Nutraceutical or pharmaceutical composition for cardiovascular health

Abstract

The present invention relates to a composition of substances, ef fective in the prevention and / or treatment of cardiovascular disease. The composition of the invention comprises an extract of a plant belonging to the genus Berber! s, astaxanthin and an extract of a plant belonging to the genus Sal via. The composition of the invention is prepared in solid, semisolid or liquid pharmaceutical dosage form, preferably for oral administration.

Description

[0001] "Nutraceutical or pharmaceutical composition for cardiovascular health"

[0002] DESCRIPTION

[0003] The present invention relates to a nutraceutical or pharmaceutical composition effective in the prevention and / or treatment of cardiovascular pathologies in both humans and animals.

[0004] Background of the invention

[0005] The term "cardiovascular diseases" includes all diseases affecting the heart and blood vessels. The most common are diseases of atherosclerotic origin, in particular, cardiac diseases (e.g., acute myocardial infarction, angina pectoris, cardiomyopathies, heart failure, and arrhythmias), cerebrovascular diseases (e.g., ischemic and hemorrhagic stroke), and peripheral vascular disorders (e.g., peripheral arteriopathy obliterans).

[0006] Hypertension

[0007] The risk of developing cardiovascular disease increases with increasing blood pressure values. When maximum (systolic blood pressure) and minimum (diastolic blood pressure) pressor values are equal to or greater than 130 / 85 mmHg, this is called hypertension.

[0008] Hypertension is a condition in which the heart, having to overcome an increase in peripheral resistance, exerts a pressure on the arterial walls that exceeds the reference values. Hypertension can be classified into primary and secondary.

[0009] Primary hypertension has no precise etiology: high blood pressure values are the result of a disruption of physiological mechanisms that regulate pressure (autonomic nervous system, plasma mediators, etc.). Secondary hypertension, on the other hand, is the consequence of diseases affecting the kidneys, adrenals, vessels, and heart.

[0010] In such cases, treatment of the disease may result in normalization of blood pressure values. The main classes of antihypertensive drugs are: diuretics (thiazide, loop, and potassium-sparing), peripherally acting (p-blockers, a- blockers, and mixed adrenergic antagonists) and centrally acting (ganglioplegics and adrenergic neuron blockers) sympatholytics, vasodilators, calcium channel blockers, ACE inhibitors, and sartans. However, taking these drugs results in several side effects including orthostatic hypotension, cough, headache, cramps, vomiting, nausea, itching, rash, sedation, bradycardia, and libido disturbances.

[0011] Dyslipidemias

[0012] Dyslipidemias represent a group of pathological conditions characterized by abnormal blood concentrations of lipids, in particular, cholesterol and triglycerides.

[0013] One of the most significant risk factors for cardiovascular disease is precisely elevated cholesterolemia . Total cholesterolemia should be less than 200 mg / dL. In particular, an HDL cholesterol value of more than 40 (man)- 45(woman) mg / dL is desirable and LDL cholesterol less than 100 mg / dL in patients at high cardiovascular risk and less than 70 mg / dL in patients who have already had a cardio or cerebrovascular event. High plasma triglyceride concentration (over 150 mg / dL) also contributes to higher LDL cholesterol values. The main hypolipidemic drugs are:

[0014] - antilipogenics, which inhibit triglyceride and cholesterol synthesis at the hepatic level (e.g., fibrates and statins); antilipolytics, which inhibit lipolysis at the level of adipose tissue resulting in reduced levels of fatty acids necessary for hepatic triglyceride synthesis (e.g., nicotinic acid and derivatives); and

[0015] - sequestrants, which stimulate the conversion of cholesterol to bile acids or limit intestinal absorption of fats (e.g., cholestyramine, probucol, and ion exchange resins).

