EP1414469A2

EP1414469A2 - Formulation containing (lyso-) phosphatidylserine for the prevention and treatment of stress states in warm-blooded animals

Info

Publication number: EP1414469A2
Application number: EP02754989A
Authority: EP
Inventors: Ralf JÄGER; Dirk BÖKENKAMP
Original assignee: Degussa Food Ingredients GmbH
Current assignee: Cargill Food Ingredients GmbH
Priority date: 2001-08-09
Filing date: 2002-08-09
Publication date: 2004-05-06
Also published as: KR20040019382A; WO2003013549A2; WO2003013549A3; BR0211814A; JP2004537577A; US20040234544A1; CN1625406A; NZ530981A; KR100680121B1

Abstract

The invention relates to a formulation containing phosphatidylserine (PS) and/or lyso-phosphatidylserine for the prevention and treatment of mental and physical stress states. The phosphatidylserine is combined inter alia with vegetable extracts. According to the invention, daily doses range from 50 -1000 mg PS, administered over a maximum period of six months. Preferred subjects are human beings of 10-50 years of age.

Description

Formulation containing (lyso-) phosphatidylserine for the prevention and treatment of stressful conditions in warm-blooded animals

description

The present invention relates to a formulation containing phosphatidylserine (PS) and / or lysophosphatidylserine for the prevention and treatment of stressful conditions in warm-blooded animals.

Stress is a condition of the organism that is characterized by a specific syndrome (increased sympathetic activity, increased release of catecholamines, increased blood pressure, etc.) and by various non-specific stimuli (infections, injuries, burns, exposure to radiation, but also anger, joy, Performance pressure and other factors) can be triggered. Stress can also be understood as external influences to which the body is not adequately adapted, e.g. Operations, poisoning, pregnancy (Anon, Pschyrembel - Klinisches Wörterbuch, 1 990, Walter de Gruyter, Berlin-New York (1 990)).

Stress can generally be described as environmental processes that trigger processes in the body via perceptual impulses, whereby eustress is understood to mean stimulating influences with a positive effect and distress-destroying influences with a negative effect.

People react to stress with headaches, insomnia, heart problems, stomach pains, diarrhea, irritated skin, allergies, tension and / or cramping. Typical psychological stress reactions are nervous restlessness, irritability, lack of concentration and sleep disorders. This is mainly due to the stress hormones cortisone and ACTH (adrenocorticotropin hormone). Cortisone is formed in the adrenal glands, two hormonal glands that are slightly above the kidneys, but perform completely different tasks than the kidneys. Cortisone is one of the most important hormones in the body and its absence is fatal within a short period of time. The main effects of cortisone are:

Mobilization of energy reserves in stressful conditions such as illness, surgery, physical exercise, maintenance of blood pressure and cardiovascular functions ^• Influence the inflammatory response of the body in infections and chronic inflammatory diseases Regulation of the protein, sugar and fat metabolism

The formation of cortisone is precisely controlled by the body to enable it to be produced as required. The pituitary gland plays a crucial role here, which is a bean-sized structure below the cerebrum and approx. 6 cm behind the eyes. This is where the control hormone (control messenger) ACTH is formed, which induces the release of cortisone via the bloodstream in the adrenal glands.

Flooding the body with cortisone can have several causes. Long-term treatment with cortisone-containing medications for inflammatory diseases such as rheumatoid arthritis or bronchial asthma is a common cause. In these cases, it is an unavoidable medication side effect that disappears after the medication is stopped.

Chronic increased stress hormones can lead to a decrease in lean body mass and suppression of the immune system, as well as lethargy followed by a deterioration in physical functions (decrease in bone and muscle mass). The Harmful effects resulting from the overproduction of stress hormones have already been intensively investigated. They include type II diabetes mellitus, obesity, depression and Cushing's syndrome.

Cushing's syndrome is caused by long-term and excessive formation of the hormone cortisone, the consequences of which were first described as a disease in 1 909 by the doctor Harvey Cushing. 70% of all cases of Cushing's syndrome are caused by benign tumors (adenomas) of the pituitary gland that produce too much ACTH.

