JPH0532627A - Drug for curing disease and syndrome caused by or resulting in muscle convulsion and preparation thereof - Google Patents

Abstract

PURPOSE: To obtain drugs having skeleton relaxing action for treating diseases and syndromes that are caused by muscular spasm or that are sequelae caused by muscular spasm.

CONSTITUTION: (A) Fulpirtin [2-amino-3-carbethoxyamino-6-(4-fluorobenzylamino)- pyridine] or its pharmaceutically acceptable salt known as a sedative is contained as an active substance in a tablet or capsule in a dosage of 50-500 mg. Optionally, (B) a drug for Parkinson's disease, preferably (-)-deprenyl, biperiden or L-dopa, may be formulated together with a conventional pharmaceutical carrier, auxiliary and/or diluent. They may be formulated simultaneously with the active substance (A) or separately or as combined drugs for delayed- releasing mode. Thereby, drugs for treating the above-mentioned diseases, particularly drugs for treating Parkinson's disease, is obtained.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a medicament for treating diseases and syndromes attributed to or as a result of muscle spasms and a process for their preparation.

[0002]

2. Description of the Prior Art Flupirtine (compound name: 2-amino-3-carbethoxyamino-6- (4
-Fluorbenzylamino) -pyridine) is an analgesic. The production of this compound and its physiologically usable salts is described in West German Patent Nos. 1795858 and 31335.
No. 19 specification.

By the way, it has been found that flupirtine has a skeletal muscle relaxing action and is suitable for the treatment of diseases, syndromes and illnesses that are attributed to muscle spasms or are the result of muscle spasms.

[0004]

The object of the present invention is to provide a medicament for the treatment of diseases and / or syndromes which are attributable to or are the result of muscle spasms. .

[0005]

For example, flupirtine exhibits a well-known analgesic effect and a good skeletal muscle relaxing effect when continuously measuring the resistance of the flexor and extensor muscles, for example, in the hind legs of Latte.

Experimental Method Female SIV50-latte (160-20) was used as an experimental animal.
0 g) was used. The animals were kept at room temperature 20 ° C.-24 ° C., relative humidity 60% -70% and light-dark time 12-12 hours. A feed (Atromin (registered trademark; hereinafter omitted), Altroge) and water were appropriately used. Flupirtine was used as the maleate salt.

The muscle-relaxing effect was measured by continuous measurement of flexor and extensor resistance in the hind legs of Latte. Therefore, the leg of the right hind leg of Latte was rapidly moved upward and then downward at intervals of 30 seconds by an electrically controlled servomotor. The reflex response of the flexor and extensor muscles of the latte caused by the forced exercise of the latte's foot is recorded by a motion recorder (Krafta).
ufnehmer), a computer (IBM / P
It was evaluated by C). In parallel with the on-line evaluation, the data were recorded on a recording device customary for this purpose and simultaneously stored on magnetic tape. Before starting the experiment,
The experimental unit was calibrated by calibrating the kinematic recorder with a weight of 50 g. The animals were then placed in the experimental apparatus and acclimated for 30 minutes. Flupirtine maleate was applied intraperitoneally after measurement of the initial resistance (control value) of the latte flexor and extensor muscles and the effect of this compound on the flexor and extensor muscles for 90 minutes It was continuously recorded (for 10 minutes), stored and evaluated online.

The difference between the mean values of the experimental animal groups was examined for their significance by the Student Large-test.

After intraperitoneal application of flupirtine in a range of analgesic doses, the muscle-relaxing effect was measured, in which case the dose range tested examined in animals treated with flupirtine had central side effects, such as ataxia or spontaneous locomotion. There was no decrease in physical exercise capacity.

For example, in the above experimental method, a dose of 1 mg / latte body weight reduces by 50% drug-induced ankylosis in the skeletal muscle group of growing latte.

The minimum effective dose in the above-mentioned animal experiment is, for example, Oral 1 mg / kg Peritoneal 0.1 mg / kg Is.

As a general dose range (animal experiment as described above) for obtaining the action, the following is applicable, for example: Oral 1-100 mg / kg, especially 10-40 mg / kg Peritoneum 0.1 to 30 mg / kg, especially 1 to 20 mg / kg.

Flupirtine differs from other active substances of the same propensity in particular in the following respects: Flupirtine does not induce dependence and has a strong analgesic effect.

