WO1999055331A1 - Use of alpha lipoic acid to reduce appetite and/or body weight - Google Patents

Abstract

The invention relates to the use of R- alpha -lipoic acid and/or S- alpha -lipoic acid and/or one of its physiologically biocompatible salts to reduce appetite and/or body weight, at a preferred daily dose of between 10 mg and 10 g of the free acid form. Recommended single doses are between 10 mg and 5 g of either alpha -lipoic acid variant and are administered orally especially to patients with a body mass index (BMI) > 25 kg/m<2>, preferably in the form of a nutritional supplement as part of an antiobesity therapy.

Description

 - 1 -

Use of alpha lipoic acid to reduce appetite and / or to reduce body weight

description

The present invention relates to the use of σ-lipoic acid to reduce appetite and / or to reduce body weight.

Obesity in general is undisputed as a major health risk factor. A percentage of body fat that goes beyond what is necessary to maintain health and physical well-being is the hallmark of overweight and obesity. Patients with a body mass index above the 85% percentile are classified as clinically obese. The body mass index (BMI) is generally the quotient of body weight to the square of body height, which is represented with the help of so-called nomograms. Terms such as body mass number or Quetilet index are also common. Caused by malnutrition, an oversupply of food and a lack of exercise, obesity can be seen as widespread, especially in the highly industrialized countries of the western world: about 20 to 40% of the population suffer from obesity.

The potentially life-shortening effects of obesity are generally known. Increased circulatory stress and increased blood pressure are associated with an increased risk of cardiovascular diseases and the occurrence of e.g. B. arteriosclerotic vascular changes, diabetes mellitus, arthrosis and hyperlipidemia. The benefits of effective treatment of these symptoms are by no means limited to clinical cases; rather, many people classified as non-obese would also experience a moderate reduction - 2 - benefit from the body weight percentage and the associated weight reduction.

The causes of obesity, which are pathological disorders of the physiological energy balance, are manifold: physical peculiarities, eating and exercise behavior, fat storage, ratio of energy intake and energy consumption, genetic and psychological factors, etc. The treatment options of the are accordingly diverse Obesity, if only because, for example, the mechanisms of the body's own fat deposition are just as immune to external influences as genetic factors. A consistent and continued limitation of calorie intake through appropriate dietary measures makes sense from a therapeutic point of view. However, regardless of the possible consequences, many patients tend to disregard the reduction diet regulations ("negative compliance"), and therapy concepts that include changing eating habits or psychotherapeutic treatment are generally only partially successful.

This fact led to the development of appetite suppressants, so-called anorexigen means, which reduce the craving for food and the appetite and thus reduce the amount of food consumed. However, many anorectics in pharmacologically effective doses show harmful side effects, they partially lose their effectiveness when used over a longer period of time, or they have considerable addictive potential. For example, caffeine (1, 3,7-trimethylxanthine) is associated with increased nervousness and irritability, the use of fluoxetine (Prozac ^Φ , N-methyl-3-phenyl-3- (4-trifluoromethylphenoxy) propylamine) can be too Difficulty sleeping, feeling anxious and suffering from nerves, and dizziness or diarrhea have been observed with fenfluramine (pondimin ^* , N-ethyl-σ-methyl-3- (trifluoromethyl) phenethylamine). In - 3 - In some cases, low doses of fenfluramine decreased responsiveness, while ingestion of large amounts caused central excitation effects. Anorexigenic effects have also been observed with some prescription drugs and stimulants (e.g. ephedrine). In the case of erythromycin (Pediazole ^* or Ilosone ^* , a tridecanolide obtained from cultures of Streptomyces erythreus, for example), this affected only a negligibly small (<3%) part of the test subjects, and digestive problems, nausea were the likely side effects of such an application , Nausea, abdominal pain and diarrhea registered. The prolonged use of Aminorex (Menocil ", 2-amino-5-phenyloxazoline), a substance that is no longer on the market, led to the particularly severe side effect of pulmonary hypertension, with occasionally even fatal outcome.

It is therefore desirable to have a mild medicinal treatment of obesity with therapeutic agents that are effective but have no or only negligible side effects.

The object of the present invention was therefore to provide a new anorectic. An anorectic of natural origin with the broadest possible profile of indications should be used, which does not show any of the harmful side effects that are known from the active ingredients used to date.

