Compositions based on annurca apple, quercetin and licorice and uses thereof

Abstract

The object of the present invention is a composition comprising a mixture that comprises or, alternatively, consists of Annurca apple, quercetin and licorice and, optionally, prickly pear and olive. A further object of the present invention is a composition comprising a mixture that comprises or, alternatively, consists of Annurca apple, quercetin and licorice and, optionally, prickly pear and olive, said composition being for use in a method for the treatment of diseases of the digestive system, preferably for the treatment of gastric disorders. Finally, an object of the present invention is pharmaceutical formulations, medical devices or nutraceutical formulations containing said mixture and / or composition, for example in the form of oral formulations (briefly, the formulations of the invention).

Description

[0001] COMPOSITIONS BASED ON ANNURCA APPLE, QUERCETIN AND LICORICE AND USES THEREOF

[0002] ***

[0003] The object of the present invention is a composition comprising a mixture that comprises or, alternatively, consists of Annurca apple, quercetin and licorice and, optionally, prickly pear and olive. A further object of the present invention is a composition comprising a mixture that comprises or, alternatively, consists of Annurca apple, quercetin and licorice and, optionally, prickly pear and olive, said composition being for use in a method for the treatment of diseases of the digestive system, preferably for the treatment of gastric disorders. Finally, an object of the present invention is pharmaceutical formulations, medical devices or nutraceutical formulations containing said mixture and / or composition, for example in the form of oral formulations (briefly, the formulations of the invention). Gastroesophageal reflux disease (GERD) is a clinical syndrome characterized by symptoms correlated to the backflow of gastric contents into the esophagus. The typical symptoms are pyrosis, acid regurgitation, retrosternal pain, epigastric pain, eructation, nausea, dyspepsia and vomiting, and they are often sufficient to determine the diagnosis, but less common symptoms and signs, such as dysphagia and chronic cough frequently predominate instead. GERD is present in about 20% of the adult population in high-income countries and women seem to suffer more from it.

[0004] According to the Montreal definition, GERD is characterized by symptoms and / or tissue damage deriving from repeated or prolonged exposure of the lining of the esophagus to the acid contents of the stomach, a characteristic that arises when the lower esophageal sphincter (LES) is not able to completely seal off the esophagus to isolate it from gastric contents.

[0005] GERD is a chronic disease which has considerable repercussions on the quality of life of patients and is associated with an increased risk of esophagitis, esophageal stenosis, Barrett's esophagus and esophageal adenocarcinoma. Obesity and tobacco smoke are predisposing factors.

[0006] Studies have demonstrated that reactive oxygen species (ROS), produced on a massive scale in the gastrointestinal tract, play an important role in the etiopathogenetic mechanism of the damage to the gastric mucosa, in both inflammatory and neoplastic diseases of the gastrointestinal tract. An overproduction of free radicals manifests itself above all in the presence of a prolonged inflammatory state, generating a condition of oxidative stress followed by cell aging and damage. A diet rich in antioxidants could exert a beneficial effect in the prevention and treatment of gastric diseases and the inflammatory state associated with them.

[0007] Gastroesophageal reflux disease is usually clinically diagnosed by evaluating the symptoms and the response to pharmacological treatment. Heartburn, also in the absence of acid regurgitation, is generally sufficient for the diagnosis, especially if the symptoms worsen in the postprandial phase and / or in a lying position. Similarly, the cessation of symptoms following treatment with histamine type 2 (H2) receptor blockers or proton pump inhibitors (PPIs) is considered diagnostic. In some patients, however, the symptoms caused by reflux persist notwithstanding treatment with high-dose PPIs.

[0008] The mechanisms of action of these two classes of drugs are different: H2 blockers decrease gastric acid secretion by inhibiting the stimulation of parietal cells by histamine, whereas proton pump inhibitors act by directly reducing the amount of acid secreted by parietal cells in the stomach lumen. In particular, PPIs alter normal gastrointestinal functions by means of an irreversible inhibition of the proton pump hydrogen-potassium ATPase (H+ / K+ATPase) in the parietal cells of the gastric mucosa. The result is a direct reduction in acid secretion correlated with a blocking of the transport of H+into the gastric lumen and an indirect inhibition of the activation of the digestive enzyme pepsin.

[0009] PPI-based pharmacological therapies, both short-term and long-term, are widely used in the management of gastroesophageal reflux disease (GERD), esophagitis, peptic ulcers, Zollinger-Ellison syndrome, Barrett's esophagus, functional dyspepsia, and eradication of H. pylori. A large number of patients, however, manifest a return of symptoms after ceasing therapy with PPIs; a reason why the pharmacological treatment will often have to be continued for a whole lifetime.

[0010] Furthermore, notwithstanding the effectiveness of these compounds, their mechanism of action is correlated with a series of side effects that preclude their use for prolonged periods, without considering the maintenance periods. In fact, in patients undergoing a pharmacological treatment with proton pump inhibitors, the following disorders are frequently observed:

[0011] - vitamin B12 deficiency;

[0012] - hypomagnesemia;

[0013] - decrease in calcium absorption with a consequential increase in bone fragility and risk of fractures;

[0014] - dementia;

[0015] - fundic gland polyps (among the serious complications deriving from long-term therapy with PPIs);

[0016] - acute interstitial nephritis and renal system damage;

[0017] - electrolyte deficiencies;

[0018] - increase in infections.

[0019] In studies conducted to establish the nephrotoxic potential of PPIs, a direct correlation was established between the increase in hospitalization due to acute kidney damage and prolonged therapy with these gastroprotectants; in particular, a doubling of hospitalizations within 120 days of the start of therapy was observed. Acute interstitial nephritis also showed to be rather common in such patients compared to those who had not undergone a pharmacological treatment.

[0020] PPI-induced nephrotoxicity is caused by an alteration of lysosomal acidification with a consequent increase in oxidative stress affecting the organ involved. Research has revealed a significant association between acute kidney failure, chronic kidney disease and treatment with IPPs, a statistic based on AERS (Adverse Event Reporting System).

[0021] A higher percentage of kidney damage occurred in the first year of treatment with PPIs, with a longer average time for the development of chronic kidney disease compared to the onset of acute kidney failure. The various supporting studies demonstrate the importance of a limited and rational use of such drugs, often administered in an unsuitable manner.

[0022] Given the risk of long-term side effects, it is thus advisable to administer a greatly reduced dose of PPIs for maintenance therapy and periodic attempts to wean off from the drug should be considered. The blocking of acid secretion induced by a therapy with PPIs is also associated with a masking of H. pylori infections, the main cause of chronic gastritis and peptic ulcers.

