FR2555047A1 - NOVEL ANTHELMINTHIC COMPOSITIONS AND THEIR PREPARATION - Google Patents

Abstract

THE INVENTION RELATES TO A PHARMACEUTICAL COMPOSITION COMPRISING THE NITROXYNIL SALT OF LEVAMISOLE IN SOLUTION IN A SOLVENT COMPRISING DIMETHYLISOSORBIDE, GLYCOFUROL OR A MIXTURE OF BOTH AND CONTAINING UP TO 40 NIGHT SLEEVE.

Description

The present invention relates to new formulations of a salt

  organic having anthelmintic properties, their preparation methods and their use in the fight against helminthiasis. Levamisole (L-tetrahydro- 2,3,5,6 phenyl-6 imidazo [2,1-b] thiazole) which is widely used against intestinal nematodes and pulmonary worms in warm-blooded animals, and nitroxynil ( cyano-4 iodo2 nitro-6 phenol or hydroxy-4 iodo-3

  5-nitro benzonitrile) which is widely used against tremato-

  and certain nematode parasites in warm-blooded animals form a salt, hereinafter called "nitroxynil salt of levamisole" as might be expected from the well-known basic nature of levamisole which is delivered and used in the form hydrochloride or dihydrogenophosphate, and by the well known acid nature of nitroxynil which is commercially available in the form of an aqueous solution of eglumine salt (N-ethyl D-glucamine) of nitroxynil. Levamisole nitroxynil salt combines the activities of levamisole against nematodes, for example Haemonchus contortus, Ostertagia, Trichostrongylus (such as Trichostrongylus axei) Cooperia (such as Cooperia oncophora), Nematodirus (such as Nematodirus fillicolis), Oesaphag venulosum), Strongyloids (such as Strongyloides papillosus), Bunostomum (such as Bunostomum trigonocephalum), Chabertia (such as Chabertia ovina), Trichuris (such as Trichuris ovis) and Dictyocaulus (such as Dictyocaulus filaria and Dictyocaulus viviparus), and nitroxynil against trematodes, for example Fasciola hepatica and Fasciola gigantica and certain nematodes such as Haemonchus contortus,

  Bunostomum, Oesaphagostomum and Parafilaria bovicola.

  The nitroxynil salt of levamisole can be used to kill intestinal helminths such as nematodes and trematodes which are parasites of warm-blooded animals, for example cattle, sheep, pigs, goats, horses and dogs. The dose used depends on

  the nature of the helminth, the animal to be treated and the route of administration

  tration, but generally the administration of a single dose of levamisole nitroxynil salt between 10 and 30 milligrams (generally around 18 mg of salt) per kilo of weight

  animal body gives satisfaction in the treatment of parasites

  your. The administration can be done parenterally (intravenously

  (intramuscular or subcutaneous), orally using an oral formulation such as a tablet, pill, capsule or dragee, as a food additive, or dermally using a spray formulation by "pour-on", it being understood that preference is given to the administration of an effective amount in a single dose, more especially in a single dose per

parenteral route.

  The nitroxynil salt of levamisole can be prepared by action in stoichiometric amounts of nitroxynil and levamisole in water or an inert organic solvent such as ethanol, or by

  action in water of stoichiometric amounts of a hydrosolu salt

  nitroxynil wheat, for example the sodium salt, meglumine (N-methyl Dglucamine) or egglumine and a water-soluble salt

  levamisole, for example hydrochloride or dihydrogen phosphate.

  The aforementioned nitroxynil and levamisole salts are commercially available or can be easily prepared by known methods, from nitroxynil and levamisole, which are themselves commercially available or can be prepared

by known methods.

  Under the term "known methods" as used in the

  present description means the methods already used or

  described in the chemical literature.

  The following process illustrates the preparation of the levamisole nitroxynil salt:

PROCESS

  To a solution of 29.12 g of levamisole hydrochloride

  in 100 cm3 of water, slowly added, with stirring and at room temperature

  rature room, a solution of 63.05 of nitroxy efflumina salt

  nil in 100 cm3 of water. When the addition is complete, the precipi-

  t that has formed is collected by filtration, washed with water and dried under vacuum. 60.2 g of nitroxynil salt are thus obtained.

  levamisole, in the form of yellow needles melting at 129 C.