[0016] The most common side effects reported by patients on therapy with hypolipidemic drugs, particularly statins, are myalgia, arthralgia, pain in the extremities, muscle spasms, joint swelling, back pain, nasopharyngitis, headache, pharyngolaryngeal pain, epistaxis, constipation, flatulence, dyspepsia, nausea, diarrhea and increased creatine phosphokinase . Atherosclerosis Cholesterol is transported in the blood by specific lipoproteins such as low-density lipoproteins (LDL), which supply peripheral tissues with cholesterol, and high-density lipoproteins (HDL), which, in contrast, remove excess cholesterol from tissues (including blood vessels) and return it to the liver. Free radicals can oxidize LDL lipoproteins, which infiltrate and deposit in the intima of vessels leading to endothelial damage. The latter triggers a chronic inflammatory process with transformation of monocytes into macrophages, which, after phagocytizing the oxidized LDL, turn into foam cells. Foamy cells represent the main center of accumulation of lipids, substances derived from the inflammatory process (fibrinogen, white blood cells, macrophages, etc.) and blood elements (red blood cells, platelets, calcium, etc.) from which the atheromasic plaque (atheroma) originates. Atheromas cause a non-elastic thickening of the vessel wall that narrows or completely occludes the vessel. If atheromas are found in the coronary arteries, they can cause the onset of angina pectoris or heart attack; if, on the other hand, they are found in vessels that carry blood to the brain, they can cause an ischemic stroke.

[0017] Drugs used to treat atherosclerosis include hypolipidemic agents, antiplatelet agents, anticoagulants, antihypertensives and antidiabetics.

[0018] Angina pectoris

[0019] Angina pectoris can occur as a result of in-sufficient oxygenation of cardiac tissue due to transient interruption / slowing of blood flow in the coronary arteries when they are only partially obstructed. It manifests as acute chest pain and often arises in conjunction with increased blood demand (e.g., during physical activity). Angina can be treated with nitroglycerin, possibly combined with a p-blocker and sometimes a calcium antagonist. Antiplatelet agents are used to prevent angina. Infarction

[0020] Acute myocardial infarction can be caused by rupture of an atherosclerotic plaque and subsequent formation of a thrombus, resulting in occlusion of a coronary artery and necrosis of the myocardial tissue supplied by the obstructed artery.

[0021] In severe cases, it can complicate to the point of cardiovascular collapse and death. Treatment involves the use of antiplatelet drugs, thrombolytics, p-blockers, ACE inhibitors, analgesics and hypolipidemic drugs.

[0022] Stroke

[0023] Stroke is a cerebrovascular injury caused by the interruption of blood flow to the brain by occlusion (ischemic stroke) or rupture (hemorrhagic stroke) of a cerebral artery. An artery can become occluded because a clot forms within it (cerebral thrombosis) or because it is reached by clots that have started, for example, from the heart or atherosclerotic plaques in the arteries that carry blood to the brain (cerebral embolism). In the case of hemorrhagic stroke, on the other hand, there is cerebral hemorrhage, often due to excessively high blood pressure resulting in ruptured normal or malformed vessels (aneurysms) or abnormal blood clotting.

[0024] In either case, brain cells, deprived of oxygen and nutrients, begin to die resulting in edema that also leads to suffering of brain cells in a large surrounding area. Depending on the part of the brain affected, stroke can result in paralysis of related muscle areas and loss of some functions (speech, vision or memory). Treatment involves the use of antiplatelet drugs, thrombolytics, p-blockers, and ACE inhibitors. Heart failure

[0025] Occurs when the heart can no longer pump blood in adequate amounts relative to the body's actual demand, causing insufficient oxygenation of organs and tissues. It may initially involve only the left ventricle but, over time, can affect the entire heart muscle. In therapy, drugs such as ACE inhibitors, β-blockers, diuretics and aldosterone antagonists are used.

[0026] Therefore, given the numerous side effects of currently available drugs and the morbidity of the diseases discussed above, there remains a need for alternative compositions that are effective in the prevention and treatment of cardiovascular diseases.

[0027] The subject of the present invention is a composition comprising an extract of a plant belonging to the genus Berberis, astaxanthin and an extract of a plant belonging to the genus Salvia for the prevention and treatment of cardiovascular diseases.

