WO2012028935A1

WO2012028935A1 - Dietary supplement

Info

Publication number: WO2012028935A1
Application number: PCT/IB2011/002002
Authority: WO
Inventors: Andrea Poli
Original assignee: Salvini, Liliana
Priority date: 2010-09-03
Filing date: 2011-08-31
Publication date: 2012-03-08
Also published as: IT1402330B1; ITMI20101600A1

Abstract

The present invention has as an object a food supplement based on a multicomponent formulation, and its use to improve the functionality of the human body, in particular its use In arterial blood pressure regulation.

Description

"Dietary supplement"

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DESCRIPTION STATE OF THE ART

Nitroxide (NO), or nitric oxide, is a small gaseous molecule playing an extremely important role in controlling the normal functionality of the human body. Its specific activities, subject of a now extremely wide and continuously enriching scientific literature, are important both in healthy and pathological conditions, and concern a wide range of body organs and systems. Particularly, the action of nitroxide can be said to bring significant advantages to the areas reported hereinafter.

In the cardiovascular system, a suitable availability of NO is fundamental for a normal response of the arterial endothelium to the stimuli, of different nature, controlling the vascular tone (and then inducing vasodilatation/vasoconstriction processes); likewise, a normal availability of NO can antagonize, or at least slow down, processes promoting the development of plaques, typical of the atherosclerotic disease.

In fact, nitroxide is fundamental to protect arteries from atherosclerosis, which Ieads to cerebrovascular stroke or to myocardial infarction. If endothelium does not produce a suitable amount of nitroxide (and then it does not work properly) processes leading to atherosclerosis may be greatly facilitated.

Additionally, today it is known that all the common risk factors for cardiovascular diseases, such as for example cigarette smoke, hypertension, high blood cholesterol level, diabetic disease itself, cause, long before inducing the appearance of severe anatomical damages of the arterial structure, a clinical picture corresponding to a situation in which the endothelium is not correctly functioning (it is, as they say, "dysfunctioning"). The step prior to cardiovascular system damage is represented, in other words, by the so-called "endothelial dysfunction" that expresses itself in an insufficient, or inadequate, production of nitroxide. The mechanism through which all of these risk factors promote the appearance of atherosclerosis (and then of infarction or stroke) passes in fact, with any probability, through their ability to inhibit normal production of nitroxide by the endothelium.

Additionally, a normal availability of nitroxide. can directly contribute to the control of arterial blood pressure values, in particular it can contribute to the maintenance of blood pressure levels within values today considered optimal, or anyway below values today considered high (140/90 mmHg) and then to the reduction of one of the major atherosclerosis risk factors.

Additionally, it is known that a normal endothelial function, assured by a suitable availability of nitroxide, also allows to improve male erectile function, as well as a suitable blood afflux to the muscles during an effort, thus improving the physical performance of the body.

According to some recent data, the improvement of cutaneous microcirculation associated with a higher availability of NO, can contribute to slow down the skin ageing processes.

Additionally, a normal availability of nitroxide also contributes to keep the normal bronchial smooth muscle tone, and then it can allow to control bronchospasm associated with an allergic disease or specific physiological conditions.

On a more strictly metabolic level, a defect in nitroxide synthesis and/or catabolism, which reduces its availability, appears to be involved in the mechanisms leading to overweight and/or obesity, and to complications thereof, such as for example diabetic disease.

Then, solid preconditions exist explaining and inducing interventions aimed at improving, increasing, inducing the availability of NO in the human body. The key aspects of nitric oxide (NO) synthesis and catabolism (globally defined as "nitroxide pathway") are highlighted hereinafter.

The starting compound for the production of nitroxide (NO) is arginine (arg), or (S)-2-amino-5-guanidino-pentanoic acid, having the following formula:

Arginine is one of the 20 natural aminoacids composing proteins. The body obtains arginine partly from food proteins, and partly by direct synthesis, starting from other compounds. Arginine is in fact considered a "semi- essential" aminoacid.

