WO2014128639A1

WO2014128639A1 - Composition for the treatment of metabolic disorders

Info

Publication number: WO2014128639A1
Application number: PCT/IB2014/059125
Authority: WO
Inventors: Andrea RONDI
Original assignee: Rondi Andrea
Priority date: 2013-02-21
Filing date: 2014-02-20
Publication date: 2014-08-28
Also published as: EP2958627A1; ITMI20130241A1

Abstract

The present invention concerns a composition, a pharmaceutical one and/or a dietary supplement, for treatment use of metabolic disorders derived from or connected with the metabolic of insulin-resistance syndrome, that is hyperinsulinemia, diabetes, hyperglycemia, steatosis, cirrhosis, hyperlipidemia, atherosclerosis and cardiovascular risk.

Description

TITLE

COMPOSITION FOR THE TREATMENT OF METABOLIC DISORDERS

DESCRIPTIO ·

Technical field

The present invention concerns a composition, for the use as a medicament and/or as a special dietary supplement, for use in the treatment of metabolic disorders, such as those derived from or connected with the metabolic syndrome or insulin-resistance, that is hyperinsulinemia, diabetes, hyperglycaemia, steatosis, cirrhosis, hyperlipidemia, atherosclerosis and cardiovascular risk.

Background art

The so-called metabolic syndrome is one of the most widespread pathological forms in the occidental world and comprises a series of metabolic alterations, among which the most important are insulin-resistance and dyslipidemia . Moreover, the metabolic syndrome is often accompanied by other comorbidities, for example diabetes, hyperinsulinemia, steatosis, atherosclerosis.

Definitions [from Wikipedia: "Metabolic syndrome"]

The definition of Metabolic Syndrome (M.S.), according to the World Health Organization (W.H.O.- 1999) , foresees the presence of one among the following dysfunctions:

• Diabetes ;

• Altered glucidic regulation;

• Insulin-resistance;

and of two among:

• Hypertension: (≥ 140/90 mmHg) ;

• Hypertriglyceridemia: (> 150 mg/dl) and/or low HDL cholesterol level (< 35 mg/dl in males and < 39 mg/dl in females) ;

• Central obesity: (waist to hip ratio >0, 9 in males and >0,85 in females; and/or BMI >30) ;

• Microalbuminuria.

In turn, the NCEP (US National Cholesterol Education Program Adult Treatment Panel-2001), with the purpose of avoiding confusion with the insulin-resistance of diabetes, has proposed new criteria, establishing as definable as Metabolic Syndrome the presence of three or more of the disorders listed below:

• waist circumference: (≥ 102 cm in males, ≥ 88 cm in females) ;

• fasting glycaemia: (> 110 mg/dl) ;

arterial hypertension: (≥ 130/85 mm Hg) ;

hypertriglyceridemia: (> 150 mg/dl);

reduced HDL cholesterol: (< 40 mg/dl in males; < 50 mg/dl in females). Insulin is a hormone that allows the passage of glucose from the blood to the cells, impeding that its hematic concentration (or glycaemia) increases too much. Not all the body cells need insulin to absorb glucose; the hormone is nevertheless essential for the muscular tissue and the adipose tissue, which on their own represent about the 60% of the body mass .

We talk about insulin-resistance when the cells of the organism diminish their own sensitivity to the action of insulin; the consequence is that the release of the hormone produces a biological effect that is inferior with respect to what is normally foreseeable in a sane individual. In reply to the insulin-resistance, the organism implements a compensation mechanism based on the increased release of insulin: in this case the so-called hyperinsulinemia is verified, which is the formation/presence of high levels of the hormone in the blood. If in the initial phases this compensation is capable of maintaining glycaemia at normal levels, in a more advanced stage the pancreatic cells deputed to the production of insulin (the β-cells, located in the islets of Langerhans) are not capable anymore to adequate the synthesis thereof: the result of this is an increase of the post-prandial glycaemia. In the even more advanced stage, last, the further reduction of the plasmatic concentration of insulin, due to the progressive exhaustion of the pancreatic β-cells, determines the appearance of fasting hyperglycaemia too. Therefore, insulin-resistance often represents the anteroom to diabetes. In brief, insulin- resistance determines, in the first place:

- an increase of the hydrolysis of the triglycerides at adipose tissue level (with an increase of the amount of fat acids in plasma) ;

- a decrease of the uptake of the glucose at muscular level (with a decrease of the deposits of glycogen) ;

- an increased hepatic synthesis of the glucose in reply to the increased concentration of the fat acids in blood and in the absence of the processes that inhibit it (with an increase of the fasting glycemic levels ) .