This form of Cushing's syndrome is also known as central Cushing's syndrome or Cushing's disease (Cushing's disease) and affects women 5 times more often than men. In 1 5% of all patients with Cushing's syndrome, there is a tumor outside (ectopic) of the pituitary gland that forms ACTH. Often these tumors, which can also be malignant, are found in the lungs, but they can also be located in the thyroid, thymus or pancreas. In 1 5% of all cases, benign or malignant adrenal tumors lead to Cushing's syndrome due to the excessive formation of cortisone.

However, distress can also trigger diabetes mellitus. A study showed that over 2200 patients between 50 and 74 years old were newly diagnosed with diabetes mellitus within three years, with a dependency on the number of stress experiences that was not related to work-related stress, but to serious life events past five years. This relationship remained demonstrable even when family influences, alcohol consumption and physical activities were taken into account.

Stress has a huge impact on the potential performance of the brain. The stimulus processing takes place in very specific areas in the brain. For body movements as well as for speaking, seeing and hearing are the responsible centers in the cortex of the cerebrum, which is also the seat of consciousness, will, intelligence, 'memory and learning ability. This area is responsible for our nature and character. The cerebellum is responsible for the correct sequence of all body movements and also enables orientation in space. The cerebellum is located between the cerebellum and cerebrum and controls vital vegetative functions such as heat, water and energy balance. The forehead is obviously of particular importance for the development of consciousness, in which human beings differ from most other living things. It is assumed that only a small part of the information arriving in the forehead is actually known to humans and that parts of the hindbrain are more likely to be involved, particularly in the case of emotional stress and stress. In order to stimulate the forehead, we have to consciously choose the "decision", that is, an intentionally associative way of thinking.

Last but not least, the ability of people to learn at any age also depends on their stress level and stress tolerance. Enormous stressful situations, such as Exam situations during school or university education can lead to complete failure ("black out") of brain performance.

Numerous examples of forms of treatment and therapy are known from the literature, which relate to the use of i.a.

Support phospholipids or formulations containing them and should bring about improvements in the central nervous area.

Phospholipids play an extremely important role in connection with the function of cell membranes, in whose construction they are approximately 75% involved, whereby they ensure, among other things, the intercellular exchange of information by means of neurotransmitters. The group of phospholipids is composed of sphingolipids and phosphoglycerides, an important representative of the latter being phosphatidylserine.

Phosphatidylserine occurs in naturally elevated concentrations in the brain, where it positively influences the extremely sensitive functions of the nerve cells and the cells connected to them.

As a food supplement, phosphatidylserine, like the rest of the other phospholipids, not only has a beneficial direct effect on health. Phosphatidylserine can also improve the absorption of numerous other nutrients or dietary supplements or work together with these to work synergistically. This has been demonstrated in numerous double-blind clinical studies.

Phosphatidylserine is also known to help the brain generate energy, to have a beneficial effect on the cell / cell connections (synapses), to enhance the action of chemical transmitter substances such as acetylcholine, dopamine and noradrenaline and serotonin, which improves cognitive abilities of the brain, such as concentration, learning ability, short-term memory and word memories, and thus counteracts the natural loss of brain performance in old age.

So WO 99/371 55 describes the use of combinations of tyrosine, methylating agents, phospholipids such as. B. phosphatidylserine, fatty acids and active substances of evening primrose in mental disorders. The effect is aimed at strengthening the central nervous system (CNS), whereby anorexia-related neurochemical deficits in the form of a premature deactivation of neurotransmitters in the CNS are remedied by increasing the dopamine and serotonin levels should be. The claimed effect is exemplified in older, human subjects between 48 and 65 years of age.

In addition, there is also published patent application DE 1 99 43 1 98, which describes the use of vegetable phosphatidylserine exclusively in

Combination with a large proportion of docosahexaenoic acid

Therapeutic also indicates central nervous dysfunction.

It can be seen from the two US Patents 5,900,409 and 6, 1 1 7,853 that PS can be used as a so-called "cerebration improver", that is, to improve mental reflection and memory performance in dementia and Parkinson's disease.

