredients in the oil. The test is continued for the time necessary for a significant depletion of the samples in active principles. At the end of the test, an extraction can be carried out on the oil of the soaked boxes to validate the results of the weighings (reconciliations).

The results obtained demonstrate that the active ingredients incorporated into the matrix migrate well in the lipidic medium in a reproducible diet (Table 1), regardless of the pest control composition used (here for example GIN2 based on terpeneic alcohols and GIN3 based on plant extracts).

Table 1: Different constituents assayed in the olive oil contained in the nonwoven (extraction support) after the test time. Rate compared to initial quantities contained in the V sample matrix with an EVA matrix.

A: GIN 3

PRINCIPLE α-teipinene linalool linalyl acetate l-terpinene-4-ol Geraniol ACTIVE

GIN3 91.6 62.7 74.6 63.7 56.5

B: GIN2

PRINCIPLE Tetrahydrogeraniol β-Citronellol Nerol Geraniol ACTIVE

GIN2 74.2 71.4 73.9 71.9

The profile of the release curves, based on the weight loss of the objects, which represents the overall loss of active composition by considering the stable matrix, made from the daily weighings (FIG. 2), makes it possible to precisely visualize the impact of the principle antipa - rasites in spot mode on the first 3 days, and in support of this impact spot on the following days. The spot on impact of GIN3 is more intense than that of GIN2 for the same matrix. This characteristic of operation is exploited by the invention; the fit allows to better target the antiparasite principles to use.

Example 3 Diffusion Test of a Composition in an EVA Matrix Compared to a PVC Matrix

The protocol of Example 2 is repeated with this time only one composition, but two different matrices namely: - an EVA matrix PA-541 (57%) and PA-440 (43%) for a first group of samples, - a PVC matrix as a reference for a second group of samples.

The comparison between the two matrices, EVA and PVC (FIG. 3), can be easily performed by noting that for the same antiparasitic active ingredient, in this case GIN3, the spot impact obtained with the EVA matrix is clearly greater. intense than that obtained with PVC.

Example 4 In Vivo Dispersion Test of a Composition in an EVA Matrix Compared to a PVC Matrix

In vivo tests make it possible to validate on a representative example the practical use of an EVA matrix. The principle of this experiment is to measure the amount of active released in real condition, the sample being applied to an animal.

The test uses the same parts as in Examples 2 and 3. These parts are subject to a canvas collar by means of an easily removable fastening system. The collar is placed around the neck of a group of dogs of similar size and type of hair and housed in a similar manner, so as to limit the variables of the test.

Protocol:

For this test two types of GIN3 samples were used: an EVA polymer sample of about 2.0 g at 15% active and a PVC based at about 3.0 g at 13%. , 5% of assets. These samples are exactly weighed and then mounted as above and placed on male adult German shepherd dogs.

The date and time of installation are noted accurately. At regular intervals, the collars are removed from the dogs' necks, the sample is disassembled, cleaned with an absorbent paper soaked in alcohol and weighed exactly.

The results are expressed in weight loss and thus in active released as a function of time.

Results:

The results obtained (FIG. 4) confirm the kinetic profiles obtained in vitro. In the first 20 hours, an average flow rate of the order of 2 mg / hour is observed, which then drops to a regime value of the order of 0.75 mg / hour. The therapeutic dose is estimated at 50 mg / m ² of surface or for dogs of this size (0.8 m ² ) 40 mg of released active. It can be seen that despite the small size of the device having an EVA matrix, the therapeutic dose is reached as early as the twentieth hour. The rate of flow after 50 hours is 18 mg / day. This value is closer to the rate of degradation of the asset on the animal. Depending on the measurements made with concentrated liquid forms, the loss of active ingredient is estimated at 8 mg / day. It can be seen that this loss of assets by degradation and by evaporation is largely compensated by the amount of active material released by the device equipped with an EVA matrix.

Example 5 In Vivo Diffusion Test of a Composition in an EVA Matrix

The follow-up of the kinetic study was carried out by approximating the temperature conditions animals, ie 38 ⁰ C, and thus create the elements of appreciation obtained exactly without the vagaries of the variables that are the factors that can influence the operating regime of the subject of the invention.

The follow-up of the kinetic study consists in putting an object comprising an EVA matrix under operating conditions and measuring by weighing the quantities of antiparasite principles released daily.

The matrix used for this example is the EVA, while the antiparasite principle used is GIN3, charged at a rate of 30%.