  For parenteral administration to animals, it is desirable to have a sterile solution suitable for injections, which contains an amount of levamisole nitroxynil salt in a pharmaceutically acceptable solvent allowing the desired amount to be administered in the form of a single unit dose that is well tolerated by the animal. It is desirable that such solutions contain from 5 to 70% (weight / volume) and in particular from 5 to 40% (weight / volume), of levamisole nitroxynil salt. The nitroxynil salt of levamisole is only sparingly soluble in water and it has been found that the suspensions of the salt are poorly tolerated by animals parenterally, even when additives are added to the suspensions for the purpose of

  reduce local intolerance. Solvents suitable for obtaining

  tion of levamisole nitroxynil salt solutions which have been mentioned are acceptable pharmaceutical solvents for example

  alcohols such as benzyl alcohol and tetrahydrofurfury alcohol-

  lique, ketones, esters like ethyl lactate, amides like N- (2-hydroxyethyl) lactamide, sulfoxides like dimethylsulfoxide, sulfones like sulfolane, cyclic ethers derivatives, condensation products formalin with alcohols (for example with glycerol), hydrocarbons, perfluorinated hydrocarbons such as perfluorodecaline, glycols and glycol derivatives such as ethylene glycol, propylene glycol and mono and dialkyl ethers of ethylene glycol, mono ethers and

  propylene glycol dialkylates, polypropylene glycols, polyethylene

  neglycols, for example polyethylene glycols having an average molecular weight of the order of 100 to 600, mono and dialkyl ethers of polypropylene glycol or polyethylene glycol, for example dimethyl ether of diethylene glycol, pyrrolidones, for example Nmethylpyrrolidone and poly (N-vinylpyrrolidone), silicone oils, for example polymethylsiloxane,

  aprotic solvents, for example dimethylformamide, dimethyla-

  ketamide and tetramethylurea and mixtures of these solvents.

  As indicated previously, it is desirable to have the possibility of preparing solutions of levamisole nitroxynil salt which contain from 5 to 40% (weight / volumes) of salt, which are well tolerated by the animal in parenteral administration and which use solvents which are otherwise accepted as suitable for use as a diluent or vehicle in a

  pharmaceutical composition. In practice, we have found that these

  mothers are hard to reach. For example, although the nitroxynil salt of levamisole is highly soluble in pure benzyl alcohol, the latter is biologically active when used as a preservative in pharmaceutical compositions

  liquids at concentrations up to 2% (by volume) and use

  high concentrations of benzyl alcohol in such

  compositions is unacceptable; solutions in dimethylsulfo-

  xyde and mixtures of N-methylpyrrolidone and polyethylene glycol

  400 were found to be fairly poorly tolerated in animals by adminis-

parenteral tration.

  As a result, there was a need to find levamisole nitroxynil salt solutions which satisfied the

criteria listed above.

  As a result of research and experimentation, it has been found that these levamisole nitroxynil salt solutions which meet these criteria, i.e. which may contain up to 40% (weight / volume) of the salt , which are well tolerated in animals in parenteral administration, and which use a solvent which may moreover be suitable as diluent or vehicle in a liquid pharmaceutical composition, can be prepared using the

  dimethylisosorbide or glycofurol or a mixture of dimethyliso-

  sorbide and glycofurol as the sole diluent or vehicle or

  mixture with one or more co-solvents.

  Consequently, the present invention relates to new pharmaceutical formulations comprising salt solutions of

  levamisole nitroxynil in dimethylisosorbide and / or glyco-

  furol containing up to 40% (weight / volume) of levamisole nitroxynil salt. The lower limit of the amount of levamisole nitroxynil salt contained in the compositions according to the present invention is not critical, the amount of salt being chosen such that the amount of levamisole nitroxynil salt

  is contained in a volume of solution suitable for the intended purpose.

  In practice, the amount of levamisole nitroxynil salt in the solution is preferably at least 5% (weight / volume), although, as already indicated, it is possible to

  use lower concentrations if desired.

  When, in the present description,

  subject of the solutions according to the present invention, the term "nitroxynil salt of levamisole", it is understood that one includes not only the salt formed between nitroxynil and levamisole, but also any combination of nitroxynyl and levamisole in

equimolecular proportion.

  Dimethylisosorbide, glycofurol or a mixture of the two can be used alone as a vehicle or diluent in the pharmaceutical compositions according to the present invention, but one or more co-solvents can be added, if desired, by

  for example water, butyrolactone and alcohols for example etha-

  nol, glycols such as ethylene glycol, propylene glycol, polyethylene glycols and polypropylene glycols, glycerol, tetrahydrofurfuryl alcohol and benzyl alcohol, or mixtures of

these solvents.

  Preferably, the proportion of dimethylisosorbide or glycofurol or mixtures of dimethylisosorbide and glycofurol

  in the solvent should not be less than 25% (by volume).

  When using mixtures of dimethylisosorbide and glycofu-

  rol as sole diluent or vehicle or in combination with co-solvents, the level of dimethylisosorbide relative to glycofurol in the mixture used as sole diluent or vehicle in the dimethylisosorbide-glycofurol component of the diluents or vehicles which may additionally comprise a or several co-solvents, can vary in large proportions, for example from 100 for 1 to 1 for 100 by volume. As suitable solvents, there may be mentioned mixtures 80-20 Z (by volume) of dimethylisosorbide and water and the ternary mixture in equal volumes of dimethylisosorbide,

glycofurol and water.