[0023] Furthermore, it has recently been demonstrated that PPIs have an inhibitory activity against cytochrome P450, responsible for the metabolism of many drugs such as, for example, clopidogrel, a prodrug activated by the action of cytochrome P450 and used as a platelet antiaggregant. The inhibitory activity performed by PPIs on the cytochrome enzyme could thus lead to the ineffectiveness of therapy with other drugs that the patient takes together with PPIs to treat coexisting diseases.

[0024] GERD also has a considerable socioeconomic impact at the level of both health system resources and the personal resources of the individual patient. As mentioned, in addition to some fundamental and necessary changes in lifestyle (for example losing weight and quitting the smoking habit), drugs and surgery are the main treatment options. PPIs are the most common pharmacological treatment and, as noted, after the initial therapy at a full dose the objective is to arrive at using the lowest possible effective dose to avoid, or at least reduce, the likelihood of onset of long-term side effects.

[0025] Laparoscopic fundoplication is an alternative invasive surgical treatment which has been proposed and practiced on selected patients, above all young ones in good health who respond poorly to pharmacological treatments. New less invasive endoscopic surgical techniques are under study but are not yet mature.

[0026] Optimal management of GERD leaves many questions open, such as the diagnostic definition, clinical assessment, and recourse to endoscopic techniques and functional studies. In the current state of the art, the therapeutic approach is substantially tied to the use of PPIs, which are associated with antacids, alginates, and hyaluronic acid, with a large portion of patients who respond poorly or not at all and with the possible previously mentioned contraindications of the aforesaid drugs.

[0027] Thus, there remains a great need to have pharmacological and / or nutraceutical therapies as alternatives to what is known in the prior art and novel mixtures or compositions which are effective in the prevention and treatment of disorders affecting the digestive system and free of the side effects of the therapies used to date, are not capable of limiting the activity of cytochrome P450, and can thus supplement or replace the current pharmacological treatments.

[0028] The technical problem that the present invention addresses and resolves is that of providing mixtures and / or compositions that are capable of treating disorders affecting the digestive system. Furthermore, said mixtures and / or compositions are free of side effects, well tolerated and stable over time.

[0029] The use of said mixtures and / or compositions for the treatment of disorders affecting the digestive system, preferably for the treatment of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux, is another aim of the present invention.

[0030] The present invention provides compositions (pharmaceutical compositions, nutraceutical compositions, compositions for medical devices as per Regulation (EU) 745 / 2017), briefly: compositions of the invention, comprising Annurca apple, quercetin and licorice and, optionally, prickly pear and olive. These aims, and still others which will become clear from the detailed description that follows, are achieved by the compositions, mixtures and processes of the present invention, thanks to the technical features claimed in the appended claims.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] Following an intense research activity, the Applicant has developed innovative compositions and uses thereof in methods of treatment, both therapeutic and non-therapeutic, as disclosed in detail in the present description.

[0033] An object of the present invention is a composition (briefly, composition of the invention) comprising (I) and, optionally, (II), wherein:

[0034] (I) is a mixture (briefly, mixture of the invention) comprising or, alternatively, consisting of:

[0035] (a) a dry extract of Annurca apple (fruit, botanical name Malus domestica Bork cultivar Annurca)',

[0036] (b) quercetin;

[0037] (c) a dry extract of licorice (root, botanical name Glycyrrhiza glabra),' and, optionally,

[0038] (II) is at least one pharmaceutical or food grade additive and / or excipient.

[0039] Preferably, said composition being for use in a method of treatment of individuals affected by I) gastric disorders selected from the group comprising or, alternatively, consisting of heartburn, abdominal and epigastric pain, gastric ulcer and / or gastroesophageal reflux.

[0040] An object of the present invention is a composition (briefly, composition of the invention) comprising (I) and (I') and, optionally, (II), wherein:

[0041] (I) is a mixture (briefly, mixture of the invention) comprising or, alternatively, consisting of:

[0042] (a) a dry extract of Annurca apple (fruit, botanical name Malus domestica Bork cultivar Annurca),'

[0043] (b) quercetin;

[0044] (c) a dry extract of licorice (root, botanical name Glycyrrhiza glabra),'

[0045] (I') is a mixture of prickly pear and olive (leaf) extracts; and, optionally,

[0046] (II) is at least one pharmaceutical or food grade additive and / or excipient.

[0047] Preferably, said composition being for use in a method of treatment of individuals affected by I) gastric disorders selected from the group comprising or, alternatively, consisting of heartburn, abdominal and epigastric pain, gastric ulcer and / or gastroesophageal reflux.

[0048] An object of the present invention is a composition (briefly, composition of the invention) comprising (I) and (I') and, optionally, (II), wherein:

[0049] (I) is a mixture (briefly, mixture of the invention) comprising or, alternatively, consisting of:

[0050] (a) a dry extract of Annurca apple (fruit, botanical name Malus domestica Bork cultivar Annurca),'

[0051] (b) quercetin;

[0052] (c) a dry extract of licorice (root, botanical name Glycyrrhiza glabra),'

[0053] (I') is a mixture of prickly pear and olive (leaf) extracts; and, optionally,

[0054] (II) is at least one pharmaceutical or food grade additive and / or excipient;

[0055] - wherein said composition is for use in a method of treatment of individuals affected by I) gastric disorders selected from the group comprising or, alternatively, consisting of heartburn, abdominal and epigastric pain, gastric ulcer and / or gastroesophageal reflux, and II) chronic diseases selected from the group comprising or, alternatively, consisting of diabetes, heart diseases and neurodegenerative diseases.

[0056] Preferably, thanks to its high antioxidant and anti-inflammatory activity, said composition has valid application toward a subpopulation of individuals having a very complex clinical situation, said subpopulation being represented by individuals who, in addition to having a need to reduce gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer and gastroesophageal reflux, simultaneously have a need to reduce the risk of chronic diseases such as diabetes, heart diseases and neurodegenerative diseases.

[0057] Preferably, diabetes mellitus is a chronic disease characterized by an excess of sugars (glucose) in the blood, known as hyperglycemia. It is divided into two main forms: type 1 diabetes and type 2 diabetes.

[0058] Preferably, cardiovascular diseases are all those diseases related to the heart and blood vessels, such as:

[0059] - cerebrovascular diseases (stroke and transient ischemic attacks);

[0060] - ischemic cardiomyopathy (atherosclerotic coronary heart disease, microcirculation disease, coronary vasospasm) with a risk of angina or myocardial infarction;

[0061] - heart failure;

[0062] - atherosclerosis of the main arteries;

[0063] - aortic aneurysm;

[0064] - hyperkinetic heart arrhythmias (extrasystole, atrial or ventricular tachycardia, fibrillation and atrial or ventricular flutter) and hypokinetic ones (bradycardia, sinoatrial, atrioventricular or intraventricular blocks);

[0065] - genetic-based cardiomyopathies and channelopathies;

[0066] - right heart failure and pulmonary hypertension;

[0067] - hypertrophic cardiomyopathies due to arterial hypertension;

[0068] - congenital, degenerative or inflammatory heart valve diseases;

[0069] - immune-based or infective endocarditis and pericarditis.