It is believed that compensatory hyperinsulinemia renders the pancreatic β-cell incapable of activating all those molecular mechanisms necessary to its correct functionality and to its normal survival. The diminished functionality of the pancreatic β-cells opens the doors to diabetes mellitus type II.

The muscular tissue represents the main seat of the peripheral insulin-resistance; nevertheless, during physical activity this tissue loses its dependency from insulin and the glucose is able to enter the muscular cells also in the presence of particularly low insulinemic levels.

The causes of insulin-resistance are numerous. For example, insulin-resistance can be caused by hormonal factors: it is in fact possible that a quality defect is verified in the production of insulin, as well as an excessive synthesis of hormones with effects that are opposed to the ones of insulin. In this class of substances are included all those hormones, such as adrenaline, Cortisol, glucagon, cortisone, the growth hormone, capable of antagonizing the action of insulin up to determining the insulin-resistance when they are present in excess (as it usually happens in the Cushing's syndrome). Also the exogenous provision of these hormones (for example, cortisone or the growth hormone) can determine insulin-resistance. There can exist, further, genetic causes provoked by mutations of the insulin receptor. In most cases, anyway, the causes of insulin-resistance cannot be clearly determined. Apart from the ^'inevitable hereditary component, in most cases insulin- resistance affects subjects who suffer illnesses or conditions such as hypertension, obesity, pregnancy, hepatic steatosis, metabolic syndrome, the use of anabolic steroids, atherosclerosis, polycystic ovary syndrome, hyperandrogenism and dyslipidemia (it presents high triglycerides and LDL cholesterol levels, associated with a reduced amount of HDL cholesterol). Such conditions, associated with the inevitable genetic component, represent also possible causes/consequences of insulin-resistance and are important for its diagnosis; in ordinary clinical practice, the fasting glucose and insulin plasmatic concentrations are examined. Sometimes, the glucose curve is used also that, in the presence of insulin- resistance, initially presents a relatively normal course, except that it presents, after some hours, a quick decline of giycaemia (due to hyperinsulinemia) . The most effective treatment to fight insulin- resistance consists in practising regular physical activity, associated to weight loss, to the adoption of a low-calorie diet and to the consumption of low glycemic index foods. A certain utility has been demonstrated also by those products capable of reducing or slowing down the intestinal absorption of sugars and fats (acarbose and supplements of fiber such as glucomannan and psyllium) . Some medicaments used for the cure of diabetes, such as metformin, have proved to have a certain efficiency also in the treatment of insulin-resistance; nevertheless, it is always very important to intervene first of all on the diet, on the level of physical activity, or also on natural remedies, resorting to a pharmacological therapy only when lifestyle changes are not enough. As for the nearest background art, for example, WO2007/113748 Al describes compositions that have a certain beneficial effect on the cardiovascular system, in particular on the metabolic syndrome, which comprise a combination of red fermented rice, berberine and an anti-oxidant . The activity of the combination is described as synergic. Also, Guido Carlomagno et al., "A Nutraceutical Combination Improves Insulin Sensitivity in Patients With Metabolic Syndrome: Results of a Randomized, Double- Blind, Placebo-Controlled Trial", Journal of The American College of Cardiology, vol . 57, no. 14, April 2011, page E546, describe that a nutraceutical combination of berberine, red fermented rice and policosanol is effective for reducing cholesterol in blood and the resistance to insulin.