This object was achieved by using an active ingredient selected from R-σ-lipoic acid, S-σ-lipoic acid, racemic σ-lipoic acid or mixtures or physiologically acceptable salts thereof for the production of an agent for reducing appetite and / or for reducing body weight. - 4 - σ-Lipoic acid (thioctic acid, 1, 2-dithiolane-3-pentanoic acid) is a natural product that occurs in low concentrations in plant or animal cells in the form of the R-enantiomer. The σ-lipoic acid originally discovered as a growth factor has a physiological effect in hydrophilic and lipophilic media as a coenzyme for the oxidative decarboxylation of σ-ketocarboxylic acids (e.g. pyruvates) and as an antioxidant. It is also used to regenerate vitamin C, vitamin E, glutathione and coenzyme ^Q 10.

σ-Lipoic acid is therefore not a pharmaceutical in the usual sense, but is a naturally occurring substrate for primary metabolism.

Racemic σ-lipoic acid is approved for the treatment of liver diseases and neuropathies (e.g. diabetic polyneuropathy); their use as an effective inhibitor of the replication of HIV-1 viruses has been discussed (see Klin. Wochenschr. 1991, 69 (15), 722-724). The racemate of σ-lipoic acid also has cytoprotective, antiphlogistic and antinociceptive (analgesic) properties, whereby it has been found that in the pure optical isomers of σ-lipoic acid (R-σ-lipoic acid or S-σ-lipoic acid) in In contrast to the racemate, the R enantiomer shows a predominantly antiphlogistic and the S enantiomer shows a predominantly antinociceptive activity profile (cf. EP 812 590 A2).

Surprisingly, it has been found that racemic or enantiomerically pure σ-lipoic acid and its salts have pronounced anorexigenic properties in practical use on humans in physiologically effective doses. However, the disadvantages and side effects described above that occur when other appetite suppressing agents are administered are not observed.

The present invention therefore describes a simple, therapeutically effective and practical method for reducing the feeling of hunger - 5 - and appetite and thus to reduce calorie intake. The use according to the invention is therefore suitable for bringing about a significant weight reduction in overweight, but also in normal weight people. No additional therapeutic or dietary measures are required to achieve this goal; nonetheless, the present use is problem-free and harmless in addition to other forms of treatment, such as, for. B. physical activity, formula diets, psychotherapeutic behavior training, etc. applicable. These advantages were not predictable in their form and, above all, in their sum.

As described, the σ-lipoic acid according to the invention can be used as optically pure R-σ-lipoic acid, as optically pure S-σ-lipoic acid, as racemic σ-lipoic acid or in the form of a physiologically acceptable salt of one of these optically pure compounds or the racemate . Daily doses between 10 mg and 10.0 g have proven to be particularly effective, this information relating to the free acid form. In order to achieve measurable and above all sustainable success, a period of at least two weeks should be preferred. A time limit for the use according to the invention is not to be observed with a suitable dosage.

Of the claimed salts, salts of racemic σ-lipoic acid or salts of optically pure isomers with metals of the 1st and 2nd main groups of the periodic table of elements and elements of III. to VI. Main group of the Periodic Table of the Elements (e.g. selenium) has proven to be particularly suitable. Also particularly suitable as salt formers for the claimed salts of racemic or optically pure σ-lipoic acid are the hydroxides of alkali and alkaline earth metals, ammonium hydroxide, amines of the general formula NR _! R ₂ R ₃ , in which the radicals R _{1 f} R ₂ and R ₃ independently of one another are hydrogen, C 1-4 alkyl or C 1-4 oxyalkyl, such as monoethanolamine, diethanolamine, 1-amino-propanol or - 6 -

Trometamol (2-amino-2- (hydroxymethyl) -1, 3-propanediol), alkylenediamines with an alkylene chain of 2 to 6 carbon atoms, such as hexamethylene diamine, cyclic amines with 4 to 6 carbon atoms, such as piperidine, piperazine, pyrrolidine or morpholine , basic amino acids such as lysine or arginine, aminocarboxylic acid derivatives, such as. B. creatine, camitin, ornithine, choline or taurine. But also for salts of selected metals in the transition series, such as. B. zinc, and for complex oxocations or organic cations of these transition metals and the preferred elements mentioned, the use according to the invention is conceivable. Examples of such organic cations are ammonium derivatives of open-chain or cyclic amines. However, other bases or cations that are physiologically compatible in the salt form can also be used to form suitable σ-lipoic acid salts.

Racemic σ-lipoic acid, optically pure R- or S- σ-lipoic acid and the salts mentioned are prepared in a known or analogous manner.

The claimed administration of the σ-lipoic acid variants takes place in the preferred single doses between 10 mg and 5 g, doses between 50 mg and 2 g being particularly suitable. With regard to the daily dose, the administration of 0.5 to 6 g has proven to be particularly suitable for certain applications. It is completely irrelevant to the success of the use according to the invention whether the pure σ-lipoic acid enantiomers, the racemic mixture or one of the salts described are administered. It is also possible to apply all of these variants in any mixture.