[0070] Preferably, the neurodegenerative diseases can include Alzheimer's disease, frontotemporal dementia, Parkinson's disease, ALS (amyotrophic lateral sclerosis) and Huntington's disease, among the best known, which affect the central nervous system and result in the loss of neurons in selective areas of the brain.

[0071] The Annurca apple is a fruit that has a high content of minerals (iron, phosphorous, manganese, potassium), vitamins (B1 , B2, B3 and C) and fibers. Numerous supporting studies demonstrate the ability of this fruit to regulate intestinal functions, stimulate diuresis and counter increases in the blood cholesterol level. Furthermore, in this fruit, and in the extract thereof, numerous phenolic compounds are present, namely chlorogenic acid, caffeic acid, catechin, epicatechin, rutin and phlorizin, which possess a high antioxidant power.

[0072] Preferably, said (a) dry extract of Annurca apple is a dry extract deriving from the fruit of Malus domestica Bork cultivar Annurca with an extract / drug (E / D) ratio of 1 : 10 in water / ethanol.

[0073] Quercetin is a flavonoid present in numerous varieties of fruit, vegetables and beverages. It is not present in nature in its isolated form, but rather generally as a component of rutin and quercitrin. Its potentialities as an antioxidant make it possible to effectively counter the action of free radicals (ROS).

[0074] Preferably, said (b) quercetin, is granular quercetin with a minimum degree of purity of 95%, obtained from Sophora japonica L.

[0075] Licorice (Glycyrrhizza glabra) is a Mediterranean herbaceous plant with demonstrated anti-inflammatory and antioxidant properties due to its complex phytochemical composition. The roots and rhizomes are in fact rich in triterpenoid saponins (including glycyrrhizin), flavonoids (liquiritin, isoliquiritin), tannins, resins and phytosterols. Glycyrrhizin is a saponin glycoside with anti-inflammatory action. Flavonoid compounds ensure an antispastic effect on gastric and duodenal smooth muscle which enhances the anti-inflammatory mechanism of glycyrrhizin.

[0076] Preferably, said (c) dry extract of licorice is a dry extract deriving from the aqueous extraction of the root of Glycyrrhiza glabra titrated at 10% glycyrrhizic acid.

[0077] According to a preferred aspect of the present invention, said (a) extract of Annurca apple, is present in said mixture (I) in an amount by weight comprised from 60% to 95%, preferably in an amount by weight comprised from 70% to 85%, with respect to the total weight of the mixture.

[0078] Preferably, said (b) quercetin, is present in said mixture (I) in an amount by weight comprised from 2% to 20%, preferably in an amount by weight comprised from 5% to 10%, with respect to the total weight of the mixture.

[0079] According to another preferred aspect, said (c) licorice extract, is present in said mixture (I) in an amount by weight comprised from 2% to 20%, preferably in an amount by weight comprised from 8% to 15%, with respect to the total weight of the mixture.

[0080] A composition preferred according to the present invention consists of (I), a mixture containing 400 mg of dry extract of Annurca apple, 52.64 mg of 95% quercetin (corresponding to 50 mg of quercetin), 75 mg of dry extract of licorice, and (II), at least one pharmaceutical or food grade additive and / or excipient.

[0081] According to a particularly preferred aspect of the invention, said mixture (I), further comprises a mixture (I') of extracts of prickly pear (botanical name Opuntia ficus-indica) and of olive (leaves, botanical name Olea europeae). Preferably, said mixture of extracts (I') has a high polyphenol content.

[0082] Preferably, the mixture (I') has the following composition: Opuntia ficus-indica (CAS 90082-21-6) extract, in a percentage comprised from 32% to 35% by weight with respect to the total weight of the mixture (I'); Olea europeae (leaf) extract, in a percentage comprised from 23% to 25% by weight with respect to the total weight of the mixture (I'); and maltodextrins (CAS 9050-36-6) as a support, in a percentage comprised from 40% to 45% by weight with respect to the total weight of the mixture (I'). Preferably, the total polyphenols present in the mixture (I'), measured according to an HPLC method, are present in a percentage comprised from 3.5% to 4.5% by weight with respect to the total weight of the mixture (I').

[0083] The mixture (I') as previously described represents another object of the present invention, as does the use thereof in the treatment of symptoms related to gastroesophageal reflux, thanks to its protective and antioxidant action, as will be demonstrated in the experimental section of the present application.

[0084] A preferred composition according to the present invention consists of (I), a mixture containing 800 mg of dry extract of Annurca apple, 52.64 mg of 95% quercetin (corresponding to 50 mg of quercetin), 100 mg of dry extract of licorice, 800 mg of mixture (I') as previously described and (II), at least one pharmaceutical or food grade additive and / or excipient.

[0085] A preferred composition according to the present invention consists of (I), a mixture containing 800 mg of dry extract of Annurca apple, 52.64 mg of 95% quercetin (corresponding to 50 mg of quercetin), 100 mg of dry extract of licorice, 400 mg of mixture (I') as previously described and (II), at least one pharmaceutical or food grade additive and / or excipient.

[0086] The composition of the invention can be a pharmaceutical composition, a composition for a medical device or a nutraceutical composition.

[0087] Preferably, the composition of the invention comprises the mixture (I) comprising or, alternatively, consisting of:

[0088] (a) an extract of Annurca apple (fruit) in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg;

[0089] (b) quercetin in an amount comprised from 30 mg to 60 mg, preferably 50 mg;

[0090] (c) a licorice extract (root) in an amount comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg.

[0091] Preferably, the composition of the invention comprises the mixture (I) comprising or, alternatively, consisting of:

[0092] (a) an extract of Annurca apple (fruit) in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg;

[0093] (b) quercetin in an amount comprised from 30 mg to 60 mg, preferably 50 mg;

[0094] (c) a licorice extract (root) in an amount comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg; and

[0095] (I') a mixture of an Opuntia ficus-indica extract with an Olea europeae (leaf) extract, supported on maltodextrins and in the relative amounts as previously described, in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg.

[0096] An object of the present invention is the compositions of the invention disclosed in the present description comprising: (I) the mixture of the invention, comprising or consisting of (a), (b), (c) and, optionally (I') (as defined above), and, optionally, (II) at least one pharmaceutical or food grade additive and / or excipient, said compositions being for use come as a medicament when administered to an individual in need.