[0028] GLOSSARY

[0029] The terms used in this description are as generally understood by the technical expert, except where otherwise indicated.

[0030] The term "extract, " in the context of this description, means any product attributable to a plant drug including all products derived from mechanical processing (pulverization, crushing, mixing, and / or other methods) or extractive processing (solvent extraction, distillation and / or other specific methods) operated on a drug.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] Several species belong to the genus Berberis of which the main ones are Berberis aristata , Berberis vulgaris , Berberis aquifolium.

[0033] Numerous components are present in the extracts of these plants but certainly the characteristic marker is the component berberine.

[0034] Berberine is an isoquinoline alkaloid compound and is the most widely distributed bioactive component in plants belonging to the genus Berberis, as well as being present in other plant species in the genera Coptis, Hydrastis, Mahonia, Tinospora and Xanthorhiza.

[0035] Specifically, in the genus Berberis, the distribution of berberine and other alkaloid compounds associated with it may occur predominantly in the rhizome, bark, or petioles of the plant at different concentrations and depending on the species considered.

[0036] Berberine is found commercially as a yellow, odorless powder with a bitter aftertaste that is characteristic of alkaloid compounds. For clinical uses it is often used in salt form associated with chloride and sulfate ions and is relatively soluble in water.

[0037] In the past, the remarkable pharmacological properties of berberine have been used to treat various conditions such as diarrhea, hypertension, diabetes mellitus, and carcinogenesis, using this alkaloid compound mainly in Chinese medicine. In recent decades, however, interest in its therapeutic effects has grown significantly, especially in Europe, as scientific studies have shown that berberine can also be used to treat cardiovascular diseases.

[0038] In this regard, the cardioprotective action of berberine in patients mainly depends on four different activities such as reduction of blood cholesterol levels, induction of the vasodilation process, anti-platelet aggregation activity, and anti-inflammatory activity.

[0039] Studies conducted in vitro have shown that the mechanism of berberine underlying the regulation of blood cholesterol levels appears to be different from that of statins. Specifically, berberine has been observed to increase the cellular concentration of messenger RNA of receptors that interact with low-density lipoprotein (LDL).

[0040] The over-expression of these receptors occurs at the level of liver cell membranes and enables the removal of more than 70% of circulating LDL by binding these molecules and internalizing them into the cell cytoplasm through processes of endocytosis. It has also been shown that, berberine is able to inhibit the expression of the protein proprotein convertase subtilisin / kexin type 9 (PCSK9).

[0041] The latter is responsible for the repression of LDL-binding receptors. Thus, inhibition of PCSK9 by berberine ensures the expression of receptor proteins and consequently a reduction of LDL in the blood.

[0042] Such experimental evidence was later also confirmed by clinical trials in which berberine administration reduced total cholesterol and LDL values in patients.

[0043] In addition to regulating blood cholesterol levels, berberine is also involved in the process of vasodilation. In this regard, impaired vasodilation of the cardiovascular epithelium is closely related to the phenomenon of epithelial dysfunction, leading to an increased risk of developing diseases affecting the heart and blood vessels. In fact, epithelial dysfunction in patients with atherosclerosis is one of the main causes of atheromatous plaque formation, thus leading to coronary artery disease.

[0044] Scientific studies have shown that berberine is able to induce the expression of the enzyme endothelial nitric oxide synthase (eNOS), thus resulting in the production of nitric oxide molecules involved in vasodilation processes in the cardiovascular epithelium. In this case, berberine regulates the expression of AMP-dependent kinase (AMPK), which is able to activate the eNOS enzyme by phosphorylation.

[0045] In addition to this, berberine is also able to inhibit the expression of monocyte chemotactic protein (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) to preserve the functions of the cardiovascular epithelium from monocyte adhesion.

