Composition for use in treating hypertension

Abstract

The present invention describes a pharmaceutical / nutraceutical composition comprising L-arginine and pomace extract (Vitis vinifera) titrated in polyphenols. The nutraceutical composition of the present invention, by virtue of a synergistic effect between the two active components, has proven useful for lowering blood pressure and thus treating hypertension.

Description

[0001] COMPOSITION FOR USE IN TREATING HYPERTENSION

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of pharmaceutical compositions and food supplements for use in treating hypertension, in particular food supplements adapted to promote the control of blood pressure.

[0004] BACKGROUND ART

[0005] Hypertension is defined as systolic blood pressure (SBP) values greater than or equal to 140 mmHg and / or diastolic blood pressure (DBP) values greater than or equal to 90 mmHg. This is based on evidence from several randomized trials showing how treating patients with these blood pressure (BP) values leads to benefits in terms of prevention and treatment of diseases at the systemic level. The same classification is used in younger, middle-aged and older people, while BP centiles are used in children and adolescents, for whom data from interventional studies are not available.

[0006] Based on outpatient measurement, the global prevalence of hypertension was estimated at 1.1 billion individuals in 2015, with an incidence of over 150 million in Central and Eastern Europe.

[0007] The continuous relationship between blood pressure and risk of cardiovascular events has been demonstrated at all ages and in all ethnic groups and extends from high blood pressure levels to relatively low values. The overall prevalence of hypertension in adults is approximately 30-45%, with an age-standardized global incidence of 24% and 20% in men and women, respectively. SBP seems to be a better predictor of events than DBP after the age of 50. Hypertension becomes progressively more common with advancing age, with a prevalence of more than 60% in people over the age of 60. High DBP is instead associated with an increased cardiovascular risk and is more commonly elevated in younger patients (<50 years) than in older patients. DBP tends to vary starting in middle age as a result of arterial stiffening; therefore, SBP takes an even greater importance as a risk factor starting in middle age. In middle-aged and elderly people, the increase in differential pressure (the difference between SBP and DBP values) has a further unfavorable prognostic significance. Meta-analyses of randomized trials including several hundred thousand patients have shown that a 10 mmHg reduction in SBP or a 5 mmHg reduction in DBP is associated with a greater than 20% significant reduction in all-cause cardiovascular events, 10-15% all-cause mortality, 35% stroke, 20% coronary events, and 40% heart failure. As populations age, adopt more sedentary lifestyles and increase body weight, the incidence of hypertension worldwide will continue to rise. This high prevalence of hypertension is constant worldwide, regardless of income status.

[0008] The mortality index does not provide a complete picture of the burden of disease borne by individuals belonging to different populations. The overall burden of disease is assessed using the disability-adjusted life year (DALY), a time-based measure, which combines years of life lost due to premature mortality (YLL) and years of life lost due to time lived in states with less than full health or years of healthy life lost due to disability (YLD). One DALY represents the loss of the equivalent of one year of full health. Elevated blood pressure was the leading global contributor in 2015 to over 200 million DALYs. Importantly, despite advances in diagnosis and treatment over the past 30 years, DALYs attributable to hypertension have increased by 40% since 1990. A systolic blood pressure of 140 mmHg or above accounts for the majority of the mortality burden and DALYs (70%), and the largest number of annual deaths related to systolic blood pressure is due to ischemic heart disease (4.9 million), hemorrhagic stroke (2.0 million), and ischemic stroke (1 .5 million).

[0009] Hypertension has an independent and ongoing relationship with the incidence of several cardiovascular events [hemorrhagic stroke, ischemic stroke, myocardial infarction, sudden death, heart failure, and peripheral artery disease (PAD)]. More and more evidence is closely linking hypertension with an increased risk of developing atrial fibrillation (AF), and evidence is emerging that links early increases in blood pressure to an increased risk of cognitive decline and dementia.

[0010] Factors that increase the risk of having an increase in pressure can be distinguished into: modifiable risk factors, which include an incorrect diet (excessive consumption of salt, diet rich in saturated fats and trans fats, low intake of fruits and vegetables), physical inactivity, consumption of tobacco and alcohol, overweight or obesity; unmodifiable risk factors, which include a family history of hypertension, an age over 65 years and co-existing diseases such as diabetes or kidney disease.