[0097] An object of the present invention is the compositions of the invention comprising (a), (b), (c) and, optionally, (I') (according to all the embodiments described in the present description) for use in a method of treatment, preventive and / or curative and / or symptomatic, of diseases, symptoms or disorders of the digestive system and, preferably, for the treatment of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux.

[0098] Preferably, the compositions of the invention for use in a method of treatment of the diseases, symptoms or disorders of the digestive system as identified above comprise the mixture (I) comprising or, alternatively, consisting of:

[0099] (a) an extract of Annurca apple (fruit) in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg;

[0100] (b) quercetin in an amount comprised from 30 mg to 60 mg, preferably 50 mg;

[0101] (c) a licorice extract (root) in an amount comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg; and, optionally,

[0102] (I') a mixture of an Opuntia ficus-indica extract with an Olea europeae (leaf) extract, supported on maltodextrins and in the relative amounts as previously described, in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg; and, optionally, (II) at least one pharmaceutical or food grade additive and / or excipient.

[0103] Preferably, the compositions of the invention for use in a method of treatment of diseases, symptoms or disorders of the digestive system as identified above comprise the mixture (I) comprising or, alternatively, consisting of:

[0104] (a) an extract of Annurca apple (fruit) in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg;

[0105] (b) quercetin in an amount comprised from 30 mg to 60 mg, preferably 50 mg;

[0106] (c) a licorice extract (root) in an amount comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg;

[0107] (I') a mixture of an Opuntia ficus-indica extract with an Olea europeae (leaf) extract, supported on maltodextrins and in the relative amounts as previously described, in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg; and, optionally, (II) at least one pharmaceutical or food grade additive and / or excipient.

[0108] Said compositions of the invention for use in a method of treatment of diseases, symptoms or disorders of the digestive system, as defined above, are preferably administered to said individual orally.

[0109] The compositions of the invention can be formulated for oral administration in a liquid form, such as solutions, emulsions, suspensions, or sprays; or, more preferably, in a solid form, such as tablets, capsules, granules, powders and equivalent forms known to the person skilled in the art. In a preferred embodiment of the invention, said compositions are in granular form, packaged in single-dose sachets or stick packs.

[0110] The methods for producing these forms are known to the person skilled in the art, who, for their preparation, can choose any technique suited to the purpose.

[0111] An object of the present invention is methods for the treatment of diseases, symptoms or disorders of the digestive system, as defined above, preferably by oral administration of an efficacious amount of one of the compositions of the invention comprising (a), (b), (c) and, optionally, (I'), as disclosed in the present description, to an individual in a state of need.

[0112] The appropriate dosage of the composition of the present invention will depend, for example, on the condition to be treated / prevented, the severity and course of the condition, whether the composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the composition and the discretion of the attending physician.

[0113] The composition of the invention is suitably administered to the individual once or distributed in a series of treatments. Preferably, the composition of the invention is administered once a day in a single dose.

[0114] The composition can be administered as a single treatment and / or in combination with other compositions or therapies (i.e. , with adjuvant action) that are useful in the treatment, preventive and / or curative and / or symptomatic, of diseases, symptoms and / or disorders of the digestive system, preferably, for the treatment of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux, as disclosed in the present description.

[0115] In the context of the present invention, the term "individuals” is used to indicate human individuals or animals (e.g., pets such as dogs or cats or other mammals). Preferably, the compositions of the invention are for use in methods of treatment on human individuals.

[0116] In the context of the present invention, "method of treatment” means an intervention, comprising the administration of a substance, or mixture of substances or combination thereof, having as its purpose the elimination, reduction / decrease or prevention of a pathology or disease and of the symptoms or disorders.

[0117] In the context of the present invention, the term "medical device" is used within the meaning according to Italian Legislative Decree no. 46 of 24 February 1997 (or according to the new Medical Devices Regulation (EU) 2017 / 745 (MDR)), i.e., it means a substance or another product, used alone or in combination, intended by the manufacturer to be used in humans for purposes of diagnosis, prevention, monitoring, treatment or alleviation of a disease, and which does not achieve its principal intended action, in or on the human body, with pharmacological or immunological means or by means of a metabolic process, but which may be assisted in its function by such means. The compositions of the invention optionally comprise (II) at least one pharmaceutical or food grade additive and / or excipient, such as a substance devoid of therapeutic activity suitable for pharmaceutical or food use, such as, for example, but not limited to, diluents, glidants, disintegrating agents, solubilizers, anti-caking agents, sweeteners, flavor enhancers, colorants, surfactants, antimicrobials, antioxidants, preservatives, pH stabilizing buffers, acidifiers, and all the auxiliary substances known to the person skilled in the art.

[0118] Unless specified otherwise, the indication that a composition "comprises” one or more components or substances means that other components or substances can be present in addition to the one or ones specifically indicated. For example, if desired or necessary, other extracts or active substances can be added to said substances (a), (b), (c) and, optionally, (I'), where they contribute to the efficacy of the composition.

[0119] Unless specified otherwise, the expression composition comprises a component in an amount "comprised in a range from x to y” means that said component can be present in the composition in all the amounts present in said range, even if not specified, including the endpoints of the range.

[0120] The composition of the present invention is prepared by mixing the individual components making it up or according to any other method deemed valid by the person skilled in the art.

[0121] An object of the present invention is a composition comprising (I) and, optionally, (II), wherein:

[0122] (I) is a mixture comprising or, alternatively, consisting of:

[0123] (a) a dry extract of Annurca apple (fruit) in an amount by weight comprised from 60% to 95%, with respect to the total weight of the mixture (I); (b) quercetin in an amount by weight comprised from 2% to 20%, with respect to the total weight of the mixture (I);

[0124] (c) a dry extract of licorice (root) in an amount by weight comprised from 2% to 20%, with respect to the total weight of the mixture (I); and, optionally,

[0125] (II) is at least one pharmaceutical or food grade additive and / or excipient;

[0126] - wherein said composition is for use in a method of treatment of individuals affected by I) gastric disorders selected from the group comprising or, alternatively, consisting of heartburn, abdominal and epigastric pain, gastric ulcer and / or gastroesophageal reflux, and ii) chronic diseases selected from the group comprising or, alternatively, consisting of diabetes, heart diseases and neurodegenerative diseases.

[0127] Preferably, said composition comprises:

[0128] - said (a) dry extract of Annurca apple (fruit) is present in an amount by weight comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg;

[0129] - said (b) quercetin is present in an amount by weight comprised from 30 mg to 60 mg, preferably 50 mg;

[0130] - said (c) dry extract of licorice (root) is present in an amount by weight comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg.

[0131] Preferably, said composition further comprises a mixture (I') of prickly pear and olive (leaf) extracts.

