NL8403528A - ANTHELMINTIC COMPOSITIONS. - Google Patents

Description

r "N.0. 32861

Anthelmintic compositions. ~

The present invention relates to new formulations of an organic salt with anthelmintic properties, to methods for the preparation of such formulations and to their use in combating helmetintiasis.

5 Lev amisole (L-2,3,5,6-tetrahydro-6-phenyl-imidazo [2,1-b] -thiazole, widely used to control intestinal nematodes and lungworm in warm-blooded animals , and nitroxynil (4-cyano-2-iodo-6-nitrophenol or 4-hydroxy-3-iodo-5-nitrobenzonitrile), which is widely used to control trematode and certain ne-10 matode parasites in warm-blooded animals form a salt, which was, as was to be expected, due to the known basic nature of levamisole, which is generally provided and used in the form of its hydrochloride or dihydrogen phosphate salts, and the known acidic nature of nitroxynil, which is is commercially available in the form of an aqueous solution of the eglumine (N-ethyl-D-glucamine) salt of nitroxynil The nitroxynil salt of levamisole combines the activity of levamisole against nematodes, for example Haemonchus con-tortus, Ostertagia spp ., Trichostrongylus spp., E.g. Trichostrongylus axel, Coope ria spp., e.g., Cooperia oncophora, Nematodirus spp., e.g.

Nematodirus fillicolis, Oesaphagostomum spp., Eg Oesaphagostomum venulosum, Strongyloides spp., Eg Strongyloides papillosus, Bunosto-mum spp., Eg Bunostomum trigonocephalum, Chabertia spp., Eg Cha-bertia ovina, Trichuris. Trichuris ovis and Dictyocaulus spp., Eg Dictyocaulus filaria and Dictyocaulus viviparus, and the activity of nitroxynil against trematodes, eg Fasciola hepatica and Fasciola gigantica and certain nematodes, eg Haemonchus contor-tus, Bunostomum spp. and Parafilaria bovicola. The nitroxynil salt of levamisole can be used to kill intestinal worms, eg nematode and trematode parasites of warm-blooded animals, eg cattle, sheep, pigs, goats, horses and dogs. The dose used will depend on the nature of the intestinal worms, the animal to be treated and the route of administration, but the administration of a single dose of the nitroxynil salt of levamisole at dose levels of 10 to 30 mg, and usually about 18 mg of the salt per 35 kg body weight, generally gives satisfactory control of the parasites. The administration can be parenterally, ie by intravenous, intramuscular or subcutaneous injection, orally, eg in an oral dosage form such as a tablet, pill, capsule or drink, as an additive 8403528, 5, 2, of food, or dermal by a "pour-on" dosage form, with administration of an effective dose in a single unit dose, more particularly a single parenteral unit dose, being preferred.

The nitroxynil salt of levamisole can be prepared by reaction of stoichiometric amounts of nitroxynil and levamisole in water or an inert organic solvent, eg ethanol, or by the reaction in water of stoichiometric amounts of a water-soluble salt of nitroxynil, eg sodium meglumine (N-methyl-D-10 glucamine) or eglumine salt and a water-soluble salt of levamisole, for example the hydrochloride or dihydrogen phosphate salt. The aforementioned salts of nitroxynil and levamisole are commercially available or can be readily prepared by known methods from nitroxynil and levamisole, which are themselves commercially available or can be prepared by known methods. (The term "known methods" as used in the present invention means methods which have been used previously or which have been described in the chemical literature). The following method illustrates the preparation of the nitroxynil salt of levamisole.

20 Method

A solution of the elgumine salt of nitroxynil (63.05 g, 0.125 mol) in water (100 ml) was slowly added with stirring at ambient temperature to a solution of levamisole hydrochloride (29.12 g, 0.125 mol) in water (100 ml). After completion of the addition, the precipitate formed was removed by filtration, washed with water and dried under reduced pressure to form the nitroxynil salt of levamisole (60.2 g), mp. 129eC, in the form of yellow needles.

For parenteral administration to animals, it is desirable to provide a sterile solution suitable for injection containing an amount of the nitroxynil salt of levamisole in a pharmaceutically acceptable solvent which allows the desired dose to be administered in a single unit dose which is well tolerated by the animal. Desirably, such solutions will contain 5 to 70% w / v and in particular 5 to 40% w / v of the nitroxynil-35 salt of levamisole.