In the therapeutic use according to the invention, the body mass index (BMI), which should preferably be> 25 kg / m ^{2, has} proven to be an advantageous criterion for a clear effect in humans. - 7 -

According to a preferred use variant, the lipoic acid variants essential to the invention should be administered orally (for example in the form of tablets). Preparations in the form of dietary supplements or additives to so-called dietary supplements have proven to be particularly suitable, since this has a positive effect on compliance. The present use is not restricted to certain dosage forms, which is why any mixtures and combinations, for example with flavorings, but also with other compatible active ingredients, are possible.

To produce an exemplary suitable galenic formulation, homogeneously mixed racemic or enantiomerically pure R- or S-σ-lipoic acid or a physiologically active σ-lipoic acid salt with 3 mass equivalents of microcrystalline carboxymethyl cellulose are then added, customary auxiliaries such as. B. magnesium stearate, sorbitol, maltodextrin and / or highly disperse silica gel and finally processes the resulting mixture into tablets of 800 mg each. The equivalent content of σ-lipoic acid per tablet should be 100 mg.

Because of its pronounced advantages, which can be seen above all in the absence of side effects which are harmful to health or even impair well-being, the use of σ-lipoic acid according to the invention is preferably suitable as obesity therapy, which can also be carried out over a longer period without problems.

The following examples in the form of results from a study impressively demonstrate the effects of a significant reduction in daily energy intake by σ-lipoic acid on human body weight. - 8th -

Examples

Participants in the study were 9 male and 1 1 female subjects between the ages of 33 and 63 years. 7 participants (3m, 4w) had a body mass index (BMI) below 25 kg / m ² . 13 participants (6m, 7w) had a BMI of more than 25 kg / m ² and were therefore assigned to first, second or third degree obesity.

For each subject, individual daily diet plans were created in an initial starting week ("zero week") based on normal eating habits, which were then specified in the following eight test weeks. During the study phase, the amounts of food consumed and any deviations from the daily diet were explicitly noted in personal food diaries. The nutrient calculations were based on the manufacturer's information on the food packaging. An external check was carried out once a week by weighing on a calibrated scale (weighing accuracy ± 0.5 kg, average values in Table 2 rounded to 0.5 kg).

The subjects were divided into a therapeutic group (TG) and a control group (KG) of 10 people each. The therapeutic group (TG) received racemic σ-lipoic acid two hours before each meal by oral administration in tablet form with a single dose between 10 mg and 5 g, preferably between 50 mg and 2 g. The active levels thus achieved should then preferably be in the range between 20 and 80 mg per kg of body weight. The total daily dose of σ-lipoic acid should preferably be 0.5 to 6 g. The control group (KG) received an orally administered placebo in tablet form two hours before each meal.

Of the twenty subjects, 18 (8m, 10w; 6 participants with an initial BMI <25 kg / m ² , 12 with an initial BMI> 25 kg / m ² ) completed the study by the end of the eighth test week; 9 each belonged to the - 9 - therapeutic group (TG) or to the control group (KG). Reasons for the early termination of participation were external circumstances that no longer allowed eating according to a predetermined daily diet.

Results of the use study:

The change in weight during the start week of the study (setting up daily diet plans) was negligible in all subjects (<0.5 kg); this also corresponded to the requirement to keep the weight of each participant as constant as possible during this period. At the beginning of the first week of the test, there was a significant difference between the therapeutic group (TG) and the control group (KG), both in terms of the amount of food consumed and the weight loss achieved within the two groups.

While in the therapeutic group, the administration of σ-lipoic acid (average daily dose: 750 mg, administered in three single doses of 250 mg each) reduced the average daily food intake (Table 1, Figure 1) and reduced the average body weight (Table 2, Figure 2), no significant deviations were found in the placebo group beyond mere statistical fluctuations. The two trends in food intake and weight loss in the therapeutic group solidified over the eight weeks of the study. With regard to the reduction in the amount of calories consumed, a maximum effect was already detectable after approximately 2 to 3 weeks in the subjects treated with σ-lipoic acid. In contrast, no reduction in calorie intake was observed in the control group. Regarding body fat reduction, a more or less steady weight loss was recorded in the therapeutic group. The average weight loss was present in overweight subjects with BMI> 25 kg / m ² - 10 - significantly higher (3.0 kg) than in the group of normal weight test subjects with BMI <25 kg / m ² (1.5 kg).

Administration of a galenical formulation of racemic or enantiomerically pure R- or S-σ-lipoic acid or a physiologically active σ-lipoic acid salt resulted in a significant reduction in the required daily dose to 3 x 200 mg = 600 - with comparable effects regarding appetite suppression and weight reduction mg.