The results (Figure 5) confirm those described in Example 2. In fact on the first day the EVA object releases incorporated GIN3 45%, down to 18% on ^day 2 and 7% the ^3rd day. The spot effect is thus obtained during the first three days with 70% antiparasitic principle. The period of support of the spot impact is ensured with 28% of antiparasites principle delivered over a period at least equal to the period of remanence of concentrated solutions type "spot-on", given the storage capacity of adipose tissue , which makes it possible to obtain an efficiency far exceeding the apparent release time (7 days).

The objective in this case being to do at least as well as the "spot on" liquid concentrated from the therapeutic point of view but without the disadvantages associated with this form of treatment, the object in EVA fully fulfills its function. The losses of active principle by oxidative degradation and by evaporation are eliminated, as are the risks of undesirable contact with the product for a child or another animal and even the animal itself. The amount of active ingredient administered is optimized, which avoids any risk of overdose.

Example 6 Comparison Test of an EVA Device with a PVC Pest Control Collar

The therapeutic advantage of an object comprising an EVA matrix on a conventional suppressor is readily demonstrated in this example.

The object consisting of an EVA matrix is compared to a traditional Repul'7 collar composed of a PVC SK70 matrix which has been provided with a plasticizer and other forming aids. The two objects compared are loaded with the same anti-parasitic principle namely GIN3 and are placed under operating conditions for 14 days: 38 ° C in a ventilated oven. Samples are weighed every 24 hours. At the end of this period, samples of 1 g are made on each object of the different batches subjected to the test in order to qualitatively and quantitatively analyze the active ingredient remanent. The antiparasite principle is extracted and assayed by Gas Chromatography (GPC).

The results obtained (FIG. 6) show that the EVA object emitted 89 mg / day, ie 10% of the incorporated GIN3, and the conventional collar only 34 mg / day, ie 0.7% of the incorporated GIN3. Indeed, the object in EVA weighs 3 grams and contains 900 mg of GIN3 while the collar weighs 30 grams and contains 4500 mg of GIN3.

Monitoring the kinetics of release of these two types of object makes it possible to highlight a difference in operation, in that:

- the EVA object releases up to 4 times more antiparasite principle for the first three days than the collar according to the antiparasite principle incorporated, during the next 7 days, the EVA object loses more intensely its antiparasite principle until exhaustion , while the collar releases less and tends to a regularity that can last another 27 days.

The EVA object thus delivers in a short time an effective amount of antiparasitic active ingredient, allowing a "shock" effect in the same way as concentrated "spot-on" solutions but without the disadvantages of the latter.

Indeed, unlike concentrated solutions, in the case of an object in EVA only the therapeutic dose is released and not the entire dose. This limits the risk of overdose and toxic risks associated with accidental contact with the active ingredients by the animal itself, another animal of his entourage or even his masters.

The active principles not released remain safe from degradation and evaporation. This limits the losses and allows or decreases the doses of active ingredients needed or to prolong the effectiveness. The remaining product is then progressively released at a slower rate and offsets losses due to evaporation and degradation of the asset. By this means, the therapeutic dose is maintained longer than in the case of spot type concentrated solutions where the entire dose is subjected at the same time to evaporation and degradation.

Compared to the conventional pest control collar which is intended for long-term preventive treatment, the EVA object has the advantage of providing a therapeutic action of shock. The two objects can also be used in a complementary way, the conventional pest control collar relaying the action of the object in EVA. Example 7 Diffusion Test of an EVA Device Comprising Several Active Compositions in the Same Matrix

In a particular embodiment, the present invention comprises two or more antiparasitic active ingredients with complementary effects and differential kinetics. To illustrate this aspect of the invention, it was retained to compare the GIN3 incorporated in the EVA already presented in Example 5 and the DIAZINON also incorporated in the EVA under the same conditions namely:

§ formatting of the object according to the steps already listed in the patent application No. 06/04455 of 18/05/2006 cited in example 1: we chose to work for this example with a copolymer matrix d ethylene and vinyl acetate (EVA). Two grades of EVA were chosen: EVA ALCUDIA ^® PA-541 having 20% vinyl acetate and PA-440 having 28% vinyl acetate, REPSOL YPF, in a ratio of

