HU196307B - Process for producing vermicides comprising levamisole-nitroxinil salt - Google Patents

Abstract

The compositions contain the nitroxynil salt of levamisole in solution in a solvent comprising dimethyl isosorbide, glycofurol or a mixture thereof, and contain up to 40% w/v of the nitroxynil salt. The compositions can be administered orally, parenterally or in a pour-on form.

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of new compositions containing an organic salt having an antifungal activity.

Levamisole (L-2,3,5,6-tetrahydro-6-phenyl-imidazo [2,1-b] thiazole), which is widely used to control intestinal anodes and pulmonary nematodes in warm-blooded animals, and nitroxynil (4-cyano-2-iodo-6- nitrophenol, also known as 4-hydroxy-3-iodo-5-nitrobenzonitrile), which is used to form salt in trematode and certain N-mode parasites in warm-blooded animals. This is not new as levamisole is known to be basic in nature and is prepared and used in the form of its hydrochloride or dihydrogen phosphate salt, nitroxane! and is known to be of an acidic nature and is commercially available as an aqueous solution of its salt with eglumin (N-ephyl-D-g) mecamine). The nitroxynyl salt of the levamisole combines the action of the levamisole nuclide, e.g. Hacmoncbus contortus, Ostcrtagia species, Trichostrongylus species, e.g. Trichoslrongylus axei, Cooperia species such as Cooperia oncophora, Nematodirus species e.g. Nematodirus fillicolis, Oesaphagostonum species, e.g. Oesaphagostomum vcnulosum, Slongongoid species, e.g. Strongyloidcs papillosus, Bunostoinuin species, e.g. Bunoslomum trigonocephalum, Chabertia species, e.g. Chabertia ovina, Trichuris species, e.g. Trichuris ovis and Dictocaulus species, e.g. Dictocaulus filaria and Dictocaulus vuviparus, and the anti-trematode activity of nitroxynil, e.g. Fasciola hepatica and Fastiola giganlica, and certain nematodes, e.g. Haemonchuscontrortus, Bunostomuin species, Ocsaphagostomum species cs Paralilari bovicola. The nitroxynil salt of levamisole is an internal intestine, e.g. nematode and trematode, warm-blooded animals, e.g. used to control parasites in cattle, sheep, pigs, goats, horses and dogs. The dose employed will depend on the nature of bclfcrcg, the animal being treated and the mode of administration, but administration of a single dose of levamisole nitroxynil salt of from 10 to 30 ng, and generally a dose of 18 mg salt / animal body weight / kg will generally produce a satisfactory anthelmintic effect. The administration may be parenteral, that is, intravenous, intramuscular or subcutaneous injection, orally, e.g. oral dosage forms such as tablets, pills, capsules or liquid formulations, feed additives, or transdermally, can be administered in a "pour-on" dosage form, preferably in an effective dosage unit, especially in a single parenteral dosage unit.

The nitroxynil salt of levamisole is the stoichiometric amount of nitroxynil and levamisole in water or in an inert solvent such as ethanol, or the water soluble salt of nitroxynil, such as Nalomethyl-D-glucamine sodium or eglumin salt, and the water soluble salt of levamisole, e.g. . by reaction of stoichiometric amounts of its hydrochloride or dihydrogen phosphate salt. The aforementioned salts of nitroxynil and levamisole are commercially available or can be prepared by known methods. (The term "known methods" as used herein refers to methods previously described or used in the chemical literature.)

French Patent Publication No. 2,516,923 discloses pharmaceutical compositions containing levamisole-nitroxynil salt in various solvents. The solvents listed herein do not include isosorbides.

European Patent Application Publication No. 0 052 962 relates to the stabilization of water-soluble salts of clavulinic acid, alpha-aminopenicillins and cephalosporins by the use of glucofural. There is no reference to the solubility of glucofural in increasing its solubility.

U.S. Patent 4,082,881 relates to the preparation of formulations containing up to 3% steroid and optionally 3% or more other active ingredients using isosorjides. Levamisole nitroxynyl salt is not included in the active ingredients. The examples described herein describe the processing of steroids or refer to econazole nitrate as a different active ingredient, but at concentrations up to 0.5%.

Australian Patent No. 527,154 describes the preparation of nitroxynil microcellulates of tetranisol or levamisole starting from an aqueous solution of the acid addition salt of tetramisole or levamisole.

The prior art does not suggest the possibility of preparing a solution of the levamisolenitroxynil salt with dimclyl isosorbide and / or glucofural.