[0011] The treatment of most patients will require drug therapy in addition to lifestyle measures to achieve optimal blood pressure control. The main classes of drugs recommended for the treatment of hypertension are: ACE inhibitors, angiotensin receptor antagonists (ARBs), beta-blockers, alpha-blockers, calcium channel blockers (CCBs), and thiazide and non-thiazide diuretics, such as chlorthalidone and indapamide. Such indications derive from: i) proven ability to reduce blood pressure; evidence from placebo-controlled studies, confirmed by recent metaanalyses, capable of reducing cardiovascular events; ii) evidence of a broad equivalence on overall cardiovascular morbidity and mortality, with the conclusion that the benefit deriving from their use derives mainly from the reduction of blood pressure.

[0012] There are several side effects resulting from the use of such drugs. Among the most common are: persistent dry cough (ACE inhibitors); dizziness (ARB); rashes, headaches, constipation, dizziness, fatigue (CCB); gastrointestinal disorders (diuretics); fatigue, slow heartbeat, diarrhea and nausea, sleep disorders (betablockers); drowsiness, postural hypotension, syncope, asthenia, dizziness, headache and dry mouth (alpha-blockers). For such a reason, scientific research of recent years has focused on safer alternative therapeutic remedies, possibly of natural origin, which can promote a more physiological regulation of blood pressure, also in support of classic pharmacological therapies, in order to reduce the doses of active ingredients and, therefore, also their side effects.

[0013] Very recently, clinical research has focused on an important therapeutic target represented by the NO-soluble GC pathway (sGC)-cGMP, one of the main cascade signaling pathways for blood pressure regulation, the impairment of which can lead to hypertension. This signaling requires a sufficient supply of L-arginine, which is a substrate for NOSs (endothelial NOS [eNOS], neuronal NOS [nNOS], and inducible NOS [iNOS]) to generate nitric oxide NO. NO is an endogenous gaseous mediator that can easily diffuse through cell membranes and bind to soluble cytosolic guanylate cyclases (sGC), represented by a heterodimeric protein consisting of an a and a [3 subunit, with a heme iron structure that binds NO (H-NOX domain). The binding of NO to sGC triggers a conformational change in the enzyme and activates the catalytic site, which converts GTP into the second messenger cGMP which, in turn, binds and activates especially protein kinases (PKG1 and PKG2) of fundamental importance for regulating vascular tone and therefore blood pressure. The pathophysiological impairment of the NO-sGC-cGMP signaling pathway contributes to a dysregulation of blood pressure. The weakening or interruption of this pathway could be caused by various factors, such as the decrease in the bioavailability of endogenous L-arginine, due to the increase in the activity of the arginase enzyme, resulting in a reduction in the production of NO and therefore in the tissue levels of cGMP, which could be associated with the genesis of the hypertensive phenomenon. Accordingly, it is logical to consider the dietary supplementation of L-arginine, as a source of NO to restore cGMP-dependent signaling, as a useful approach.

[0014] It is also important to point out that the activity of enzyme sGC is very sensitive to the conditions of cellular oxidative stress which, by converting the Fe+2atom of the heme group to Fe+3, favor a lower response of sGC to NO, resulting in a reduced production of cGMP, which translates into a difficulty in maintaining the functional homeostasis of the organ concerned, including blood pressure. On the other hand, the increase in oxidative stress conditions can also alter the functionality of the eNOS enzyme, resulting in a lower production of endogenous NO, or they can oxidize the NO produced to peroxynitrite (NOs-), factors that lead to a reduced production of cGMP, with all the pathological consequences that derive therefrom, including hypertension. Therefore, a further useful approach to the maintenance of physiological homeostatic conditions can be represented by dietary supplementation with antioxidant molecules. In fact, the intake of such compounds could promote protection against the state of oxidative stress, preventing in particular the oxidation of the Fe+2atom of the heme group with maintenance of the activity of enzyme sGC and consequent production of cGMP, which translates into the possibility of maintaining the functional homeostasis of the organ concerned and in particular the regulation of blood pressure. Natural polyphenols can be particularly useful for such a purpose, as hydrophilic molecules capable of diffusing at the cytosolic level and of interacting with catalytic sites of protein subunits, preventing the oxidation of physiological metal species, including the iron ion.

[0015] It is the aim of the present invention to provide a nutraceutical composition which can be a useful alternative for use in treating hypertension or which can at least be used as an adjuvant to the already commercially known hypertension drugs.