The muscular-relaxing action of flupirtine also leads to a reduction in reserpine-induced ankylosis, as in typical anti-Parkinsonian agents.

The combination of flupirtine with such anti-Parkinson's agents results in an overly additive skeletal muscle relaxant action. Thus, for example, flupirtine is
In diseases such as Parkinson's disease where muscle relaxation is increased, skeletal muscle tension is reduced. The action amount for this is described above.

The effects of flupirtine alone on reserpine-induced ankylosis and in combination with other known anti-Parkinson's agents such as (-)-deprenyl, biperiden and L-dopa are shown in the following table.

Tolerance Removal Substance Quality Flexor Extensor mg / kg ip * Action (%) Action (%) Flupirtine 5 53 56 (-)-Deprenyl 1 18 14 Flupirtine 5 + + 96 93 (-)- Deprenyl 1 piperidene 0.1 12 16 flupirtine 5 + + 89 96 piperidene 0.1 L-dopa 5 17 11 flupirtine 5 + + 93 88 L-dopa 5 * i.p = peritoneum This tonic removal is latte hind leg The resistance of flexor and extensor muscles was measured by continuously measuring as described above. The only difference when measuring tonicion removal is that animals receive intraperitoneal administration of reserpine at a dose of 2.5 mg / kg latte 16 hours before the start of the experiment. This reserpine causes rigidity. The removal or inhibition of this ankylosis by flupirtine, various anti-Parkinson's agents and combinations thereof with flupirtine is then measured as described.

Indications that the novel effect flupirtine according to the invention may be used: all diseases associated with muscle spasms (tonicity) and the resulting syndromes, such as neuralgia, arthritis, non-inflammatory arthrosis, chronic or transient Tension headache, post-operative disorders, pervasive tendon muscular disease, tendon attachment disease, Parkinson's disease (especially during ankylosis that appears parallel to Parkinson's disease). Contraindications: Myasthenia g
ravis).

The pharmaceutical preparation contains flupirtine-base generally from 50 mg to 500 mg, preferably from 100 mg to 2 mg.
Contains 00 mg.

The application is, for example, tablets, capsules, pills, dragees, suppositories, salves, jellies, creams, powders, powders,
It can be carried out in aerosol form or in liquid form.

The following liquid form forms apply: oily or alcoholic or aqueous solutions and suspensions and emulsions. An advantageous use form is flupirtine 10
A capsule or tablet containing 0 mg to 200 mg or a solution containing 0.1 to 10% by weight of flupirtine.

A unit dose of flupirtine-base is, for example: a) 70 mg to 300 mg, preferably 100 mg to 200 mg in the oral pharmaceutical form, b) parenteral pharmaceutical forms (eg intravenous, intramuscular) 8
It may be from mg to 80 mg, preferably from 10 mg to 100 mg (dose for each free flupirtine base).

It is recommended, for example, to take 1-2 capsules or tablets containing 50 mg to 200 mg of the active substance three times daily.

When flupirtine is used in a method or form in which it is combined with an anti-Parkinson agent, the weight ratio of flupirtine to the anti-Parkinson agent is, for example, 1: 0.01 to 1: 1.
It is 1. Thus, in the corresponding drug, for example, flupirtine and the anti-Parkinson agent are present in such weight ratios.

Acute toxicity of flupirtine in mice (LD
Displayed at 50 mg / kg; Mirror and tinter (Mi
by Ller und Tainter): Pr
oc. Soc. Expert. Biol. a. Med. 5
7 (1944) 261) is, for example, 600 for oral application.
mg / kg to 800 mg / kg or 500 mg / k
g or more.

The invention also relates, for example, to the following process for the preparation of the corresponding flupirtine-containing pharmaceutical products: a) Flupirtine or a therapeutically usable salt thereof and optionally an anti-Parkinson agent as a customary pharmaceutical carrier, auxiliary and And / or with a diluent, a pharmaceutical product for the treatment of said diseases and syndromes comprising prescribing a pharmaceutical product for the treatment of diseases and syndromes that are attributed to or a sequela of muscle spasms. Method of manufacturing.