The synthesis of nitroxide starting from arginine is catalysed by a family of enzymes called nitroxide synthases, also known as NOS. NOS cleave a fragment of the arginine molecule, transforming it into NO, while the remaining part of arginine itself is converted into another aminoacid, citrulline.

Nitroxide (NO) is a short half-life compound, and is readily catabolised. Responsible of its catabolism are mainly oxygen free radicals (ROS) that transform nitric oxide into substances deprived of any biological activity, then excreted with the urine.

Arginine, however, can be attacked and catabolized also by arginases that transform it into molecules deprived of any relevant biological effect. When arginases activity is high, or predominant, then there will be a deficiency of substrate and main source for NO production by the body.

Arginine can be attacked also by a family of enzymes (altogether called PRMT) that act binding one or two methyl groups to the molecule. Arginine is then transformed into different substances, such as for example monomethyl arginine, symmetric dimethyl arginine, asymmetric dimethyl arginine (ADM A), the latter able to inhibit NOS, i.e. enzymes transforming arginine into NO, then limiting nitroxide production. I† appears then evident that the most simple solution to increase and/or stimulate the so-called nitroxide pathway (NO) is represented by the possibility to administer high doses of arginine, so that, although a part of i† is, as said above, attacked and transformed by enzymes not leading to the formation of NO, at least a consistent part is anyway made available to the attack of nitroxide synthase (NOS), to produce NO in a sufficient amount to give the described advantages.

The administration of arginine at high doses, though, displays some side effects, mainly due to the fact that the chosen dosage must be significantly overestimated in order to assure that a part of arginine undergoes the attack of NOS and then generates a sufficient amount of NO to induce the beneficial effects already described above.

Some side effects due to high oral administration of arginine are, for example, of gastrointestinal type, such as abdominal pain and diarrhoea, while in some cases symptoms connected to the onset of gout attacks due to the accumulation of uric acid were observed. Instead, in the case that arginine was administered intravenously, the observed side effects were nausea, redness and migraine.

Hence, object of the present invention is to provide a composition or formulation that is administrate as a drug and/or food supplement, allowing to improve, promote or increase the availability of endogenous nitroxide in the body without causing significant and/or incapacitating side effects.

Again, object of the present invention is to provide a formulation or composition that can be embodied both as a drug and as a diet supplement, allowing to improve, promote or increase the availability of nitric oxide or nitroxide (NO) in the body, acting on the nitroxide pathway promoting the formation of NO.

Further object of the present invention is to provide a formulation or composition that can be embodied both as a drug and as a diet supplement that allows to favourably act on blood pressure regulation in particular contributing to the maintenance of arterial blood pressure levels within values today considered optimal, and anyway below values today considered high (140/90 mmHg), on cardiovascular system function, diabetic pathology and obesity cases, on male erectile function, sport performances, respiratory system function, skin ageing, renal function.

DESCRIPTION OF THE INVENTION

These and more objectives and related advantages that will be better clarified in the following description, are achieved through a composition consisting of:

A. - Arginine (Arg)

- Folic acid

- Creatine

- Vitamin E

B. possible additional components selected from BhU or tetrahydro biopterin, proline and/or citrulline, EPA (eicosapentaenoic acid) and/or DHA

{docosahexaenoic acid),

C. possible usual additives and excipients.

Components, active compounds or active ingredients called ingredient A represent the essential components of the composition according to the present invention.

The composition additionally comprises ingredient B, which is constituted by one or more active ingredients that are not essential, but that can be present in alternative embodiments of the composition according to the invention, among which are also EPA (eicosapentaenoic acid, a fatty acid of the omega-3 group) and/or DHA (docosahexaenoic acid, a fatty acid of the omega-3 group too).

Ingredient C, instead, also non essential, if present is constituted by additives and/or excipients usually and commonly used in pharmaceutical preparation techniques. Among the non essential active compounds there is BhU or tetrahydro biopterin, an enzymatic cofactor of nitroxide synthetase, involved in the enzymatic reaction of the attack of arginine for the production of nitroxide (NO).

