IE84029B1 - Use of the compound flupirtin for the preparation of a medicament against muscle bracing - Google Patents

Description

USE OF THE COMPOUND FLUPIRTIN FOR THE PREPARATION OF A MEDICAMENT AGAINST MUSCLE BRACING ASTA MEDICA AKTIENGESELLSCHAFT fluorobenzylamino)pyridine) Description The medicamentally active ingredient flupirtine (chemical name 2—amino—3-carbethoxyamino(4- is an analgesic. The preparation of this compound and of its physiologically utilisable salts are described in the German patent DE 17 95 858 as well as in DE 31 33 519.

The known results from the literature (Jakovlev et al., Arzneimittelforschung/Drug Research 35(1); 44-55, 1985) were ascertained from healthy, previously untreated mice, in which the tonus of the striated muscles was normal. The supposed modifying effects on the tonus of the skeletal muscles shown for flupirtine were also shown for other substances, such as phenacetin, and even for codeine phosphate (Table 2). the stumbling of the mice in the inclined lattice test carried out is a sign of Here, however, a general sedation or of motor ataxia, which were also observed in the case of other substances at high doses within the range likely to produce side effects. The results obtained in this test are in no way to be identified with a relaxing action of flupirtine on the skeletal muscles, although the chapter heading of the publication by Jakovlev erroneously suggests this. Neither phenacetin nor codeine possess properties of the kind demonstrated. On the contrary, codeine is known to result in an increase in the muscle tonus.

The object of this invention is to provide a medicament which has a relaxing action on the skeletal muscles and is suitable for treating syndromes, symptoms and disorders which are caused by muscle tenseness or are a result of such muscle tenseness.

It has now been found that flupirtine has a potent relaxing action on the skeletal muscles where a pathological muscular rigidity exists.

Flupirtine is therefore suitable for treating syndromes, symptoms and disorders which are caused by muscle tenseness or are a result of such muscle tenseness.

Experimental method The experimental animals used were female SIV 50 rats, 160 g to 200 g. The animals were kept at room temperatures of 20°C to 24°C, a relative atmospheric humidity of 60% to 70% and light-dark periods of 12 to 12 hours. Food (Atromin®, Altrogge) and water were available ad libitum. Flupirtine was used in the form of the maleate.

The muscle—re1axing action was measured by continuous measurement of the resistance of the flexor and extensor muscles of the hind leg of the rat. To this end, the foot of the right hind leg of a rat was moved rapidly upwards and then downwards, at intervals of 30 seconds, by The reflex reaction of the flexor and extensor of the rat, means of an electronically controlled servomotor. caused by the compulsive movement of the rat's foot, was transmitted to a force transducer and evaluated with the aid of a computer (IBM PC).

Parallel to the on—line evaluation, the data were recorded on a recorder conventionally used for the purpose and simultaneously stored on a magnetic tape. Prior to the beginning of the experiment, the experimental unit was calibrated by placing a calibrated 50 g weight on the force transducer. The animals were then introduced into the experimental set—up and had a period of 30 minutes in which to adapt themselves. After the initial resistance of the flexors and extensors of the rats (control values) had been determined, flupirtine maleate was administered intraperitoneally and the influence of the compounds on the flexor and extensor was continuously registered over a period of 90 minutes, with a recording being made for a period of 10 minutes in each case, stored and evaluated on- line.

The differences between the average values of the groups of experimental animals were tested for significance by means of Student's t-test.

After intraperitoneal administration of flupirtine in the analgesically effective dose range, a muscle- relaxing effect was ascertained, and no central side effects such as ataxia or decrease of spontaneous motility were observed in the animals treated with flupirtine in the dose range being investigated.

For example, in the above experimental method, at a dose of 1 mg/kg rat body weight, the medicinally induced rigidity of the skeletal muscles decreased by 50%. in the awake rat was The lowest effective dose in the animal experiment described above is, for example, 1 mg/kg oral 0.1 mg/kg intraperitoneal.