B) at least flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinson agent together with conventional carriers and / or diluents or auxiliaries at 0 to 120 ° C., preferably 20 to 80 ° C. For the preparation of a formulation containing flupirtine or a pharmaceutically usable salt of flupirtine in a dosage unit of 50-500 mg, which is mixed at temperature or homogenized and, optionally, the mixture thus obtained. For this purpose, they are filled into hollow cells of corresponding size or granulated and then compressed into tablets, optionally with the addition of other customary auxiliaries, or filled into capsules. A process for the manufacture of a medicament for the treatment of diseases and syndromes which are attributable to or are the result of muscle spasms.

C) Flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinsonian agent, the following substances: starch, cyclodextrin, urea, cellulose, lactose, formalin-casein, modified starch, magnesium stearate, Mixing with one or more of calcium hydrogen phosphate, silicic acid, talc, phenoxyethanol and the resulting mixture optionally containing at least gelatin, starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate-copolymer and / or polyoxyethylenesorbitan mono. Granulating with an aqueous solution containing oleate, homogenizing the granules, optionally with one or more of the abovementioned auxiliaries, and compressing the mixture into tablets or capsules, in which the tablets or Capsules are the active substance Flupirtine or its salt 5 each
A process for the preparation of a medicament for the treatment of diseases and syndromes which are attributable to or are the result of muscle spasms, which comprises containing in a dosage unit of 0-500 mg.

D) flupirtine or a pharmaceutically usable flupirtine salt and optionally an anti-Parkinsonian agent, together with the following auxiliaries: soybean lecithin, oxynesque, phenoxyethanol, solidified at a temperature of 31-65 ° C. The mixture is suspended and homogenized in a fat or other fatty acid glyceride-containing mixture and subsequently this mixture is poured into hollow cells or filled into capsules, the dosage unit being the active ingredient flupirtine or its 50 salt
A process for the preparation of a medicament for the treatment of diseases and syndromes which are attributable to or are the result of muscle spasms, which comprises-500 mg.

E) flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinsonian agent at a temperature of 20 to 120 ° C., optionally in the presence of one or more emulsifiers and / or complexing agents, The following substances: water, glycerin, paraffin, vaseline, C-atoms 12-25
Alcohol having 1 to 20 carbon atoms, aliphatic monocarboxylic acid having 15 to 20 C atoms, sorbitan monopalmitate, polyoxyethylene polyol fatty acid ester,
Attributed to a muscle spasm comprising homogenizing and / or emulsifying with at least one monohydric or polyhydric bottom molecule fatty alcohol, fatty acid glyceride, wax, silicone, polyethylene glycol, silicon dioxide,
Alternatively, a method of manufacturing a drug for the treatment of diseases and syndromes that are the result of muscle spasms.

F) flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinson agent, optionally in the presence of complexing agents and / or emulsifiers,
Dissolve in water, physiologically harmless alcohol, polyglycol, polyglycol derivative, dimethyl sulfoxide, triglyceride, partial ester of glycerin, paraffin or oil or a mixture thereof at a temperature of 30 to 100 ° C.,
And optionally, the final solution, the final suspension or the final emulsion is added to the solution obtained with the agent flupirtine 0.1-10.
A process for the preparation of a medicament for the treatment of diseases and syndromes which are attributable to or are the result of muscle spasms, which comprises the addition of said solvent in an amount of up to% by weight.

The pharmaceutical composition, eg a medicament, contains as active substance flupirtine or a physiologically tolerable salt thereof. The active substance is optionally present in admixture with other pharmacologically active substances or pharmacologically active substances, especially in admixture with anti-Parkinson's agents. The production of the medicinal product is carried out by known methods, in which known and customary pharmacological auxiliaries and other customary carriers and diluents can be used.

Examples of such carriers and auxiliaries are substances which are recommended or described as auxiliaries in the fields of pharmacy, cosmetics and adjacent fields in the following documents: Ullmann's Encyclopedia Der Tehishchen Chemie (Ullmanns Enc)
yklopadie der technische
n Chemie), Volume 4 (1953), 1-39.
Page; Journal of Pharmacy Oytical Sciences (Jununal of Pharmace
Technical Sciences), Volume 52 (196)
3), page 918 et seq .; V. Kutsch-Lindenwald, Hilfstofe Für Pharmazi und Angrenzend Gewite (HVCze)
tsch-Lindenwald, Hilfstof
fe fuer Pharmazie und ang
renzende Gebiete); Pharm. I
nd. , Heft 2 (1961), p. 72 et seq .; Dr. H. P. Fiedler, Lexicon Der
Hilfusftfe Für Pharmazi, Cosmetic und Angrenzende Gevite Cantor KG. Ourendorff in Wurttemberg (D
r. H. P. Fiedler, Lexikonder
Hilfstoffe fuel Pharmazi
e, Kosmetik und angelzend
e Gebijet Cantor KG. Aulen
dorf in Wuerttemberg) 198
1.