Moreover, Harrihar A Pershadsingh : " [alpha] -Lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome" , EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 16, no. 3, 1 March 2007, pages 291-302; and In-Kyu-Lee: "Adenosine monophosphate kinase activator alpha-lipoic acid: A promising therapeutic agent for metabolic syndrome?", Journal of Diabetes Investigation, 1 August 2011, both describe the alpha-lipoic acid as a therapeutic agent for the treatment of the metabolic syndrome. None of the documents of the background art, however, describes the triple combination of berberine, red fermented rice extract and alpha lipoic acid, or describes or suggests in some way a possible synergy of action of the said three active principles for the effective treatment of metabolic disorders, such as those derived from or connected with the metabolic syndrome or insulin-resistance.

Therefore, to date, there does not exist a unique and focused treatment for the metabolic syndrome, and this is why what is sought is to normalize the altered parameters, above all, with the diet and with sports, in the refractory or more serious cases with hypoglycemic medicaments or lipid-lowering medicaments or both. Therefore, to date, there is still no availability of products capable of giving an adequate and satisfying answer to the problems previously described relative to the treatment of insulin-dependence .

Technical problem

In the light of what has been exposed above, the need is much felt in the field to have new pharmaceutical formulations and/or of special co-adjuvant dietary supplements, which are particularly effective for the treatment of insulin-resistance, which do not present collateral effects, can be well tolerated by patients and are of easy administration.

The aim of the present invention is to give an adequate answer to the technical problem described above.

Summary of the invention

The Applicant has now unexpectedly found that a composition comprising, or consisting of, at least an adequate association between berberine, a red fermented rice extract (containing Monascus Purpureus) and lipoic acid or the derivatives thereof is capable of giving an adequate answer, to the technical problem above for the treatment of a metabolic disorder provoked by insulin-resistance, improving at least some of the parameters linked to metabolic disorders thanks to a synergic effect, not known to date, of the said three components. It is, therefore, an object of the present invention a composition substantially based on an association of berberine and/or the analogues thereof, of red fermented rice extract (containing Monascus Purpureus, titrated in total monacolin) and of a- lipoic acid and/or of the derivatives thereof, as stated in the independent claim below.

It is another object of the present invention the use of the composition above as a medicine and/or as a dietary supplement, as stated in the independent claims below.

It is another object of the present invention the use of said medicine and/or supplement for the treatment of a metabolic disorder, as stated in the independent claim below.

Preferred embodiments of the present invention are stated in the dependent claims below.

Preferred embodiments of the present invention are stated, just as a way of example and absolutely not limiting of the wide applicative field of the present invention, also in the detailed description that follows .

Detailed description of the invention

Berberine, one of the three essential constituents of the composition of the present invention, is a vegetal alkaloid, of bitter taste and deep yellow color, present in the bark, the roots and the stems, including the rhizomes, of plants belonging to the Berberis genre, like the barberry {Berberis vulgaris L.) . Berberine is typical also of the goldenseal (Hydrastis canadensis) and of the Huang lian (Coptis chinensis) . Berberine is known for its cholesterol- lowering action that is generated by a mechanism of action that is completely different from that of the statins and that, unlike these, does not involve the expression or the activity of the HMG-CoA reductase. The therapeutic activity of the red fermented rice extract, another one of the three essential constituents of the composition of the present invention, is linked to the presence in the same of the Monascus purpureus yeast. During its fermenting activity, this yeast is enriched with a group of substances, cumulatively called monacolins (monacolin K, dehydro monacolin K, monacolin L, monacolin K in open-ring form, etc.), to which a cholesterol- lowering action has been attributed. Among these, it stands out, for example, monacolin K, which reflects the chemical structure and the pharmacological action of lovastatin (a medicament belonging to the category of the statins) . In fact, also the monacolin K of the red fermented rice has resulted to be capable of inhibiting the HMG-CoA reductase, a key enzyme in the biosynthesis of cholesterol. The integration with a red fermented rice extract has revealed of a certain efficiency to normalize the levels of total cholesterolemia, LDL cholesterol and triglyceridemia. The fermentation controlled in laboratory can make the composition of the Monascus purpureus vary slightly and permits to select strains enriched with Monacolin K or with other substances, similar to it or derived from it, provided with particular pharmacological actions.