Thus, the use of phosphatidylserine as a therapeutic or dietary supplement is well known. Its effect in connection with disorders in the area of the CNS and here only in older people and the intake of PS from cattle brain in connection with stress studies in the sports area is also described. So far, no improvements have been observed with PS supplementation in people under the age of 40 and in people whose brain function corresponds to their average age.

F. Drago et al. describes the protective effect of phosphatidylserine in stress-induced behavior in old rats (Neurobiology of Aging 1 2 (5), 437-440, 1 991), which is said to have shown in particular in a normalization of body temperature. A positive effect of phosphatidylserine is also said to have been shown in gastric wall lesions, but this is only proven for older rats; this effect was not observed in young rats.

A protective influence of phosphatidylserine against muscle damage is described in Nutrition Science News Vol. 5, No. September 9, 2000, after which, in one study, trained runners received 300 or 600 mg PS per day for 1 5 days.

Until recently, phosphatidylserine was only commercially extractable from bovine brain. Administered in large quantities (800 mg per day), it was shown that bovine brain phosphatidylserine, administered orally, could reduce the increase in cortisone and ACTH in the case of physical stress induced by intensive cycling training (P. Monteleone et al., Blunting by chronic phosphatidylserine administration of stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men, Eur. J. Clin. Pharmacol., 42, 385-388, 1 992; P. Monteleone et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans, Neuroendocrinology, 52, 243-248, 1 990).

If the results refer to PS from cattle brain sources, E.R. Burke and T.D. Fahey in "Phosphatidylserine (PS): Promise for Athletic Performance" (Keats Publishing, Inc., USA; 2001) and others. Effects of soy PS on physical stress ("PS: The Supplement to Help you Adjust to the Stress of Hard Training").

D. Benton et al. describe in "The Influence of Phosphatidylserine Supplementation on Mood and Heart Rate when Faced with an Acate Stressor" (Nutritional Neuroscience, Vol. 4, p. 1 69-1 78, 2001) the positive influence of 300 mg PS per day in young adults on the subjective feeling of stress, the pulse rate and mood.

Extracts and extracts of plant origin are known from numerous publications and preparations known on the market, which are intended to alleviate or even prevent typical stress symptoms. The best known in this context are gingko biloba, kava kava, St. John's wort and ginseng. Extracts from Rhodiola rosea, a well-known plant of traditional medicine in Eastern Europe and Asia, are also known, which are said to have an effect on the nervous system, an antidepressant activity and an improvement in physical performance. Rhodiola rosea has been studied in particular by Russian researchers who attribute an adaptogenic effect to it. Ginseng species and here in particular the so-called American, Siberian, Korean and Manchurian ginseng species, which are among the oldest medicinal plants, are believed to reduce stress.

Schisandra species, whose common name is Wu-Wei-Zi (Schisandra chinensis) mostly occurs as a woody vine plant in northern and northeastern China and the adjacent regions of Russia and Korea. The full ripe and sun-dried red berries are used medicinally for relaxation symptoms, hepatitis, infectious diseases, for liver support, but also for stress symptoms. Suma or Para toda, which is the dried root of Pfaffia panicolata, a plant that occurs in the Atlantic rainforest area of Brazil, has also been found to have numerous active components. This South American plant known as "Brazilian ginseng" is also attributed to the adaptogens because it can strengthen the immune system and can have positive effects in pain and chronic fatigue syndromes. In addition, this plant is said to have an accelerating effect in wound healing.

According to "Your Guide to Standardized Herbai Products" by R. Flynn and M. Roest (Oneworld Press 1995), in addition to the plants just mentioned, chamomile, willow (Salix alba), passion flower and certain ephedra species (especially Ma Huang ) attributed to stress-related effects. The object of the present invention is therefore to provide a formulation which can be used in a well-dosed manner in stressful conditions in warm-blooded animals or for their prevention, shows good resorbability and has no negative side effects and is based on the known action of phosphatidylserine.