57/43;

the antiparasite principles chosen are DIAZINON and GIN3;

firstly, DIAZINON is incorporated into the EVA granules using a rapid mixer [Patent Application No. 06/04457 of 18/05/2006] at a rate of 30% of DIAZINON for 70% EVA;

secondly, GIN3 is incorporated into the EVA granules using the same rapid mixer already mentioned at the rate of 30% GIN3 for 70% EVA;

then the DIAZINON granules are mixed with the granules loaded with GIN3 in the proportions of 40/60; and the mixed granules are processed in a injection molding machine, brand ARBOURG 221M350-75 to 1,35T, according to the following temperature pattern: 7O ⁰ C - 8O ⁰ C - 90 ° C - 120 ⁰ C and is programmed the mold at 40 ° C;

the EVA objects obtained (FIG. 1) are medallions of 0 35 mm, 2.5 mm thick, weighing 3 grams, and are divided into three batches: o a batch intended for in vitro tests o a batch intended for testing in vivo o a batch intended for the kinetic study

It appears that the release behavior of the two active compositions is not the same (Figure 7). Indeed, the diazinon will be released in smaller quantities the first three days, 28% against 68% GIN3 for the same period, to stabilize from the fourth day to 1.30% per day for the remaining 70%, while the GIN3 will run out very quickly because it will be released 80% in 12 days.

DIAZINON is a much heavier molecule than GIN3, which is very volatile. Its intra-matrix transfer is therefore slower, which gives smaller amounts of antiparasites made available. The antiparasitic activity of DIAZINON will prolong that of GIN3 which will have stopped, knowing that the two compositions have different modes of action with DIAZINON which is an organophosphorus and GIN3 which acts both as an organochlorine and as an organophosphorus.

Two compositions with different effects and actions can therefore be incorporated in the same matrix to obtain a complementary operation with conjugated effects.

Example 8 Diffusion Test of a Device Comprising a Matrix Composed of Several Different Polymers

The object of the invention offers the advantage of a modulated operation by combining two polymers in the matrix: 1) "Polyether Block Amides" or PEBAX ^® marketed by ARKEMA have the advantage of having a glass transition temperature (Tg) at 6O ⁰ C, but a melting point between 130 and 17O ⁰ C. The PEBAX ^® decomposes between 300 and 350 ° C. 2) We chose to work for this case with a mixture of two grades of ethylene-vinyl acetate copolymer (EVA) namely: EVA ALCUDIA ^®

PA-541 having 20% vinyl acetate and PA-440 having 28% vinyl acetate, REPSOL YPF, in a ratio of 57/43. The EVA has a glass transition temperature (Tg) around 60 ^° C. and a melting point of 84 ° C., for a decomposition temperature of more than 200 ^° C.

Due to their differences in characteristics, PEBAX and EVA are loaded separately into active compositions in the proportions of 25% GIN3 in EVA and 37.5% GIN3 in PEBAX, as already described. in the previous examples and then proceed as follows: • the granules loaded with GIN3 in the proportions of 60% EVA and 40% PEBAX are mixed;

• the granules of EVA and PEBAX charged thus mixed are treated in an injection press, brand ARBOURG 221M350-75 of 1.35T, according to the following temperature diagram: 70 ⁰ C - 80 ⁰ C - 11O ⁰ C - 14O ⁰ C and the mold is programmed at 40 ⁰ C;

• the "fit on" objects obtained (FIG. 1) are medallions of 0 35 mm, 2.5 mm thick, weighing 3 grams, and are divided into three batches: o a batch intended for in vitro tests o a lot intended for in vivo tests o a lot for the kinetic study

GIN3 release studies previously carried out separately on the two polymers (Figure 8) show that the EVA releases 73% GIN3 in 4 days while the PEBAX relays only 31%. In the end, EVA releases almost all of the active ingredient incorporated while PEBAX continues to release small quantities for a long time.

The combination of the two polymers contributes to synergistically combining the two actions which are: a large amount of active ingredients released for the shock effect of the first days brought by the EVA, - a small amount of active ingredients regularly released for the first time. longer maintenance effect provided by the PEBAX.

It is thus possible to obtain two therapeutic effects with the same active composition, by acting on the composition of the matrix, in particular by combining a fast-acting polymer (eg EVA) and a slow-acting one (eg PEBAX) in proportions ranging from 90 to 50% for EVA, preferably 60% by weight.

The operation can be carried out in the same manner but with two or more different active compositions having a different mode of action, so as to obtain a therapeutic effect which is the resultant of the combined effects of the different active compositions.

