JPS60123419A - Pharmaceutical composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel compositions of organic salts having anthelmintic properties, methods for making such compositions, and their use in the control of parasites.

Levamisole (leva-m) is widely used to control intestinal nematodes and lungworms in warm-blooded animals.
isole) (L-2,3r 5 + 6-tetrahydro-6-phenylimidazo-[2,1-b,11-thiazole) and trematode of warm-blooded animals.
and certain nematode parasitoid
Nitroxynil (4-cyano-2-iodo-6-nitrophenol-4-hydroxy-3-iodo-5-nitropenzonitrile) is widely used for the extermination of the following sites: Forms a salt referred to as the nitroxynil salt of leno(mizole). This salt is commonly prepared and used in the form of the hydrochloride or dihydrogen phosphate salt and is based on the known basic properties of levamisole and the eglumine salt of nitroxynil ( The nitroxynil salt, which is commercially available in the form of an aqueous solution of the N-ethyl-D-glucamine salt, exhibits the properties expected from the known acid properties of the nitroxynil salt. laemonchus cont.
ort-us), Ostertagia sp.
ia spp,), Trichostrodae
ngylus spp,), for example, To! J Tricho-strongylus
axei), Cooperia spp.
pp, ), e.g. Cooperia onchophora (Co
operia oncophora), nematode species (Nem
aio-dirus spp, ), e.g. Nematodirus filicoris
licolis), Oesophagostomum sp.
phagostomum spp,), for example Oe-saphagostomum venulosum (Oe-saphagostomum spp,)
oumum venulosum), Strongyloides spp., such as Strongyloides spp.
o-1 des papillosus), Bu-nostomum spp., e.g.
trigonoce-phalum), Chabertia spp., e.g.
), whipworms ('l'richuris spp,), such as Trichuris ovi
s), and Dictyocaulus sp.
p, ), e.g. lung fluke (Di-ctyocaulus
filaria) and bovine lungworm (1) ict-yocau
The activity of repamisole against trematodes such as Fasciola hepatica and Fa-sciola gigantica, and certain nematodes such as Fasciola hepatica and Fa-sciola gigantica,
emonchus contortus), Bunos tomum spp., Qesaphago-stomum 5pp.
), and Parafilaria bovicola
It has the same activity as nitroxynil against Ria bovicola). The nitroxynil salt of levamisole may be used to kill internal worms (helmH-nth) such as nematodes and fluke parasites in warm-blooded animals such as cattle, sheep, pigs, goats, horses and dogs. Dosage used? 'ii Depending on the parasite, the animal being treated and the method of administration, 10
A single administration at a dosage of ~30~, usually about 18 mg/kg of animal body weight, generally provides satisfactory parasite control.

Administration may be parenteral, i.e. by intravenous, intramuscular or subcutaneous injection, orally, in oral dosage forms such as tablets, pills, capsules or drenches, as an additive to feed, or transdermally. ,
Administration of the effective dosage in a single unit dose, more particularly in a single parenteral unit dose, is preferred, for example in a pour-on J dosage form.

The nitroxynil salt of levamisole can be prepared by reacting nitroxynil and repamisole in stoichiometric amounts in water or an inert organic solvent such as ethanol, or by reacting a water-soluble salt of nitroxynil in water such as sodium, meglumine ( N
-methyl-D-glucamine) or eglumine (eglu
(mine) salt and a water-soluble salt of levamisole, such as the hydrochloride or dihydrogen phosphate, in stoichiometric amounts.

The above-mentioned salts of nitroquinonyl and levamisole are commercially available or can be easily prepared by known methods from nitroxynil and levamisole, which are themselves commercial products or can be prepared by known methods. (As used herein, "known methods" means methods conventionally used or described in the chemical literature). The following method illustrates the preparation of the nitroxynil salt of levamisole.

Method Eglumine salt of nitroxynil (63°C) in water (10o*)
, 0 sr, 0.125 mol) in water (100 W) with stirring at room temperature.
2f; 0.125 mol). After the addition is complete, the formed precipitate is separated by filtration,
Washing with water and drying under vacuum gave the nitroxynil salt of levamisole (60,21) in the form of yellow needles with a melting point of 129°C.

For parenteral administration to animals, the nitroxynil salt of levamisole is contained in a pharmaceutically acceptable solvent in an amount that allows the desired dosage to be administered in a single dose and is well tolerated by the animal. It is desirable to provide a sterile solution suitable for injection.

Also, desirably, such a solution has a power of 5 to 70 W/V (
weight/volume), especially 5 to 40% W/V of the nitroxynil salt of levamisole.