The third essential component of the composition in accordance with the present invention, a-lipoic acid (colloquially indicated also, for simplicity purposes, just as lipoic acid) and/or its reduced form, dihydrolipoic acid, are known substances with an antioxidant action, in particular against hydroxyl radicals, hypo hydrochloric acid, peroxynitrites and singlet oxygen. The dihydrolipoic acid, further,, has a "scavenger" activity with respect to the superoxide and peroxyl radicals and is also capable of regenerating other compounds with antiradical activity such as thioredoxin, vitamin C and glutathione, which in turn reconstitutes vitamin E. The α-lipoic acid has shown a certain utility in the prevention and/or treatment of the diabetic complications due to an increase of reactive oxygen and of nitrogen species. Moreover, the -lipoic acid increases the uptake of the glucose and, therefore, increases the availability thereof also in patients with diabetes of type II, insulin-resistant.

As a consequence, the present invention is directed to a composition, pharmaceutical and/or as a dietary supplement, in which the biologically active part comprises at least an adequate association of berberine (and/or the derivatives or analogues thereof) , of red fermented rice extract (titrated in monacolin (s) ) and of a-lipoic acid (and/or derivatives or analogues thereof) .

In a preferred embodiment, in said composition in accordance with the present invention (hereinafter, for simplicity purposes, the term "composition" alone will indicate both the composition for pharmaceutical use and the one for use as a dietary supplement) , the biologically active part consists of an adequate association of berberine (and/or derivatives thereof) , of red fermented rice extract (titrated in monacolin ( s ) ) and of α-lipoic acid (and/or derivatives thereof) . For greater clarity, with the term "berberine", in the present description, is intended both berberine per se, as defined above, and the derivatives or analogues thereof with a similar structure.

Always for greater clarity, with the term "lipoic acid", in the present description, is intended both lipoic acid per se, as defined above, and the derivatives or analogues thereof with a similar structure .

Moreover, said composition of the present invention can further comprise excipients, technological additives, co-formulating agents, polar and/or semi- polar polymer-matrices, carriers, stabilizing agents and the like, which are pharmaceutically acceptable. Just as a way of example, not limiting, the pharmaceutically acceptable excipients are selected from: thickening agents such as xantan gum and/or guar gum; sweeteners such as sorbitol and sucralose; acidifiers such as citric acid; malto-dextrines ; anti-binders such as silicon dioxide and magnesium stearate; and various fragrances, and/or mixtures thereof .

In another embodiment, the composition of the present invention can further comprise also effective amounts of one or more forms of statins (for example, lovastatin, pravastatin, rosuvastatin, atorvastatin, simvastatin) .

In another embodiment, the composition of the present invention can further comprise an effective amount of one or more actives known in the field, with adjuvant and/or improving and/or complementary function of the biologic activity, for example selected from: vitamins, vitamin C, vitamin E; bio-compatible zinc, selenium or chromium salts; carnitine, L-acetyl- carnitine; N-acetylcysteine; inositol; melatonin; vegetal/phytotherapeutic extracts and/or the mixtures thereof; and so on.

In the composition in accordance with the present invention, berberine (eventually comprising also the analogues and/or derivatives thereof) is present in an amount comprised from 10 to 60% by weight, with respect to the total weight of the composition; preferably, between 20 and 50% in weight, with respect to the total weight of the composition; more preferably, between 30 and 40% in weight, with respect to the total weight of the composition.

In the composition in accordance with the present invention, the red fermented rice extract (that is, the monacolin ( s ) , eventually comprising also the analogues and/or derivatives thereof) is present in an amount comprised from 2 to 30% by weight, with respect to the total weight of the composition; preferably, between 5 and 25% in weight, with respect to the total weight of the composition; more preferably between 10 and 20% in weight, with respect to the total weight of the composition.

In the composition in accordance with the present invention, the a-lipoic acid (eventually comprising also the analogues and/or derivatives thereof) is present in an amount comprised from 20 to 70% by weight, with respect to the total weight of the composition; preferably, from 30 to 60% by weight, with respect to the total weight of the composition; more preferably, from 40 to 50% by weight, with respect to the total weight of the composition.