Examples of this are gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starch (eg corn starch) cyclodextrin and cyclodextrin derivatives, polyvinylpyrrolidone, polyvinyl acetate, gelatin, acacia, alginic acid, tylose (Tyl).
ose), talc, lycopodium, silicic acid (eg, colloidal), cellulose, cellulose derivatives (eg, cellulose-hydroxy groups thereof are partially lower aliphatic saturated alcohols and / or lower aliphatic saturated oxyalcohols). Cellulose ethers which are etherified, such as methyloxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate); fatty acids and fatty acids having 12 to 22 C-atoms, in particular saturated fatty acids (eg stearic acid) magnesium salts, Calcium or aluminum salts, emulsifiers, oils and fats, especially vegetable ones such as peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod Oil, each also hydrates; saturated fatty acid C
₁₂ H ₂₄ O ₂ -C ₁₈ H ₃₆ O ₂ mono-, di- and triglycerides and mixtures thereof, pharmaceutically acceptable mono- or polyhydric alcohols and polyglycols such as polyethylene glycol and its derivatives, saturated or unsaturated. Fatty acid (C-
2 to 22 atoms, especially 10 to 18) and aliphatic monohydric alcohols (1 to 20 C atoms) or polyhydric alcohols,
For example, an ester with glycol, glycerin, diethylene glycol, pentaerythritol, sorbit, mannite, etc. (these may be etherified in some cases), an ester with citric acid and a primary alcohol, acetic acid, benzyl benzoate, dioxolane. , Glycerin formal, tetrahydrafurfuryl alcohol,
C ₁ -C ₁₂ - polyglycol ethers of alcohols,
Dimethylacetamide, lactamide, lactate, ethyl carbonate, silicon (particularly medium viscosity polydimethylsiloxane), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

Other auxiliaries are also those which have a degrading action (so-called disintegrants), for example: crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose are microcrystalline cellulose. . Similarly, known coating agents can also be used. As such, the following applies, for example: polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters; consisting of acrylic and methacrylic acid esters containing small amounts of ammonium groups. A copolymer (for example, Eudragit (registered trademark; hereinafter omitted) RS), a copolymer of acrylic and methacrylic acid esters and trimethylammonium methacrylate (for example,
Eudragit RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropylmethylcellulose phthalate or -acetate succinate; cellulose-, starch- and polyvinylacetate phthalate; carboxymethylcellulose; methylcellulose-phthalate, -succinate,- Phthalate succinate and -phthalate-acid half ester; zein; ethyl cellulose and -succinate; shellac, gluten; ethyl carboxyethyl cellulose; ethacrylicate-maleic anhydride-copolymer; maleic anhydride-vinyl methyl ether-copolymer; styrene-maleic acid- Copolymer; 2-ethyl-hexyl-acrylate maleic anhydride; crotonic acid-vinyl acetate-copolymer; glutamic Acid / glutamic acid ester - copolymer; carboxymethyl ethyl - cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

Suitable plasticizers for the coating substance are the following: citric acid- and tartaric acid esters (acetyltriethyl-, acetyltributyl-, tributyl-, triethyl-citrate); glycerin and glycerin esters ( Glycerin diacetate, -triacetate, acetylated monoglyceride, castor oil);
Phthalates (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), D- (2
-Methoxy- or ethoxy-ethyl) -phthalate, ethylphthalyl-, butylphthalylethyl- and butylglycolate; alcohols (propylene glycol, polyethylene glycols of various chain lengths), adipates (diethyl adipate, di (2-methoxy-or Ethoxyethyl) -adipate); benzophenone; diethyl- and dibutyl sebacate, -succinate, -tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate Ate (polysorbate, eg polysorbate 80); sorbitan monooleate.

For the production of solutions or suspensions, for example water or physiologically tolerable organic solvents such as ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethylsulfoxide, fatty alcohols, Examples thereof include triglyceride, partial ester of glycerin, and paraffin. In order to obtain an injectable solution or suspension, for example, a non-toxic parenteral acceptable diluent or solvent, such as water, 1,3-
Butanediol, ethanol, 1,2-propylene glycol, polyglycol mixed with water, Ringer's solution,
Solidified oils containing isotonic saline or synthetic mono- or diglycerides or fatty acids such as oleic acid are also used.