The nitroxynil salt of levamisole is poorly soluble in water, and suspensions of the salt are poorly administered by parenteral administration to animals, even if they contain additives expected to reduce local intolerance. I found out that it is not allowed. Solutions suitable for providing solutions of the mentioned nitroxynil salt of levamisole include pharmaceutically acceptable alcohols such as benzyl alcohol and tetrahydrofurfuryl alcohol, ketones, esters such as ethyl butyrate,
Amides such as N-(2-hydroxyethyl)lactamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, cyclic ether conductors, formals such as glycerol formal, hydrocarbons, perfluorinated hydrocarbons such as perfluorodecalin, glycols and glycol derivatives such as ethylene. Glycol, propylene glycol, ethylene glycol mono- and di-alkyl ether, glopylene glycol mono- and di-alkyl ether, polypropylene glycol, polyethylene glycol such as polyethylene glycol, polypropylene glycol mono- and dialkyl ether, polyethylene glycol mono- and dialkyl having an average molecular weight of 100 to 600. Ethers such as diethylene glycol dimethyl ether, pyrrolidones such as N-methylpyrrolidone and poly(N-vinylpyrrolidone), silicone oil filt
hapolymethylsiloxane, aprotic solvents such as dimethylformamide, dimethylacetamide and tetoshimethylurea and mixtures of such solvents.

As mentioned above, levamisole can be prepared by using solvents that are well tolerated in parenteral administration to animals and that are recognized as suitable for use as diluents or carriers in pharmaceutical compositions. nitroxynil salt from 5 to 40'
It is desirable to prepare a solution of the salt containing % W/V. However, in practice these standards have proven difficult to achieve. For example, the nitroxynil salt of levamisole is very well soluble in pure benzyl alcohol, the latter being biologically active and used as a preservative in liquid pharmaceutical compositions at a concentration of 2V/V%t; Also, the use of high concentrations of benzyl alcohol in such compositions is unacceptable. Solutions in dimethyl sulfoxide and in mixtures of N-methylpyrrolidone and polyethylene glycol 400 were found to be poorly tolerated for parenteral administration to animals. There therefore exists a need for a nitroxyni/14 solution of levamisole that meets the above criteria.

As a result of research and experimentation, it has been found that it meets the above criteria, i.e. can contain up to 40% W/W of salt, is well tolerated for parenteral administration to animals and as a diluent or carrier for liquid pharmaceutical compositions. The nitroxynil salts of levamisole that have been found suitable for use include dimethyl isosorbite or glycofurol or mixtures of dimethyl isosorbite and glycofurol as the sole diluent or carrier or in admixture with co-solvents. It has been discovered that it is possible to produce

Accordingly, the present invention provides a new method containing the nitroxy-l salt of levamisole in the form of a solution in a solvent comprising dimethyl insorbite and/or glycofurol and containing up to 40% W/V of the nitroxy-nyl salt of repamisole. A pharmaceutical composition is provided. The lower limit of the content of the nitroxynil salt of repamisole in the composition according to the invention is not strict, and the salt content is selected such that the required amount of the nitroxynil salt of repamisole is contained in an amount of solution suitable for the intended purpose. Ru. In practice, it is preferred that the content of the nitroxynil salt of levamisole in the solution is at least 5 W/V, but as mentioned above, lower concentrations can be used if desired.

Regarding the solution of the present invention, as used herein, "[nitroxinil salt of repamisole"] does not mean the salt formed between nitroxynil and repamisole, but also includes an association of nitroxynil and repamisole in equimolar proportions. be understood.

Dimethyl sorbite or glycofurol or mixtures thereof can be used alone as carriers or diluents for the pharmaceutical compositions according to the invention, but optionally in the presence of one or more co-solvents such as water, butyrolactone and hyalcohols such as ethanol, Examples of glycols may include ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol, glycerol, tetrahydrofurfuryl alcohol and hbenzyl alcohol, or mixtures thereof. Preferably,
The proportion of dimethyl isosorbite or glycofurol or a mixture of dimethyl isosorbite and glycofurol in the solvent must not be less than 25 parts by volume. When a mixture of dimethyl isosorbite and glycofurol is used as the sole diluent or phase or in combination with a co-solvent, the ratio of dimethyl isosorbite to glycofurol in the mixture used as the sole diluent or carrier and further 1 The ratio of dimethyl isosorbite to glycofurol in the dimethyl insorbite-glycofurol component of the diluent or carrier containing one or more co-solvents can vary over a wide range, e.g. from 100:1 to 1:100 by volume. be able to. Suitable solvents include an 80:20 V/V% mixture of dimethyl isosorbite and water and a 1:1:I mixture of dimethyl isosorbite, glycol and water.
Contains V/V mixtures.