A suitable general dose range for the action (animal experiment as above) is, for example: — 100 mg/kg oral, in particular 10 to 40 mg/kg 0.1 — 30 mg/kg intraperitoneal, in particular 1 to 20 mg/kg Compared with other active ingredients having the same action, flupirtine exhibits in particular the following differences: flupirtine does not cause dependence and has a potent analgesic action.

The action of flupirtine and of various comparison substances on the reserpine—induced rigidity is shown in the following Table.

Decrease (—) or increase (+) in rigidity Substance Dose Flexor Extensor mg/kg i.p* % action % action Flupirtine 2.5 -23 -17 .0 -53 -48 .0 -81 -87 (-)—Deprenyl 1 -18 -14 Morphine 2.5 + 8 + 4 .0 +31 +49 .0 +74 +80 Codeine 25 +11 + 9 50 +21 +19 100 +48 +52 Phenacetin 50 — 5 + 4 100 + 8 + 6 200 -10 — 8 400 +11 + 9 Ibuprofen 20 — 6 2 40 + 8 - 9 80 + 3 - 6 Indomethacin 2.5 + 8 - 2 .0 + 6 + 9 .0 8 Amitriptylin 5.0 — 9 — 6 .0 + 8 + 2 .0 -11 - 1 i.p. = intraperitoneal Decrease (+) or decrease (—) in rigidity Substance Dose Flexor Extensor mg/kg p.o' % action % action Flupirtine 5.0 -13 -16 .0 -43 -35 .0 -69 -71 40.0 -88 -91 Morphine 10.0 + 6 + 9 .0 +27 +31 40.0 +54 +69 Codeine 50 + 8 + 4 100 +25 +21 200 +53 +59 Phenacetin 200 — 8 1 400 + 4 - 6 800 + 7 - 5 1000 -12 + 6 Ibuprofen 40 -12 -10 80 + 9 5 160 — 7 — 9 Indomethacin 5.0 + 4 + 1 .0 — 1 — S .0 + 8 -11 Amitriptylin 10.0 + 2 — 3 .0 +12 + 9 40.0 + 6 -11 * per os This decrease in rigidity is determined by continuous measurement of the resistance of the flexor and extensor muscles of the hind leg of the rat, by the procedure already described. The sole difference in the determination of the decrease in rigidity is that, 16 hours .5 mg/kg rat. The reserpine produces the rigidity. The decrease or removal of this rigidity by flupirtine is then determined as described. prior to the beginning of the experiment, reserpine is administered intraperitoneally to the animals in a dose of Indications for which flupirtine having the novel action according to the invention may be suitable: all disorders which are associated with muscle tenseness (rigidity) and its consequences such as, for example, neuralgia, arthritis, arthrosis, chronic or episodic tension headache, post-operative disabilities, generalised tendomyopathy, insertion endopathy, rigidity accompanying Parkinson's disease. Contraindications: myasthenia gravis.

The pharmaceutical formulations generally contain between 50 mg and 500 mg, preferably between 100 mg and 200 mg, flupirtine base.

The administration may be in the form of tablets, capsules, pills, dragées, suppositories, ointments, gels, creams, powders, dusting powders, aerosols, or in liquid form.

Examples of suitable liquid forms of application: oily or alcoholic or aqueous solutions, as well as suspensions and emulsions. Preferred forms of application are capsules or tablets containing between 100 mg and 200 mg flupirtine, or solutions containing between 0.1 and wt.% flupirtine.

A single dose of flupirtine base may be, for example, a) for oral dosage forms, between 70 mg and 300 mg, preferably between 100 mg and 200 mg b) for parenteral dosage forms (for example, intravenous, intramuscular), between 8 mg and 80 mg, preferably between 10 mg and 100 mg.

The doses are in each case based on the free flupirtine base.

