The treatment for amyotrophic lateral sclerosis

 

(57) Abstract:

The invention relates to medicine, specifically to the use of 2-amino-6-triptoreline-benzothiazole or a salt of this compound with a pharmaceutically acceptable acid as a drug for the treatment of lateral Amyot-trophic sclerosis and, in particular amyotrophic lateral sclerosis with bulbar beginning or in the bulbar form. 2 C.p. f-crystals.

The invention relates to the use of 2-amino-6-triptoreline-benzothiazole or a salt of this compound with a pharmaceutically acceptable acid to obtain a medicinal product intended for the treatment of motoneuronal diseases, particularly amyotrophic lateral sclerosis and, in particular amyotrophic lateral sclerosis with bulbar beginning or in the bulbar form.

It is known that 2-amino-6-triptoreline-benzothiazole (international name: riluzole) is recommended as an anticonvulsive, anxiolytic and hypnotic (sleeping pill) medicines ( EP 50551), for the treatment of schizophrenia (EP 305276), for the treatment of sleep disorders (EP 305277), for the treatment of disorders of the brain and as usual means (EP 28 the pharmaceutically acceptable acid may be used to treat motoneuronal diseases, especially amyotrophic lateral sclerosis and, in particular amyotrophic lateral sclerosis with bulbar beginning or in the bulbar form.

This application was installed on the people in the study in a double-blind method and experience with placebo: 77 patients affected motoneurone diseases and especially amyotrophic lateral sclerosis, was given 2 times a day 50 mg of riluzole oral tablets with a dose of 50 mg) over a period of 12 - 18 months, and 78 patients received placebo.

The results were analyzed in terms of survival in the research process, with the view that "death in the research process" (Exodus experience) include both really dead people, and people, clinical condition which causes the need for tracheotomy or transition to respiratory support.

In this study, 51% of patients receiving placebo died, whereas this percentage drops to 44% in patients who received riluzole { probability in the test Wilcoxona (R. L. PREUCTICE, Biometrika 65, 167-179 (1978)) equal 0,018, and the probability stratified Logrank test (R. PETO and J. PETO, Journal of the Royal Statistical Society series A, I. 135, 185-207 (1972)) is 0.06}.

In the case of patients affected naturalnumber median survival of this type of patients is less than 3 years), 65% of patients receiving placebo died, whereas this percentage decreases to 47% in patients treated with riluzole (the probability in the test Wilcoxon equal to 0.011, and the probability of Logrank test (R. PETO and J. PETO, Journal of the Royal Statisticul Society, series A, I. 135, 185-207 (1972)) equal to 0.032).

2-Amino-6-triptoreline-benzothiazole, consequently, increases statically significant, the survival of patients affected motoneurone diseases and especially amyotrophic lateral sclerosis, and this effect is especially evident in patients affected amyotrophic lateral sclerosis with bulbar beginning or in the bulbar form.

2-Amino-6-triptoreline-benzothiazole can be obtained by the method described in EP 50551.

As pharmaceutically acceptable salts especially can be called the salt of the accession of inorganic acids such as hydrochloride, sulfate, nitrate, phosphate, or organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theophylline-acetate, salicylate, phenolphthalein, methylene-bis-xinafoate, or derived from substitution of these derivatives.

Medicinal product according to the invention, formed 2-emnd acid, in its pure form or in the form of a composition in which 2-amino-6-triptoreline-benzothiazole (or its salt) is associated with any other pharmaceutically acceptable product, which can be inert or physiologically active. Medicinal product according to the invention, it is possible to introduce oral, parenteral, rectal or tapicerki.

As solid compositions for oral administration can be used in tablets, pills, powders (gelatin capsules, wafers or pellets. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, in a stream of argon. These compositions can also include substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a safety sheath (pills) or lacquer.

As liquid compositions for oral administration can use solutions, suspensions, emulsions, syrups, and elixirs, and containing pharmaceutically acceptable inert diluents, such as water, ethanol, glycerol, vegetable oils or paraffin oil. These songs mohottala, flavouring substances or stabilizers.

Sterile compositions for parenteral administration can be a preferably aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or excipient you can use water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, complex injectable organic esters, for example, etiloleat or other suitable organic solvents. These compositions can also contain auxiliary funds, in particular wetting, isotonic agents, emulsifiers, dispersing agents and stabilizers. Sterilization can be done in several ways, for example by asamisimasa filtering inclusion in the composition of sterilizing agents, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions, which when used can be dissolved in sterile water or any other sterile injectively environment.

Compositions for rectal injection are candles or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, polysynthetic a, for example, creams, lotion, liquid for rinsing, nasal drops or aerosols.

Doses depend on the desired effect, the duration of treatment and the route of administration; they are usually 50 to 400 mg per day orally for an adult with unit doses of 25 to 200 mg of active substance.

Typically, the physician determines the appropriate dosage depending on the age, weight and all other factors inherent to the patient.

The following examples illustrate the medicinal product according to the invention.

Example A. the Usual way to prepare tablets with a dose of 50 mg of active product having the following composition mg:

2-Amino-6-triptoreline-benzothiazol - 50

Mannitol - 64

Microcrystalline cellulose - 50

Polyvidone - excipient - 12

Sodium salt of carboxymethyl amylum - 16

Talc - 4

Magnesium stearate - 2

Anhydrous colloidal silica - 2

A mixture of methylhydroxypropylcellulose, polyethylene glycol 6000, titanium dioxide (72 - 3,5 - 24,5) to obtain film-coated tablets with a total weight of 245 mg.

Example B. the Usual method of preparing a gelatin capsule with 50 mg of active product having the following composition mg:

2-Amino-6-triptoreline-Ben is carboxymethylamino - 10

Talc - 10

Magnesium stearate - 1

Example C. Prepare a solution for injection containing 10 mg of active product and having the following composition:

2-Amino-6-triptoreline-benzothiazol - 10 mg

Benzoic acid 80 mg

Benzyl alcohol - 0,06 cm3< / BR>
Sodium benzoate - 80 mg

95% ethanol - 0.4 cm3< / BR>
Sodium hydroxide - 24 mg

Propylene glycol - 1.6 cm3< / BR>
Water To a total volume of 4 cm3.

1. The use of 2-amino-6-triptoreline-benzothiazole or a salt of this compound with a pharmaceutically acceptable acid as an agent intended for the treatment of amyotrophic lateral sclerosis.

2. Application under item 2 for the treatment of amyotrophic lateral sclerosis with bulbar beginning.

3. Application under item 2 for the treatment of literalnode amyotrophic sclerosis in the bulbar form.

 

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