WO1997013508A1

WO1997013508A1 - Topical liquid composition, method for preparing same and uses thereof

Info

Publication number: WO1997013508A1
Application number: PCT/FR1996/001589
Authority: WO
Inventors: Vincent Beuvry
Original assignee: Virbac S.A.
Priority date: 1995-10-13
Filing date: 1996-10-11
Publication date: 1997-04-17
Also published as: EP0859609A1; FR2739778A1; FR2739778B1; AU7304196A

Abstract

A topical liquid endoparasiticidal composition for treating helminthic diseases caused by flukes in homoiothermic animals, a method for preparing said composition and the uses thereof are disclosed. Said composition essentially consists of a solution of closantel soda salt in at least one non-aqueous solvent selected from the group which consists of polyalcohols, ethers thereof and mixtures thereof.

Description

LIQUID COMPOSITION FOR TOPICAL USE, PROCESS FOR PREPARING SAME AND APPLICATIONS THEREOF.

The present invention relates to a liquid endoparasiticidal composition for topical use, active on helminthiasis caused by the fluke (Fasciola hepatica or Fasciola magna), in warm-blooded animals, excluding humans; such a composition comprises sodium salt of closantel as the main anthelmintic active principle, optionally combined with another anthelmintic agent, in solution in a solvent or a mixture of non-aqueous solvents, chosen for their property of passage through the barrier cutaneous. Such a composition is particularly well suited to obtaining an effective systemic amount of closantel. Different clinical symptoms are associated with a fluke infection; they depend in particular on the stage of advancement of the infestation and the number of sites. Acute fluke infestation appears when the metacercariae invades the liver; in the most serious cases, the damage produced in the hepatic tissues and the inflammatory reactions are such that a fatal outcome is foreseeable. Chronic conditions develop slowly, causing cholangitis, biliary obstruction, destruction of liver tissue, fibrosis and anemia. This infection obviously limits the growth of the animal and its food assimilation capacity, thereby reducing the production of meat in cattle and the production of milk in dairy cows.

Closantel or (N- [5-chloro-4- [(4-chlorophenyl) cyano methyl] -2-methylphenyl] -2-hydroxy-3, 5-diodo benzamide) has been used for many years for the treatment of fasciololic or animal douvicide, injectable or orally. The closantel's douvicide activity against Fasciola hepatica has been widely confirmed in the field (Maes L. Rev. Médet Vet. Toulouse, 1990, 14, 12, 991-995 and comparisons of activity between various anthelmintics demonstrate good efficacy 5 mg / kg and 10 mg / kg orally (Guerrero J. Préventive Veterinary Medicine, 2 (1984) 317-327). Rothwell JT, in Int. J. Parasi tol, 1993, 23, 5, 573 -578 and 23, 7, 885-889, demonstrates a comparable efficacy in goats and sheep, while Hennessy DR in J. Vet. Pharmacol. Ther., 1993, 16, 3, 254-260 notes a different pharmacokinetic profile, depending on the species, during treatment by injection, in particular at the dose of 7.5 mg / kg.

This difference between species can call into question the choice of routes of administration. In addition, in many regions, the dispersal of cattle in extensive farms makes the mode of topical administration preferable to other modes of administration. Much more suitable for unrestricted breeding, this route of administration is also preferred by its ease of use both in relation to administration by the oral route and by the parenteral route. In addition to the ease of use, the breeder administering a topical treatment appreciates the time saved, the absence of irritation, pain or nervousness in the animal as well as the resulting gain in labor. .

This is why the Applicant has set itself the goal of providing a composition based on closantel for topical use but with systemic action, easy to administer to the animal, in the field.

For effective administration, such a composition for topical use must be dissolved or dispersed in a solvent suitable for the active principle, favorable for passage through the skin barrier (percutaneous or transdermal route} and well tolerated by the animal. The active principle thus formulated must be well assimilated after its passage through the skin of the animal .

The Applicant has found, unexpectedly, that the sodium salt of closantel is absorbed through the skin of the animal, when it is in solution in a non-aqueous solvent, suitable for being poured in greater or lesser quantities onto the animal. The Applicant has thus obtained excellent results in the control of the liver fluke in warm-blooded animals, by administering the sodium derivative of closantel in a non-aqueous composition.