For example, 1 to 2 capsules or tablets containing 50 mg to 200 mg of active substance, 3 times per day, can be recommended.

Exper. Biol. a. for example, Medicaments for treating disorders and symptoms which are caused by muscle tenseness or are a consequence of muscle tenseness are produced by formulating flupirtine or its therapeutically utilisable salts together with conventional pharmaceutical carriers, auxiliary substances and diluents.

Flupirtine or a pharmaceutically usable salt of flupirtine, together with conventional carriers and/or diluents or auxiliary substances, is mixed or homogenised at temperatures of between 0 and 120°C, preferably 20 and 80°C, and in order to produce formulations a single dose of which contains 50 to 500 mg flupirtine or a pharmaceutically usable salt of flupirtine, the mixture optionally put into hollow cells of or granulated and then optionally pressed thus obtained is appropriate size to form tablets, with the addition of other conventional auxiliary substances, or is put into capsules.

Flupirtine or a pharmaceutically usable salt of flupirtine can be mixed with one or more of the following substances: starch, cyclodextrin, urea, cellulose, lactose, formalin—casein, modified starch, magnesium stearate, calcium hydrogen phosphate, silica, talc, phenoxyethanol, the mixture obtained is optionally granulated using an aqueous solution which contains as constituents at least gelatine, starch, polyvinylpyrrolidone, vinylpyrrolidone— vinyl acetate copolymer and/or polyoxyethylene—sorbitan monooleate, the granular material is optionally homogenised together with one or more of the above—mentioned auxiliary substances, and this mixture is pressed to form tablets or put into capsules, the tablets or capsules containing 50 to 500 mg of the active ingredient flupirtine or a salt thereof in a single dose.

In addition, one or more of the auxiliary substances soybean lecithin, oxynex, phenoxyethanol can be suspended and homogenised at temperatures of between 31 and 65°C in mixtures containing melted solid fat or other fatty acid glycerides and the mixtures subsequently poured into hollow cells or put into capsules, a single dose containing 50 to 500 mg of the active ingredient flupirtine or a salt thereof.

Flupirtine or a pharmaceutically usable salt of flupirtine, at a temperature of between 20 and 120°C, optionally in the presence of one or more emulsifiers and/or complexing agents, can be homogenised and/or emulsified using at least one of the following substances: water, glycerol, paraffin, Vaseline, aliphatic alcohol having 12 to 25 C atoms, aliphatic monocarboxylic acid having 15 to 20 C atoms, sorbitan monopalmitate, polyoxyethylene polyol fatty acid ester, monohydric or polyhydric aliphatic alcohols of low molecular weight, fatty acid glyceride, wax, silicone, polyethylene glycol, silicon dioxide.

Flupirtine or a pharmaceutically usable salt of flupirtine, optionally in the presence of a complexing agent and/or of an emulsifier, at temperatures of between and 100°C, is dissolved in water, physiologically safe alcohols, polyglycols, polyglycol derivatives, dimethyl sulfoxide, triglycerides, partial esters of glycerol, paraffins or oils or mixtures thereof, and optionally the solution obtained is made up with the above-mentioned solvents in a quantity such that the end solution, end suspension or end emulsion contains 0.1 to 10 per cent by weight of the active ingredient flupirtine.

Other suitable carriers and auxiliary substances are, for example, those substances which in the following literature references are recommended or mentioned as auxiliary substances in pharmacy, cosmetics and related fields: Ullmanns Enzyklopédie der technischen Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 and ff.; H. v. Czetsch—Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete, Pharm. Ind., No. 2, (1961), pages 72 and ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in Wfirttemburg, 1981.