The nitroxynil salt of levamisole is only sparingly soluble in water and suspensions of the salt are found to be poorly tolerated by parenteral administration to animals, even when additives expected to reduce local intolerance are included in the suspensions. Suitable solvents for the formation of levamisole nitroxynil salt solutions which have been reported are pharmaceutically acceptable alcohols, e.g. benzyl alcohol and tetrahydrofurfuryl alcohol, ketones, esters, e.g. ethyl lactate, amides e.g. N- (2-hydroxyethyl) lactamide, sulfoxides, e.g. dimethyl sulfoxide, sulfones, e.g. sulfolan, cyclic ether derivatives, formals, e.g. glycerol formal, hydrocarbons, perfluorinated hydrocarbons, e.g. perfluorodecalin, glycols and glycol derivatives, e.g. ethylene gly -col, propylene glycol, ethylene glycol mono- and di-alkyl ethers, propylene glycol mono- and di-alkyl ethers, polypropylene glycols, polyethylene glycols, for example polyethylene glycols with an average molecular weight in the range of 100 to 600, polypropylene glycol mono and di-alkyl ethers , polyethylene glycol mono and di-alkyl ethers, for example diethylene glycol dimethyl ether, pyrrolidones, for example N-methylpyrrolidone and poly- (N-vi nylpyrrolidone), silicone oils, eg polymethylsiloxane, aprotic solvents, eg dimethylformamide, dimethyl acetarnide and tetramethyl urea, and mixtures of such solvents.

As indicated above, it is desirable to be able to prepare solutions of the nitroxynil salt of levamisole containing 5 to 40 20 w / v% of the salt, which are well tolerated when administered to the animal in parenteral form and those solvents which, incidentally, are suitably accepted for use as a diluent or carrier in a pharmaceutical composition. Practice has shown that these criteria are difficult to achieve. For example, although the nitro-25 xynil salt of levamisole is highly soluble in neat benzyl alcohol, the latter is biologically active, when used at concentrations up to 2 vol./vol.Z as a preservative in liquid pharmaceutical compositions and using high concentrations of benzyl alcohol in such compositions are unacceptable and solutions in dimethylsulfoxide and mixtures of N-methylpyrrolidone and polyethylene glycol 400 have been found to be poorly tolerated when administered parenterally to animals. As a result, there remains a need for levamisole nitroxynil salt solutions that meet the above criteria.

As a result of research and experimentation, it has been found that solutions of the nitroxynil salt of levamisole that meet these criteria, ie which may contain up to 40% w / v of the salt, are well tolerated when administered parenterally to animals and using a solvent, otherwise accepted as being suitable for use as a diluent or carrier in a liquid pharmaceutical composition, which may be prepared using dimethylisosorbide or glycofurol or a mixture of dimethylisosorbide and glycofurol as the sole solvent or carrier or mixed with a cosolvent or cosolvents.

The present invention accordingly provides new pharmaceutical formulations containing the nitroxynil salt of levamisole in solution in a solvent containing dimethylisosorbide and / or glycofurol and containing up to 40% w / v of the nitroxynil salt of levamisole. The lower limit of the nitroxynil salt content of leva-10 misole of the compositions of the present invention is not critical, the salt content being selected so that the required amount of the nitroxynil salt of levamisole is present in a solution volume, which is the intended purpose is appropriate. In practice, it is preferred that the nitroxynil-15 salt content of levamisole of the solution is at least 5% w / v, although, as already indicated, lower concentrations may be used if desired.

As used herein in connection with solutions of the present invention, the term "nitroxynil salt of levamisole" includes not only the salt formed between nitroxynil and levamisole, but also an association of nitroxynil and levamisole in equimolar proportions.

Dimethylisosorbide or glycofurol or mixtures thereof can only be used as a carrier or diluent in pharmaceutical compositions according to the present invention, but if desired one or more co-solvents, for example water, butyrolactone and alcohols, for example ethanol, glycols, for example ethylene glycol, Propylene glycol, polyethylene glycols and polypropylene glycols, glycerol, tetrahydrofurfuryl alcohol and benzyl alcohol or mixtures thereof are included. Preferably, the ratio of dimethylisosorbide or glycofurol or mixtures of dimethylisosorbide and glycofurol in the solvent should not be less than 25% by volume. When mixtures of dimethylisosorbide and glycofurol are used as the sole diluent or carrier or in association with co-solvents, the ratio of dimethylisosorbide to glycofurol in the mixture used as the sole diluent or sole carrier and the ratio of dimethylisosorbide to glycofurol in the dimethylisosorbide-glyco-furol component of diluents or carriers, additionally containing one or more co-solvents, vary widely, for example from 100: 1 to 1: 100 by volume. Suitable solvents contain 80:20 8403528 * 5 * v / v mixtures of dimethylisosorbide and water and 1: 1: 1 (by volume) mixtures of dimethyl sorbide, glycofurol and water.