  The pharmaceutical formulations according to the present invention

  tion can be used to administer the nitroxynil salt of levamisole to kill intestinal helminths, such as nematodes, trematodes, which are parasites of warm-blooded animals such as cattle, sheep, goats, horses and dogs, in doses

  and for purposes as described above for the nitroxy salt-

  nil of levamisole, parenterally, e.g. intravenously, intramuscularly or subcutaneously, orally as

  dragees or dermally as a formulation for spraying

  by "pour-on", it being understood that preference goes to the adminis-

  tration of an effective amount of levamisole nitroxynil salt into a single unit dose of the formulation according to the present

  invention, more particularly in a single unit dose

  teral. Consequently, it is mentioned as a preferential characteristic of the present invention, but without being limiting, of new pharmaceutical compositions comprising sterile solutions of levroisole nitroxynil salt in the

  dimethylisosorbide, glycofurol or mixtures of dimethylisoside

  sorbide and glycofurol alone or in mixture with one or more co-solvents as described above, containing up to 40% (weight / volume) and preferably at least 5% (weight / volume) of levamisole nitroxynil salt, in which , when one or more co-solvents are used, the proportion of dimethylisosorbide or

  glycofurol or mixtures of the two in the solvent is preferably

  this equal to at least 25% of the volume. As you might think, when

  whether dragees for oral administration or formulas

  tions for spraying "pour-on" for dermal administration, the pharmaceutical formulations according to the present invention need not be sterile, but it is however possible, if desired,

  use such sterile formulations in this case.

  The new pharmaceutical formulations according to the present invention can be prepared by dissolving the nitroxynil salt of levamisole in dimethylisosorbide, glycofurol or mixtures of the two alone or as a mixture with one or more co-solvents as defined above, or by dissolving stoichiometric amounts of levamisole or one of its salts, such as the hydrochloride or dihydrogenophosphate and nitroxynil, or one of its salts, such as egglumine, meglumine or sodium salt, in dimethylisosorbide, glycofurol, or mixtures of both, alone or

  mixed with one or more co-solvents as defined above

  demment. These solutions of nitroxynil salt of levamisole, or of levamisole and nitroxynil or of salts thereof can be made at room temperature or under slight heating, for example at

  -70 C, with stirring. The solution thus obtained can then be

  te, if desired, sterilized, for example by passing through

  a bacteriological filter to give pharmaceutical compositions

  sterile ticks according to the invention, suitable for parenteral administration. These solutions are then placed and sealed under sterile conditions in unit dose packages.

  single or multi-dose packaging.

  The pharmaceutical compositions according to the present invention

  If desired, bases may be added, for example organic bases such as egglumine or mineral bases such as sodium hydroxide, to obtain complete dissolution of the nitroxynil salt of

  levamisole in mixtures of dimethylisosorbide and / or glyco-

  furol and co-solvents in which the salt is only partially soluble, such as water which contains significant proportions of one or more co-solvents and could otherwise precipitate in these solvents.

  It is also possible, if desired, to incorporate into the components

  pharmaceutical positions according to the invention, biological preservatives

  gics such as benzyl alcohol up to 2% (volume / volume),

  additives to improve chemical and physical stability in storage

  and additives to reduce tissue reactions at the injection site. Dimethylisosorbide can be obtained from HERE

  AMERICAS INC and ATLAS CHEMICALS INDUSTRIES LTD (G. B.). Glycofu-

  rol is available from LUSOCHIMICA S.p.a. (Italy).

  the following examples given without limitation my-

  how the invention can be put into practice:

EXAMPLE 1

  A clear 20% (weight / volume) solution of levamisole nitroxynil salt is obtained by stirring at room temperature

  11.7 g of nitroxynil and 8.3 g of levamisole in 100 cm3 of dimer

  thylisosorbide, until the solids are completely dissolved. The solution thus obtained is sterilized by passage through a bacteriological filter, distributed under sterile conditions in ampoules in an amount such that a dose suitable for parenteral administration is obtained and the ampoules are

  sealed under sterile conditions.

  Sterile solutions, similarly prepared, can be placed and sealed under sterile conditions, in

  multi-dose packaging from which we can subtract

  re unit doses suitable for parenteral administration

for a specific use.

EXAMPLE 2

  A clear solution at 20% Z (weight / volume) of levroisole nitroxynil salt is obtained in an 80/20% (by volume) mixture of dimethylisosorbide and water by stirring a suspension of 11.7 g of nitroxynil and 8, 3 g of levamisole with a mixture of 80 cm3 of dimethylisosorbide and 20 cm3 of water, at 40 C until dissolved

full of solids.