Examples of these are gelatine, natural sugars such as cane-sugar or lactose, (for example, maize starch), cyclodextrins and cyclodextrin derivatives, polyvinylpyrrolidone, polyvinyl acetate, gelatine, gum arabic, alginic acid, tylose, talc, Lycopodium, silica (for example, colloidal), cellulose, cellulose derivatives (for example, cellulose ethers, in which the hydroxyl groups of the cellulose are partially etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic oxyalcohols, for example, methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate); fatty acids and magnesium salts, lecithin, pectin, starch calcium salts or aluminium salts of fatty acids having 12 to 22 C atoms. in particular of the saturated (for example, stearates), emulsifiers, oils and fats, in particular alcohols and polyglycols, such as polyethylene glycols and derivatives of these, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms, to 18 C atoms) with monohydric aliphatic alcohols C atoms) in particular 10 (l to 20 or polyhydric alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol et cetera, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, benzoyl benzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol ethers containing C1-C12-alcohols, dimethylacetamide, lactamides, lactates, ethyl carbonate, silicones (in particular, moderately viscous polydimethylsiloxanes), calcium carbonate, carbonate, sodium calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Other suitable auxiliary substances are those substances which effect disintegration (so—called disintegrants) such as: cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Known coating substances may also be used. Suitable examples of these are: polymers and copolymers of acrylic acid and/or methacrylic acid and/or esters thereof; copolymers of acrylic and methacrylic esters having a low content of ammonium groups (for example, Eudragit® RS), copolymers of acrylic and methacrylic esters and trimethylammonium methacrylate (for example, Eudragit® RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or hydroxypropyl methyl cellulose acetate succinate; cellulose acetate phthalate, starch acetate phthalate and polyvinyl acetate phthalate; carboxymethyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, methyl cellulose phthalate succinate and methyl cellulose phthalate half ester; zein; ethyl cellulose and ethyl cellulose succinate; shellac, gluten; ethyl carboxyethyl cellulose; ethacrylate-maleic anhydride copolymer; maleic anhydride—vinyl methyl ether copolymer; styrene—maleic acid copolymer; 2—ethylhexyl acrylate maleic anhydride; crotonic acid—vinyl acetate copolymer; glutamic acid—glutamic acid ester copolymer; acarboxymethylethyl cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

Suitable plasticisers for coating substances are: Citric and tartaric esters (acetyltriethyl citrate, acetyltributyl citrate, tributyl citrate, triethyl citrate); glycerol and esters of glycerol (glycerol diacetate, glycerol triacetate, acetylated monoglycerides, Castor oil); phthalic esters (dibutyl phthalate, diamyl phthalate, diethyl phthalate, dimethyl phthalate, phthalate), D—(2-methoxy) phthalate or ethoxyethyl phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butyl glycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di(2—methoxy) adipate or ethoxyethyl adipate); benzophenone; diethyl sebacate and dibutyl sebacate, diethyl succinate and dibutyl succinate, diethyl tartrate and dibutyl tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, dibutyrate, dipropyl ethylene glycol tributyl tributyrin; polyethylene glycol sorbitan monooleate (polysorbates, such as polysorbate 80); sorbitan monooleate. ethylene glycol dipropionate; phosphate, Examples of suitable media for preparing solutions or suspensions are water or physiologically well—tolerated organic solvents such as, for example, ethanol, propanol, isopropanol, l,2—propylene glycol, polyglycols and derivatives thereof, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esters of glycerol, paraffins and the like.

For injectable solutions or suspensions, non—toxic parenterally well—tolerated diluents or solvents are suitable such as, for example: water, 1,3—butanediol, ethanol, 1,2—propylene glycol, polyglycols mixed with water, Ringer's solution, isotonic sodium chloride solution or even cured oils including synthetic mono- or diglycerides or fatty acids such as oleic acid.

Known and conventional solubilisers, for example, emulsifiers, can be used in the preparation of the formulations. Suitable solubilisers and emulsifiers are, for example: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides, such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fat, polyoxyethylated oleotriglycerides, linoleated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, of alkylphenols or of fatty acids or even 1—methyl—3~(2— hydroxyethyl)imidazolidone-(2). Here, "polyoxyethylated" means that the substances in question contain polyoxyethylene chains wherein the degree of polymerisation is generally between 2 and 40 and in particular between 10 and 20.