In the composition in accordance with the present invention, the excipients and/or the other additional substances previously described, such as technological additives, co-formulating agents, polar and/or semi-polar polymer-matrices, carriers and stabilizing agents, are present in a total amount comprised from 5 to 40% by weight, with respect to the total weight of the composition; preferably, from 15 to 25% by weight, with respect to the total weight of the composition. In the composition in accordance with the present invention, the eventual forms of statins are present in an amount on average comprised from 0 to 10% by weight, with respect to the total weight of the composition .

In the composition in accordance with the present invention, the eventual other additional substances with adjuvant and/or improving and/or complementary function are on average present in the following amounts :

- vitamin C: from 0 to 30% by weight, with respect to the total weight of the composition;

- vitamin E; from 0 to 10% by weight, with respect to the total weight of the composition;

- Zn salts: from 0 to 10% by weight, with respect to the total weight of the composition;

selenium salts: from 0 to 5% by weight, with respect to the total weight of the composition;

chromium salts: from 0 to 2% by weight, with respect to the total weight of the composition;

carnitine, L-acetyl-carnitine : from 0 to 30% by weight, with respect to the total weight of the composition ;

- N-acetylcysteine : from 0 to 40% by weight, with respect to the total weight of the composition; - inositol: from 0 to 40% by weight, with respect to the total weight of the composition;

- melatonin: from 0 to 5% by weight, with respect to the total weight of the composition;

- vegetal/phytotherapeutic extracts: from 0 to 30% by weight, with respect to the total weight of the composition .

In the composition in accordance with the present invention, the suggested daily dose of berberine is comprised on average from 100 to 1000 mg/die; preferably from 200 to 500 mg/die.

In the composition in accordance with the present invention, the suggested daily dose of monacolin (or mixture of monacolin) is comprised on average from 5 to 10 mg/die; preferably from 5 to 10 mg/die.

As already anticipated, monacolin (s) (and/or the analogues and/or derivatives thereof) is normally found inside red fermented rice extracts titrated to the various concentrations obtained (generally at 3/5/10% of monacolin ( s) ) . Therefore, the amount of red rice extract suggested is comprised on average from 50 to 200 mg/die.

In the composition in accordance with the present invention, the suggested daily dose of a-lipoic acid (and/or the derivatives thereof) is comprised on average from 100 to 1800 mg/die; preferably, from 400 to 1200 mg/die.

In a preferred embodiment, the composition of the present invention contains -lipoic acid.

In the composition in accordance with the present invention the a-lipoic acid is present in the embodiment R(+ ) and/or in the embodiment S(-) or under the form of a racemic mixture R(+)/S(-).

Advantageously, the α-lipoic acid is also present under the form of one of its pharmaceutically acceptable salts; for example, a sodium salt.

In a preferred embodiment of the present invention, the α-lipoic acid can be present in a controlled- release micro-encapsulated form or, alternatively, in a non-micro-encapsulated form, on the basis of the type of pharmaceutical form that wants to be realized .

For example, in the case of a tablet the a-lipoic acid is present in a non-micro-encapsulated form. However, it can also be formulated in a tablet that contains excipients capable of modifying the release according to different times (Fast, Fast/Slow, Retard) . In the case of a granulated substance for sachets or a gel capsule the α-lipoic acid is preferably present in a controlled-release micro- encapsulated form. The micro-encapsulation is realized according to the methodologies and the techniques known to the expert in the field that is surely capable of selecting the most suitable coating materials among those available in the market.

Advantageously, the composition of the present invention contains a-lipoic acid R( + ) or one of its racemic mixtures in a controlled-release microencapsulated form, preferably under the form of sodium salt, preferably in a daily dose comprised from 100 to 1.200 mg/die, more preferably from 300 to 800 mg/die.

The pharmaceutical composition and/or the supplement product that is the object of the present invention comprise a qualitative-quantitative chemical composition endowed with the features indicated above, in combination with one or more excipients and/or with one or more other actives with adjuvant function, as described above.

The pharmaceutical composition and/or the supplement of the present invention are prepared by means of the use of traditional apparatuses and of methods that are well known by the expert in the field.