[0046] Berberine also exerts its cardioprotective function through anti-platelet aggregation activity. The mechanism behind this probably involves regulation of arachidonic acid metabolism and specifically involves a reduction in blood levels of thromboxane A2, known to be a potent inducer in the process of coagulation and vasoconstriction. These beneficial effects derived from the use of berberine are then also associated with its anti-inflammatory activity. Indeed, the inflammatory process is a key factor in the development of cardiovascular disease. In this regard, berberine exerts its anti-inflammatory function by reducing the levels of pro-inflammatory cytokines such as IL-6, IL-lp, and tumor necrosis factor (TNF-a) and by inhibiting the expression of the enzyme inducible nitric oxide synthase (iNOS) through activation of the enzyme AMPK in macrophages.

[0047] All this experimental evidence underscores the multiple cardioprotective effects of berberine making plant extracts belonging to the genus Berberis excellent candidates for the treatment of major cardiovascular risk factors.

[0048] Astaxanthin is a carotenoid classified as xanthophyll (red pigment) that occurs naturally mainly in the aquatic environment. In particular, this pigment is produced by certain types of algae and plankton that are the main source of food of animal species such as shrimps, prawns, salmon, trout and lobsters, to which it imparts pink-red color. Astaxanthin is derived primarily from the microalga Haematococcus pluvialis, which produces the carotenoid in an autonomous form when environmental conditions induce oxidative stress. The molecular structure of astaxanthin has an extended form involving a conjugated polyene chain (apolar) at the ends of which is a ring equipped with hydroxyl and ketone groups (polar). This amphipathic structure allows astaxanthin to position itself in the phospholipid bilayer of cell membranes and gives it better biological activity than other antioxidants. In fact, the polyene chain traps radicals, and the terminal ring can release them both inside and outside the cell membrane.

[0049] Human clinical trials have used astaxanthin administered orally in a dose of 4 mg to 100 mg / day without occurrence of adverse events. Specifically, astaxanthin has been reported to inhibit low-density lipoprotein (LDL) oxidation and increase HDL lipoprotein and adiponectin levels. A study in 24 healthy men shows that astaxanthin consumption, already at a dose of 3.6 mg / day, significantly prolongs LDL oxidation resistance time (LAG time). Another study, conducted in subjects with average hypertriglyceridemia, showed that astaxanthin administered at 12 and 18 mg / day significantly reduced triglyceride levels and increased adiponectin levels, and, administered at 6 and 12 mg / day, produced an increase in HDL lipoprotein. Administering astaxanthin has also been shown to reduce biomarkers of oxidative stress and inflammation. Inhibiting intracellular free radical production in fact is also a way to suppress pro-inflammatory signals. In several studies, moreover, astaxanthin has been shown to suppress the activity and reduce the expression of several mediators of inflammation such as TNF-a, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), and COX-2 in THP-1 macrophages. Inhibition of pro-inflammatory cytokine secretion from macrophages could be one of the mechanisms underlying the beneficial effects of antioxidants on atherosclerosis.

[0050] Therefore, experimental evidence suggests that astaxanthin exerts a preventive action against atherosclerotic cardiovascular disorder.

[0051] To the genus Salvia belong several species known to be used for health purposes among which the most studied are: Salvia officinalis,Salvia miltiorrhiza , Salvia sclarea, Salvia pratensis, Salvia lavandulifolia.

[0052] Salvia miltiorrhiza, also known as red sage or "danshen, " is a perennial plant belonging to the Lamiaceae family.

[0053] This compound has been known since ancient times for its traditional use in China, and since 1953 it has been included in the Chinese Pharmacopoeia for its use in cardiovascular diseases such as atherosclerosis, thrombosis, and angina pectoris .

[0054] Phytochemical study of the plant has revealed the presence of more than 200 compounds that have been classified into two major groups: hydrophilic phenolic compounds and lipophilic diterpenoid compounds. Among the main hydrophilic components are salvianolic acids, which are found in aqueous, methanolic, ethanolic, and acetone extracts.

[0055] In contrast, diterpene compounds include tanshinone IIA, cryptotanshinone, miltiron, etc.