[0016] SUMMARY OF THE INVENTION

[0017] The present invention relates to a pharmaceutical / nutraceutical composition, comprising L-arginine and a grape pomace extract of Vitis vinifera. For the purposes of the present invention, it is apparent that the two active ingredients are contained in a therapeutically effective amount.

[0018] The nutraceutical composition of the present invention has surprisingly proven useful in lowering blood pressure, i.e., it is useful in treating hypertension due to a synergistic effect of the two components.

[0019] DETAILED DESCRIPTION OF THE INVENTION

[0020] Preferably, for the purposes of the present invention, the grape pomace extract is a polar extract obtained from grape pomace. For the purposes of the present invention, grape pomace extract means a hot aqueous extract at a temperature of 45-55°C. Since the extraction solvent is water, in which the polyphenols are poorly soluble, the extraction must be carried out at a temperature higher than that of the environment so as to increase the solubility of the polyphenols in water. However, it is not recommended to exceed 55°C to avoid the degradation of the polyphenols themselves.

[0021] For the purposes of the present invention, the grape pomace from which the extract is to be made can be obtained from the recovery of the grape pomace of any winemaking process of any cultivar, preferably from an Aglianico cultivar. The grape pomace extract according to the present invention contains Resveratrol, Gallic acid, Catechin, Ferulic acid, Quercetin, Procyanidin B2. The grape pomace extract of the cultivar Aglianico has a peculiar polyphenol profile, whereby 1000 mg of dry extract contains:

[0022] Resveratrol 2.5-20 mcg;

[0023] Gallic acid 300-900 mcg;

[0024] Catechin 3500-4500 mcg; Chlorogenic acid 10-30 mcg;

[0025] Quercetin 100-400 mcg;

[0026] Procyanidin B2 200-600 mcg;

[0027] More preferably, the grape pomace extract, rich in polyphenols, is microencapsulated in maltodextrins (Maltdextrinated Grape Pomace Extract: MaGPE) as described in EP3884955A1 incorporated herein by reference.

[0028] Even more preferably, the extract of the present invention is a grape pomace extract of the Aglianico cultivar, rich in polyphenols, microencapsulated in maltodextrins (Aglianico MaGPE).

[0029] Preferably the pharmaceutical / nutraceutical composition of the invention is in the form of a gastro-resistant oral formulation.

[0030] It has been surprisingly discovered that the combination of L-arginine and MaGPE produces a synergistic effect in contributing to the decrease in blood pressure, i.e. , in the treatment of hypertension.

[0031] The nutraceutical composition of the present invention is useful in contributing to the regulation of blood pressure.

[0032] A preferred method for preparing a grape pomace extract, microencapsulated in maltodextrins (MaGPE), with high polyphenol bioavailability, is described in described in EP3884955A1 incorporated herein by reference. Said method comprises: i) recovering the grape pomace after the winemaking process; ii) extracting the grape pomace with water at 45-55°C; iii) centrifugation of the extractive solution; iv) drying the extractive solution by spray-drying technique, in the co-presence of maltodextrins. Preferably the extraction (ii) occurs for 160-200 min, more preferably 180 min.

[0033] Preferably the centrifugation (iii) occurs by using a Macfuge 260 type centrifuge, continuously operating at 9600 rpm.

[0034] Preferably, the drying (iv) occurs by spraying an aqueous solution of maltodextrins at a concentration of 40-70%. The composition, according to the invention, is obtained simply by mixing the components in the required amounts with normal mixers.

[0035] The composition will normally be formulated into powders, capsules, tablets, using known techniques (encapsulation, compression, controlled release, microgranules, nanocapsules, multilayer) as described in the pharmacopoeia for the preparation of gastro-resistant pharmaceutical formulations for oral use.

[0036] Preferably, a composition according to the invention comprises or consists of:

[0037] L-arginine 10 - 70%

[0038] MaGPE 20 - 70%

[0039] Excipients q.s. where the percentages indicated are expressed in weight calculated with respect to the total weight of the composition.

[0040] The excipients are preferably selected from the group consisting of silicon dioxide, com starch, microcrystalline cellulose, calcium phosphate, talc, aluminum silicate. A preferred embodiment of the pharmaceutical formulation according to the invention consists of gastro-resistant capsules or tablets, containing:

[0041] 50 - 350 mg L-arginine, preferably 200 mg;

[0042] 100 - 350 mg of MaGPE from Aglianico, preferably 300 mg.