[0132] Preferably, said (I') consists of an Opuntia ficus-indica extract, in a percentage comprised from 32% to 35% by weight with respect to the total weight of the mixture (I'); and an Olea europeae (leaf) extract, in a percentage comprised from 23% to 25% by weight with respect to the total weight of the mixture (I').

[0133] Preferably, said (I') also consists of maltodextrins in a percentage comprised from 40% to 45% by weight with respect to the total weight of the mixture (I').

[0134] Preferably, said (I') has a polyphenol content in a percentage comprised from 3.5% to 4.5% by weight with respect to the total weight of the mixture (I').

[0135] Preferably, said mixture (I') is present in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg.

[0136] Preferably, said composition is formulated for oral use.

[0137] The present invention will now be illustrated by way of non-limiting example in the experimental part that follows.

[0138] DESCRIPTION OF THE FIGURES

[0139] Figure 1 : Histogram relating to the mean values of patient self-assessment of symptoms, expressed on a scale of 1 to 5, at time 0 (t 0) and after thirty days of treatment (t 30) with the composition according to the invention (Table 1). The values are expressed as the mean of the data recorded by the ten subjects, the bars represent the standard deviation, the P values the statistical difference between the results.

[0140] Figure 2: Precise trend in the mean values of patient self-assessment of symptoms, expressed on a scale of 1 to 5, at time 0 (t 0) and after thirty days of treatment (t 30) with the composition according to the invention (Table 1). The values are expressed as the mean of the data recorded by the ten subjects.

[0141] Figure 3: Precise trend in the values of self-assessment of symptoms by the individual subjects, expressed on a scale of 1 to 5, at time 0 (t 0) and after thirty days of treatment (t 30) with the composition according to the invention (Table 1).

[0142] Figure 4: GIQLI (Gastrointestinal Quality of Life Index) self-assessment score, expressed on a scale of 1 to 5, at time 0 (t 0) and after 8 weeks of treatment (t 8) with the mixture (I') according to the present invention (Table 2) compared to treatment with a placebo. The parameters considered are: abdominal pain, post-prandial fullness, bloating, flatulence, eructation, nausea, constipation, heartburn, and reflux.

[0143] Figure 5: GSAS (GERD Symptom Assessment Scale) score relating to gastrointestinal symptoms, expressed on a scale of 1 to 5, at time 0 (t 0) and after 4 and 8 weeks of treatment (t 4 and 18) with the mixture (I') according to the present invention (Table 2) compared to treatment with a placebo.

[0144] Figure 6: GSAS (GERD Symptom Assessment Scale) score relating to distress, expressed on a scale of 1 to 5, at time 0 (t 0) and after 4 and 8 weeks of treatment (t 4 and 18) with the mixture (I') according to the present invention (Table 2) compared to treatment with a placebo.

[0145] Figure 7: effect of exposure to increasing concentrations of the composition according to the present invention (Table 1) on the activity of the enzymes CYP2D6 and CYP3A4, belonging to the cytochrome P450 family. IC50: concentration at which a 50% reduction in the activity of the enzyme is observed compared to the control (vehicle alone).

[0146] Figure 8: PGA of the total phenol content; total flavonoids; DPPH; Total antioxidant activity (TAG) ABTS; vitamin A; vitamin E in the different matrices.

[0147] Figure 9: PGA of the cations in the different matrices

[0148] Figure 10: PGA of the individual phenolic acids in the different matrices

[0149] Figure 11 : PGA of the individual flavonoids in the different matrices analyzed.

[0150] 1. EXPERIMENTAL PART

[0151] Efficacy of the composition according to the invention - Preliminary in vivo study

[0152] The efficacy of a composition according to the present invention was tested on ten volunteer subjects with symptoms typical of GERD such as, for example: heartburn, also in the absence of acid regurgitation, especially in the postprandial phase or in a lying position; pain that radiates from the chest to the mouth due to the backflow of gastric acid; coughing due to reflux; hoarseness.

[0153] In particular, the patients, 10 subjects (7 women and 3 men) aged between 34 and 80 were enrolled based on a history of the following symptoms: pyrosis, regurgitation, post-prandial fullness, morning cough. No subject was undergoing a concomitant therapy based on PPIs, antiacids, alginates, low-dose acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs) and / or corticosteroids.

[0154] The assessment was made personally by the individual subject; the patient attributed to every symptom a score from 1 =very mild to 5=very severe, for the purpose of quantifying its severity. Every patient made a quantitative assessment, according to the described scale of 1 to 5, of the symptoms pyrosis, regurgitation, post-prandial fullness and morning cough, comparing the entity of the symptoms before the start of treatment (time 0, 1 0) and after 30 days (t 30). The results were analyzed with a Student's t-test (P-value shown in Figure 1) and the variation from the mean was expressed as standard deviation. The tested composition is shown in Table 1 and was taken by all the subjects in the form of orally disintegrating granules packaged in stick packs, twice a day after the main meals.

[0155] Table 1 : qualitative and quantitative breakdown of the composition according to the present invention tested in the in vivo study

[0156] Table 1

[0157] The patients interviewed declared that all the symptoms considered (pyrosis, regurgitation, post-prandial fullness and morning cough) showed a significant reduction at 30 days (t 30) compared to the start (t 0); the improvement was more marked in particular as regards the symptoms of pyrosis and post-prandial fullness. The comparison of symptoms at time 0 and after 30 days, performed with a Student's t-test, showed the following results: pyrosis 4.1 ±0.7 vs 2.6±0.7 P= 0.000004; post-prandial fullness 3.8±0.9 vs 1.7±0.5 P= 0.000005; pyrosis 4.1 ±0.7 vs 2.6±0.7 P= 0.000004; regurgitation 3.5±1 .3 vs 2.9±1 .3 P= 0.002; morning cough 3.4±1 .6 vs 2.2±1 .0 P= 0.004 (Figure 1). The best result was recorded in the assessment of pyrosis and post-prandial fullness (Figures 1-3); the improvement described for regurgitation and morning cough was also significant (Figure 1-3).

[0158] It is particularly interesting to note that the symptom of pyrosis was nearly halved in the perception of the study subjects, passing from an initial mean score of 4.1 ±0.7 to a value at 30 days of 2.6±0.7. The data relating to postprandial fullness are somewhat similar: from an initial value of 3.8±0.9 to 1.7±0.5 after 30 days. As regards regurgitation, on the other hand, the trend in the individual patients, shown in Figure 3, reveals that 6 patients reported a remission of the symptom with an improvement in the score of about one unit, whereas 4 of them did not report variations. With regard to morning cough, the trend does not show any improvement only in the case of 2 patients (20% of the cases); however, of the 8 patients who declared a reduction in the score, 3 reported a distinct improvement in the symptom. Overall, morning cough was the symptom that showed greatest heterogeneity in the clinical response to the novel therapy (Figure 3).