The following procedure illustrates the preparation of the nitroxynil salt of levamisole.

process

63.0 g (0.15 mole) of the nilroxynylglutamine salt are dissolved in 100 ml of water and added at room temperature with stirring to a solution of 29.12 g (0.125 mole) of levaminsole in 100 ml of water. After the addition was complete, the resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 60.2 g of levamisole-nitroxynil salt as a yellow solid, mp 129 ° C.

For parenteral administration to animals, it is desirable to provide a sterile injectable solution containing the levamisole nitroxynyl salt in a pharmaceutically acceptable solvent in an amount sufficient to deliver the desired dose in a single dose and which is well tolerated by the animal. Such solutions preferably contain from 5 to 70% (w / v), preferably from 5 to 40% (w / v) of levamisole-nitroxynyl salt.

Levamisole nitroxynyl salt is sparingly soluble in water and is difficult to tolerate for parenteral administration of suspensions, even if suspensions are presumed to reduce local intolerance. Suitable solvents for the preparation of the levamisole-nitroxynil salt are pharmaceutically acceptable alcohols, e.g. benzyl alcohol and tetrahydrofuryl alcohol; ketones; esters such as ethyl lactate; amides, e.g. N- (2-hydroxyethyl) - lactate; sulfoxides, e.g. dimethyl sulfoxide; sulfones, e.g. sulfolane; cyclic ether derivatives; formaldchid accents, e.g. glycerol formal; hydrocarbons, perfluorinated hydrocarbons, e.g. perlluor, decalin; glycols and glycol derivatives, e.g. ethylene glycol, propylene glycol, ethylene glycol mono- and dialkyl esters, propylene glycol monoctyl dialkyl, polypropyl glycols, polyctylene glycols such as polyethylene glycols having an average molecular weight of 100 to 600, polypropylene mono- and dialkyl ethers, polyethylene glycol mono- and dialkyl ethers, e.g. diethylene glycol 23

196,307 dimethyl ether; pyrrolidines, p !. N-methylpyrrolidone and poly (N-vinylpyrrolidone); silicone oils, e.g. polymethylene siloxane; aprotic solvents, e.g. dimethylformamide, dimethylacetamide and tetramethylurea and mixtures of these solvents.

As mentioned above, it is desirable to be able to prepare a 5 to 40% w / v solution of levamisole-nitroxynil salt which is good for the parent when administered parenterally. and is formulated with a solvent acceptable for use as a diluent or carrier in pharmaceutical compositions. In practice, we have found that these requirements are difficult to meet. For example, the nyl hydroxynil salt of levamisole is very soluble in pure benzyl alcohol, but the latter is biologically active and is used in liquid pharmaceutical formulations up to a concentration of up to 2%, so that high concentrations of benzyl alcohol in such formulations are unacceptable. It has been found that solutions in dimethylsulfoxide and solutions in N-methylpyrrolidone and polyethylene glycol 400 are difficult to tolerate when administered parenterally. Thus, there remains a need to make solutions of the nitroxynyl salt of the levamisole which meet the above requirements.

As a result of research and experimentation, it has been found that solutions of levamisole nitroxynyl salt that meet these conditions, i.e. containing up to 40% w / v salt, are well tolerated by the parenteral route and can be prepared with a solvent, which are otherwise acceptable as diluents or carriers for liquid pharmaceutical compositions, i.e., dimethyl isosorbide or glucofural or a mixture of dimethyl isosorbide and glucofural as a single diluent or carrier, or a mixture thereof with cosolvent (s).

Accordingly, the present invention relates to the preparation of novel pharmaceutical compositions containing up to 40% w / v of the nitroxynil salt of levamisole in a dimethylisosorbide or glucofural solvent. The lower limit of the amount of levamisole-nitroxynil salt in the compositions of the present invention is not critical and the salt content is selected so that the required amount of levamisole-nitroxynil salt is included in the appropriate volume of solution. In practice, it is preferred that the solution has a levamisole nitroxynyl salt content of at least 5% w / v, but as indicated above, lower concentrations may be used if desired.

The term "levamisole nitroxynyl salt" as used herein in connection with the solutions of the present invention includes not only the salt formed by levamisole and nitroxynil, but also the equimolar amount of levamisole and nitroxynil.