This problem was solved by a formulation which, in addition to phosphatidylserine (PS) and / or lysophosphatidylserine, as an active component, an active ingredient from rhodiola, ginseng, schisandra, suma, chamomile, salix, ephedra, passion flower, gingko, kava kava, St. John's wort , Valerian, garlic, Reishi mushrooms (Reishi mushrooms) and / or guarana, phosphatidylcholine, ethanolamine, inositol, taurine, serine, choline, carnithine, phenylalanine, melatonin, tyrosine, theanine, ethanol, creatine citrate, creatine pyruvate, barbituric acid ( Derivatives) and any mixtures thereof.

All of the compounds belonging to the class of phosphatidylserines, e.g. Phosphatidyl-L-serine or lyso-phosphatidyl-L-serine, as well as their physiologically compatible salts such as e.g. Phosphates and (earth) alkali compounds, which are abbreviated in this context as phosphatidylserine or PS. All other phospholipids mentioned also fall within this definition.

The proportion of PS to other active component is preferably 99: 1 to 1:99% by weight /% by weight, more preferably 95: 5 to 5:95% by weight /% by weight and most preferably 90 : 10 to 1 0:90 wt% / wt%.

It has now surprisingly been found with the formulation according to the invention that the well-known compatibility of PS also with

Administration of high doses and prolonged supplementation

It can be ascertained over time that compliance is none Difficulties arise and in the subjects with stress-related problems there are no habituation effects. In addition, typical distress symptoms improved noticeably and sustainably, which was not to be expected in this form.

When using PS-containing formulations according to the invention, it has been shown that PS in particular has a particularly good positive effect if it is obtained from plant sources, preferably soya, but also from milk or eggs; lecithin-containing oils from rapeseed and sunflowers are also suitable as vegetable sources. A formulation in which the PS by transphosphatidylation, that is, by a so-called. and mostly enzymatically achieved "head group exchange", or was obtained synthetically. The transphosphatidylation is generally carried out on lecithins, such as those found in the vegetable oils mentioned, for example in rapeseed, soya and sunflower, but also in eggs. PS from non-bovine brain sources is preferably used.

In the context of the present invention, the term starting material is therefore not only to be understood in the sense that it actually contains phosphatidylserine, but also that the starting material contains substances such as e.g. Contains lecithins from which PS is obtained enzymatically or synthetically.

In the present context, however, it has also proven to be very advantageous if the phosphatidylserine is administered in daily doses of 50 to 1000 mg, with 200 to 600 mg being preferred. The respective daily amount is of course especially in children and adolescents to their body indices, such as height and weight, and not least depending on whether PS is used for prophylaxis or for acute treatment. It is to be regarded as preferred if the claimed formulation, in addition to the components (lyso) phosphatidylserine essential to the invention and the further active components, further components with stress-preventing / reducing effects such as creatine and its suitable derivatives, vitamins of the B series, which are different from creatine citrate and pyruvate and C as well as docosahexaenoic acid and mixtures thereof.

The optional creatine component can be present as creatine monohydrate, another creatine salt, a creatine-containing compound or mixtures thereof in the claimed formulation, with the further component generally preferably in amounts of from 1.0 to 99.0% by weight. -% should be included based on the total formulation.

The aggregate state of the claimed formulation is also not restricted within wide limits, but the solid and liquid form are to be regarded as preferred.

The long range of suitable physiologically compatible and / or physiologically active additives have been found for the novel ones

Formulation of (lyso) PS and the others already mentioned

Components from various representatives of the Sugar, Alcohols,

(un) saturated fatty acids, vitamins, trace elements, amino acids,

Neurotransmitters, stimulants, blood circulation-promoting compounds and (plant) extracts have been found to be very suitable, with, of course, preferably also additive- or synergistic combinations of

Phosphatidylserine with the compounds and / or medications known to date or other suitable for the treatment of mental distress, but preferably medicaments which inhibit cortisol formation in the adrenal glands, are suitable. Depending on the particular formulation, the present invention provides carbohydrates (for example methyl cellulose), SiO ₂ , stearates, solubilizers, colorants and flavorings, preservatives and release agents and texturants as particularly suitable formulation auxiliaries.