[0159] Finally, all the patients in the study declared an excellent palatability of the product and no side effect. All intended to continue taking it.

[0160] This in vivo study, despite being only of a preliminary character, clearly demonstrated that the composition according to the present invention is capable of treating the symptoms of patients with GERD, improving their conditions of life even in the absence of a classic pharmacological therapy, based for example on PPIs. Efficacy of mixture according to the invention - in vivo study

[0161] A double-blind placebo-controlled clinical trial was conducted in which 100 volunteers received 400 mg per day of mixture (I'), whose composition is shown in Table 2, for a total of 8 weeks. The same number of subjects received a placebo instead.

[0162] Table 2: qualitative / quantitative composition of mixture (I') according to the present invention tested in the in vivo study

[0163] Table 2

[0164] At the end of the first 4 weeks and of the total 8 weeks of the study, all the subjects were asked to fill out selfassessment questionnaires relating to the GIQLI (Gastrointestinal Quality of Life Index) and GSAS (Gerd Symptom Assessment Scale).

[0165] In particular, in the case of the GIQLI they were asked to rate, on a scale of 1 to 5, the intensity of the symptoms related to abdominal pain, post-prandial fullness, bloating, flatulence, eructation, nausea, constipation, heartburn, and reflux.

[0166] In the GSAS questionnaire two parameters were identified, gastrointestinal symptoms and distress, to be rated on a scale from 1 to 10 and on a scale from 1 to 2, respectively.

[0167] The results obtained, shown in Figures 4-6, clearly show that a considerable improvement was recorded in terms of the reduction of all symptoms in the subjects to whom the mixture (I') according to the present invention was administered compared to the subjects who took the placebo. In fact, in general a reduction of about 70% was reported in the symptoms tied to gastroesophageal reflux.

[0168] Safety of the composition according to the invention - in vitro study

[0169] For the purpose of evaluating the safety of the formulation according to the present invention, the inhibitory effect of the qualitative / quantitative composition as per Table 1 above on the enzymatic activity of the two subtypes of cytochrome P450, in particular CYP2D6 and CYP3A4, was measured.

[0170] The potential inhibitory effect is assessed by means of a luminometric test, that is, a test that quantifies the luminous intensity emitted by a given species; in the case in question, when an increase in luminous intensity is measured, it indicates a greater presence of metabolic product and thus a lower inhibition of the cytochrome P450 (CYP450) subtypes. The test used provides for the use of two membranes containing recombinant human CYP2D6 or CYP3A4 and cytochrome-free membranes as a negative control. For the purpose of carrying out the test, a substrate is added, which on reacting with the cytochrome p450 (be it CYP2D6 or CYP3A4) generates a product, which on reacting with luciferase emits light. The amount of light emitted will thus be proportional to the amount of product obtained and consequently to the percentage of CYP that was not subjected to any inhibition.

[0171] Cytochrome p450 (CYP450) is meant to indicate a family of enzymes responsible for metabolism of an oxidative type in the body. These enzymes play a primary role in the metabolism of many drugs and are implicated in the majority of phase 1 metabolic processes at the level of the liver. Following the administration of an active substance, in fact, only a certain portion will arrive intact in the bloodstream, precisely because of the first-pass metabolic processes which take place in the liver (phase 1).

[0172] The induction and inhibition of these enzymes can be modulated by a number of factors, which are both of a genetic nature (sex, race, age...), and exogenous (diet, lifestyle, drugs...). Alterations affecting this system can lead to consequences on the absorption, metabolism, half-life and bioavailability of active ingredients. For this reason, it is important to measure the impact the composition of the present invention could have on this family of receptors. In particular, the measured inhibition effect must be as low as possible, in order to demonstrate the non-interference of the composition according to the present invention with the metabolism of other drugs or nutrients.

[0173] The inhibition effects of the composition according to the present invention (as shown in Table 1), are compared with those deriving from compounds which are known inhibitors selective for both receptor sub-forms considered. The scientific literature divides the inhibitors of CYP450, and the isoforms thereof, into strong, moderate or weak inhibitors, on the basis of measured IC50 values (concentration inhibiting enzymatic activity by 50%). In particular, a molecule is considered a strong inhibitor when it shows an IC50 value < pg / mL, a moderate inhibitor when IC50 is between 10 pg / mL and 100 pg / mL, a weak inhibitor when IC50 is > 100 pg / mL, and as not having any inhibitory activity when IC50 is much > 100 pg / mL.

[0174] The active ingredients used by way of comparison for this experiment are two specific inhibitors for two isoforms, namely: quinidine (CYP2D6 inhibitor) and ketoconazole (CYP3A4 inhibitor). Both compounds are suspended respectively in DMSO and acetonitrile (solvent), at an initial concentration of 13 pg / mL in the case of quinidine and 2.7 pg / mL in the case of ketoconazole and are then further diluted in deionized water in order to identify, with the luminometric assay previously described, the IC50 values, that is, the concentration of the active ingredient necessary to reduce the activity of the cytochrome isoforms by 50%. These values correspond to 0.0015 pg / mL of quinidine for CYP2D6 and 0.005 pg / mL of ketoconazole for CYP3A4. This assay validates the luminometric method and confirms that the substrates used for the experiment are strong inhibitors of the two CYP isoforms and compatible with the data present in the literature.

[0175] The inhibitory activity of the composition according to the present invention against CYP2D6 and CYP3A4 was measured with the luminometric method using a suspension of the formulation shown in Table 1 in DMSO in order to obtain a concentration of 100 pg / mL, which was then diluted, after vigorous mechanical stirring, in a wide range of concentrations from 0.0025 pg / mL to 2,500 pg / mL.

[0176] The results obtained, shown in Figure 7 and in Table 3, demonstrate that at the concentration of the composition according to the invention of 1 , 162 pg / mL one observes an IC50 value for CYP2D6, and at the concentration of 72.27 pg / mL for CYP3A4.

[0177] Table 3: effect of the exposure at increasing concentrations of the composition shown in Table 1 on the activity of the enzymes CYP2D6 and CYP3A4, belonging to the cytochrome P450 family (activity of the enzyme expressed as a percentage compared to the control (vehicle alone)) the results are shown as a mean ± standard deviation. able 3

[0178] Based on these data it may be affirmed that CYP3A4 reveals to be more sensitive to the composition of the invention (Table 1) than CYP2D6. More precisely, making reference to the previously described classification in the literature, the composition of the invention is considered a moderate inhibitor of CYP3A4 (10 pg / mL < IC50 < 100 pg / mL), whereas it does not show to have any inhibitory capacity (IC50 much > 100 pg / mL) for CYP2D6.