[0043] In a particularly preferred manner, the composition can contain:

[0044] Resveratrol 0.8-6 mcg, preferably 3.5 mcg;

[0045] Gallic acid 330-430 mcg, preferably 230 mcg;

[0046] Catechin 1370-1625 mcg, preferably 1250 mcg;

[0047] Chlorogenic acid 5-8 mcg, preferably 6 mcg;

[0048] Quercetin 7-13 mcg, preferably 70 mcg;

[0049] Procyanidin B2 120-140, preferably 140 mcg;

[0050] L-arginine 50 - 350 mg, preferably 200 mg.

[0051] A particularly preferred embodiment of the pharmaceutical formulation according to the invention is a gastro-resistant capsule consisting of:

[0052] L-arginine, 200 mg; Aglianico MaGPE, 300 mg; capsule constituents (titanium dioxide 1.9%; gellan gum 5.0%; hypromellose q.s. to 100%). In particular, the composition preferably comprises: L-arginine, 200 mg; Resveratrol, 3.5 mcg; Gallic acid, 230 mcg; Catechin, 1250 mcg; Chlorogenic acid, 6 mcg; Quercetin, 70 mcg; Procyanidin B2, 140 mcg.

[0053] The present invention can be better understood in the light of the following embodiments.

[0054] EXPERIMENTAL SECTION

[0055] EXAMPLE 1 - Preparation of MaGPE

[0056] The grape pomace of the Aglianico cultivar is recovered after the winemaking process and extracted with water at +50°C. The extractive solution is centrifuged with the Macfuge 260 system, operating at 9600 rpm continuously. The extractive solution is dried by spray-drying technique, using a Pilotech YC-500 system, in the co-presence of maltodextrin at a concentration of 40-70%.

[0057] EXAMPLE 2 - Preparation of gastro-resistant capsules

[0058] 500 mg gastro-resistant capsules were chosen, the heads and bodies of which consist of 1.9% titanium dioxide, 5.0% gellan gum, hypromellose q.s to 100%. A powder mixture of MaGPE and L-arginine in appropriate proportions was set up to fill the capsules so as to ensure an overall content thereof as follows: L-arginine, 200 mg; MaGPE, 300 mg. In particular, the composition preferably comprises: Resveratrol, 3.5 mcg; Gallic acid, 230 mcg; Catechin, 1250 mcg; Chlorogenic acid, 6 mcg; Quercetin, 70 mcg; Procyanidin B2, 140 mcg.