In addition to the actual formulation, the present invention also relates to its use, in particular in the case of mental distress and here preferably in the case of disorders of the ability to concentrate, disorders of the memory, disorders of the memory, disorders of the ability to learn, with reduced mental receptivity, reduced brain perfusion, mental fatigue, mental exhaustion, in the event of anxiety and symptoms, a disturbed ACTH (adrenocorticotropic hormone) household, e.g. Cushing syndrome as well as mental stress in the context of sporting activities such as Golf, biathlon and chess.

Alternatively or in addition, the use of the claimed formulation for typical symptoms of physical distress, such as Muscle twitching, nerve and headache, disorders of physical performance, circulatory disorders, reduced digestive processes, impaired sexual function, disorders of the immune system, impaired wound healing, symptoms of disturbed ACTH (adrenocorticotropic hormone) balance and physical stress in the context of sporting activities, such as e.g. Golf, claimed.

In particular, phosphatidylserine, as the body's own substance, is usually metabolized very quickly and completely and therefore has its good effect after only a short “flood time”. Nevertheless, a minimum period of use of one week should be provided for stress-related applications. According to the invention, a maximum of 6 months is to be observed as the upper limit for the regular intake of phosphatidylserine in stress-related applications, but the Supplementation periods after breaks and / or readjustment of the daily dose can be repeated several times without any problems whatsoever.

All in all, a clientele of test persons has proven to be very suitable for the use according to the invention of phosphatidylserine-containing combination formulations for the prophylaxis and treatment of mental and / or physical stress conditions, who are between the ages of 10 and 50 and preferably between the ages of 20 and 35 years moved. Of course, the formulation according to the invention can also be used at any other age in connection with stress symptoms.

Because of its good physiological tolerance and significant effect for reducing stress hormones, the formulation containing PS and other active components is very well suited in the context of the present invention, in particular as a therapeutic agent and / or nutritional supplement, the dosage being kept low and the administration especially in the latter case can also take place over longer periods of time, which is particularly important in connection with targeted stress prophylaxis. In addition, the present invention also provides for the use of the formulation in functional foods and / or as part of a special nutrition (clinical nutrition).

With the solid formulations in particular powder, chewable, lozenge and effervescent tablets, dragees and capsules and, considering the mostly small age of the preferred subjects, candy are possible. In the case of liquid formulations, juices and soft drinks have proven to be particularly suitable in connection with compliance.

The following examples illustrate the advantages associated with the present invention. Examples

1 . Use of phosphatidylserine and an extract from Rhodiola rosea in schoolchildren (mental stress)

In an open pilot study, 2 students (ages 8 and 1 2 years; male) were examined. The performance was checked using suitable empirical tests. The pupils were supplemented over a period of 3 months with a mixture of 200 mg PS from soy and 50 mg of a rhodiola extract per day. The direct comparison with the baseline values, determined under identical conditions before supplementation, showed a significant improvement in general school performance, but especially under stressful situations such as exams.

2. Use of PS and an extract from American Ginseng in students (mental stress)

Two students (ages 24, male and 28, female) were examined. The performance was checked using suitable empirical tests. The students were supplemented with 200 mg PS from soy and 50 mg of a ginseng extract per day over a period of 5 months. The direct comparison with the initial values, determined under identical conditions before supplementation, showed a clear improvement in general and in particular mental performance, but especially under examination conditions, whereby the subjects consistently indicated a subjectively increased resilience and balance.

3. Using a combination of PS and creatine citrate in golfers (physical and mental stress) Two golfers (ages 32 and 33; male) were examined. The performance was checked on the basis of repetitive putting (punching) within a specified period. The subjects were supplemented with 200 mg PS from soy and 10 g creatine citrate per day over a period of 3 months. A direct comparison with the baseline values, determined under identical conditions before supplementation, showed a significantly increased number of balls that had been holed in, whereby the test subjects themselves spoke of a significantly increased ability to concentrate.

The present invention relates to a formulation containing phosphatidylserine (PS) and / or lysophosphatidylserine for the prevention and treatment of mental and physical stress conditions, the phosphatidylserine and others. is combined with herbal extracts or extracts. In the context of the use according to the invention, daily doses of 50 to 1,000 mg PS are provided, which should be administered over a maximum period of six months. People between the ages of 10 and 50 are considered as preferred test subjects.