[0179] The result of the studies described demonstrates that the inhibitory capacity of the composition according to the present invention against the CYP450 isoforms under examination is to be considered negligible. This result is particularly positive in that it is indicative of the fact that the potential undesirable interactions that could arise from the coadministration of the formulation according to the present invention with other drugs are thus to be considered equally negligible. For this reason, the formulation of the present invention proves to be advantageous also with respect to the traditional PPIs used in therapy. This class of compounds, in fact, has the disadvantage of inhibiting cytochrome P450 and the isoforms thereof, thus causing problems due to the failure to metabolize any other molecules taken by the patient to treat coexisting diseases.

[0180] 2. EXPERIMENTAL PART

[0181] The following experimental phase was conducted on the following samples:- 50 g licorice extract

[0182] - 50 g quercetin extract

[0183] - 50 g extract of Annurca apple

[0184] - about 50 g of mixture M1 prepared according to the following proportions: 400 mg of extract of Annurca apple (dry extract (d.e.)), 75 mg of licorice extract (d.e. 10% glycyrrhizic acid) and 50 mg of quercetin. The mixture was prepared as shown in Table 4.

[0185] - about 50 g of mixture M2 prepared according to the following proportions: 800 mg of extract of Annurca apple (dry extract (d.e.)), 100 mg of licorice extract (d.e. 10% glycyrrhizic acid), 50 mg of quercetin and 800 mg of Mucosave®). The mixture was prepared as shown in Table 5.

[0186] Table 4: proportional composition of mixture MIX M1

[0187] Table 5: proportional composition of mixture MIX M2

[0188] The objective of the experimental phase was to evaluate the activity and the efficacy of the compositions of the present invention in accordance with the embodiments claimed for the treatment of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux. Furthermore, the experimental phase also set the objective of verifying whether the compositions of the present invention could be intended and indicated, based on their efficacy, also for particular categories of individuals having a very complex clinical situation, that is, a subpopulation of individuals who in addition to having a need to reduce gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux, also have, at the same time, a need to reduce the risk of chronic diseases such as diabetes, heart diseases and neurodegenerative diseases.

[0189] Chemical characterization of different plant matrices

[0190] MIX 1 ; MIX 2; Annurca apple; quercetin; and licorice were characterized from a chemical standpoint by determining total flavonoids, total phenols, individual phenolic acids, individual flavonoids, the antioxidant capacity expressed as ABTS, DPPH and TAG (total antioxidant capacity), cations, and vitamins A and E.

[0191] The results obtained demonstrate that MIX 1 and MIX2 have a higher content of phenols and total flavonoids compared to the other matrices analyzed. MIX1 shows a high amount of these compounds, albeit to a less degree than MIX2. These data are consistent with the results on antioxidant activity, which shows to be highest in MIX2, followed by MIX1.

[0192] DPPH, ABTS and TAG (Table 6) are assays commonly used to evaluate the antioxidant activity (scavenging) of various substances. Though they are all aimed at measuring the capacity of antioxidants to neutralize free radicals or reactive species, they differ in their mechanism, sensitivity, versatility and the type of antioxidants detected. The DPPH (2,2- diphenyl-1 -picrylhydrazyl) method envisages the use of a violet-colored organic nitrogen radical. In the presence of an antioxidant compound, which donates a hydrogen atom to the radical, a reduced form of the molecule is obtained that is visible through the decolorization of the solution, monitored by spectrophotometry. The TAG (total antioxidant capacity) assay provides an overall evaluation of the antioxidant capacity, as it takes into consideration different mechanisms of action (e.g. radical scavenging and reduction of metal ions), thereby offering a holistic vision of the antioxidant capacity, useful for comparing samples with complex antioxidant profiles. The ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assay is based on the decolorization of the solution containing the radical cation, which is generated through the oxidation of the diammonium salt of 2,2'-azino-bis(3- ethylbenzothiazoline-6-sulfonic acid (ABTS) thanks to potassium persulfate (K2S2O8). The radical cation that is generated has an absorption peak at 734 nm and antioxidant compounds cause a decolorization of the solution. The decolorization, monitored by spectrophotometry, is proportional to the antioxidant load present in the sample. The DPPH method is particularly suitable for lipophilic antioxidants, whilst ABTS is effective for both hydrophilic and lipophilic antioxidants.

[0193] The results obtained showed that MIX2 and MIX1 possess overall a greater antioxidant activity, as highlighted by the increase in the values in all three assays compared to the other matrices analyzed. The concentration of vitamin A shows to be higher in MIX2 and in MIX1 , which implies a greater antioxidant activity and a potential benefit also in reducing cardiometabolic diseases.

[0194] The data relating to vitamin E are also significant: MIX2, MIX1 and the licorice matrix contain higher amounts compared to the other matrices.

[0195] Table 8, which shows the concentration of the individual phenolic acids in the matrices analyzed, reveals a prominent presence of protocatechuic acid in MIX2. Furthermore, higher contents of p-coumaric, m-coumaric, trans-4-hydroxycinnamic, 3-hydroxycinnamic acid, sinapic acid, and 2,5-dihydroxybenzoic acid were also detected in MIX2.

[0196] A higher concentration of chlorogenic acid (CGA) was detected in MIX 2 and MIX 1 compared to the other matrices. The phenolic acids present in MIX2, such as p-coumaric, m-coumaric, trans-4-hydroxycinnamic, 3-hydroxycinnamic acid, sinapic acid, and 2,5-dihydroxybenzoic acid, are very important for the efficacy of the tested mixture.

[0197] The results obtained with the PGA (principal component analysis) and shown in Figure (8-11) demonstrate that MIX1 and MIX2 are positively and significantly correlated with numerous bioactive compounds compared to the individual matrices, further confirming the analytic data reported in the tables (6-9). This confirms the utility of using MIX 1 and MX2 for individuals having a need to reduce gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux. It emerges clearly from the results obtained that both MIX 1 and MIX 2, preferably MIX2, have a superior chemical composition compared to the other matrices analyzed, i.e. compared to the individual components. MIX2 is distinguished by an optimal, more complete blending, with a higher percentage of the individual bioactive compounds compared to the other formulations. Furthermore, it contains unique compounds, not present in the other matrices, which are very useful for the efficacy of the tested mixture.