The pharmaceutical formulations of the present invention can be used to administer the nitroxynil salt of levamisole to kill intestinal worms, eg nematode and trematode parasites of warm-blooded animals, for example cattle, sheep, pigs, goats, horses and dogs, in the dosages and for the purposes as described above for the nitroxynil salt of levamisole, by parenteral administration, ie by intravenous, intramuscular or subcutaneous administration, by oral administration as a beverage or dermal as a "pour-on" dosage form, wherein administration of an effective dose of the nitroxynil salt of levamisole in a single unit dose of the pharmaceutical formulation of the present invention, more particularly a single parenteral unit dose, is preferred. Accordingly, as a preferred feature of the present invention, new pharmaceutical compositions are provided , which are sterile solutions containers of the nitroxynil salt of levamisole in dimethylisosorbide or glycofurol or mixtures of dimethylisosorbide and glycofurol alone or mixed with a co-solvent or co-solvents, as described above, containing up to 40% w / v, and preferably at least Containing 5% w / v of the nitroxynil salt of levamisole, wherein when a cosolvent or cosolvents is or are present, the ratio of dimethylisosorbide or glycofurol or mixture thereof in the solvent is preferably at least 25% by volume. As will be appreciated, when administered orally as a beverage or dermal with a "pour-on" dosage form, the pharmaceutical formulations of the present invention need not be sterile, but sterile formulations may be used for these purposes if desired. »

The new pharmaceutical formulations of the present invention can be prepared by dissolving the nitroxynil salt of levamisole in dimethylisosorbide or glycofurol or a mixture thereof alone or mixed with a co-solvent or co-solvents, as described above, or by solution of stoichiometric amounts of levamisole or a salt thereof, eg the hydrochloride or dihydrogen phosphate, and nitroxynil or a salt thereof, eg the eglumin, meglumine or sodium salt, in dimethylisosorbide or glycofurol or a mixture thereof alone or mixed with a co-solvent or co-solvents as described above. These solutions of the nitroxynil salt of levamisole or levamisole and nitroxynil or salts thereof can be carried out at ambient temperature or with gentle heating, for example at 60 to 70 ° C and with stirring. The solution thus obtained can then be sterilized, if desired, for example, by passage through a suitable bacteria retaining filter to form the sterile pharmaceutical compositions of the present invention suitable for parenteral administration, which are then preferred under sterile conditions in sterile single unit dose or multi-dose containers and be sealed.

Bases, for example, organic bases, for example, eglumine, or inorganic bases, for example, sodium hydroxide, can be included, if required, in the pharmaceutical compositions of the present invention to completely dissolve the nitroxynil salt of levamisole in mixtures of dimethylisosorbide and / or glycofurol and co solvents in which the salt is only sparingly soluble, for example water, which contains considerable amounts of the co-solvent (s) and from which precipitation would otherwise take place.

If desired, biological preservatives, for example up to 2% by volume of benzyl alcohol, additives to improve chemical and physical storage stability, and additives to reduce localized tissue reaction after injection, may be included in the pharmaceutical compositions of the present invention.

Dimethylisosorbide is offered by ICI Americas Inc. and Atlas Chemicals Industries (UK) Ltd.

25 Glycofurol is offered by Lusochimica S.p.a., Italy.

The following non-limiting examples illustrate the present invention.

Example I

A transparent 20 w / v% solution of the nitroxy-30 nil salt of levamisole was obtained by dissolving nitroxynil (11.7 g) and levamisole (8.3 g) in dimethylisosorbide (100 ml) with stirring at ambient temperature. until solution of the solid product was complete.

The solution thus obtained was sterilized by passage through a bacteria-retaining filter and divided into sterile ampoules under sterile conditions and sealed in amounts to obtain a suitable unit dose for parenteral administration. Similarly prepared sterile solutions may, if desired, be placed in sterile multi-dose containers and sealed under sterile conditions from which appropriate unit doses may be withdrawn as required for use for parenteral administration.

Example II

A clear 20% w / v solution of the nitroxynil salt of levamisole in an 80:20% w / v mixture of dimethylisorbide and water was obtained by adding nitroxynil (11.7 g) and levamisole (8.3 g) with stirring to a mixture of dimethylisosorbide (80 ml) and water (20 ml) and stirring the solution thus obtained at 40 ° C until solution of the solid product was complete * 10 The solution thus obtained was sterilized by passage through a bacteria-retaining filter and dispensed into sterile ampoules under sterile conditions and sealed in amounts to obtain an appropriate unit dose for parenteral administration. Similarly prepared sterile solutions can be introduced into sterile multi-dose containers and sealed under sterile conditions, from which unit doses for parenteral administration can be withdrawn, if required, for use.