In the pharmaceutical compositions of the invention, dimethyl isosorbide or glucofural or mixtures thereof may be used alone as carriers and diluents, but optionally one or more co-solvents such as water, butyrolactone and alcohols such as ethanol, glycols, e.g. ethylene glycol, polypropylene glycol, polyethylene glycols and polypropylene glycols, glycerol, tetrahydrofuryl alcohol, benzyl alcohol or their living solvents. Preferably, the proportion of dimethylisosorbide or glucofural or a mixture of dimethylisosorbide and glucofural in the solvent is not less than 25% by volume. When the mixtures of dimethylisosorbide and glucofurol are used alone or in combination with co-solvents, the ratio of dimethylisosorbide and glucofurol in the mixture when used alone as diluent or carrier and the ratio of dimethylisosorbide and glucofurol is one or more co-solvents. - or in the dimethylisosorbide-glucofural component of the carrier, with broad limits, e.g. 100: I cs I: 100 volume ratio may vary. Suitable solvents are, for example, 80:20 v / v dimethyl isosorbide tube water and 1: 1: 1 v / v dimethyl isosorbide / glucofural / water.

The pharmaceutical compositions of the present invention are thus administered by intravenous administration, e.g. ncatode and trematode can be used to control parasites of warm-blooded animals such as cattle, sheep, pigs, goats, horses and dogs, at the dosage described above for the nitroxynil salt of levamisole and, for example, parenterally (i.e., intravenously, intramuscularly or subcutaneously). or transdermally, in an infusible dosage form, preferably by administering an effective amount of lcminisolc-nitroxynil salt in a unit dosage form, especially a parenteral unit dosage form. Accordingly, it is a preferred embodiment of the present invention to provide novel pharmaceutical compositions which are prepared in a sterile, thinner form with one or more co-solvents or co-solvents of the lcvamisole-nitroxynil alone or in a mixture of dimethyl isosorbide or glyeofural or a mixture of dimethyl isosorbide and glucofural. in a solution by volume, and preferably at least 5% w / v, in which, when co-solvent or co-solvents are present, the dimethyl isosorbide or glucofural or a mixture thereof is preferably at least 25% by volume of the solvent. It will be appreciated that when the pharmaceutical composition of the present invention is administered orally in a liquid dosage form or in a "drip" dosage form on the skin, it need not be sterile, but the sterile compositions may also be used if desired.

The novel pharmaceutical compositions of the present invention are prepared by dissolving the levamisole nitroxynyl salt in dimethyl isosorbide or glycofurol or a mixture thereof, or as a mixture thereof with additional co-solvent or co-solvents, or stoichiometric amounts of levamisole or its salt, e.g. or a stoichiometric amount of dihydrogen phosphate and nitroxynil or a salt thereof, such as egium, noluminium or its sodium salt, in dimethyl isosorbide or glycofurol, or a mixture thereof, or in a further co-cosolvent or cosolvent. Dissolution of Icvamisole-nitroxynil salt or levamisole and nitroxynil or their salts at room temperature or with slight heating, e.g. 60-70 ° C and with stirring. The resulting solution is optionally sterilized, e.g. by passage through a bacterial screen and thus the preferred sterile drug of the invention

196,307 is formulated for parenteral administration, which are then placed under sterile conditions in sterile unit dose or multiple dose containers and sealed under sterile conditions.

Where appropriate, bases such as organic bases such as eglumin or inorganic bases such as sodium hydroxide may be included in the pharmaceutical composition of the invention so that the levamisole nitroxynyl salt is completely dissolved in a mixture of dimethyl isosorbide and / or glucofural and co-solvents. in water, for example, the salt is poorly soluble and the lime solvent (ck) forms a significant proportion (s) of the mixture and would otherwise precipitate.

The pharmaceutical compositions of the present invention optionally include biological preservatives, e.g. may contain up to 2% v / v benzyl alcohol as well as additives to improve chemical and physical stability during storage, and additives that reduce local tissue reactions following injection.

Dimethyl isosorbide was supplied by ICI Americas Inc. and Atlas Chemicals Industries (UK) Ltd.

Glucofural is from Lusochimica S.p.a. (Italy).

The invention is illustrated by the following non-limiting examples:

i. example

A 20% w / v solution of levamisole e-nitroxynil salt was prepared by stirring 11.7 g of nitroxynil and 8.3 g of levamisole with 100 ml of dimethyl isosorbide at room temperature until the solid was completely dissolved .

The resulting solution is passed through a bacterial strainer and filled under sterile conditions into sterile ampoules in an amount sufficient to provide a suitable unit dose for parenteral administration. The sterile solutions prepared as above are, if desired, placed under sterile conditions in a sterile multiple dose container and closed under sterile conditions, from which single unit doses suitable for parenteral administration can be removed.