The subject of the present invention is a liquid composition for topical use, comprising at least one anthelmintic in a nonaqueous solvent as active substance, which composition is characterized in that it consists essentially of sodium salt of closantel. dissolved in at least one non-aqueous solvent, chosen from the group consisting of polyalcohols, their ethers and mixtures thereof, which cross the skin barrier and which promote the transdermal passage of said closantel.

According to an advantageous embodiment of said composition, it further comprises at least one co-solvent, capable of stimulating the passage of closantel towards the deep layers of the skin, which co-solvent is selected from the group consisting of fatty alcohols, amides, fatty acid esters, functional monocyclic derivatives, essential oils, tallow oxides and nonionic surfactants, for obtaining an effective systemic endoparasiticide (douvicide) amount of closan¬ tel. Such compositions are perfectly stable, especially under the difficult climatic conditions of large extensive farms.

According to another advantageous embodiment of said composition for topical use, the polyalcohols and their ethers are selected from the group consisting of glycerol; sorbitol; glycols, such as: propylene glycol, diethylene glycol, butyl diglycol, polyethylene glycol or their mono- or poly-ethers such as methoxyethanol, butoxyethoxyethanol, propylene glycol or ethylene glycol monobutyl ether, dipropylene glycol monomethyl ether, monomethyl ether, monobutyl ether or tripropylene glycol monopropyl ether, dimethyl isosorbide. While N- [5-chloro-4- [(4-chlorophenyl) cyanomethyl] -2-methylphenyl] -2-hydroxy-3, 5-diodo benzamide has been used as a douvicide in animals, especially in bovine, parenterally at a dose of 2.5 mg to 5 mg / kg of animal weight, the Applicant has found that, unexpectedly, the sodium salt of closantel, which is very slightly soluble in water, but which offers a fairly good solubility in solvents of the hydroxyether or poly¬ alcohol type such as diethylene glycol or monobutylethylene glycol, passes actively through the epidermis and the deep layers, when it is in solution in said solvents, thus resulting in a plasma level equivalent to that obtained during IM, SC or oral administration.

According to another advantageous embodiment of said composition, the co-solvent, capable of enhancing the passage of the active ingredient (s) towards the deep layers of the skin is in particular selected from fatty alcohols, more particularly n-dodecanol, amides , such as the di- methylacetamide (DMAC), n-butyl-n-dodecylamide, di¬ methylformamide (DMF), fatty acid esters chosen, preferably from isopropylmyristate, methyl laurate, glycerol monolaurate or propylene glycol , functional monocyclic derivatives such as cycloalkanone, N-methylpyrrolidone, l-alkylazacycloheptane-2-one, essential oils or derivatives including menthol, 1-carvone, eucalyptol, eugenol, sulfur derivatives, such as dimethylsulfoxide (DMSO), decylmethylsulfoxide, surfactants, and more specifically nonionic surfactants, including sorbitan esters such as monolaurate, polyoxyethylene esters (POE) of sorbitan, in particular POE monooleate (20) (Tween 80).

Said co-solvent is advantageously present in a proportion generally less than 20%, more generally between 0.5 and 10%.

Advantageously, depending on the concentration and the type of co-solvent, it can modify the viscosity of the composition. According to an advantageous arrangement of this embodiment, said co-solvent is preferably selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC) and N-methylpyrrolidone. According to another embodiment of said composition, it can also advantageously comprise additives such as film-forming agents such as acrylic polymers or copolymers; dyes which allow the application to be traced on the animal, in particular chosen from non-toxic products such as patent blue, Rhodamine or even Gentian violet, at concentrations of a few milligrams per liter; of the stabilizing agents, such as phenolic derivatives at concentrations less than or equal to 1%, preferably between 0.05 and 0.1%.

According to another embodiment of said formulation, it comprises a second anthelmintic, present in proportions of between 0.01% and 10% (w / v), preferably between 0.01 and 2%.

According to the invention, said composition essentially comprises between 10 and 40% of sodium salt of closantel, between 0.1 and 1% of an avermectin, between 49 and

88.9% of solvent such as propylene glycol and 1 to 10% of co-solvent, such as dimethylformamide.

The present invention also relates to a process for preparing the composition according to the invention, characterized in that it comprises the following steps:

dispersion of the sodium salt of closantel in at least one solvent or a mixture of at least one solvent and at least one co-solvent, with vigorous stirring, at a suitable temperature to facilitate dissolution, but not too high in order to avoid thermal decomposition of the active principle (s), between 30 ° C and 100 ° C, preferably between 40 ° and 80 ° C, to obtain a sodium salt solution of closantel,

- cooling the solution obtained to room temperature, possible addition of additives and other antiparasitic active principles intended to combat other parasites.

The present invention also relates to the use of a liquid composition for topical use according to the invention, for obtaining a medicament with systemic activity, intended for the treatment of helminthiasis. According to an advantageous embodiment of said use, said topical administration is carried out by application to a more or less large area of the animal, at a rate of 10 to 40 mg / kg. According to the invention, the composition is applied topically to the animal by pouring it onto the back of the animal, along the spine for example or applied over a less extensive area for more concentrated preparations. Means such as brushes or applicator rollers can be used as well as pouring dosing containers or dosing syringes equipped with an appropriate nozzle.

In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the process which is the subject of the present invention, as well as to the accompanying drawing , in which :

- Figure 1 shows the average plasma concentration of closantel in mg / ml, depending on the route of administration.

It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation. Example 1

30 g of closantel sodium salt are dispersed with vigorous stirring, in the following mixture of solvents: propylene glycol monobutyl ether 12 ml ethylene glycol monobutyl ether 9 ml polyethylene glycol 400 1 ml diethylene glycol 60 ml, keeping the temperature of the medium close to 50 ° C. After about 15 minutes, the dissolution is complete; then allowed to cool and added: the co-solvent (Tween 80) 1 ml a dye (Rhodamine B) 0.1 mg, then made up with one of the solvents: diethylene glycol qs 100 ml Example 2

20 g of closantel sodium salt are dispersed with vigorous stirring as above, in 70 ml of propylene glycol, to obtain a solubilization of closantel sodium salt and it is made up to 100 ml, to reach a salt concentration. closantel sodium 20% (g / 100 ml solution). Example 3 By operating as above, by dissolving

20 g of closantel sodium salt in 70 ml of propylene glycol, a concentrated solution of closantel sodium salt is obtained, to which is added, after cooling, a solution of 0.5 g of ivermectin in 10 ml of propylene glycol, then it is made up to 100 ml with propylene glycol. Example 4

30 g of closantel sodium salt are dispersed with vigorous stirring, in a mixture comprising 10 ml of DMSO (co-solvent) and 60 ml of propylene glycol monobutyl ether (solvent) and the mixture is brought to 80 ° C. for 5 minutes , then at 50 ° C for 30 minutes. We cool the solution obtained and 1 ml of Tween 80 (co-solvent) and the equivalent of 1 mg of Patent Blue, in solution in propylene glycol, are added to complete the preparation to 100 ml.

Example 5 The procedure is carried out under the conditions of the preceding example, using 30 g of closantel sodium salt, 10 ml of dimethylacetamide (co-solvent), 5 ml of N-methylpyrroli¬ done (co-solvent) and 65 ml of ethylene glycol (solvent). After complete dissolution, 1 g of semi-synthetic polysaccharide (Klucel-HF-Aqualon ^® ) and 0.5 ml of Tween 80 are added, followed by optional addition to 100 ml. Example 6

The composition according to Example 1 is applied to the back of cattle at the rate of 10 mg, 20 mg, 30 and 40 mg / kg of bodyweight. Four groups of six cattle weighing approximately 300 kg were thus formed. A fifth group is treated subcutaneously at 2.5 mg / kg, while a sixth group is treated orally at 10 mg / kg and serve as positive controls. Blood samples are taken from all the animals on the following days: D0, Dl, D3, D7, D10, D12, D14, D16, D18, D21, D28. The samples are centrifuged and the plasma concentration of closantel is determined by known HPLC methods. The results are collated in Table I. It is noted that a topical administration of a composition according to the invention at 20 mg / kg provides a plasma concentration in closantel comparable to that obtained with a subcutaneous injectable formulation at 2 , 5 mg / kg. Likewise, a topical formulation at 40 mg / kg has an efficacy comparable to an administration of 10 mg / kg orally. (See figure 1). Table I

EXAMPLE 7 An experimental infestation is carried out with fluke larvae (at least 200) at the metacercaria stage, on cattle weighing 300 kg. After a period of 14 weeks, corresponding to the stage of development and migration of the immature forms to their final target organ, the liver, the liquid formulation according to Example 1 is administered, at a rate of 30 mg / kg live cattle. This is achieved by pouring 30 ml of liquid formulation on the back of the animal, along the spine. After two weeks, the animals are slaughtered, the liver is removed, then the parasites are counted. On 6 treated animals, the efficiency is 97.4%. Table II illustrates the results obtained and shows the systemic efficacy of closantel sodium salt, administered locally, at 1 ml / 10 kg (30 mg / kg), in the form of a liquid solution as defined above. , on an endoparasite, Fasciola hepa tica.