[0056] Several animal studies have been conducted in which the components of Salvia extracts, particularly tanshinones and danshensu, have been shown to be of interest in models of hypertension, atherosclerosis, and myocardial reperfusion injury. Plausible mechanisms of action are many, for example, action on calcium channels, nitric oxide, cytokines, and NF- KB-induced enzymes (interleukins, metalloproteases, ICAMs, VCAMs, lipoxygenases, growth factors such as VEGF, etc.). Tanshinones, danshensu and salvianolic acids are able to inhibit platelet aggregation and increase the process of fibrinolysis .

[0057] Since 2000, about 40 clinical trials have been conducted in which about 2,400 patients have taken danshen extract alone or in combination with other natural substances.

[0058] Most of these studies referred to the treatment of coronary artery disease, stable, unstable or associated angina pectoris. Other studies targeted cardiovascular ischemic disorders, heart failure, hypertension, hypercholesterolemia in postmenopausal women, diabetes coupled with myocardial ischemia, etc.

[0059] Clinical trials have demonstrated the efficacy of Salvia miltiorrhiza treatment in cardiovascular disease by showing improvements in the frequency of angina attacks, heart function, electrocardiogram, and markers of antioxidants, inflammation, and lipid profile. Reported side effects are mild (nausea, abdominal pain, and dyspepsia) and tend to disappear completely after cessation of treatment.

[0060] The multiple pharmacological activities attributed to the compounds contained in Salvia miltiorrhiza extracts make this extract potentially useful in the prevention and treatment of cardiovascular diseases of various entities.

[0061] The nutraceutical or pharmaceutical composition according to the invention is as defined in the appended claim 1.

[0062] Additional features and advantages of the invention are defined in the dependent claims. The claims form an integral part of this description.

[0063] A detailed description of some preferred embodiments of the invention is provided below.

[0064] As indicated, the nutraceutical or pharmaceutical composition of the present invention comprises an extract of a plant belonging to the genus Berberis, astaxanthin and an extract of a plant belonging to the genus Salvia for the prevention and treatment of cardiovascular disease.

[0065] The words "a plant extract belonging to the genus Berberis" in the context of this description mean that the composition may include an extract chosen from Berberis aristata, Berberis aquifolium, Berberis vulgaris.

[0066] The words "an extract of a plant belonging to the genus Salvia" in the context of this description means that the composition may include at least one extract chosen from Salvia officinalis, Salvia miltiorrhiza , Salvia pratensis, Salvia lavandulifolia, Salvia sclarea.

[0067] The present invention constitutes a prompt and valuable intervention useful for the prevention and / or treatment of cardiovascular disease.

[0068] This effect is ascribed to the combined action of its constituent substances. The extract of a plant belonging to the genus Berberis stimulates the production of LDL receptors by improving the lipid profile and also acts simultaneously as a hypoglycemic and anti-inflammatory agent. Astaxanthin due to its unique chemical structure has potent antioxidant activity on LDL and increases HDL cholesterol. Plant extract belonging to the genus Salvia improves the lipid profile as well as providing antiplatelet power.

[0069] The synergistic activity of the aforementioned active ingredients can be studied by using in vitro and / or in vivo assays capable of evaluating the activity of the compositions according to the present invention.

[0070] In vitro tests on murine or human-derived cells may be useful for evaluating the anti-inflammatory action of the formulation under investigation. Cells are grown in complete DMEM growth medium and kept, for example, at 37°C and in a humid atmosphere in 5% CO2. Following treatment with the composition of the invention, total RNA extracted from the samples is subjected to specific treatments such as RT-PCR to assess expression levels of pro-inflammatory proteins such as IL 1β, TNF-a and iNOS.

[0071] An in vitro assay to assess levels of oxidative stress involves treating cells with specific agents such as 2,7- dichloro-dihydrofluorescein acetate. Gene-rata fluorescence can be measured by fluorescence microscopy 5 at 529 nm.