  The solution thus obtained is sterilized by passage through a bacteriological filter and distributed under sterile conditions in ampoules in an amount such that a dose suitable for parenteral administration is obtained, then the ampoules are

  sealed under sterile conditions.

  Sterile solutions, similarly prepared, can be placed and sealed under sterile conditions in

  multi-dose packaging from which we can subtract

  re unit doses suitable for parenteral administration

for a specific use.

EXAMPLE 3

  To a mixture of 33 cm3 of dimethylisosorbide, 33 cm3 of glycofurol, 32 cm3 of water and 2 cm3 of benzyl alcohol, 20 g of levamisole nitroxynil salt and 8.4 g of d are added, with stirring at 40 ° C. and the agitation is continued at 40 ° C until

complete dissolution.

  The clear 20% (weight / volume) solution of levamisole nitroxynil salt in a mixture of dimethylisosorbide,

  glycofurol, water and benzyl alcohol in the respective proportions

  ves of 33/33/32/2% (by volume) thus obtained is sterilized by passage through a bacteriological filter and distributed under sterile conditions in ampoules in an amount such that a dose suitable for parenteral administration is obtained and then

  the ampoules are sealed under sterile conditions.

  Sterile solutions similarly prepared can be placed and sealed under sterile conditions in

  multi-dose packaging from which we can

  milk unit doses suitable for administration

  parenteral for a specific use.

EXAMPLE 4

  Has a mixture of 60 cm3 of glycofurol and 1.5 cm3 of alcohol

  benzyl, 20 g of nitro salt are added, with stirring at 60 ° C.

  levamisole xynil and the volume is completed to 100 cm3 with glycofurol, and stirring is continued at 60 C until dissolution

complete.

  The clear 20% (weight / volume) solution of levamisole nitroxynil salt in a 98.5 / 1.5 (by volume) mixture of glycofurol and benzyl alcohol thus obtained is sterilized by passage through a filter. bacteriological and distributed under sterile conditions in ampoules in a quantity such that a dose suitable for parenteral administration is obtained, then

  the ampoules are sealed under sterile conditions.

  Sterile solutions similarly prepared can be placed and sealed under sterile conditions in

  multi-dose packaging from which we can subtract

  re unit doses suitable for parenteral administration

for a specific use.

l1

Claims (12)

  1 - Pharmaceutical composition, characterized in that it comprises the nitroxynil salt of levamisole in solution in a solvent comprising dimethylisosorbide and / or glycofurol and which may contain up to 40% (weight / volume) of levroisole nitroxynil salt . 2 - Composition according to claim 1, characterized in that it contains at least 5% (weight / volume) of nitroxynil salt levamisole.   3 - Composition according to claim 1 or 2, character-   in that it contains one or more co-solvents.   4 - Composition according to claim 3, characterized in that the cosolvents are chosen from water, butyrolactone and alcohols.   5 - Composition according to claim 3 or 4, character-   sée in that the proportion of dimethylisosorbide or glycofurol or mixture of dimethylisosorbide and glycofurol in the solvent   is not less than 25% by volume.   6 - Composition according to any one of claims   above, characterized in that dimethylisosorbide and glycofurol are in a ratio varying between 100 for 1 and 1 for in volumes. -   7 - Composition according to any one of claims   above, characterized in that the solvent is a mixture of dimethylisosorbide and glycofurol in a ratio of 80/20 by volume.   8 - Composition according to any one of claims   1 to 6, characterized in that the solvent is a mixture in quantities   equal (by volume) of dimethylisosorbide, glycofurol and water.   9 - Composition according to any one of claims   above, characterized in that it is in a suitable form   ble for parenteral or oral administration, or for administration   dermal tration for use by "pour-on" spraying.   - Sterile pharmaceutical composition, characterized in that it comprises the nitroxynil salt of levamisole in a solvent comprising dimethylisosorbide or glycofurol or a   mixture of the two, alone or in mixture with one or more co-   solvents, and containing up to 40% (weight / volume) of nitro salt levamisole xynil.   11 - Composition according to claim 10, characterized   in that it comprises at least 5% (weight / volume) of nitro salt levamisole xynil.   12 - Composition according to claim 10 or 11, character-   in that, when one or more co-solvents are used, the proportion of dimethylisosorbide or glycofurol or of the mixture of   two in the solvent is at least 25% by volume.   13 - Composition according to any one of claims   above, characterized in that a base is used to obtain a dissolution of the nitroxynil salt of levamisole in a solvent comprising dimethylisosorbide and / or glycofurol and a   co-solvent in which the salt is only slightly soluble.   14 - Composition according to any one of claims   previous, characterized in that it is in the form of a unit dosage.   - Composition according to claim 14, characterized   in that it is intended for parenteral administration.