SK12593A3 - Medicament for therapy of neurological and psychical disorders, caused by an abusing of alcohols - Google Patents

Abstract

A pharmaceutical composition for the prophylaxis and therapy of neurological and psychiatric damage due to alcohol abuse contains as active ingredients thiamine, folic acid and an amount of cobalamines which makes possible the biological utilisability thereof, and/or pharmacologically equivalent analogues of the aforementioned substances, in a pharmaceutically acceptable vehicle.

Description

The second active ingredient thiamine contributes, in combination with the aforementioned active ingredients, particularly effective in treating the polyneuronies observed in alcohol.

It has been found that the proposed combination of thiamine, folic acid and cobalamin exhibits a very good bioavailability, which is equally good in a variety of dosage forms. A measure of cover is the maximal drug concentration in serum C _has. It has now surprisingly been found that, even in the various forms of administration, the peak serum concentration, i.e. the peak serum level of the individual active ingredients, is always the same. Thus, the combination of active ingredients is equally bioavailable at the same time and thus can be useful in the prophylaxis and treatment of neurological and psychiatric disorders caused by alcohol abuse. Research has shown that when drug is administered in aqueous solution or in the form of a vitamin capsule, the maximum serum concentration is reached after approximately one and a half of the current bioavailability, so that the bioavailability also results in the individual components. in different application forms, the combination is different. Thus, in acute cases, patient dosage forms such as a beverage, drops or capsules that can be used without difficulty can be rapidly reduced. Thus, acute phenomena of neurological damage by alcohol abuse, manifested in extreme cases by severe itching, can also be eliminated in a short time by repenting the capsule. Investigations have shown that the administration of the active compound combination according to the invention can eliminate typical symptoms of alcohol abuse problems.

Suitable pharmacologically active analogues of the same may be used materials which are chemically modified with, which, however, the organism can once again converted to the active substance, thiamine, or acid folcvou kobalaminy.Jakožto same pharmacologically active a6 _ηε the logo is also used metabolites of the metabolism, it is 1ikož The active substances thiamine, folic acid and cobalamins change in the metabolism itself as they pass through the metabolic forms. Thus, in particularly acute cases, it is possible to offer, for example, the use of, for example, a folate instead of its metabolite, tetrahydrofolic acid, which is formed in the first step of the lath exchange of folate in the body. Adding tetrahydrofolic acid instead of folic acid can then save the time it takes to convert the supplied folate to tetrahydrofolic acid. This is also possible, for example, also with thiamine, i.e. thiamin tri phosphate or thiaminpyrophosphate can already be used.

The use of chemically modified active substances serves, for example, to improve the shelf life or shelf-life of the active substances or their suitability for certain dosage forms. Thus, it can improve the water solubility of a hydrophilic group, for example. These groups are cleaved in the body and the active substances are converted into their initial forms of metabolism, i.e., thiamine, folic acid and cobalamin.

Thus, the task according to the invention is perfectly solved.

In a particularly preferred embodiment of the invention, thniamine hydrochloride or the corresponding salts thereof are used as the active ingredient benfotamine, acetiamine hydrochloride, bentiaminlauryl sulfate, bisbenthiamine, fursuitiamine, fursulthiamine hydrochloride, thiamine disulfide disulfate, disulfate disulfate or disulfate disulfate or disulfate disulphate disulfate. vitamin B 1, octothiartin, thiamidium sulfide, thiamindisulphid-OO-dinicotinate.

Thiamine nitrophosphate (TTP) or thiaminpyrophosphate (TPP) is used as the thiamine metabolite.

According to a particularly preferred embodiment of the invention, lipophilic soluble thiamines are used, in particular from the group of alithiamines.

As folic acid metabolites, tetrahydrofolic or folinic acid are particularly suitable.

Particularly suitable derivatives of cobalamin are cyanocobaiamine, hydroxocobalamin, methylcobalamin or the metabolites methylcyclamin, 5-adenosylcobalamin.

Benfotiamine, which is better available than thiaminohydrochloride, appears to be particularly advantageous and, in contrast to thiamine hydrochloride, even crosses the blood-brain boundary and enriches in the cerebrospinal fluid, which is important in the treatment of Wernick's and Korsakcwa syndrome.

It has been found that when plowing the medicaments according to the invention with the active substance benfotiamine, the plasma concentrations of thiamine and thiamides of phosphate coenzyme are increased by a factor of 10, and the thiamine and phosphate coenzyme increase by 130-fold.

Particularly preferred are medicaments which contain benfotiamine, folic acid and cyanocobaiamine as the active ingredient.

In this embodiment, an effective partner of cyanocobaiamine in a favorable resorptive form to form a complex in the lower part of the ileum is provided for the first drug substance, namely folic acid, in a favorable resorptive form, and at the same time a second drug substance is available in a favorable rosorbable form soluble in water. lipoids, namely benfothiamine.

The amount of active ingredient per dose is 1 mg to 500 mg of thiamine, in particular benphothiamine, 0.1 mg to 50 mg of phelic acid and 1 mcg to 5 mg of cobalamin.

In this mutual amount, optimal bioassayability of the active drug substances by the organism is achieved.

Oral dosage forms, for example capsules, dragees, are particularly preferred as a dosage form of the medicament. tablets, film coated tablets, cucsci tablets, chewable tablets, effervescent tablets, beverages or drops. It is also possible to administer the drug parenterally, for example as a solution for injection or infusion, or rectally in the form of a suppository or nasal. It is also possible to administer the drug in inhalable form.