[0072] Other methods conventionally known to the branch expert can be used to evaluate the antioxidant activity of the formulation of the present invention. For example, it is possible to study the expression of SOD1 and NOX4 under conditions of LPS- induced stimulation or hyperglycemia before and after treatment with the substances of the present invention. Antioxidant and anti-inflammatory action, relevant to protect the endothelium from damage associated with atheroma formation, can be determined by tests conducted on human umbilical vein endothelial cells (HUVECs). Specifically, antioxidant activity can be assessed by inducing oxidative stress in HUVEC cells cultured in the presence of the compounds under investigation by addition of hydrogen peroxide (H2O2). Similarly, anti-inflammatory activity can be determined by pre-incubating HUVEC cells with the substances of interest, and subsequently adding tumor necrosis factor-a (TNF-a) in order to induce the release of vascular cell adhesion molecules (VCAMs) and E-selectin, the presence of which can be detected by ELISA method.

[0073] An additional experimental model useful for the evaluation of the substances under consideration is based on human hepatocarcinoma cells (HepG2), as it allows to analyze possible changes in the expression of the receptor for low- density lipoprotein (LDL-R). Indeed, induction of LDL-R increases hepatic LDL uptake and, consequently, its plasma reduction. In addition, the same cell line can be used to test for changes in the expression levels of genes involved in the biosynthesis of triglycerides, cholesterol, and very low- density lipoprotein (VLDL), such as DGAT2, APOB100, SREBP1 / 2, and HMGCR. These determinations can be performed by conventional techniques such as RT-PCR and Western-blotting.

[0074] In order to test the ability of the so-stances of interest to inhibit the process of differentiation of monocytes into macrophages, a preliminary condition for the onset of atherosclerosis, an in-vitro assay on monocytic cell line U937 can be employed. In this case, cells can be treated with macrophage colony-stimulating factor (M-CSF) and / or oxidized LDL in order to induce differentiation. Simultaneously, any substances or associations to be evaluated are added to test their effect on cellular levels of mRNA and proteins involved in the differentiation process. Inhibition of monocyte differentiation into macrophages indicates the protective activity of the substances on maintaining physiological endothelial morphology.

[0075] To assess cholesterol uptake, an in vitro assay can be conducted on a murine or human cell line. Treated and untreated cells are incubated with labeled cholesterol and subsequently-washed to remove the excess. At the end of the assay, the radioactivity of the solubilized cells is measured. Using the latter test, it could be appreciated that the composition of the present invention can result in a reduction of cholesterol uptake in the range of 1 to 80% compared with individual ingredients. The efficacy of the present invention can also be evaluated by an in vivo test on experimental animals in line with European Community and Ministry of Health guidelines. The test is conducted on Apoe mice that, after a period of acclimation, are divided into groups and subjected to the treatment. At time zero and at set intervals until the end of the treatment period, plasma samples are taken and total cholesterol, LDL cholesterol and HDL cholesterol levels are measured.

[0076] At the end of the treatment period, ex vivo tests may be performed. Therefore, mice are sacrificed and liver, intestinal and arterial tissue samples are taken. The harvested and lysed tissues are subjected to western blot to assess the levels of certain proteins of interest in particular, on the liver tissue the levels of HMG-5 CoA reductase and squalene monoxidase can be assessed, on the arterial tissue the levels of pro-inflammatory proteins such as IL-1β, TNF-a, TLR2, TLR4, and MAP kinase can be assessed, and on the intestinal tissue the total function of the tissue of interest can be assessed by assessing the levels of splicing proteins such as occludin or JAM-1.

[0077] Any of the in vitro or in vivo assays described herein can be used to evaluate the synergistic activity of the compounding referred to in the present invention.

[0078] As indicated above, the nutraceutical or pharmaceutical composition of the present invention is included within a pharmaceutical product or a dietary supplement, which is formulated in a suitable dosage form, the composition and preparation of which is within the capabilities of the person skilled in the art.

[0079] In a preferred embodiment form, the extract of a plant belonging to the genus Berberis in the nutraceutical or pharmaceutical composition of the invention is present in an amount between 1 mg and 7000 mg, preferably between 10 mg and 5000 mg, even more preferably between 20 mg and 3500 mg per single dosage unit.