Example 9 Diffusion Test of a Device Comprising a Matrix Composed of Several Different Polymers Compared to the Dispersion Test of a Trade Collar

The object of the invention is carried out identically to Example 8 in which the GIN3 is replaced by 98% minimum technical Deltamethrin, VETPHARMA, in the final proportions of 5.5% Deltamethrin for 94.5%. of composite matrix. The distribution of Deltamethrin in the various components of the matrix is as follows:

- 60% EVA with 4.58% Deltamethrin "40% PEBAX 6.88% Deltamethrin

The necklace of the chosen trade is SCALIBOR with 4% of Deltamethrin for 96% of matrix PVC.

Protocol:

Diffusion is observed in vitro in an accelerated manner as follows:

"Collection of 5 g of sample with 3 repetitions for each object (object of the invention and collar to be compared), which represents 200 mg of Deltamethrin for the necklace and 275 mg for the purpose of the invention) "Dissemination of each sample in a beaker containing 50 ml of olive oil with continuous stirring

- Collection of oil at TO, T3, T5, T72 (hours) to assay the amount of deletamedrine released Deltamethrin extraction in samples at TO and T72 to confirm the quantities released

Results:

The results presented graphically in FIG. 9 show that the object of the invention has a deltamethrin release peak at the start of the application 9 times higher in absolute value than that of the SCALIBOR collar, ie for the first 3 hours. 1.58 mg of Deltamethrin salted out by the sample of the collar against 14.3 mg by the sample of the subject of the invention. In parallel, it has been observed in vivo that the SCALIBOR collar does not begin to be effective until about 48 hours after its application, much later than the subject of the invention, the effectiveness of which is observed only 4 hours after its application. Furthermore, the 2- ^mε polymer, in this case the PEBAX plays well its role of maintenance tank insofar as it prevents a brutal emptying of the object of the invention in Deltamethrin if we had only one matrix in EVA. The release becomes even equivalent to that of the necklace taken in comparison.

The advantage of the object of the invention on the collar taken in comparison is therefore devoted in this example, as well as the role played by each of the polymers composing its matrix.

EXAMPLE 10 Diffusion Test of a Device According to the Invention Comprising Insect Repellent GIN5 in a Matrix Composed of Several Different Polymers Compared to a GIN4 Bracelet Dispersion Test

The bracelet chosen is a product of AB7 INDUSTRIES loaded with 15% GIN4 in 85% PVC matrix. GIN4 is an insect repellent from AB7 INDUSTRIES made from geraniol, linolol, essential oils of peppermint, basilica, coconut oil, citric acid, perfumes of mure and litchee.

The object of the invention is identical to Example 8 in which GIN3 is replaced by GIN5, from AB7 INDUSTRIES, in the final proportions of 20% of GIN5 for 80% of compound matrix. GIN5 is an improved GIN4 formula to promote the release rate while reducing the risk of toxicity that may be due to too much of the active ingredient released in a very short period of time. The distribution of GIN5 in the various components of the matrix is as follows: - 60% of EVA at 17% of GIN5

"40% PEBAX 25% GIN5

Protocol:

The diffusion is observed in vitro by kinetic monitoring of the release of the active ingredient (which is volatile) by placing the samples in an oven at 38 ° C.

The samples are weighed daily to determine the amount of active ingredient lost.

Results:

The results presented graphically in FIG. 10 show that the object of the invention has a GIN5 release peak at the beginning of the application that is 4 times higher in absolute value than that of the GIN4 bracelet.

The formulation of the active ingredient and that of the matrix obviously have an important influence in the operation of these two objects, taking into account that the levels of active ingredients incorporated in the matrices are not so far apart with 15% in the case of the bracelet and 20% in the case of the object of the invention. The advantage of the object of the invention on the bracelet is obvious and largely justifies its interest.

EXAMPLE 11 Diffusion Test of a Device According to the Invention Comprising the Active Ingredient LINALOL in a Matrix Composed of Several Different Polymers Compared to a LINALOL Bracelet Dispersion Test

The bracelet chosen is a product of AB7 INDUSTRIES loaded with 15% LINALOL in 85% PVC matrix. LINALOL is one of the main components of AB7 INDUSTRIES insect repellent, GIN4.