Always according to the invention, said composition can additionally comprise proline, among non essential active ingredients too.

Always according to the invention, the composition includes the presence of arginine in amounts within 0.5 g and 5.5 g, folic acid in amounts within 100 pg and 500 pg, creatine in amounts within 0.1 g and 3 g, vitamin E in amounts within 5 mg and 30 mg. Particularly preferred are the following amounts: arginine in amounts within 1 g and 2 g, folic acid in amounts within 150 yg and 200 pg, creatine in amounts within 0.3 g and 1 .5 g, vitamin E in amounts within 8 mg and 15 mg. Again, preferred are the following amounts: arginine in amounts within 1 g and 2 g. folic acid in an amount equal to 200 pg, creatine in amounts within 0.5 g and 1 g, vitamin E in an amount equal to 10 mg. These latter amounts are suggested for a formulation foreseen to be administrable as a single unit dose. Concerning the total daily dose, preferred amounts of essential components are the following: arginine in amounts within 2 g and 4 g, folic acid in an amount equal to 400 yg, creatine in amounts within 1 g and 2 g, vitamin E in an amount equal to 20 mg.

Concerning non essential ingredients, EPA and/or DHA are present in amounts comprised between 0.01 mg and 20 mg, in particular, suitable amounts for the formulofion of the composition according to the invention are preferably comprised between 0.01 mg and 15 mg, and most preferably between 0.01 mg and 10 mg.

Always concerning non essential additional components, referred to as ingredient B, the composition according to the invention is advantageously formulated as follows:

Citrulline 0.1-2.0 g BH₄ 50-150 mg

EPA, DHA 0-15 mg

Proline 0-1.5 g.

In this case, the preferred dosages are selected equal to:

atruHine 0.5-1 .0 g

BH, l OO mg

EPA, DHA 0-10 mg

Proline 0-1.0 g

and in this case said amounts will be particularly preferred in the case of single administration, while concerning the total daily dose, preferred amounts will be the following;

Citrulline 1 .0-2.0 g

BH* 200 mg

EPA, DHA 0-20 mg

Proline . 0-2.0 g.

The composition according to the present invention is advantageously used as a drug and/or food supplement to improve, promote or increase the availability of nitric oxide or nitroxide (NO) in the body, intervening on the nitroxide pathway promoting the formation of NO.

Always according to the present invention, the composition is advantageously used both as a drug and as a diet supplement, for its positive action exerted on cardiovascular system function, in particular in the regulation of blood pressure. In fact, as it is known, arterial hypertension is a pathological condition characterized by an increase of systolic, or maximum, arterial blood pressure (as measured during systole, which is the heart contraction phase) and diastolic, or minimum, blood pressure (as measured during the rest or release phase of the cardiac muscle). Hypertension is a dangerous cardiovascular risk factor because the heart, in its function, has to bear a higher than normal effort, which in case of a prolonged effort, can bring to an enlargement of the heart itself; moreover, vessels through which blood flows at high pressure, are exposed to excessive wear that can severely damage them, involving in this situation also tissues and organs supplied by the affected vessels, in particular heart, brain, kidneys and eyes.

Hypertension can be treated but not cured. Medical therapy has high efficacy if it is scrupulously and constantly followed, and significantly reduces the problem and its possible complications keeping pressure at acceptable levels, but if drugs are discontinued, hypertension inevitably tends to return. The decision of treating patients with hypertension should not be based only on arterial blood pressure levels, but also on the presence of other risk factors, concomitant diseases, organ damage, cardiovascular or renal diseases, as well as personal, medical and social characteristics or elements concerning the patient.

Age, sex, smoking, diabetes, cholesterolemia, familiar history of previous cardiovascular or renal diseases should be taken into account

One or more drugs with antihypertensive activity are administered, such as diuretics, vasodilators, calcium antagonists, beta blockers, and the like, then medical supervision is essential to define the most suitable therapy and the best drug combination to address the specific problem and to constantly keep control on hypertension and possible alterations in other districts.