[0198] MIX 1, but even better MIX 2, have a particularly efficacious nutraceutical profile (high antioxidant and antiinflammatory value) and, therefore, they have valid application for the treatment of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux. MIX 1 and MIX 2 represent a natural preparation that combines different active ingredients in a synergistic manner, offering benefits for health (reduction of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux) which go beyond those offered by the individual components. The formulation containing MIX 1 or MIX 2 contains molecules with antioxidant and anti-inflammatory properties, which are protective for the cardiovascular and metabolic systems. This synergy, exerted by the various ingredients present, makes it possible not only to increase the efficacy of each compound, but also to include substances which, acting in combination and on different targets simultaneously, can also reduce the risk of chronic diseases such as diabetes, heart diseases and neurodegenerative diseases. For this reason MIX 1, but even better MIX 2, are particularly indicated for a subpopulation of individuals having a very complex clinical situation, that is, a subpopulation of individuals who in addition to having a need to reduce gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux, also have, at the same time, a need to reduce the risk of chronic diseases such as diabetes, heart diseases and neurodegenerative diseases.

[0199] Thanks to its balanced composition and to the presence of compounds which are essential for the wellbeing of the body (high antioxidant and anti-inflammatory value), MIX2 can be considered a valid ally in prevention and health promotion, as it offers a natural support for maintaining an optimal state of health not only in individuals who need a treatment to reduce gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer and / or gastroesophageal reflux, but also in a subpopulation of these individuals who at the same time have a need to reduce the risk of chronic diseases such as diabetes, heart diseases and neurodegenerative diseases. antioxidant activity (TAG, mg a-tocopherol, *100g1d.m.); ABTS (% inhibition); vitamin A (pg Re* g1d.m.); vitamin E (mg alpha-tocopherol * 100 g1d.m.) in the different matrices. The results are the final mean of 5 determinations. *Different letters in the same row indicate significant variations with p<0.05

[0200] Table 7: Content of cations in the different matrices, expressed in mg / g d.m. The results represent the mean ol

[0201] 5 determinations. Different letters in the same row indicate significant variations with p<0.05.

[0202] Table 8: Content of the individual phenolic acids (mg / g d.m.) in the different matrices analyzed. The results represent the mean of 5 determinations. Different letters in the same row indicate significant variations with p<0.05.

[0203] Table 9: Content of the individual flavonoids (mg / g) in the different matrices analyzed. The results represent the mean of 5 determinations. Different letters in the same row indicate significant variations with p<0.05.

Claims

CLAIMS1. A composition comprising (I) and, optionally, (II), wherein:(I) is a mixture comprising or, alternatively, consisting of:(a) a dry extract of Annurca apple (fruit) in an amount by weight comprised from 60% to 95%, with respect to the total weight of the mixture (I);(b) quercetin in an amount by weight comprised from 2% to 20%, with respect to the total weight of the mixture (I);(c) a dry extract of licorice (root) in an amount by weight comprised from 2% to 20%, with respect to the total weight of the mixture (I); and(II) is at least one pharmaceutical or food grade additive and / or excipient.

2. The composition according to claim 1 , wherein said (a) dry extract of Annurca apple (fruit) is in an amount by weight comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg.

3. The composition according to claim 1 or 2, wherein said (b) quercetin is in an amount by weight comprised from 30 mg to 60 mg, preferably 50 mg.

4. The composition according to any one of claims 1-3, wherein said (c) dry extract of licorice (root) is in an amount by weight comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg.

5. The composition according to any one of claims 1-4, wherein said mixture (I) further comprises a mixture (I') of prickly pear and olive (leaf) extracts.

6. The composition according to claim 5, wherein said (I') consists of Opuntia ficus-indica extract, in a percentage comprised from 32% to 35% by weight with respect to the total weight of the mixture (I'); Olea europeae (leaf) extract, in a percentage comprised from 23% to 25% by weight with respect to the total weight of the mixture (I'); maltodextrins in a percentage comprised from 40% to 45% by weight with respect to the total weight of the mixture (I'); and has a polyphenol content in a percentage comprised from 3.5% to 4.5% by weight with respect to the total weight of the mixture (I').

7. The composition according to claim 5 or 6, wherein said mixture (I') is in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg.

8. The composition according to any one of claims 1-7, wherein said composition is for use as a medicament.

9. The composition for use according to claim 8, wherein said composition is for use in a method of treatment of diseases, symptoms or disorders of the digestive system, preferably for the treatment of gastric disorders such as heartburn, abdominal and epigastric pain, gastric ulcer, and gastroesophageal reflux.

10. The composition for use according to claim 8 or 9, wherein said composition is formulated for oral use.

11. A composition comprising (I) and, optionally, (II), wherein:(I) is a mixture comprising or, alternatively, consisting of:(a) a dry extract of Annurca apple (fruit) in an amount by weight comprised from 60% to 95%, with respect to the total weight of the mixture (I);(b) quercetin in an amount by weight comprised from 2% to 20%, with respect to the total weight of the mixture (I);(c) a dry extract of licorice (root) in an amount by weight comprised from 2% to 20%, with respect to the total weightof the mixture (I); and(II) is at least one pharmaceutical or food grade additive and / or excipient;- wherein said composition is for use in a method of treatment of individuals affected by I) gastric disorders selected from the group comprising or, alternatively, consisting of heartburn, abdominal and epigastric pain, gastric ulcer and / or gastroesophageal reflux, and ii) chronic diseases selected from the group comprising or, alternatively, consisting of diabetes, heart diseases and neurodegenerative diseases.

12. The composition for use according to claim 11 , wherein:- said (a) dry extract of Annurca apple (fruit) is present in an amount by weight comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg;- said (b) quercetin is present in an amount by weight comprised from 30 mg to 60 mg, preferably 50 mg;- said (c) dry extract of licorice (root) is present in an amount by weight comprised from 50 mg to 150 mg, preferably comprised from 75 mg to 100 mg.

13. The composition for use according to claim 11 or 12, wherein said mixture (I) further comprises a mixture (I') of prickly pear and olive (leaf) extracts.

14. The composition for use according to claim 13, wherein said (I') consists of an Opuntia ficus-indica extract, in a percentage comprised from 32% to 35% by weight with respect to the total weight of the mixture (I'); and an Olea europeae (leaf) extract, in a percentage comprised from 23% to 25% by weight with respect to the total weight of the mixture (I').

15. The composition for use according to claim 14, wherein said (I') also consists of maltodextrins in a percentage comprised from 40% to 45% by weight with respect to the total weight of the mixture (I').

16. The composition for use according to claim 14 or 15, wherein said (I') has a polyphenol content in a percentage comprised from 3.5% to 4.5% by weight with respect to the total weight of the mixture (I').

17. The composition for use according to any one of claims 14-16, wherein said mixture (I') is present in an amount comprised from 300 mg to 900 mg, preferably 400 mg or 800 mg.

18. The composition for use according to any one of claims 11-17, wherein said composition is formulated for oral use.

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