The pharmaceutical composition of the present invention combines the nitroxynil salt of repamisole with the nitroxynyl salt of levamisole for killing parasites of internal parasites such as nematodes and whipworms in warm-blooded animals such as cattle, sheep, pigs, goats, horses and dogs. For nitroxynil salts, it may be administered parenterally, i.e., by intravenous, intramuscular, or subcutaneous injection, by oral transmembrane force as an ingestion, or transdermally, in the dosages and for the purposes described above for the nitroxynil salts. It can be used for administration as a dosage form. In this case, the effective dosage of the nitroxynil salt of repamisole in one unit dose of the composition according to the invention, and also 11=Ir
A single parenteral unit dosage is preferred.

Accordingly, a preferred feature of the invention is that the nitroquinonyl salt of levamisole contains up to 40% W/V, preferably at least 5% W/V, of dimethyl isosorbite or glycochlor or dimethyl isosorbite. A novel pharmaceutical composition is provided comprising a sterile solution of a mixture of glycofluor and glycofurol, alone or in a mixture with a co-medium as described above. If a co-solvent is then present, the proportion of dimethyl isosorbite or glycofurol or a mixture thereof in the solvent is preferably at least 25 volumes. It will be appreciated that the pharmaceutical compositions of the present invention need not be sterile when administered orally as a draught or transdermally in a "dispensable" dosage form, but may, if desired, be sterile for these purposes. A sterile composition may also be used.

The novel pharmaceutical compositions according to the invention can be prepared by dissolving the nitroxynil salt of levamisole in dimethyl isosorbite or haglycofurol or a mixture thereof alone or in a mixture with a co-solvent as described above; A stoichiometric amount of a salt such as the hydrochloride or dihydrogen phosphate and nitroxynil or a salt thereof such as eglumine, meglumine or the thorium salt, alone or in a co-solvent as described above, of dimethyl insorbite or glycosyl 70-ol or a mixture thereof. It can be produced by dissolving it in a mixture with. Dissolution of the nitroxynil salt of levamisole or levamisole and hinitroxinil or their salts can be carried out at room temperature or, for example, at 60-70°C.
This can be carried out by gently heating and stirring until The solution thus obtained is optionally passed through a suitable antibacterial filter in order to provide a suitable sterile pharmaceutical composition of the invention suitable for oral administration.
It can then be rendered sterile by placing and sealing under sterile conditions into a sterile single unit dose or multi-dose container.

If necessary, the nitroxynil salt of levamisole, dimethyl isosorbite and/or glycofurol and a co-solvent in which the salt is only slightly soluble, such as water, in a mixture containing a significant proportion of the co-solvent and otherwise causing precipitation. A base, such as an organic base such as eglumine or an inorganic base such as sodium hydroxide, may be included in the pharmaceutical composition of the invention in order to achieve complete dissolution.

Also optional are biological preservatives such as benzyl alcohol up to 2 V/V%, additives to improve chemical and physical stability during storage, and additives to reduce local tissue reactions upon injection. can be incorporated into pharmaceutical compositions of the invention.

dimethyl isosorbite (dimethyl 1sos)
orbide) is ICI America engineering nc
, and At1asC++emicals Industries
ries (OK) Ltd.

Glycofurol/L/ (glycofurol) is
l, usochi-mica S, p, a,, It
This is a product provided by aly.

The following non-limiting examples illustrate the invention.

nitroxynil (11,71) and repamisole (8,
A clear 20 W/V% solution of the nitroxynil salt of levamisole was prepared by dissolving 37) in dimethyl isosorbite (100 at) with stirring at room temperature until dissolution of the solid material was complete.

The solution thus obtained was made sterile by passing through an antibacterial filter and then divided into sterile ampoules and sealed under sterile conditions in amounts to give suitable unit doses for parenteral administration. Similarly prepared sterile solutions may be placed into sterile multi-dose containers and sealed under sterile conditions as desired. From this, unit dosages suitable for parenteral administration can be extracted as required.

Example 2 Nitroxynil (11,7F) and Repamisole (8,
Dimethyl isosorbite (so
m) and water (20 t/) and the suspension thus obtained was heated at 40° C. until complete dissolution of the solid material.
levamisole nonitroxynil salt, dimethyl isosorbite and water at 80:20 V/ by stirring at
A clear 20 W/V% solution in V mixture was prepared.