Such polyoxyethylated substances can be obtained, for example, by the reaction of hydroxyl-containing compounds (for example, mono- or diglycerides or unsaturated compounds such as, for example, those containing oleic acid groups) with ethylene oxide (for example, 40 mol ethylene oxide per mol glyceride).

Examples of oleotriglycerides are olive oil, peanut oil, Castor oil, sesame oil, Dr. H. P. cottonseed oil, maize oil.

See also: Fiedler, "Lexikon der Hilfstoffe fur 191-195. is possible to add preservatives, Pharmazie, Kosmetik und angrenzende Gebiete" p.

Moreover, it buffer hydrogen phosphate, stabilisers, substances, for example, calcium colloidal aluminium hydroxide, taste improvers, sweeteners, colouring matter, antioxidants and complexing agents (for example, ethylenediaminetetraacetic acid) and the like. Optionally, in order to stabilise the molecule of active ingredient, the pH value may be adjusted to within a range of approximately 3 to 7 by means of physiologically well-tolerated acids or buffers. In general, a pH value which is as far as possible neutral to weakly acid (up to pH 5) is preferred.

Suitable substances for the preparation of formulations for dermal application are those mentioned above and spreadable or liquid hydrocarbons such as Vaseline or paraffin or gels consisting of paraffin hydrocarbons and polyethylene; fats and oils of vegetable or animal origin, which may also be partially hydrogenated, or synthetic fats such as glycerides of the CB—C13 fatty acids, then beeswax, cetyl palmitate, wool wax, wool wax ‘ alcohols; fatty alcohols such as cetyl alcohol, stearyl alcohol, polyethylene glycols having molecular weights of 200 to 20,000; liquid waxes such as isopropyl myristate, isopropyl stearate, ethyl oleate; emulsifiers such as the sodium, potassium and ammonium salts of stearic acid or of palmitic acid, alkali as well as triethanolamine stearate, salts of oleic acid and of ricinoleic acid, salts of sulfonated fatty alcohols such as sodium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, salts of bile sterols such as cholesterol, partial fatty acid esters of polyhydric alcohols such as ethylene glycol monostearate, partial fatty acid esters of sorbitan, partial fatty acid esters of polyoxyethylene sorbitan, sorbitol ethers of polyoxyethylene, fatty acid esters of polyoxyethylene, acid, fatty alcohol ethers of polyoxyethylene, fatty acid esters of saccharose, fatty acid esters of polyglycerol, lecithin.

Antioxidants used are, for example, sodium metabisulfate, ascorbic acid, gallic acid, alkyl esters of gallic acid, butylhydroxyanisole, nordihydroguaiaretic acid, tocopherols as well as tocopherols + synergists (substances which bond heavy metals by complex formation, for example, lecithin, ascorbic acid, phosphoric acid). The addition of synergists considerably increases the antioxidising action of the tocopherols. Examples of suitable preservatives are sorbic acid, p~hydroxybenzoic esters (for example, lower alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and derivatives of formalin.

The compounds according to the invention are handled pharmaceutically and galenically by the conventional standard methods.

For example, flupirtine and the auxiliary substances and carriers are thoroughly mixed together by stirring or homogenisation (for example, by means of conventional mixing devices), the operation generally being carried out at temperatures of between 20 and 80°C, preferably between 20 and 50°C and in particular at room temperature.

Moreover, reference is made to the following standard work: Sucker, Fuchs, Speiser, Pharmazeutische Technologie, Thieme Verlag, Stuttgart, 1978.

The medicament can be applied to the skin or mucous membrane or internally, for example, orally, enterally, pulmonarily, rectally, nasally, vaginally, lingually, intravenously, intraarterially, intracardially, intramuscularly, intraperitoneally, intracutaneously, subcutaneously.