[0080] Astaxanthin in the nutraceutical or pharmaceutical composition of the invention is present in an amount between 0.01 mg and 1500 mg, preferably between 0.05 mg and 800 mg, even more preferably between 0.1 mg and 500 mg per single posological unit.

[0081] The extract of a plant belonging to the genus Salvia in the nutraceutical or pharmaceutical composition of the invention is present in an amount between 1 mg and 5000 mg, preferably between 5 mg and 3000 mg, even more preferably between 10 mg and 1500 mg per single posological unit.

[0082] All the above preferred forms of embodiment are combinable with each other.

[0083] The pharmaceutical product or dietary supplement, which comprises the pharmaceutical or nutraceutical composition of the invention, is formulated in a preferably oral pharmaceutical form, which may be solid, semisolid or liquid. Examples include a powder, an orosoluble powder, a granulate, a hard capsule, a soft-gel capsule, a tablet, a sachet, a solution, a syrup, a suspension or an emulsion.

[0084] Non-limiting examples of nutraceutical or pharmaceutical compositions that are the subject of the present invention are provided below. As indicated above, such nutraceutical or pharmaceutical compositions are formulated as pharmaceuticals or dietary supplements and administered in a suitable oral dosage form.

[0085] The following examples are provided for illustrative purposes only and not limiting the scope of the invention as defined by the appended claims. EXAMPLES

[0086] EXAMPLE 1

[0087] Tablet

[0088] EXAMPLE 2

[0089] Tablet EXAMPLE 3

[0090] Capsule

[0091] EXAMPLE 4

[0092] Capsule

Claims

CLAIMS1.Nutraceutical or pharmaceutical composition comprising the combination of an extract of a plant belonging to the genus Berberis, astaxanthin and an extract of a plant belonging to the genus Salvia.2.Nutraceutical or pharmaceutical composition according to claim 1, for the use in the treatment or the prevention of cardiovascular diseases such as: hypertension, hypercholesterolemia, dyslipidemias , atherosclerosis, angina pectoris, heart attack, stroke, heart failure in both humans and animals.3.Nutraceutical or pharmaceutical composition according to claims 1 and 2, in which the extract of a plant belonging to the genus Berberis is Berberis aristata or Berberis vulgaris or Berberis aquifolium.4.Nutraceutical or pharmaceutical composition according to claims 1 to 3, in which the extract of a plant belonging to the genus Salvia is Salvia officinalis or Salvia miltiorrhiza or Salvia sclarea or Salvia pratensis orSalvia lavandulifolia.5.Nutraceutical or pharmaceutical composition for the use according to claims 1 to 4, comprising an amount of an extract of a plant belonging to the genus Berberis ranging from 1 mg to 7000 mg, preferably ranging from 10 mg to 5000 mg, still more preferably ranging from 20 mgto 3500 mg for a single dosage unit.6.Nutraceutical or pharmaceutical composition for the use according to any one of claims 1 to 5, comprising astaxanthin in an amount ranging from 0.01 mg to 1500 mg, preferably ranging from 0.05 mg to 800 mg, still more preferably ranging from 0.1 mg to 500 mg for a single dosage unit.7.Nutraceutical or pharmaceutical composition for the use according to any one of claims 1 to 6, comprising the extract of a plant belonging to the genus Salvia in an amount ranging from 1 mg to 5000 mg, preferably ranging from 5 mg to 3000 mg, still more preferably ranging from10 mg to 1500 mg for a single dosage unit.8.Nutraceutical or pharmaceutical composition for the use according to any one of claims 1 to 7, formulated in a liquid, semi-solid or solid oral dosage form.9.Nutraceutical or pharmaceutical composition according to claim 8, in which the dosage form is a powder, an orosoluble powder, a granulate, a hard capsule, a soft- gel capsule, a tablet, a sachet, a solution, a syrup a suspension or an emulsion.

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