FR2517205A1 - TETRAMISOLE COMPOSITION FOR TOPICAL APPLICATION TO ANIMALS - Google Patents

Abstract

THE INVENTION RELATES TO THE FIELD OF VETERINARY MEDICINE. IT CONCERNS A COMPOSITION INTENDED TO BE APPLIED TOPICALLY TO ANIMALS, COMPRISING A MIXTURE OF LEVAMISOLE OR TETRAMISOLE FREE BASE IN A VEHICLE FORM OF SPECIAL ASSOCIATIONS BETWEEN AN ALCOHOL-TYPE SOLVENT AND A CO-ESD-SOLVENT . APPLICATION TO THE CONTROL AGAINST ENDOPARASITES.

Description

The present invention relates to compositions for application

  topical of chemicals to animals for the control of parasites It relates in particular to compositions containing levamisole free base, for the control of endoparasites The topical application of parasiticides for combating endoparasites is a well known method, and it is usually done by injecting the animals or making them absorb suitable formulations of the parasiticides into potions. Attempts have recently been made to develop pourable formulations, that is, formulations which are totally

  effective against pests when a suitable amount

  is applied to a particular region of the

  face of the body of the animal, normally along the spinal region This mode of application offers its own advantages over other techniques by eliminating the need to impede animals and keep sterile formulations In addition, experienced personnel It is not necessary Formulations prepared to be applied for the application of endoparasiticides have heretofore had several disadvantages. The range of parasiticides which are effective in this art is limited, and the compositions of the prior art are associated with tissue reactions caused by solvent systems used for the preparation of these compositions These tissue reactions lead to considerable discomfort for the treated animals, and further, to a serious deterioration of the skins, large and small, animals, with the resulting loss of money for the breeder This particular problem exists in Australia in the sheep, or the main breed of sheep is Merino or Merino cross, as this breed has been very sensitive even to the solvent systems that have been tolerated.

  to a certain degree by other breeds.

  One of the aims of the present invention is to provide efficient and non-toxic solvent systems that are tolerated by animals with a wide range of

  range of types and degrees of sensitivity.

  When applying a composition to sheep by pouring it, the period immediately following

  mowing can be a good time to treat

  for the purpose of combating pests by topical application, since the sheep are already gathered together and the wool is relatively short. However, the wool layer is still an important barrier to topically applied compositions, particularly in the case of Merino, because the individual fibers are thin and in tight packs In addition, there is a layer of suintine covering the skin, which is another barrier to the penetration of the drug This layer of suintine can reach a very great thickness in Merinos Another object of the present invention is to find compositions which are effective in penetrating these wool and suintine barriers while excluding adverse reactions.

in the skin and tissues.

  Degreasing solvents such as for example paraffins, isoparaffins, cycloparaffins

  and aromatic hydrocarbons such as xylene,

  Although these solvents are well known,

  which penetrate the suintine layer effectively, producing

  severe tissue reactions such as pain, swelling, drying and cracking of the skin.

  leads in turn to a loss of wool and a deterioration

definitive ration of the skin.

  Other solvents such as alcohols and

  Alcohol ethoxylates do not produce tissue reactions.

  but are relatively ineffective with respect to

  the penetration of the wool or the suintine layer.

  The Applicant has just discovered certain compositions which are effective for topically applying to animals the endoparasiticides called tetramisole.

  and levamisole, and which do not show a negative reaction

  tissue even when applied to sensitive breeds of animals Another

  advantage of these compositions is that the organic materials

  metal can be easily incorporated to combat deficiencies of specific mineral substances in animals. Accordingly, the invention provides compositions for topical application to animals.

  to combat endoparasites, compositions that contain

  levamisole or tetramisole in its free base form in a vehicle comprising a first solvent selected from the group of C 3 or C 4 alcohols alkoxylated with 1 to 3 moles of ethylene oxide per mole of alcohol and C 1 -C 4 alcohols alkoxylated with from 1 to 3 moles of propylene oxide per mole of alcohol and mixtures thereof; and a co-solvent selected from di (C 1 to C 6) alkyl esters of C 2 to C 6 dicarboxylic acids, di (C 1 to C 6) alkyl esters of C dihydric alcohols. 2 to C 6 and C 2 to C 6 carboxylic esters of alcohol alkoxylates prepared by reacting one mole of a C 3 to C 6 alcohol with 1 to

  3 moles of an alkylene oxide selected from ethylene oxide

  ethylene oxide and propylene oxide, and mixtures thereof.