The parenteral forms of preparation in particular are sterile or sterilised products.

Examples Tablets kg 2—aminocarbethoxyamino(4- fluorobenzylamino)pyridine maleate is mixed with 2.5 kg calcium hydrogen phosphate and 2.5 kg maize starch and the mixture is granulated in known manner using a solution of 1 kg polyvinylpyrrolidone in 4 kg demineralised water.

After admixture of 1.3 kg maize starch, 2 kg microcrystalline cellulose, 0.6 kg magnesium stearate and .1 kg highly disperse silicon dioxide, the mixture is pressed to form tablets of 200 mg in weight and 9 mm in diameter, the disk radius being 10 mm with a notch to facilitate breakage. The breaking strength of the tablets is 80 N to 100 N (Schleuniger hardness tester). The disintegration time in accordance with DAB 8 is 5 minutes.

Each tablet contains 100 mg active ingredient.

Capsules In a similar manner to the method of tablet production described above, a capsule filling is prepared and packed into hard gelatine capsules of the appropriate 200 mg.

One capsule contains 100 mg active ingredient. size. Quantity of filling per capsule: Oily suspension containing 15% flupirtine maleate 32.5 g highly disperse, amorphous hydrophobic silicon dioxide (trade name: Aerosil R 972/Degussa), 0.5 g micronised saccharin sodium, 1.5 g finely ground sodium cyclamate, 0.1 g red iron oxide, 0.5 g strawberry flavouring, 75 g flupirtine maleate and 0.375 g Oxynex LM (E. Merck/Darmstadt) are homogeneously suspended in 400 g triglycerides of medium chain length (trade name: Miglyol 812/Hfils Troisdorf). The suspension is made up to 500 g with triglycerides of medium chain length and mixed.

One gram of the suspension contains 150 mg flupirtine.

Injection solution The method of production is for a 20—litre batch (= 6500 ampoules) Method of production: . 10.0 1 water is heated to 70°C and, after addition of 1562.0 g delta-gluconolactone, the solution is allowed to stand for one hour at 70°C. In the course of this, the solution is exposed to nitrogen gas. . 8000.0 g polyethylene glycol, molecular weight 380 to 420, is weighed and introduced into solution 1 and the solution is heated to 70°C with exposure to nitrogen gas. . 30.0 g sodium disulfite is dissolved in 500.0 ml water exposed to nitrogen gas.

. Solution 3 is added to solution 2. . 666.6 g flupirtine base is screened through a screen having a mesh size of 0.3 mm and is dissolved in solution 4, with intense exposure to nitrogen gas.

. Solution 5 is cooled and made up to 20 litres with water exposed to nitrogen gas.

. Solution 6 is filtered aseptically through a membrane filter having a pore size of 0.2 pm and provided with a glass fibre prefilter.

. In-process control:— Measurement of the oxygen content of solution 7 by means of oxygen electrode.

Measurement of the pH value of solution 7.

. Solution 7 is put into colourless ampoules, content 3 ml, under aseptic conditions and with exposure to nitrogen gas.

One ampoule contains 164.5 mg flupirtine gluconate in 3 ml solution.

Claims (5)

Claims

1. Use of flupirtine or its therapeutically utilisable salts for the production of a medicament for treating disorders and symptoms which are caused by muscle tenseness or are a result of muscle tenseness.

2. Use of flupirtine or its therapeutically utilisable salts according to claim 1 in the treatment of chronic or episodic tension headache.

3. Use of flupirtine or its therapeutically utilisable salts according to claim 1 in the treatment of neuralgia.

4. Use of flupirtine or its therapeutically utilisable salts according to claim 1 in the treatment of arthritis and arthrosis.

5. Use of flupirtine or its therapeutically utilisable salts according to claim 1 in the treatment of post— operative disabilities. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS