EP0859609A1 - Flüssige zusammensetzung für die topische anwendung, verfahren zur herstellung und verwendung - Google Patents

Flüssige zusammensetzung für die topische anwendung, verfahren zur herstellung und verwendung

Info

Publication number
EP0859609A1
EP0859609A1 EP96934896A EP96934896A EP0859609A1 EP 0859609 A1 EP0859609 A1 EP 0859609A1 EP 96934896 A EP96934896 A EP 96934896A EP 96934896 A EP96934896 A EP 96934896A EP 0859609 A1 EP0859609 A1 EP 0859609A1
Authority
EP
European Patent Office
Prior art keywords
solvent
closantel
composition according
sodium salt
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96934896A
Other languages
English (en)
French (fr)
Inventor
Vincent Beuvry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virbac SA
Original Assignee
Virbac SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virbac SA filed Critical Virbac SA
Publication of EP0859609A1 publication Critical patent/EP0859609A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil

Definitions

  • 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.
  • 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.
  • the dispersal of cattle in extensive farms makes the mode of topical administration preferable to other modes of administration.
  • 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.
  • 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. .
  • compositions 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.
  • composition 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.
  • 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.
  • 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.
  • 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 isosorb
  • 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.
  • 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 surfact
  • fatty alcohols more particularly
  • Said co-solvent is advantageously present in a proportion generally less than 20%, more generally between 0.5 and 10%.
  • said co-solvent is preferably selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAC) and N-methylpyrrolidone.
  • 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%.
  • 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
  • stabilizing agents such as phenolic derivatives at concentrations less than or equal to 1%, preferably between 0.05 and 0.1%.
  • a second anthelmintic present in proportions of between 0.01% and 10% (w / v), preferably between 0.01 and 2%.
  • said composition essentially comprises between 10 and 40% of sodium salt of closantel, between 0.1 and 1% of an avermectin, between 49 and
  • 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:
  • 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.
  • 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.
  • 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.
  • FIG. 1 shows the average plasma concentration of closantel in mg / ml, depending on the route of administration.
  • 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.
  • DMSO co-solvent
  • propylene glycol monobutyl ether solvent
  • 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.
  • Klucel-HF-Aqualon ® semi-synthetic polysaccharide
  • Tween 80 0.5 ml of Tween 80
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP96934896A 1995-10-13 1996-10-11 Flüssige zusammensetzung für die topische anwendung, verfahren zur herstellung und verwendung Withdrawn EP0859609A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9512458 1995-10-13
FR9512458A FR2739778B1 (fr) 1995-10-13 1995-10-13 Formulation topique destinee a traiter la maladie de la douve du foie chez l'animal
PCT/FR1996/001589 WO1997013508A1 (fr) 1995-10-13 1996-10-11 Composition liquide a usage topique, son procede de preparation et ses applications

Publications (1)

Publication Number Publication Date
EP0859609A1 true EP0859609A1 (de) 1998-08-26

Family

ID=9483817

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96934896A Withdrawn EP0859609A1 (de) 1995-10-13 1996-10-11 Flüssige zusammensetzung für die topische anwendung, verfahren zur herstellung und verwendung

Country Status (4)

Country Link
EP (1) EP0859609A1 (de)
AU (1) AU7304196A (de)
FR (1) FR2739778B1 (de)
WO (1) WO1997013508A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2386066A (en) * 2002-02-28 2003-09-10 Norbrook Lab Ltd Long-acting parasiticidal composition with improved bioavailability comprising a salicylanilide, a further anti-parasitic compound & a polymeric species
FR2839614B1 (fr) * 2002-05-14 2004-08-13 Virbac Sa Nouvelles compositions orales huileuses antiparasitaires
GB0316377D0 (en) * 2003-07-12 2003-08-13 Norbrook Lab Ltd Parasiticidal composition
US7666444B2 (en) * 2004-02-02 2010-02-23 Wyeth Antiparasitic composition

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57139012A (en) * 1981-02-23 1982-08-27 Sankyo Co Ltd Anthelmintic composition
GB8304927D0 (en) * 1983-02-22 1983-03-23 Wellcome Found Pesticidal formulations
US5169846A (en) * 1989-10-12 1992-12-08 Crooks Michael J Non-aqueous micellar solutions of anthelmintic benzimidazoles, closantel, or phenothiazine, and insect growth regulators
NZ248486A (en) * 1993-08-24 1996-07-26 Ashmont Holdings Limited Subst Stable anthelmintic formulation containing closantel and one or more avermectins or milbemycins in a glycol based solvent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9713508A1 *

Also Published As

Publication number Publication date
WO1997013508A1 (fr) 1997-04-17
FR2739778A1 (fr) 1997-04-18
AU7304196A (en) 1997-04-30
FR2739778B1 (fr) 1997-12-12

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