The solution thus obtained was rendered sterile by passing through an antibacterial filter and then divided and sealed into sterile ampoules in quantities to give unit dosages suitable for parenteral administration under sterile conditions. Similarly prepared sterile solutions may be placed into sterile multi-dose containers and sealed under sterile conditions as desired. From this, unit dosages suitable for parenteral administration can be extracted as required.

Example 3 Mixture K of dimethyl isosorbite (33 M/), glycofurol (33 +++ l), water (32 ml) and benzyl alcohol ('l ml), repamisole (
20r) and the nitroxynil salt of eglumine (8,4y) were added with stirring at 40°C, then stirring at 40°C was continued until dissolution was complete.

The nitroxynil of levamisole thus obtained,
The clear 20 W/V% solution in dimethyl isosorbite, glycofurol, Mizuya Hihenzyl Alcohol I:) 33:33:32:2 V/V mixture was made sterile by passing through an antibacterial gut filter and then passed under sterile conditions. The preparations were divided into sterile ampoules and sealed in quantities to give unit dosages suitable for parenteral administration. The similarly prepared sterile solution may be placed in sterile multi-dose containers and sealed under sterile conditions F, if desired. From this point on, unit dosage reservoirs suitable for parenteral administration can be removed as needed.

Example 4 The nitroxynil salt of levamisole (201) was added to a mixture of glycofurol (60 ml) and hbenzyl alcohol (1.5 ml) with stirring at 60°C and the volume was heated to 60°C until dissolution was complete. K with glycofurol and ioomzt with stirring.

98.5 of the nitroxynil salt of levamisole thus obtained, cricotrol and hbenzyl alcohol:
A clear 20 W/V solution in a 1.5 V/V mixture was filtered with antibacterial filter & At.

sterilized and then portioned and sealed into sterile ampoules in quantities to provide unit dosages suitable for parenteral administration under sterile conditions. Similarly prepared sterile solutions may be placed in sterile multi-dose containers and sealed to sterile conditions F as desired. From this, unit dosages suitable for parenteral administration can be extracted as required.

Patent applicant: May & Baker Limited Representative Patent Attorney Heikichi Odashima

Claims (1)

[Scope of Claims] 1. The nitroxynil salt of levamisole, the nitroxynil salt of levamisole in a solvent containing dimethyl isosorbite and/or glycofurol, 4Q'W/
A pharmaceutical composition in the form of a solution containing up to %V. 2. At least 5 nitroxynil salts of repamisole
% LV/V. 3. A composition according to claim 1 or 2, comprising one or more co-solvents. 4. The composition according to claim 3, wherein the co-solvent is selected from water, butyrolactone and alcohols. 5. Dimethyl isosorbite or glycofurol or dimethyl isosorbite and glyco70 in a solvent
5. The composition according to claim 3 or 4, wherein the total amount of the mixture of 25 to 30% is not less than 25%. 6. The solvent according to any one of claims 1 to 5, wherein the solvent contains dimethyl isosorbite and glyco70-ol in a volume ratio of dimethyl isosorbite to glycofurol of 100:1 to 1:100. Composition. 7. Claim 1, wherein the solvent is a mixture of dimethyl isosorbite and glycofurol in a V/V ratio of 80:20.
The composition according to any one of items 1 to 6. 8. The composition according to any one of claims 1 to 6J#, wherein the solvent is a mixture of dimethyl isosorbite, glycochlor and water in a ratio of 1:1:IV/V. 9. A composition according to any one of claims 1 to 8 in a form suitable for parenteral or oral administration or for transdermal administration as a disseminated dosage form. 10. The nitroxynil salt of V-hamisole The nitroxynil salt of levamisole in a solvent comprising dimethyl isosorbide or glycofurol or a mixture of dimethyl isosorbite and glycofurol, alone or in a mixture with co-solvent(s). A sterile pharmaceutical composition comprising up to 40 W/V%. 11. At least 5W of nitroxynil salt of levamisole
11. The composition according to claim 10, comprising: /V%. 12. When one or more co-solvents are present, the proportion of dimethyl isosorbite or glycofurol or a mixture thereof in the solvent is at least 25% V/V. Composition of. 13. Claim 1 comprising a base in order to completely dissolve the nitroxynil salt of levamisole in a solvent comprising dimethyl isosorbite and/or glycofurol and a co-solvent in which the salt is only slightly soluble. ~1
The composition according to any one of Item 2. 14. A composition according to any of claims 1 to 13 in unit dosage form. 15. The composition according to claim 14 for parenteral administration. 16. A pharmaceutical composition according to claim 1 substantially as described below in any one of Examples 1.2.3 and 4.