Known and customary solubilizers or emulsifiers can be used in the preparation of the formulations. Suitable solubilizers and emulsifiers are, for example: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phospholipids such as lecithin,
Gum arabic, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linoleated (lin
oleisierte) oleotriglyceride, polyethylene oxide-condensate of fatty alcohol, alkylphenol or fatty acid or 1-methyl-3- (2-hydroxyethyl) -imidazolidone- (2). Here, polyoxyethylation means that the degree of polymerization of the substance is generally 2 to 4
It is meant to have a polyoxyethylene chain of 0, especially 10-20. Such polyoxyethylated substances can be obtained, for example, by reacting a compound containing a hydroxyl group (for example, a mono- or diglyceride or an unsaturated compound such as one having an oily acid group) with ethylene oxide (for example, per mol of glyceride). 40 mol ethylene oxide). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. Dr. H. P. Fiedler (Dr.
H. P. Fiedler) “Lexicon de Hilfstofe Für Pharmazie, Cosmetic und Angrenzende Gewite (Lexik)
on der Hilfstoffe fuel P
harmazie, Kosmetik und ang
renzende Gebiete) "1971, 19
See also pages 1-195.

Furthermore, preservatives, stabilizers, buffer substances, such as calcium hydrogen phosphate, colloidal aluminum hydroxide,
It is also possible to add corrigents, sweeteners, dyes, antioxidants and complexing agents (eg ethylenediaminotetraacetic acid).
In some cases, a pH range of about 3-7 can be adjusted with physiologically tolerable acids or buffers for stabilization of the agent molecule. In general, neutral-weakly acidic (up to pH 5) pH values are preferred.

For the preparation of the preparations to be used at the moment, the substances and gels which can be applied or are liquid hydrocarbons, such as petrolatum or paraffins or paraffin hydrocarbons and polyethylene, even partially hydrogenated. Fats and oils or synthetic fats of good vegetable or animal origin,
For example, glycerides of C _{8 to} C ₁₈ fatty acids, followed by beeswax, cetyl palmitate, wool wax, wool wax alcohol; fatty alcohols such as cetyl alcohol, stearyl alcohol, polyethylene glycol having a molecular weight of 200 to 20,000; liquid waxes such as isopropyl millimetre. State, isopropyl stearate, ethyl oleate; emulsifiers such as sodium, potassium, ammonium salts of stearic acid or palmitic acid and of triethanolamine stearate, oleic acid, alkali metal salts of ricinoleic acid, sulfonated fatty alcohols salt,
For example sodium lauryl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, salts of hepatic acid, sterols such as cholesterol,
Partial fatty acid esters of polyhydric alcohols such as ethylene glycol monostearate, glycerol monostearate, pentaerythritol monostearate, partial fatty acid esters of sorbitan, partial fatty acid esters of polyoxyethylene sorbitan, sorbitol ethers of polyoxyethylene, poly Oxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, sucrose fatty acid ester, polyglycerol fatty acid ester, and lecithin are used.

Examples of the antioxidant include sodium pyrosulfite, ascorbic acid, gallic acid, alkyl gallate, butylhydroxyanisole, nordihydroguaiaretic acid, tocopherol and tocopherol + synergist (with complex metal formation to form heavy metal). Bound substances, eg lecithin, ascorbic acid, phosphoric acid)
Is used. The addition of synergists significantly enhances the antioxidant effect of tocopherol. Examples of preservatives include sorbic acid, p-hydroxybenzoic acid ester (eg lower alkyl ester), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and formalin derivatives.

The pharmaceutical and galenical handling of the compounds according to the invention is carried out according to the customary standard methods. For example, the active ingredient and the auxiliaries or carriers are mixed intimately by stirring or homogenization (for example using conventional mixing equipment), generally at a temperature of 20 to 80 ° C., preferably 20 to 50 ° C., in particular Perform at room temperature. Otherwise, refer to the following standard documents: Zucker, Fuchs, Spyzer, Famazoitsche Technologie, Time Publishing (Sucker, Fuchs, Speiser, Ph.
armazeutische Technology
e, Thieme-Verlag) Stuttgart, 1
978.