It appears therefore evident that it represents a great advantage to have at disposal an additional medication and/or diet supplement able to influence arterial blood pressure trend and to regulate hypertension states bringing values back towards optimal values, as defined by the world health organizations. Further, in the case of a diet supplement, there is the double advantage of having at disposal a formulation able to reduce and regulate arterial blood pressure values and therefore of being able to contrast arterial hypertension, but at the same time of being able to administer such formulation without particular medical control and thus of treating a higher number of persons, possibly also as a preventive treatment. It is important to underline that according to available epidemiological and interventional clinical studies, also small reductions of mean blood pressure levels (of the order of 3-4 mmHg), if kept constant in time, can mean significant reductions of cardiovascular risk.

Always according to the present invention the composition is advantageously used both as a drug and diet supplement in diabetic pathology and in obesity cases, on male erectile function, sport performances, respiratory system function, skin ageing, renal function.

In practice, by means of the composition according to the invention, which is advantageously used as a food supplement for the restoration, increase of the formation/availability of nitroxide (NO) in the body, intervening on the nitroxide pathway promoting the formation of NO, it is possible to favourably intervene on the biochemical pathway of nitroxide.

In the light of what already said, it is then possible to increase the availability of nitroxide (NO), obtaining the advantages detailed hereinafter.

It is then possible to increase the availability of arginine, as well as to provide BH< in a sufficient amount to optimize the catalytic efficiency of NOS. Furthermore, it is possible to promote the phosphorylation of NOS, increasing their efficiency,

The presence of creatine as an essential ingredient in the composition according to the invention, reduces the need of the body to synthesize creatine itself through AGAL directing then arginine towards the nitroxide pathway.

Additionally, the composition according to the invention allows to inhibit the degradation of nitroxide, increasing the availability of antioxidants, controlling the action of ROS on nitroxide itself.

The use of polyunsaturated long-chain fatty acids of the omega-3 group (EPA/DHA) in this case as additional ingredients in a particular embodiment of the present invention, allows then to inhibit the formation of ADMA, which plays an antagonistic role to arginine, thus increasing the efficiency of the NOS enzyme.

Additionally, the presence of proline, a non essential ingredient in a particular embodiment of the invention, allows to inhibit the activity of arginases.

The resulting composition according to the invention is then based on a particular and studied combination of substances, all essential and called ingredient A of the composition according to the invention, already individually present in many natural aliments, and is aimed at the optimization of the nitroxide pathway, as well as proved to be able to assure a better function of organs and systems, among those already cited [cardiovascular system, particularly arterial blood pressure, organs involved in diabetic pathology and obesity cases, organs involved in male erectile function, in respiratory system, factors involved in skin ageing, urogenital system), which activity is influenced by the availability of nitric oxide (NO). Thanks to the described characteristics, the composition according to the invention shows a significant synergic effect in comparison with the action exerted by single components on the nitroxide pathway, due to the "redirection" of arginine towards the synthesis of nitroxide, to the detriment of other metabolic pathways, to the improvement of catalytic efficiency of NOS, as well as to the inhibiting activity of arginases and PRMT and to the improvement of the halMife of nitroxide.

In the particular case of the regulation of arterial blood pressure, as well as of the preventive effect on increases thereof above values considered high (140/90 mmHg) or anyway optimal (120/80 mmHg), the composition according to the invention has been shown to present significantly potentiated effects in comparison with the same effects presented by some of its essential components, taken alone.

The improvement of the NO pathway efficiency, then, is also related to the following factors; i. Promoted phosphorylation of NOS

ii. Increased availability of the BH₄ cofactor

iii. Inhibition of the synthesis of ADMA by PRMT

iv. Inhibition of oxidative catabolism of nitroxide.

The composition according to the invention allows then to obtain a general effect, due to the main synergic action of its essential components and also to the synergic action of its optional components on the availability of nitroxide [NO] in the body.