Example III

The nitroxynil salt of levamisole (20 g) and eglumine (8.4 g) were added with stirring at 40 ° C to a mixture of dimethylissorbide (33 ml), glyophofol (33 ml), water (32 ml) ) and benzyl alcohol (2 ml) and stirring was continued at 40 ° G until solution was complete.

The clear 20% w / v solution of the nitroxynil salt of levamisole in a 33: 33: 32: 2% v / v mixture of dimethyl-isosorbide, glyophofol, water and benzyl alcohol, thus obtained, was sterilized by passage through a bacteria retaining filter and divided into sterile ampoules under sterile conditions and sealed in amounts to obtain an appropriate unit dose for parenteral administration. Similarly prepared sterile solutions may, if desired, be placed in sterile multi-dose containers and sealed under sterile conditions, from which unit doses for parenteral administration can be withdrawn, if required, for use.

Example IV

The nitroxynil salt of levamisole (20g) was added to a mixture of glyeofurol (60ml) and benzyl alcohol (1.5ml) with stirring at 60 ° C and the volume was made up to 100ml with glyeofurol under stirring at 60 ° C C until solution was complete.

The clear 20% w / v solution of the nitroxynil salt 40 of levamisole in a 98.5: 1.5% v / v mixture of glycofu 8403528

V

8 roll and benzyl alcohol, thus obtained, were sterilized by passage through a bacteria retaining filter and divided into sterile ampoules under sterile conditions and sealed in amounts to obtain an appropriate unit dose for parenteral administration. Similarly prepared sterile solutions may, if desired, be placed in sterile multi-dose containers and sealed under sterile conditions, from which appropriate unit doses for parenteral administration can be withdrawn, if required, for use.

8403528

Claims (14)

1 Pharmaceutical composition containing the nitroxynil salt of leva-misole in solution in a solvent containing dimethylisosorbide and / or glycofurol and containing at most 40% w / v of the nitro-xynil salt of levamisole. The composition according to claim 1, which contains at least 5 w / v% of the nitroxynil salt of levamisole. A composition according to claim 1 or 2, which contains one or more co-solvents. The composition of claim 3, wherein the co-solvents are selected from water, butyrolactone and alcohols. The composition of claims 1 to 4, wherein the ratio of dimethylisosorbide or glycofurol or a mixture of dimethylisosorbide and glycofurol in the solvent is not less than 25% by volume. A composition according to any of the preceding claims, wherein the solvent contains dimethylisosorbide and glycofurol in a dimethylisosorbide to glycofurol ratio of 100: 1 to 1: 100 by volume. 7. A composition according to any one or more of the preceding claims, wherein the solvent is a mixture of dimethylisosorbide and glycofurol in a volume ratio of 80:20. The composition according to any of claims 1 to 6, wherein the solvent is a mixture of dimethylisosorbide, glycofurol and water in a volume ratio of 1: 1: 1. A composition according to any of the preceding claims in a form suitable for parenteral or oral administration, or for dermal administration as a top-on dosage form. 10. Sterile pharmaceutical composition containing the nitroxynil salt of levamisole in a solvent containing dimethylisosorbide or glycofurol or a mixture of dimethylisosorbide and glycofurol alone or mixed with a co-solvent or co-solvents and containing up to 40 wt. / vol.% of the nitroxynil salt of levamisole. The composition according to claim 10, which contains at least 5 w / v% of the nitroxynil salt of levamisole. A composition according to claim 10 or 11, wherein when one or more co-solvents are present, the ratio of dimethylisosorbide or glycofurol or mixture thereof in a solvent is at least 25% by volume. 13. Composition according to one or more of the preceding claims, which contains a base for obtaining complete solution 84 03 5 28 of the nitroxynil salt of levamisole In a solvent containing dimethyl isosorbide and / or glycofurol or a co- solvent in which the salt is only sparingly soluble. A composition according to any of the preceding claims in unit dosage form. The composition of claim 14 for parenteral administration. -B-H-1 -1 8403528; B. Vdi Bi 2 2 JAN 1985 Improvement of erratum in the specification associated with Patent Application No. 84.03528, proposed by the applicant, under date January 22, 1985 Page. 1, line 10 no. Insert "salt": "hereinafter referred to as nitroxinyl salt of levamisole," ****** 8403528