No complications were found in any of the test persons from the therapeutic group or from the control group, which resulted from taking tablets with the supplement σ-lipoic acid, one of their salts or the placebo.

The numbers clearly demonstrate the positive influence of regular intake of a therapeutically tolerable dose of racemic or optically pure σ-lipoic acid on the eating behavior and body weight of normal or overweight people in the sense of appetite suppression and body fat reduction, without negative side effects on the physical or / and mental well-being occur.

Table 1 SO

Food intake for all test groups

average Calorie intake per 0 1 2 3 4 5 6 7 8 meal in one week [kcal] [kcal] [kcal] [kcal] [kcal] [kcal] [kcal] [kcal] [kcal] therapeutic group with <25 790 746 738 726 733 730 721 731 729

BMI [kg / m ² ]> 25 884 832 809 821 804 81 8 809 801 807

Control group with <25 799 790 802 81 2 807 801 808 817 805

BMI [kg / m ² ]> 25 880 885 873 869 877 891 885 872 889

10 average daily dose per subject: 750 mg σ-lipoic acid racemate (therapeutic group) or placebo (control group), administered in single doses of 3 x 250 mg

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Table 2

Weight history for all test groups

average Weight after previous 0 1 2 3 4 5 6 7 8 / 7th week [kg] [kg] [kg] [kg] [kg] [kg] [kg] [kg] [kg] [kg] therapeutic group with <25 71, 5 71, 5 71, 5 71, 5 71, 0 71, 0 70.5 70.5 70.0 70.0

BMI [kg / m ² ]> 25 79.5 79.5 79.5 79.0 78.5 78.0 77.5 77.5 77.0 76.5 I for 3

Control group with <25 72.0 72.0 72.0 72.0 72.0 72.5 72.5 72.0 72.0 72.0

BMI [kg / m ² ]> 25 79.5 79.5 79.0 79.0 79.0 79.0 79.0 79.0 79.5 79.0

Average daily dose per subject: 750 mg σ-lipoic acid racemate (therapeutic group) or placebo (control group), administered in single doses of 3 x 250 mg

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Claims

- 1 3 claims 1 . Use of an active ingredient selected from R-σ-lipoic acid, S-σ-lipoic acid, racemic σ-lipoic acid or mixtures or physiologically acceptable salts thereof for the production of a Means for appetite reduction and / or for Body weight reduction. 2. Use according to claim 1, characterized in that the active ingredient is administered in a daily dose of 10 mg to 10 g based on the free acid form of σ-lipoic acid. 3. Use according to claim 1 or 2, characterized in that the administration takes place over a period of at least 2 weeks. 4. Use according to one of claims 1 to 3, characterized in that the active ingredient in the form of lipoic acid salts with metals of l. and ll. Main group of the Periodic Table of the Elements and / or Elements of III. to VI. Main group of the Periodic Table of the Elements is used. 5. Use according to one of claims 1 to 3, characterized in that as salt formers hydroxides of alkali and alkaline earth metals, ammonium hydroxide, amines of the general formula NR ^ Ra, wherein R ,, R ₂ and R ₃ independently of one another hydrogen, C ^ alkyl or C ^ -Oxyalkyl mean C ₂ . ₈ -alkylenediamines, cyclic C ₄ . ₆ amines, - 14 - basic amino acids and aminocarboxylic acid derivatives are used. 6. Use according to claim 5, characterized in that as amines monoethanolamine, diethanolamine, 1-aminopropanol or 2-amino-2- (hydrocymethyl) -1, 3-propanediol, as alkylenediamines, hexamethylenediamine, as cyclic amines, piperidine, piperazine, pyrrolidine and Morpholine, as the basic amino acid lysine and arginine and as aminocarboxylic acid derivatives creatine, carnitine, ornithine, Choline and taurine can be used. 7. Use according to one of claims 1 to 6, characterized in that single doses between 10 mg and 5 g, particularly preferably between 50 mg and 2 g, are administered. 8. Use according to one of claims 1 to 7, characterized in that the administration to people with a body mass index (BMI)> 25 kg / m ² . 9. Use according to one of claims 1 to 8, characterized in that the administration takes place orally. 10. Use according to one of claims 1 to 9, characterized in that the administration takes place in the form of a food supplement or food supplement additive. - 15 - 1 1. Use according to one of claims 1 to 10 in the form of an obesity therapy. 12. A method for reducing appetite and / or for reducing body weight, characterized in that an active ingredient selected from R-σ-lipoic acid, S-σ-lipoic acid, racemic σ-lipoic acid or mixtures or physiologically acceptable salts thereof in one for an anorexigen Effect administered sufficient amount.