  The preferred C 2 to C 6 dicarboxylic acids are adipic acid and sebacic acid and the esters of these acids which are preferred are dimethyl adipate, diethyl adipate, sebacate and the like. of

  dimethyl and diethyl sebacate Dihydric alcohols

  xylics in C 2 C 6 that are preferred are ethylene-

  glycol, propylene glycol, diethylene glycol and triethylene glycol. Tetramisole is the common name used for

  designate the hydrochloride of the anthelmintic called dl-

  2,3,5,6-tetrahydro-imidazo / -2,3-b 7thiazole Levamisole is the common name used to designate the levorotatory optical isomer of tetramisole These hydrochlorides are unsuitable for the compositions of the present invention, being little Soluble in the first solvent and substantially insoluble in the co-solvent The tetramisole and levamisole are readily converted to their respective free base for the compositions of the present invention by conventional salt-converting processes.

  in base The recommended compound is the free base of the leva-

misole.

  The first solvents recommended are 2-

  propoxyethanol, 2-butoxyethanol, 1-methoxy-2-

  propanol and 1-ethoxy-2-propanol and mixtures thereof.

  The recommended co-solvents are ethylene diacetate

  glycol, 2-propoxyethyl acetate, 2-butoxy acetate

  ethyl and 1-methoxypropyl-2 acetate, and mixtures thereof.

  The most popular vehicle is 2-

  butoxyethanol and ethylene glycol diacetate.

  These particular vehicles allow a quick wetting of the wool or hair of the animal, allowing the movement towards the skin with a minimum of flow and loss of formulation, and they have the

  desired degree of solubility with respect to endoparasites.

  The weight / weight ratio of the first solvent to the co-solvent is advantageously in the range

from 9: 1 to 1: 1.

  The concentration of levamisole free base in the compositions of the present invention is

  in the range of 0.1 to 25% w / v.

  The particular treatment may be readily selected by those skilled in the art so that when a determined amount of the endoparasiticide solution is applied topically to the animal, the parasiticide is present in an amount effective to combat infestations. parasitic

in animals.

  For animals infested with gastrointestinal and pulmonary parasitic nematodes such as Haemonchus spp, Ostertagia spp, Trichostrongylus sg, Nematodirus spp, Oesophagostomum sp, Chabestia pp, and Dictyocaulus spp, a normal effective dose of levamisole free base is approximately 10 mg / kg. kg of weight

  body of the animal by topical application.

  The recommended compositions contain 5% of levamisole free base in a suitable vehicle so that the levamisole free base is close to

  saturation point in this vehicle.

  The species of parasites combated by levamisole are well known in the prior art According to a feature of the compositions of the invention, levamisole is totally effective in topical applications in the compositions of the present invention at the same doses as those used by conventional methods of application, for example under the

  form of oral and injection potions.

  Thus, for example, a composition containing% levivisole by weightivolume applied to the dose of

  0.2 ml / kg of body weight makes it possible to combat

helminths.

  Although the compositions are particularly effective in combating endoparasites in cattle and sheep, they can also be used for pigs and domestic animals such as dogs and cats. The compositions may further contain other ingredients such as for example preservatives

  and stabilizing agents A particular stabilizing agent

  Useful is an antioxidant such as for example 4-butyl-2,5-dimethylphenol Other antioxidants

  known to those skilled in the art can be used and

  The oxidant or mixture of antioxidants selected is normally added so that its concentration in the final composition is in the range of 0.1 to 1.0%

  in weight / volume, preferably 0.5 to 1.0% w / v.

  According to another embodiment, the invention

  The invention provides compositions which additionally contain a non-solid dye so that animals treated with the poured compositions can be easily recognized and thus avoid double treatment.

unnecessary and undesirable.

  Suitable non-solid dyes soluble in the compositions may be readily selected by those skilled in the art such that the color area of the skin or wool becomes clear to sunlight in a suitable period of exposure and without any harmful effect

  be applied to the skin or wool A particular dye

  Most useful is rhodamine which is normally used in an amount giving a concentration range of 0.01 to 0.05% w / v in the final composition.