Just as a way of example, absolutely non limiting, initially, a homogeneous mixture finely subdivided is prepared. Said mixture will comprise berberine (and/or, eventually, the derivatives and/or analogues thereof), monacolin(s) (and/or, eventually, the derivatives and/or analogues thereof) oi-lipoic acid (and/or, eventually, the derivatives and/or analogues thereof) , eventually other statins, the excipie^'nts and/or technological additives and/or the co- formulating agents and/or the polar and/or semi-polar polymer-matrices and/or the carriers and/or the stabilizing agents, the eventual adjuvants, on the basis of the type of pharmaceutical form that wants to be prepared.

Some types of matrices chosen among lipid matrices, carboxymethyl cellulose, carboxypropyl cellulose, hydroxypropyl cellulose and shellac can also be used in order to formulate the composition in the desired pharmaceutical forms.

Said mixture is prepared by adding in sequence the various components inside of a specific container/mixer furnished with shaking means and heating means. The order of the addition of the components is not limiting.

Subsequently, by means of the use of apparatuses and methodologies well known in the pharmaceutical and supplements field, a formulation in solid, granular or powder form, or in dispersed or liquid form, is prepared, suitable for oral administration under the form of a liquid solution, a syrup, pills, tablets, gel capsules or orosoluble pharmaceutical forms.

In a preferred embodiment, the composition in accordance with the present invention avails itself of controlled-release technologies.

It is therefore a further object of the present invention the use of the composition of the present invention for the preparation of a pharmaceutical composition and/or of a special dietary supplement for the therapeutic treatment and/or for the improvement of a selected metabolic disorder, for example, from the group comprising metabolic syndrome or insulin-resistance, hyperglycaemia, hyperinsulinemia, diabetes, steatosis, cirrhosis, hyperlipidemia, atherosclerosis, cardiovascular risk. As already exposed, the pharmaceutical composition and/or the supplement product of the present invention have shown a surprisingly positive effect in the subjects treated.

Even if the mechanism of action is not completely clear, the efficiency of the present composition is to be ascribed to a synergic effect between the berberine, the monacolin(s) and the a-lipoic acid contained in said composition. Moreover, an additional effect has unexpectedly emerged due to a specific relation dosage (described, better in one of the preferred formulations/administration regime (type of daily administration, also indicated in detail below for the particularly preferred dosage) . The pharmaceutical composition and/or the supplement product of the present invention can be, for example, administered once or twice a day in order to administer for the subject under treatment, for each single active component, a daily dose as described before .

The pharmaceutical composition and/or the supplement product of the present invention can be administered as background therapy or as periodical therapy.

Examples

The following experimental section has the only scope of illustrating better the invention and is not to be intended as limitative of the wide applicative potential of the invention itself.

Background therapy

In a preferred embodiment, a sachet to be reconstituted in water before ingestion is administered (or a tablet of the same dosage) , as background therapy, that is forever, containing (granular composition in sachet) :

Berberine: 400 mg;

Red fermented rice extract (containing Monascus purpureus, titrated at 5% in monacolin (s) : 200 mg;

a-Lipoic acid: 400 mg;

Thickening agents: xantan gum, guar gum; sweeteners: sorbitol; acidifiers: citric acid; malto- dextrines; anti-binders: silicon dioxide; fragrances, in a total amount of: 500 mg (the amount of the single excipients/additives is variable on the basis of the type of formulation and is easily decided by the expert of the field on the basis of his own experience and of the common formulation knowledge) . The formulation exemplified releases the actives on the basis of a Fast/Slow modality.

Periodical therapy

In another preferred embodiment, one or two sachets /die, or one or two tablets/die are administered, in which the amounts of the actives are the same stated above, for a period comprised from 4 to 20 weeks on the basis of the seriousness of the status of the patient .

Live experimentations

The pharmaceutical composition and/or the supplement product of the present invention are at the moment under analysis on patients with alterations of the glucidic metabolism and dyslipidemia, in order to assess the effects of the administration of said composition on some specific parameters of the metabolic syndrome.

The study of the following parameters is at an advanced stage:

i) the insulin sensitivity, through HOMA index;

ii) the content of the lipids in the blood through vertical ultracentrifugation;

iii) the determination of the markers to assess the oxidative and inflammatory stress in the serum.