Claims

Expectations

1. Formulation containing phosphatidylserine (PS) and / or lysophosphatidylserine for the prevention or treatment of

Stressful conditions in warm-blooded animals, due to the fact that as an additional active component they contain an active ingredient from rhodiola, ginseng, schisandra, suma, chamomile, salix, ephedra, passion flower, gingko, kava kava, St. John's wort, valerian,

Garlic, Reishi mushrooms and / or guarana, phosphatidylcholine, ethanolamine, inositol, taurine, serine, choline, carnithine, phenylalanine, melatonin, tyrosine, theanine, ethanol, creatine citrate, creatine pyruvate, barbituric acid (derivatives) and any mixtures thereof ,

Formulation according to claim 1, which also means that it prefers (lyso) phosphatidylserine from plant sources

Soya, made from milk or eggs.

Formulation according to one of claims 1 or 2, ie, that the (lyso) phosphatidylserine was obtained by transphosphatidylation or synthetically.

4. Formulation according to one of claims 1 to 3, so that it contains (lyso) phosphatidylserine and / or its / its physiologically tolerable salts in amounts which contain a daily dose of 50 to 1000 mg, preferably 200 to

600 mg.

5. Formulation according to one of claims 1 to 4, d a d u rc h g e k e n n z e i c h n et that it as a further component with stress preventive / - reducing effect creatine and its suitable and different from creatine citrate and pyruvate derivatives, vitamins of

Row B and C and docosahexaenoic acid and mixtures thereof.

6. Formulation according to claim 5, so that it contains creatine monohydrate, a creatine salt, a creatine-containing compound or mixtures thereof as the creatine component.

7. Formulation according to one of claims 5 or 6, so that it contains the further component in quantities of 1.0 to 99.0% by weight, based on the overall formulation.

8. Formulation according to one of claims 1 to 7 in solid or liquid form.

9. Formulation according to any one of claims 1 to 8, d a d u rc h g e k n n z e i c h n et that it contains other physiologically compatible and / or physiologically active additives and / or formulation aids.

10. Formulation according to claim 9, dadu rc hgekennzeichn et that as physiologically compatible and / or physiologically active additives at least one of (lyso-) phosphatidylserine and the components from claim 5 different representatives of A range of sugars, alcohols, fatty acids, vitamins, trace elements, amino acids, neurotransmitters, stimulants, blood circulation-promoting compounds, (plant) extracts and / or medicines, preferably medicines that inhibit cortisol formation in the adrenal glands.

11. Formulation according to one of claims 9 or 10, dadu rc hgekennzeichn et that the formulation as formulation auxiliaries carbohydrates, SiO ₂ , stearates, solubilizers, colorants and flavorings,

Contains preservatives and release agents as well as texturizing agents.

12. Use of the formulation according to one of claims 1 to 11 for mental distress, in particular for disorders of the ability to concentrate, disorders of memory,

Memory disorders, learning disorders, with reduced mental receptivity, reduced blood flow to the brain, mental fatigue, mental exhaustion, with anxiety and symptoms of a disturbed ACTH (adrenocorticotropic hormone) household such as e.g. Cushing

Syndrome and mental stress in the context of sporting activities such as Golf, biathlon, chess.

13. Use of the formulation according to any one of claims 1 to 11, for typical symptoms of physical stress, such as

Muscle twitching, nerve and headache, disorders of physical performance, circulatory disorders, reduced digestive processes, impaired sexual function, disorders of the immune system, impaired wound healing, symptoms of an impaired ACTH (adrenocorticotropic hormone) balance and physical stress in the context of sporting activities such as golf, biathlon.

14. Use according to one of claims 12 or 13, so that the administration takes place over a maximum period of six months.

15. Use according to any one of claims 12 to 14, that the administration to humans is between 10 and 50 years old, preferably between 20 and 35 years old.

16. Use according to any one of claims 12 to 15 as a therapeutic and / or food supplement and / or in functional foods and / or as a special diet.