The application may be performed on the skin or mucous membranes or the body, for example, orally, enterally, pulmonary, rectal, nose, vagina, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, subcutaneous. You can Parenteral formulations are especially sterile or sterile products.

[0044]

【Example】

Tablet: 2-amino-3-carbethoxyamino-6-
10 kg of (4-fluoro-benzylamino) -pyridine-maleate are mixed with 2.5 kg of calcium hydrogen phosphate and 2.5 kg of corn starch, and the mixture is prepared by a known method using a solution of 1 kg of polyvinylpyrrolidone in 4 kg of deionized water. Granulate. Cornstarch 1.3k
g, microcrystalline cellulose 2 kg, magnesium stearate 0.6 kg and highly disperse silicon dioxide 0.1 kg and then compressed into tablets with a weight of 200 mg, a diameter of 9 mm and an arch diameter of 10 mm with a scoring notch. The puncture resistance of the tablets is 80N-100N (immediate puncture resistance). The disintegration time with DAB8 is 5 minutes.

Each tablet contains 100 mg of active substance.

Capsules: In the same manner as described above for tablets, capsule capsules are prepared which are filled into hard gelatin capsules of suitable size. Filling amount per capsule: 2
00 mg. One capsule contains 100 mg of active substance.

Oily suspension containing 15% flupirtine maleate: medium-chain triglyceride (trade name: Miglyol 812 / Hüls Troisdorf (Migly)
ol 812 / Huels Troisdorf)) 4
Highly disperse amorphous hydrophobic silicon dioxide (trade name: Aerosil R972 / Degussa
R972 / Degussa)) 32.5 g, micronized saccharin-sodium 0.5 g, sodium cyclamate fine powder 1.5 g, iron oxide (red) 0.1 g,
Strawberry flavor 0.5g, flupirtine maleate 75g
And Oxynex LM: E. Me
0.375 g of rck / Darmstadt) is uniformly suspended. This suspension is diluted with medium chain triglyceride to 500
Replenish to g and mix.

1 g of suspension contains 150 mg of flupirtine.

Injection: The manufacturing process applies to batches for 20 l (= ampoule 6500).

Manufacturing process: 1. Heat 10.0 liters of water to 70 ° C. and add gluconic acid-δ
-After addition of 1562.0 g of lactone
Leave for 1 hour. The solution is then gassed with nitrogen.

2. 8000.0 g of polyethylene glycol having a molecular weight of 380 to 420 is charged into the solution 1, and the solution is heated to 70 ° C. under nitrogen blowing.

3. 30.0 g of sodium disulfite are dissolved in 500.0 ml of water gasified with nitrogen.

4. Solution 3 is added to solution 2.

5. 666.6 g of flupirtine-base are sieved through a sieve with a mesh size of 0.3 mm and combed into solution 4 under strong nitrogen bubbling.

6. Solution 5 is cooled and replenished with nitrogen gasified water to a total of 20 l.

7. Solution 6 is sterile filtered through a 0.2 μm pore size filter membrane with a glass fiber prefilter.

8. In-process control: Solution 7 using oxygen electrode
Measurement of oxygen content of. Measurement of pH-value of solution 7.

9. Solution 7 is filled under aseptic conditions and under nitrogen bubbling into colorless ampoules with a volume of 3 ml. Ampoule 1
Flupirtine-gluconate 16 in 3 ml of solution
Contains 4.5 mg.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Ralf Fuenhaus             Federal Republic of Germany Hetzpenheim Vu             Soberdener Shutlerse 1 (72) Inventor Bernd Nickel             Federal Republic of Germany             ー Shoutrace 35 (72) Inventor Istovan Tzuereniyu             Federal Republic of Germany             Lucille Trace 32 (72) Inventor Jurgen Engel             Federal Republic of Germany Arzuenau Erle             New trace 3 (72) Inventor Peter Amitsu             Federal Republic of Germany Lower Dorf Erde             Taunusushiyutrase 6

Claims (10)