[0059] EXAMPLE 3 - In vitro data

[0060] To verify the duodenal bioaccessibility and bioavailability of L-arginine and the polyphenols contained in MaPGE, an experimental protocol capable of simulating gastrointestinal digestion and trans-epithelial permeation was employed. Specifically, an aliquot (5 g) of the mixture of L-arginine and MaGPE was mixed with 6 mL of artificial saliva consisting of: KCI (89.6 g / L), KSCN (20 g / L), NaH2PO4 (88.8 g / L), Na2SO4 (57.0 g / L), NaCI (175.3 g / L), NaHCOs (84.7 g / L), urea (25.0 g / L) and 290 mg of a-amylase. The solution pH was adjusted to 6.8 with 0.1 M HCI. The mixture was placed in a plastic bag containing 40 mL of water and homogenized in a Stomacher 80 Microbiomaster (Seward, Worthing, UK) for 3 min. Immediately, 0.5 g of pepsin (14,800 U) dissolved in 0.1 N HCI was added, the pH was adjusted to 2.0 with 6 M HCI, and incubated at 37°C in a Polymax 1040 orbital shaker (250 rpm) (Heidolph, Schwabach, Germany) for 2 h. After gastric digestion, pancreatic digestion was simulated as follows: the pH was increased to 6.5 with 0.5 M NaHCOs and then, 5 mL of a mixture of pancreatin (8.0 mg / mL) and bile salts (50.0 mg / mL) (1 :1 ; v / v) dissolved in 20 mL of water, were added and incubated at 37°C in an orbital stirrer (250 rpm) for 2 h. The digested intestinal sample was lyophilized and stored at -80°C until further analysis. For the evaluation of trans-epithelial permeation, the human colon cancer cell line Caco2 (HTB-37), provided by the American Type Culture Collection (LGC Promochem, Molsheim, France), was chosen. The cells were cultured (17-21 steps) in Medium Dulbecco Modified Eagle (DMEM) medium with 4.5 g / L glucose and supplemented with 12.5% fetal calf serum (FCS), 1 % non-essential amino acids, 5 mM L-glutamine, 40 U / mL penicillin, 100 pg / mL gentamicin, and 40 pg / mL streptomycin (DMEMc). The cells were maintained at 37°C in a humidified CCh / air atmosphere (5:95, v / v) and subjected to trypsinization every 7 days. Then, cells were seeded in transwells (3 pm x 24 mm Transwell® inserts) at 6 x 104 cells / cm2. The medium (15 mL of DMEM containing 12.5% FCS) was changed every 2 days until the cells reached confluence (7-8 days). The integrity of the monolayers (grown for 14-15 days) was assessed by measuring transepithelial electrical resistance (TEER) using a Millicell-ERS device (Millipore, Zug, Switzerland). Only Caco2 monolayers with TEER greater than 300 O x cm2were used for the experiments. The integrity of the monolayers was verified before, during and after the experiment. Then, the Caco2 cell monolayers were gently rinsed twice with PBS, the medium was removed from the apical and basal side of the cultures, the transport medium (TM, Hank's balanced salt solution supplemented with 25 mM glucose and 10 mM HEPES) was added to the apical (2 mL) and basolateral (2 mL) compartments, and the pH was adjusted to 6 or 7.4. After 30 minutes of incubation, the medium on the apical side was replaced with a fresh TM containing lyophilized intestinal digest solutions at increasing concentrations (0; 0.5; 1 ; 2 or 4 mg). After 4 hours of incubation at 37°C, the apical and basal solutions were collected, and aliquots (5 mL) were filtered through Phenex-PVDF 17 mm 0.45 pm syringe filters (Phenomenex, Torrance, CA). The L- arginine and main polyphenols contained in both the intestinal digest and in the apical and basal solutions were monitored with an HPLC-diode-array detector (DAD) analysis. The following data were obtained: duodenal bioaccessibility (%): 50%; bioavailability (%): 15%.

[0061] With particular reference to MaGPE, the experimental data indicate that in gastro- resistant capsules, it is characterized by a duodenal bioaccessibility and a bioavailability of polyphenols, equivalent to those obtainable with an aliquot equal to about 8 L of wine obtainable from the same Aglianico grape cultivar. Such data support the effectiveness of gastro-resistance and the microencapsulation in maltodextrin technique of Aglianico pomace extract, in increasing the duodenal bioaccessibility and the bioavailability of the polyphenols contained in MaGPE, respectively.

[0062] EXAMPLE 3 - In vivo data

[0063] 24 adult male Wistar rats (250-300 g) were used, purchased from Charles River (Calco, SO, Italy), divided into four groups (n=4). Arterial hypertension was induced by daily subcutaneous administration of dexamethasone (20 pg / kg / day) for 7 days. All the rats were aged between 6 and 9 months and were housed in polyethylene cages, subjected to a light / dark cycle of 12 / 12 h (light 8:00 - 20:00 h), at constant temperature (24 ± 1 °C) and humidity (60.5%), with free access to food and water. The study was conducted in accordance with the guidelines for the accommodation and protection of laboratory animals of the National Institute of Health. The protocol was approved by the Ethics Committee of animal testing of the Ministry of Health (Authorization Number: 157 / 2017-PR). The rats were randomly assigned to one of four groups: group 1 , placebo; group 2, L-arginine (10 mg / kg); group 3, MaGPE (20 mg / kg); group 4, mix L-arginine (10 mg / kg) and MaGPE (20 mg / kg). The placebo and treatments were administered by oral gavage technique for a period of 3 months (1 time / day). The mean arterial pressure (MAP) was monitored with a blood pressure transducer (model BLPR2, World Precision Instruments, Sarasota, FL), in contact with the catheter positioned in the left femoral artery, connected to an ad hoc bridge amplifier apparatus and provided with LabView software (National Instruments S.R.L., Milan, Italy), which automatically measured the MAP values every 60 seconds, providing an average value every 5 min. The ECG recordings (at a sampling frequency of 1 KHz) were carried out by applying electrodes under the skin according to the three Einthoven leads. The signals were captured with a differential signal amplifier and the acquisition of biomedical data was obtained by means of LabView software. The heart rate measurements were carried out with 5- second acquisitions according to the following procedure: (1 ) the signal was filtered with a low-band filter (cutoff frequencies 5-40 Hz), (2) the mean and standard deviation values of the filtered signal were determined in the interval of 5 seconds, (3) the R peaks were recognized considering the mean ± 1.5 SD as the signal threshold and the sign changes of the derivative, (4) HR was obtained by calculating the number of R peaks in the unit of time (1 minute). For statistical analysis and graphical representation, values were used at 10 and 20-minute intervals. For the baseline values, the means of three recordings obtained at 10-m inute intervals, immediately prior to the first ME, were used. For the first 30 minutes post-ME1 , recordings were used at 10-minute intervals. For the next observation period, recordings were carried out at 20-minute intervals. The blood pressure and heart rate data were summarized as mean ± SD and plotted as standard error of the mean (SEM). Statistical analysis was carried out using the one-way analysis of variance (ANOVA) method for repeated measurements. When the ANOVA revealed a statistically significant effect (P < 0.05), the Holm-Sidak test was carried out for "post hoc" comparisons. All the analyses were carried out using the Sigma Stat program, version 3.5 (Jandel Corporation San Mateo, California). The experimental data are shown in Table 1 .