  According to another embodiment, the invention

  proposes a method of treating animals,

  which consists in applying to the surface of the animals the

  of the invention comprising levamisole or tetra-

  misole in the free base form in a first solvent as defined above and in a cosolvent as defined above% The compositions of the present invention are applied in line along the back of the animal from the withers to the rump The compositions spontaneously "wet" and "penetrate" the wool or the hair and emigrate rapidly to the level of the skin. The compositions may be applied by brushing or by roller, but it is more convenient to simply pour them onto the skin.

back of the animal.

  In another preferred embodiment of the present invention, the compositions further contain one or more carboxylic acids selected from the group of C 1 -C 8 alkanoic acids. The molar ratio of alkanoic acid to levamisole free base should not be exceeding 1.1 and the alkanoic acid and the levamisole free base are very advantageously used in substantially equimolar proportions The addition of the alkanoic acid to the composition-raises the rates

  blood levels of levamisole in treated animals.

  Lower proportions of alkanoic acid produce a lower blood level, and the recommended molar ratio of alkanoic acid to

  Levamisole free base is in the range of 0.5 to 1.0.

  The preferred alkanoic acids are C 1 acids

  at C 4, especially acetic acid and propionic acid.

  Higher molecular weight acids, for example stearic acid, can be used, but promote less blood levels than C 1 -C 8 alkanoic acids.

  The invention is illustrated by the following examples:

  given in a non-restrictive manner, in which all parts and percentages are expressed in

  weight, unless otherwise specified.

EXAMPLE 1

  A formulation of the following composition is prepared: Rhodamine Levamisole base free ethylene glycol diacetate 2-Butoxyethanol

EXAMPLE 2

  0.1% by weight / volume% by weight / volume% by volume / volume complement with 100 volumes A formulation of the following composition is prepared: Rhodamine Levamisole free base Diacetate of ethylene glycol 1-Methoxy-2-propanol

EXAMPLE 3

  0.1% by weight / volume% by weight / volume% by weight / volume complement with 100 volumes A formulation having the composition of Example 2 is prepared, with the difference that 1-methoxy-2-propanol

  is replaced by 1-ethoxy-2-propanol.

EXAMPLE 4

  A formulation of the following composition is prepared: Rhodamine Levamisole free base Ethylene glycol diacetate Propionic acid 2-Butoxyethanol

EXAMPLE 5

  0.1% w / v% w / v% w / v 3.6% w / v supplement 100 vol. A formulation having the composition of Example 4 was prepared, except that butoxyethanol

  is replaced by 1-methoxy-2-propanol.

EXAMPLE 6

  A formulation having the composition of Example 4 is prepared, with the difference that propionic acid

  is replaced by an equimolar quantity of octahydrate

noique.

EXAMPLE 7

  A formulation having the composition of Example 4 is prepared, except that the concentration of

  Propionic acid is 1.8% w / v.

EXAMPLE 8

  Cattle were treated with the formulation of Example 1 which was poured along the loin. The applied dose was 1 ml / kg body weight, so that there was an effective dose rate of 10 mg / kg levamisole Control animals were treated by subcutaneous administration of an injectable levamisole formulation at a dose of 6 mg / kg body weight. Blood samples were taken from animals at regular intervals and summed. heparin The plasma obtained by centrifugation was then analyzed, for the levamisole content, by a method involving purification on the cartridges of "Sep-Pak" C 18 ("Sep-Pak" is a registered trademark of the firm Waters Associates), the operation being followed by a final determination by high performance liquid chromatography The results are reproduced in Table I and demonstrate that blood levels of 0.3 ppm and higher are It is known to those skilled in the art that this rate allows an effective destruction of parasitic helminths.

TABLE I

EXAMPLE 9

  The procedure of Example 8 was followed

  using the pour-on formulation of the following composition

  vante: Levamisole free base 10% w / v Ethylene glycol diacetate 20% w / v 2-butoxyethanol 100 volume supplement Results obtained for treated animals

are reproduced in Table II.

EXAMPLE 10

  The procedure of Example 8 was followed

  using a pourable formulation of the following composition

  Levamisole free base 10% w / v Acetic acid 2.5% w / v Ethylene glycol diacetate 20% w / v 2 Volutoxyethanol 100 vol supplement The results obtained for the treated animals

are reproduced in Table II.

EXAMPLE 11

  The procedure of Example 8 was followed using a pour-on formulation having the composition of Example 4. The results are reproduced on the

Table II.