Table II

It appears from the preceding examples that the concentration of closantel sodium salt to be used in this formulation must be between 1 and 60% and more particularly between 5 and 40%. In the event of the addition of a second antiparasitic active principle, the concentration thereof must be between 0.01% and 10%, preferably between 0.1 and 2%. This second antiparasitic active principle is chosen from the family of avermectins comprising inter alia abamectin and ivermectin.

As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which come to be described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the framework, or the scope, of the present invention.

Claims

1) liquid composition for topical use, comprising at least one anthelmintic in a non-aqueous solvent as active substance, which composition is characterized in that it essentially consists of sodium salt of closantel in solution in at least one non-aqueous solvent, chosen from the group consisting of polyalcohols, their ethers and mixtures thereof.

2 °) Composition according to claim 1, characterized in that it further comprises at least one co-solvent, selected from the group consisting of fatty alcohols, amides, fatty acid esters, functional monocyclic derivatives, essential oils, tallow oxides and nonionic surfactants. 3 °) Composition according to claim 1 or claim 2, characterized in that the polyalcohols and their ethers are selected from the group consisting of glycerol; sorbitol; glycols, such as: propylene glycol, diethylene glycol, butyl diglycol, polyethylene glycol or their mono- or poly-ethers such as methoxyethanol, butoxyethoxyethanol, the monobutyl ether of propylene glycol or ethylene glycol, monomethyl ether of dipropylene glycol, monomethyl ether, monobutyl ether or monopropyl ether of tripropylene glycol, dimethyl isosorbide.

4 °) Composition according to any one of Claims 1 to 3, characterized in that the co-solvent is in particular selected from n-dodecanol, dimethylacetamide, n-butyl-n-dodecylamide, dimethylformamide, 1 isopropylmyristate, methyl laurate, glycerol or propylene glycol monolaurate, cycloalkanone, N-methylpyrrolidone, l-alkylazacycloheptane-2-one, menthol, 1-carvone, eucalyptol, eugenol, di-methylsulfoxide, decylmethylsulfoxide, sorbitan esters, polyoxyethylene esters (POE) of sorbitan. 5 °) Composition according to any one of claims 1 to 4, characterized in that the sodium salt of closantel is at a concentration between 1 and 60%, preferably between 5 and 40% (w / v).

6 °) Composition according to any one of claims 1 to 5, characterized in that it comprises a second anthelmintic, present in proportions com¬ taken between 0.01% and 10% (w / v), preferably between 0.01 and 2%.

7 °) Composition according to any one of claims l to 6, characterized in that said co-solvent is preferably selected from the group consisting of dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and monoleate polyoxyethylene (20), in a proportion generally less than 20%, more generally between 0.5 and 10%. 8 °) Composition according to any one of claims 1 to 7, characterized in that it essentially comprises between 10 and 40% of sodium salt of closan¬ such, between 0.1 and 1% of an avermectin, between 49 and 88.9% propylene glycol and 1 to 10% dimethylformamide. 9 °) Process for preparing the composition according to any one of Claims 1 to 8, characterized in that it comprises the following steps:

dispersion of the closantel sodium salt in at least one solvent or a mixture of at least one solvent and at least one co-solvent, with vigorous stirring, at a temperature between 30 ° C. and 100 ° C., preferably between 40 ° and 80 ° C, to obtain a sodium salt solution from closantel,

- cooling of the solution obtained to room temperature, - possible addition of additives and other antiparasitic active ingredients intended to combat other parasites and, if necessary,

- adjustment of the solvent concentration to the desired level. 10 °) Use of a liquid composition for topical use according to any one of claims 1 to 8, for obtaining a medicament with systemic activity, intended for the treatment of helminthiasis.

11 °) Use according to claim 10, characterized in that said topical administration is realized by application to a more or less extensive area of the animal, at a rate of 10 to 40 mg / kg.