[0064] Table 1. Effects on mean arterial pressure (MAP) (mmHg) of placebo and treatments with L-arginine, MaGPE and a mixture of both, on rats made hypertensive with dexamethasone.

[0065] Group 1 Group 2 Group 3 Group 4

[0066] (placebo) (L-arginine) (MaGPE) (mix)

[0067] TO 228 ± 6 233 ± 5 237 ± 6 230 ± 4

[0068] T1 220 ± 4 186 ± 3 191 ± 4 165 ± 3

[0069] A% -3.5 -20.1 -19.3 -28.3

[0070] MaGPE: Maltdextrinated Grape Pomace Extract (polyphenolic extract from pomace microencapsulated in maltodextrins). Group 1 : treatment with placebo; Group 2: treatment with L-arginine; Group 3: treatment with MaGPE;

[0071] Group 4: treatment with a mixture of L-arginine and MaGPE; TO, baseline status; T1 , after 90 days of treatment. Data are expressed as mean ± standard deviation (p<0.05)

[0072] RESULTS

[0073] As can be seen from the data reported in Table 1 , the formulation called mix, consisting of the treatment of subjects belonging to group 4, comprising the mixture (mix) of L-arginine and MaGPE according to the present invention, favored a decrease in blood pressure, greater than the sum of the effects of the components taken individually.

[0074] Such a formulation clearly indicates a synergistic effect between the two active ingredients of the composition. CONCLUSIONS

[0075] The nutraceutical product based on a mixture of L-arginine and MaGPE is suggested as a useful support, or even a possible alternative to classic pharmacotherapy for controlling blood pressure. The results obtained indicate the possibility of an innovative treatment which can represent a valid alternative in clinical practice for treating hypertension and the diseases associated therewith.

Claims

CLAIMS1. A pharmaceutical composition comprising a therapeutically effective amount of L-arginine and a grape pomace extract (GPE) of Vitis vinifera.

2. The composition according to claim 1 , wherein the grape pomace extract is a polar extract.

3. The composition according to claim 2, wherein the polar extract is a hot aqueous extract at a temperature of 45-55°C.

4. The composition according to claim 3, wherein the grape pomace from which the extract is to be made can be obtained from the recovery of the grape pomace of any winemaking process of any cultivar, preferably from an Aglianico cultivar.

5. The composition according to any one of claims 1 -4, wherein the grape pomace extract is microencapsulated in maltodextrin (Maltdextrinated Grape Pomace Extract: MaGPE).

6. The composition according to any one of claims 1 -5 in the form of a gastro-resistant oral formulation.

7. The composition according to any one of claims 1 -6, comprising: L-arginine 10 - 70%; andMaGPE 20 - 70%; where the percentages indicated are expressed in weight calculated with respect to the total weight of the composition.

8. The composition according to any one of claims 1 -7 consisting of a gastro-resistant capsule or tablet comprising:50 - 350 mg L-arginine, preferably 200 mg;100 - 350 mg of MaGPE from Aglianico, preferably 300 mg.

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

10. A composition according to any one of claims 1 -8 for use in the treatment of hypertension.

11. A composition according to any one of claims 1 -8 for use as an adjuvant in treating hypertension.