  Levamasole Concentration Traitemnt Number (ppm) in plasma after animals treat Hours: 1 2 3 5 7 Formulation 1 1.1 0.6 0.6 0.3 0.2 Injectable ___ _ _ _ _ _ ___ ___ Formulation 151,2,9,5 0,2 Injection 2 Formulation at 3 0.6 0.6 0.5 0.3 0.2 Greens 4 0.4 0.5 0.4 0.3 0.3

TABLE II

Comparative Example 1

  A formulation having the composi-

  Example 1, with the exception that ethylene glycol diacetate was omitted. When this formulation was applied to three sheep by the method of the example

  8 at an application rate of 4 ml, a duration of

  curing the tissue on the animal after six days.

Comparative Example 2

  A formulation having the composi-

  Example 4, with the exception that ethylene glycol diacetate was omitted. When this formulation was applied to three sheep by the method of Example 8, at an application rate of 4 ml, the tissue on the site

  application dried up and hardened after 6 days.

Comparative Example 3

  A formulation having the composi-

  Example 7, with the exception that ethylene glycol diacetate was omitted. The formulation was applied to three sheep by the method of Example 8 at an application rate of 4 ml. After 6 days, the fabric at the application site was dry and cracked

had appeared.

  Levamisole concentration Example (ppm) in plasma after treatment Hours: 1 2 3 4 9, animal NO 1 0.22 0.33 0.39 0.44 go NO 2 0.16 0.31 0.56 0.53 , animal no. 1 0.69 1.61 1.21 1.07 "l no. 2 0.14 0.31 0.87 0.82 il 0.36 0.77 0.81 1.14 1 1

Claims (9)

  1 Composition to be poured to combat or to stop infestations due to endoparasites in animals, characterized in that it comprises an endoparasiticidal amount of free tetramisole or an optical isomer of this compound in a vehicle comprising a first chosen solvent between C 3 and C 4 alcohols alkoxylated with 1 to 3 moles of ethylene oxide per mole of alcohol and C 1 to C 4 alcohols alkoxylated with 1 to 3 moles of propylene oxide per mole of alcohol and mixtures thereof, and a co-solvent selected from di (C 1 -C 6) alkyl esters of C 2 -C 4 dicarboxylic acids.   C 6, di (C 1 -C 6) alkyl esters of dihydroxy alcohols   C 2 -C 6 and C 2 -C 6 carboxylic esters of alcohol alkoxylates prepared by reacting one mole of a C 3 to C 6 alcohol with 1 to 3 moles of alkylene selected from ethylene oxide and propylene, and mixtures thereof.   Pourable composition according to Claim 1, characterized in that the isomer of tetramisole is levamisole.   3 Pourable composition according to the claim   2, characterized in that the animals are cattle or sheep.   Pourable composition according to Claim 3, characterized in that the C 2 to C 6 dicarboxylic acids are adipic acid and sebacic acid and the C 2 to C 6 dihydroxyl alcohols are ethylene glycol,   propylene glycol, diethylene glycol and triethylene glycol.   Pourable composition according to Claim 4, characterized in that the concentration of levamisole free base is in the range of 1.0 to 25% w / v.   6 Pourable composition according to the claim   5, wherein the carrier forms 70 to 98% w / v of the composition and the weight / weight ratio of the first solvent to the co-solvent is in the range of 9: 1 to 1: 1.   7 Pouring composition according to any one   claims 4 to 6, characterized in that the   first solvent is selected from 2-propoxyethanol, 2-butoxyethanol, 1-methoxy-2-propanol and 1-ethoxy-2- propanol and mixtures thereof.   8 Pouring composition according to any one   claims 4 to 6, characterized in that the   The co-solvent is selected from ethylene glycol diacetate, 2-propoxyethyl acetate, 2-butoxyethyl acetate, and   1-methoxypropyl 2-acetate and mixtures thereof.   9 Pourable composition according to one of the claims   5 and 6, characterized in that the vehicle   comprises 2-butoxyethanol and ethylene diacetate glycol.   Pourable composition according to any one   Claims 2 to 9, characterized in that the   vehicle further comprises a C 1 to C 8 alkanoic acid so that the molar ratio of the alkanolic acid   Levamisole is in the range of 0.5 to 1.1.   11 Pouring composition according to the claim   10, characterized in that the levamisole and the acid   C 1 to C 8 alkanoic substances are present in equimolar