The object of the invention is carried out identically to Example 10 in which the GIN5 is replaced by LINALOL, in the final proportions of 30% of LINALOL for 70% of compound matrix. The distribution of LINALOL in the different components of the matrix is as follows: "60% EVA at 25% LINALOL

- 40% of PEBAX 37.5% of LINALOL Protocol:

Diffusion is observed in vitro by kinetic monitoring of the release of the active ingredient (which is volatile) by placing the samples in an oven at 3 ° C. The samples are weighed daily to determine the amount of active ingredient lost.

Results:

The results presented graphically in FIG. 11 show that the object of the invention has a peak of LINALOL release from the beginning of the application 16 times higher in absolute value than that of the bracelet.

This huge difference confirms the efficacy results observed in the previous example and in vivo. The advantage of the object of the invention on the bracelet is given here by the combination composition of the matrix and concentration of the asset.

The object of the invention is therefore adaptable to the active ingredient and to the size of the action expected. The latter small thus be dosed according to demand.

Claims

A device for storing and releasing one or more mixed active compositions for the intensive control of the external parasites of domestic animals, insects and other undesirable living organisms, characterized in that it is composed of a matrix polymer comprising a blend of ethylene / vinyl acetate copolymer with a polyether block amide, said polymer matrix being loaded in an active composition / matrix weight ratio of less than 0.66.

2- Device according to claim 1 characterized in that the polymer matrix comprises one or more grades of ethylene / vinyl acetate having vinyl acetate concentrations of between 15 and 33% by weight of ethylene / vinyl acetate.

3- Device according to claim 2 characterized in that the polymer matrix comprises two grades of ethylene / vinyl acetate, one comprising 20% vinyl acetate by weight of ethylene / vinyl acetate, the other comprising 28% vinyl acetate by weight of ethylene / vinyl acetate.

4- Device according to any one of the preceding claims characterized in that the ethylene / vinyl acetate copolymer has a glass transition temperature of between 50 and 70 ° C.

5- Device according to the preceding claim characterized in that the ethylene / vinyl acetate copolymer has a glass transition temperature equal to 58 ⁰ C.

6. Device according to any one of the preceding claims, characterized in that the thickness of the matrix is between 2 to 10 mm.

7- Device according to any one of the preceding claims, characterized in that the active composition (s) comprise natural antiparasitic principles and / or synthetic antiparasitic principles.

8- Device according to the preceding claim characterized in that the natural antiparasite principles comprise a synergistic mixture of terpene alcohols and / or essential oils and / or non-active oils. 9- Device according to claim 7 characterized in that the synthetic antiparasite principles comprise chlorpyrifos and / or diazinon and / or pyrethrinoids.

10- Device according to any one of the preceding claims characterized in that it is attached to a collar or other support placed in close contact with the animal in leather, fabric or plastic.

11- A method of manufacturing a device for storing and releasing one or more mixed active compositions for the intensive control of the external parasites of domestic animals, insects and other undesirable living organisms, composed of a polymer matrix comprising a copolymer of ethylene / vinyl acetate alone or mixed with a polyether block amide comprising the following steps: a) - choose the antiparasitic principles as a function of both their individual spectrum and synergistic in the case where they are several and formulate them in antipasitic compositions; b) - incorporate the liquid antiparasitic compositions into granules of EVA / PEBAX, brought to the appropriate temperature for this purpose, in principle less than 65 ^° C., preferably at 63 ° C. in a weight ratio of active composition / matrix less than 0.66; c) - prepare the device for applying antiparasitic principles from EVA / PEBAX granules, loaded with these antiparasitic compositions by extrusion or injection molding granules obtained in step (b).

12- Method according to claim 11 characterized in that the antiparasite principles are put in dipersed organic phase using a vegetable oil.

13- Method according to claim 11 or 12 characterized in that the antiparasitic principles are incorporated in different granules for each antiparasitic principle used in step b).

14- Method according to any one of claims 11 to 13 characterized in that the EVA granules used in step b) may comprise one or more grades depending on the vinyl acetate concentrations of between 15 and 33% by weight. weight of ethylene / vinyl acetate.

15- Process according to any one of claims 11 to 14 characterized in that the ethylene / vinyl acetate copolymer has a glass transition temperature equal to 58 ⁰ C. 16- Method according to any one of claims 11 to 15 characterized in that the active composition (s) comprise natural antiparasitic principles and / or synthetic antiparasitic principles.

17- Use of a device manufactured according to any one of claims 11 to 16, characterized in that it allows to deliver the active ingredients faster if EVA> PEBAX and less quickly and longer if EVA <PEBAX.