The preliminary results obtained have revealed quite interesting and promising; unexpectedly, on average the following has been observed: a significant lowering of the values of total cholesterol, of LDL cholesterol, of triglycerides; an increase of the HDL cholesterol (the so-called good cholesterol) , a reduction of some marker parameters of inflammatory states, such as the ICAM, the VCAM, the endotelin, the PAI-1 the 8-iso-PGF2alpha, or oxidizing agents (OxLDL) , and an increase of the sensitivity to insulin, which are not ascribable to the simple summation of the activities of the single actives, taken individually or in binary combination between them.

Industrial applicability

The association of the three actives described in the present application has unexpectedly found a valid application in the treatment of metabolic disorders derived from, or connected with, a metabolic syndrome of insulin-resistance, hyperglicemia, hyperinsulinemia, diabetes, steatosis, cirrhosis, hyperlipidemia, atherosclerosis, cardiovascular risk. Moreover, the ^■ association of the three actives mentioned above has resulted superior by efficacy and completeness of action to those of the single components or of the binary associations thereof, confirming a synergic action of said association of actives in accordance with the present invention.

Claims

1. A pharmaceutical and/or supplement composition, in which the active portion of said composition comprises at least an effective amount of an association of berberine, red fermented rice extract (titrated in monacolin ( s ) ) , and a-lipoic acid.

2. The composition according to claim 1, in which in said association:

berberine is present in an amount comprised from 10 to 60% by weight, with respect to the total weight of the composition;

red fermented rice extract is present in an amount comprised from 2 to 30% by weight, with respect to the total weight of the composition;

a-lipoic acid is present in an amount comprised from 20 to 70% by weight, with respect to the total weight of the composition.

3. The composition according to any one of the preceding claims, further comprising excipients and/or other additional substances, technological additives, co-formulating agents, polar and/or semi-polar polymer-matrices, carriers and/or stabilizing agents, which are pharmaceutically acceptable, present in a total amount comprised from 5 to 40% by weight, with respect to the total weight of the composition; preferably, said excipients are endowed with features allowing a modified release of the active principles (Fast, Fast/Slow, Retard) .

4. The composition according to any one of the preceding claims, further comprising an effective amount of one or more statins selected from: lovastatin, pravastatin, rosuvastatin, atorvastatin, simvastatin, present in a total amount comprised from 0 to 10% by weight, with respect to the total weight of the composition.

5. The composition according to any one of the preceding claims, further comprising an effective amount of one or more actives selected from: vitamins, vitamin C, vitamin E; biocompatible zinc, selenium or chromium salts; carnitine, L-acetyl-carnitine; N- acetyl-cysteine; inositol; melatonin; vegetable/ phytopharmaceutical extracts and/or mixtures thereof.

6. The composition according to any one of the preceding claims, in which said composition is in the form of a solid, granules, powder, pills, tablets, gel-capsules; in dispersed or liquid form, suitable for oral administration, in the form of a liquid solution, a syrup, or other orosoluble pharmaceutical forms, even in controlled release form.

7. The composition according to any one of the preceding claims, in which said composition is in the form of a sachet of powder or granules, to be reconstituted in water before ingestion, or of a tablet, containing:

Berberine: 400 mg; Red fermented rice extract (containing Monascus purpureus, titrated at 5% in monacolin (s) ) : 200 mg;

-Lipoic acid: 400 mg;

Thickening agents, xantan gum, guar gum; sweeteners, sorbitol; acidifiers, citric acid; malto-dextrines ; anti-binders, silicon dioxide; fragrances; in a total amount of: 500 mg.

8. A composition according to any one of claims from 1 to 7 for use as a medicament.

9. The composition according to claim 8, for use in the treatment of a metabolic disorder selected from the group comprising metabolic syndrome or insulin- resistance, hyperglycaemia, hyperinsulinemia, diabetes, steatosis, cirrhosis, hyperlipidemia, atherosclerosis, cardiovascular risk.

10. A composition according to any one of claims from 1 to 7 for use as a dietary supplement and/or nutraceutical, and/or a special food for adjuvant therapeutic and/or functional purposes.