Such availability is markedly higher than that obtainable only by an intervention limited, for example, to the administration of high amounts of arginine alone, with the great advantage of achieving not only a markedly higher effect in comparison with that obtained through the administration of arginine alone, but also the absence of undesirable side effects.

In summary, in the following Table 1 , the preferred doses for a non limiting example of formulation of the composition according to the invention are shown.

TABLE 1

The following formulation, given merely by way of an example and not limiting the invention, is intended for administration in two daily doses.

Claims

1. Composition consisting of:

A. - Arginine (Arg)

- Folic acid

- Creatine

- Vitamin E

B. possible additional ingredients selected from BH* or tetrahydro biopterin, proline and/or citrulline, EPA (eicosapentaenoic acid) and/or DHA (docosahexaenoic acid)

C. possible common additives and excipients

2. Composition according to claim 1 , characterized in that said arginine is present in amounts comprised between 0.5 g and 5.5 g, said folic acid is present in amounts comprised between 100 Mg and 500 pg, said creatine is present in amounts comprised between 0.1 g and 3 g, said vitamin E is present in amounts comprised between 5 mg and 30 mg.

3. Composition according to claim 1 , characterized in that said arginine is present in amounts comprised between 0.5 g and 5.5 g, said folic acid is present in amounts comprised between 100 pg and 500 pg, said creatine is present in amounts comprised between 0.1 g and 3 g, said vitamin E is present in amounts comprised between 5 mg and 30 mg, said EPA and/or DHA is present in amounts comprised between 0.01 and 15 mg.

4. Composition according to claim 3, characterized in that said arginine is present in amounts comprised between 1 g and 2 g, said folic acid is present in amounts comprised between 180 pg and 200 pg, said creatine is present in amounts comprised between 0.3 g and 1 .5 g, said vitamin E is present in amounts comprised between 8 mg and 15 mg said EPA and/or DHA is present in amounts comprised between 0.01 and 10 mg.

5. Composition according to claim 4, characterized in that said arginine is present in amounts comprised between 1 g and 2 g, said folic acid is present in an amount equal to 200 \ig. said creatine is present in amounts comprised between 0.5 g and 1 g, said vitamin E is present in an amount equal to 10 mg said EPA and/or DHA is present in amounts comprised between 0.01 and 15 mg.

6. Composition according to claim 1 , characterized in that said arginine is present in amounts comprised between 2 g and 4 g, said folic acid is present in an amount equal to 400 pg. said creatine is present in amounts comprised between 1 g and 2 g, said vitamin E is present in an amount equal to 20 mg said EPA and/or DHA is present in amounts comprised between 0.01 and 20 mg.

7. Composition according to claims 2 and 3, characterized in that it is administrable as a single unit dose.

8. Composition according to claim 6, characterized in that it corresponds to the total daily dose.

9. Composition according to claim 2, characterized in that it has the following composition:

Citrulline 0.1-2.0 g and/or

BH4 50-150 mg and/or

Proline 0-1.5 g.

10. Composition according to claim 3, characterized in that it has the following composition:

Citrulline 0.5-1.0 g and/or

BH< 100 mg and/or

EPA₍ DHA 0-10 mg and/or

Proline 0-1 .0 g.

1 1 . Composition according to claim 10, characterized in that it is administrable as a single unit dose.

12. Composition according to claim 2, characterized in that it has the following composition:

Citrulline 1.0-2.0 g

BH₄ 200 mg Proline 0-2.0 g.

13. Composition according†o claim 12, characterized in that it corresponds to the total daily dose.

14. Composition according to proceeding claims for use in the treatment of the regulation of arterial blood pressure.

15. Composition according to claims 1 to 12 for use in the prevention and/or treatment of cardiovascular system, male erectile function, diabetic pathology, respiratory system, urogenital system disorders.

16. Composition according to claims 1 to 12 for use in the treatment of obesity cases, treatment of skin ageing.

17. Food supplement comprising at least one composition according to claims 1 to 12.