[Claims] 1. A medicament for the treatment of diseases and syndromes that are attributable to or are the result of muscle spasms, characterized in that they contain flupirtine as an active substance or a therapeutically available salt thereof. And pharmaceutical products. 2. A medicament according to claim 1, which contains conventional pharmaceutical carriers, auxiliaries and / or diluents. 3. A therapeutic agent for Parkinson's disease, which comprises flupirtine or a therapeutically available salt thereof and an anti-Parkinsonian agent as a combined preparation for simultaneous, separate or staggered use during treatment of a Parkinsonian agent. 4. An anti-Parkinson agent containing (−)-deprenyl, biperidene or L-dopa.
The described formulation. 5. A method for producing a drug for treating diseases and syndromes that are attributed to muscle spasm or the after-effects of muscle spasm, wherein flupirtine or a therapeutically usable salt thereof and, in some cases, an anti-Parkinson agent are used. Characterized in that it is formulated with conventional pharmaceutical carriers, auxiliaries and / or diluents into a medicament for the treatment of said diseases,
Pharmaceutical manufacturing method. 6. A process for the preparation of a medicament for the treatment of diseases and syndromes that are attributable to or are the result of muscle spasms, comprising at least flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinson agent. Is mixed with conventional carriers and / or diluents or auxiliaries at temperatures between 0 and 120 ° C., or is homogenized and, if appropriate, the mixture thus obtained,
For the preparation of formulations containing flupirtine or a pharmaceutically usable salt of flupirtine in dose units of 50-500 mg, are filled or granulated in hollow cells of corresponding size and then, if appropriate, A method for producing a medicinal product, characterized by compressing into tablets or filling capsules with the addition of other conventional auxiliaries. 7. A method for the preparation of a medicament for treating diseases and syndromes that are attributable to or are the result of muscle spasms, comprising flupirtine or a pharmaceutically usable salt thereof and optionally an anti-Parkinson agent, The following substances are mixed with one or more of starch, cyclodextrin, urea, cellulose, lactose, formalin-casein, modified starch, magnesium stearate, calcium hydrogen phosphate, silicic acid, talc, phenoxyethanol, and the mixture obtained optionally. At least gelatin as an ingredient,
Starch, polyvinylpyrrolidone, vinylpyrrolidone-
Granulate with an aqueous solution containing vinyl acetate-copolymer and / or polyoxyethylene sorbitan monooleate, homogenize the granules, optionally with one or more of the abovementioned auxiliaries, and compress this mixture into tablets. Alternatively, it is filled in capsules, the tablets or capsules containing the active substance flupirtine or its salts in dose units of 50 to 500 mg each. 8. A method for the preparation of a medicament for treating diseases and syndromes that are attributable to or are the result of muscle spasms, comprising flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinson agent. , The following auxiliaries: soybean lecithin, oxynesque, phenoxyethanol, suspended in a mixture containing solid fat or other fatty acid glycerides melted at a temperature of 31-65 ° C. and homogenized, and subsequently this mixture Are injected into hollow cells or filled into capsules, the dosage unit being the active ingredient flupirtine or its salt 50-50.
A method for producing a pharmaceutical product, which comprises 0 mg. 9. A method for the manufacture of a medicament for treating diseases and syndromes that are attributable to or are the result of muscle spasms, comprising flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinson agent. Two
At temperatures from 0 to 120 ° C., optionally in the presence of one or more emulsifiers and / or complexing agents, the following substances: water, glycerin, paraffins, vaseline, aliphatic alcohols having 12 to 25 C atoms. , An aliphatic monocarboxylic acid having 15 to 20 C atoms, sorbitan monopalmitate,
Characterized by homogenizing and / or emulsifying with at least one of polyoxyethylene polyol fatty acid ester, monohydric or polyhydric low molecular weight aliphatic alcohol, fatty acid glyceride, wax, silicone, polyethylene glycol, silicon dioxide. , Pharmaceutical manufacturing method. 10. A method for the preparation of a medicament for treating diseases and syndromes which are attributable to or are the result of muscle spasms, wherein 30 flupirtine or a pharmaceutically usable salt of flupirtine and optionally an anti-Parkinson agent are used. ~
Water, physiologically harmless alcohols, polyglycols, polyglycol derivatives, dimethylsulfoxide, triglycerides, partial esters of glycerin, paraffins or oils, at a temperature of 100 ° C., optionally in the presence of complexing and / or emulsifying agents, or Dissolved in these mixtures, and optionally in the resulting solution, the final solution, the final suspension or the final emulsion contains 0.1 to 10% by weight of the active ingredient flupirtine.
A method for producing a pharmaceutical, which comprises adding the amount of the solvent up to the amount contained.