Thus, all forms of administration are possible, so that it can always be chosen in the finer form in the case of problematic groups of alcohol-impaired patients.

It will be understood that various combinations may be used within the scope of the invention, or combinations of the invention may be used in other combinations.

BRIEF DESCRIPTION OF THE DRAWINGS The invention is illustrated in greater detail by the accompanying drawing and the accompanying drawings. The enclosed drawing is a diagram showing the time course of the concentration of the individual active substances in the serum.

Vynilez also clarifies, but does not limit the following example for 'management'.

Execution Examples

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The lids also take 13, 30, 45, 60 shelf intervals

The study assesses the bioavailability of folic acid, kebaiamine and benothiamine from various pharmaceutical agents (capsule 1e / aqueous solution) in 12 subjects (6 females and 6 males).

Cross-over-design means are always administered in accordance with standardized framework conditions. For novelty, a blood test is taken immediately prior to administration at 90 and 120 minutes after administration and then up to 10 hours after administration of the composition.

The enzymes are radioimmunologically (thioic acid, cobia) or high pressure liquid chromatography (thia;) are administered. The test pharmaceutical composition is administered in the form of a vitamin capsule or in the form of a diluent.

Smi new follicle saliva 10.0 mg / capsule nokobaiamine 0.3 mg / capsule fotiamine 50.0 mg / capsule

Aqueous solution of folic acid 10.0 mg / capsule kycnocobaiamine 0.3 mg / capsule be · ´; take ami n 50.0 mg / capsule

In the attached graph, the concentrations are in the fifth. Arithmetic mean values from 12 experienced persons are entered. On the time axis, t = 0 is the time of the first measurement 15 minutes after the administration of the active ingredient combination in the form of an aqueous solution

Curve A shows the thiamine concentration trough in ng / ml. Curve B shows the concentration waveform. folate in plasma in µg / ml. Curve C shows the concentration curve of cobalamin

in. plasma in pg / ml.

FIG. it is evident that the maximum concentration in the obscure of both tbiamine and folate is reached approximately half an hour after administration. Thus, both active substances are available at maximum concentration shortly after administration and may simultaneously develop their action. Thus, the active substances are very quickly and simultaneously available to the bioavailability.

When administered in the form of a vitamin capsule, the maximum of curves A and 3 is offset by approximately 15 to 30 minutes. From the C curve, the concentration of cbaiamine or vitamin Bi? in plasma it has a control function for receiving and evaluating the synergistic components. that is to say, a specific acid, i.e. only a certain amount, but a constant increase in plasma, is observed. This points to the intrinsic factor-reduced resorption mechanism, i.e. a sufficient, moderate amount of foic acid is added to the body, which is, however, surprisingly currently bioavailable with thiamine, and rapidly and simultaneously produces a combined action on the organism in s.

Examiners with acute symptoms of alcohol-related undesirable symptoms, such as extreme sedation in extremities, show significant reductions of these symptoms in just a few minutes after administration of the combination.

Further tests have shown that phenomena such as lack of concentration, lack of attention and limited ability to express can be greatly reduced.

The drug for the treatment and treatment of neurological and psychiatric disorders caused by alcohol abuse comprises thiamine, folic acid and their bioavailability allowing the amount of cobalamin and / or their equally valuable analogues together with a pharmaceutically acceptable carrier as an effective substance.

Claims (8)

A medicament for the prophylaxis and therapy of neurological and psychiatric disorders caused by alcohol abuse, characterized in that thiamine as well as folinic acid as active substances and their biological evaluation in the amount of cobalamines and / or their pharmacologically identical analgesics are contained. in a pharmaceutically acceptable carrier. Medicament according to claim 1, characterized in that thiamine and / or the same pharmacologically active analogues thereof are selected from the group consisting of thiaminchloride, thiamihydrochloride, benfotiamine, acetiamine hydrochloride, bentisminlauryl sulfate, bisbenthiamine , fursultiamine, fursulthiamine hydrochloride d, thiamine dihydrogen phosphate chloride ester salt, thiamine hydrogen phosphate dihydrogen phosphate ester salt, thiamine nitrate, vitamin Bi, octothiamine, thiamine disulfide, thiamine disulfide-O-O'-din L cot. Medicament according to claim 1, characterized by: is that? As a valuable pharmacologically valuable thiamine analogue, it utilizes a metabolic activity of the thiamine metabolite. 4. A medicament according to claim 3, wherein the thiamine metabolite is thiaminotrophate (TTP) or thiamine pyrophosphate (TPP). 5. A medicament according to any one of claims 1 to 3, characterized in that it contains lipid-soluble thiamines selected from the group consisting of L1 and thiamines. Medicament according to claims 1 to 5, characterized by: characterized in that it contains, as pharmacologically the same valuable phallic acid analogues, folate metabolites from the group comprising tetrahydrofolic acid and folinic acid. Medicament according to one of Claims 1 to 6, characterized in that the cobalamin is selected from the group consisting of cyanocobalamin, hydroxocobalamin, methylcobalamin and 5-adenoylcobalmin. Medicament according to claims 1 to 7, characterized in that it contains a single dose 1.0 mg to 500.0 mg of thiamine, 0.1 mg to 50.0 µg of foic acid a 1.0 mcg to 5.0 mg cobaiamine.