Example 2

A solution of levamisole-nitroxynil salt in 20% w / v pure 80:20 v / v dimethyl isosorbide / water was prepared by preparing 11.7 g of nitroxynil and 8.3 g of levamisole. Add 80 ml of dimethyl isosorbide to 20 ml of water with stirring and keep the resulting slurry at 40 ° C until the solid is completely dissolved.

The resulting solution is sterilized by passing through a bacterial strainer and poured into sterile ampoules under sterile conditions in an amount sufficient to provide a suitable unit dosage for parenteral administration. The sterile solutions prepared as described above are optionally placed under sterile conditions in a sterile multiple dose container and sealed under sterile conditions Ic, where appropriate in unit dosage forms suitable for parenteral administration.

Example 3 To a mixture of dimethyl isosorbide (ml), glucofural (33 ml), water (32 ml) and benzyl alcohol (2 ml) was added 20 g of levamisole-nitroxynyl salt and 8.4 g of egluminine with stirring and stirring at 40 ° C. continue until dissolution is complete.

A solution of the levamisole nitroxynil salt in 20% w / v pure dimethyl isosorbide, glucofurol, water and benzyl alcohol 33: 33: 32: 2 by volume was sterilized by passage through a bacterial strainer and sterile. , into sterile ampoules in an amount sufficient to provide a unit dosage form suitable for parenteral administration. The sterile solutions prepared as above are optionally placed under sterile conditions in a sterile multiple dose container and sealed under sterile conditions, and if necessary a unit dose suitable for parenteral administration can be removed.

Example 4 To a mixture of ml of glucofural and 1.5 ml of benzyl alcohol was added 20 g of levamisole-nitroxynil salt with stirring at 60 ° C, the volume was added with 100 µl of glucofural and stirring was continued at 60 ° C. dissolution becomes complete.

A solution of levamisole-nitroxynyl salt in 20% w / v pure glucofural and benzyl alcohol (98.5: 1.5 by volume) is sterilized by filtration through a bacterial strainer and transferred under sterile conditions into sterile ampoules in an amount suitable for parenteral administration. get. The sterile solutions prepared as above are optionally placed under sterile conditions in a sterile multiple dose container and sealed under sterile conditions, and if necessary a unit dose suitable for parenteral administration can be removed.

1-4. 5 ml of a sterile solution prepared according to any one of Examples 1 to 4 is dispensed in a unit dose containing 20 mg / kg for a 50 kg animal or 100 ml in a multiple dose container for the treatment of 20 animals of 50 to 50 kg. A dose of -20 mg / kg is used.

Claims (12)

Claims CLAIMS 1. A process for the preparation of a pharmaceutical composition comprising as active ingredient levamisole nitroxynil salt, which is suitable for parenteral administration, characterized by. dissolving levamisole and nitroxynil or levamisole-nitroxynil salt in dimethyl isosorbide and / or glucofural, optionally in the presence of one or more co-solvents and / or bases, in amounts up to 40% (w / v) of levamisole-nitroxynil salt, if desired; the solution is sterilized and then reconstituted. 196 307 2. A process according to claim 1 wherein at least 5% w / v solution of levamisolenitroxynil salt is prepared. 3. The process according to claim 1, wherein the co-solvent is water, butyrolactone or an alcohol. where we are. The process according to claim I or 3, wherein the solvent used is dimethyl isosorbide or glucofural, or the mixture of dimclyl isosorbide and glucofural is at least 25% by volume. The process according to any one of claims J to 4, wherein the solvent is a mixture of dimethyl isosorbide and glucofural in a ratio of 100: 1 to 1: 100 by volume. jg A process according to any one of claims 1 to 5, wherein the solvent is a 80:20 by volume mixture of dimethylisosorbide and glucofural. The process according to any one of claims 1 to 5, wherein the solvent is a 1: 1: 1 by volume mixture of dimethylisosorbide, glucofural and water. The method according to any one of claims 1 to 7, wherein a dosage form suitable for parenteral or oral administration or for dermal administration is prepared. 9. A process according to claim 1, wherein when one or more co-solvents are used as the solvent component, the amount of dimethyl isosorbide or glucofural or the mixture of dimethyl isosorbide and glucofural is at least 25% by volume. The process according to any one of claims 1-9, wherein a base is added to the mixture of the levamisole-nitroxynyl salt with dimethyl isosorbide and / or glycofyrrole and a less soluble co-solvent to promote complete dissolution of the salt. The method according to any one of claims 1 to 10, wherein a dosage unit is prepared. 12. The method of claim 11, wherein the sterile composition for parenteral administration is provided.