Oral composition comprising extracts of musa paradisiaca and zingiber officinalis for use in the treatment of gastroesophageal reflux

Abstract

The present patent application relates to an oral composition comprising: palmitoylethanolamide, dry extract of Musa paradisiaca, dry extract of Zingiber officinale, a mixture containing a dry extract of Opuntia ficus-indica and a dry extract of Olea europaea, for use in the prevention and / or in the treatment.

Description

[0001] ORAL COMPOSITION COMPRISING EXTRACTS OF MUSA PARADIS I ACA AND ZINGIBER

[0002] OFFICINALIS FOR USE IN THE TREATMENT OF GASTROESOPHAGEAL REFLUX

[0003] DESCRIPTION

[0004] FIELD OF THE INVENTION

[0005] The present invention falls within the technical field of the treatment of

[0006] 5 gastroesophageal reflux and / or its symptomatology, in order to improve the Quality of Life of those who suffer from it.

[0007] STATE OF THE ART

[0008] Gastroesophageal reflux disease (GERD) is a fairly common digestive disorder worldwide.

[0009] 10 Reflux oesophagitis is defined as inflammation of the oesophageal mucosa secondary to gastroesophageal reflux disease (1).

[0010] According to the Montreal definition, GERD is currently defined as “a condition that develops when the reflux of stomach contents into the esophagus causes troublesome symptoms and / or complications at the level of the oesophagus" (2). The American College of Gastroenterology also defines GERD as "chronic symptoms or mucosal damage incurred by the abnormal reflux of gastric contents into the esophagus" (3).

[0011] The disease is mainly related to the malfunction of the lower oesophageal sphincter (LES). In normal situations, the closure of this sphincter, along with other mechanisms, prevents acidic material from rising up from the stomach to the oesophagus.

[0012] 20 The LES consists of a normally contracted layer of muscle that separates the stomach cavity and oesophagus, preventing the development of reflux. It relaxes only for short periods of time to allow the passage of the bolus during the meal. Excessive transient releases of the LES, or a steady decrease in its contraction tone, are primarily responsible for the development of reflux disease.

[0013] 25 Based on the results of an endoscopic examination, GERD is classified into two subgroups: erosive reflux disease (ERD), in the presence of mucosal damage, also with breaks in the continuity of the oesophageal mucosa called, in fact, erosions; or, non- erosive (NERD) in the absence of endoscopically assessable damage. Prevalence

[0014] The prevalence of GERD is high in Western countries: it ranges from 13% to 20% of the adult population in the US, and from 9.8% to 18% in Europe, with severe disease observed in about 6% of the population. In Asia, on the other hand, the prevalence is lower, at around 2.5-4.8% (4).

[0015] There is therefore a trend towards higher prevalence in North America than in Europe, and higher prevalence in Northern Europe than in Southern Europe (5). GERD affects both sexes, with a slight preponderance of men. With regard to subtypes, on the other hand, about 80% of the forms are NERD and only 20% ERD (2). NERD forms prevail in the female sex.

[0016] Risk factors

[0017] There are several factors, in addition to the functionality of the LES, that can contribute significantly to the development of GERD, and these can be both physiological and pathological.

[0018] Physiological risk factors include age. In fact, an age greater than 50 years entails a significant increase in the relative risk of disease. Reduced physical activity, which is often correlated with increasing age, is also considered a risk factor.

[0019] On the other hand, among the pathological factors we find: obesity (body mass index or BMI greater than 30), smoking, and conditions related to anxiety / depression (6).

[0020] The presence of hiatal hernia, a congenital anomaly, also promotes gastroesophageal reflux by increasing the severity of oesophageal acid exposure (7).

[0021] Again, eating habits can contribute to the onset of GERD. For example, excessive acidity in food and beverages can contribute to the onset of the disease, as can the timing of meals and regular sleep. Finally, the habit of eating very large meals promotes increased intra-abdominal pressure and therefore reflux. Conversely, recreational physical activity, carried out regularly, seems to be protective, except when it is practiced immediately after a meal (6) (8). Complications

[0022] Complications related to GERD are mainly represented by mucosal lesions, the most common being: mucosal erosions, strictures, Barrett's oesophagus, oesophageal adenocarcinoma, and lung diseases.

[0023] Barrett’s oesophagus (BE) is a condition that occurs almost exclusively in the presence of the ERD subtype of the disease. The presence of erosions, inflammation and processes of attempted mucosal repair lead the stratified squamous oesophageal epithelium to be replaced by columnar metaplasia, easily detectable on endoscopic examination (9). BE occurs in 2% of the adult population of Western industrialized countries and is the most feared complication of GERD because it predisposes sufferers to oesophageal adenocarcinoma.

[0024] Reflux, if it reaches the highest parts of the oesophagus, can also cause extra - gastrointestinal complications, including dental erosion, laryngitis, coughing, asthma, sinusitis, and idiopathic pulmonary fibrosis (10).

[0025] Symptoms

[0026] The classic and most common symptoms of GERD are retrosternal burning and regurgitation.

[0027] Retrosternal burning is the cardinal symptom of GERD, and is defined as a sensation of severe pain behind the sternum, a flat, long bone positioned in the center of the chest. Regurgitation, on the other hand, is often associated with a sour taste in the back of the mouth, with or without regurgitation of acid chyme towards the mouth. This is the perception of the presence of gastric contents in the mouth or hypopharynx. More rarely, other symptoms may appear including chest pain, chronic dry cough and dysphagia (7).

[0028] GERD-associated chest pain can mimic cardiac pain, and GERD patients with this symptomatology should be evaluated to rule out cardiac causes (11). Chronic dry and persistent cough can be caused by GERD (12). There are many other causes of chronic cough that must be ruled out in case of cough associated with GERD.

[0029] Saliva is vital for the oesophagus' natural defense against reflux lesions. Under conditions of physiological reflux, the swallowing of saliva, with its buffering power due to the presence of bicarbonate, acts both to buffer the refluxed gastric acid, and to promote peristaltic clearance as well as mucosal regeneration thanks to the content of trophic factors in saliva, such as the Epidermal Growth Factor (EGF) (13). The period of time when the oesophagus remains at pH less than 4, following an episode of reflux, is called the "acid clearance time". Approximately 7 mL of saliva is needed to neutralize 1 mL of reflux, containing 0.1N HC1 and the amount of saliva normally swallowed is 0.5 mL / min.

[0030] NERD and ERD

[0031] Non-erosive reflux disease (NERD) and erosive oesophagitis (ERD) are the main manifestations of gastroesophageal reflux disease (14).

[0032] Nonerosive reflux disease (NERD) is the most common phenotype of gastroesophageal reflux disease. By definition, NERD patients have typical reflux symptoms caused by intra-oesophageal reflux of gastric contents, but have no visible lesions of the oesophageal mucosa.

[0033] This is in contrast to patients with reflux oesophagitis, also known as erosive reflux disease (ERD) or Barrett's oesophagus (BE) who have obvious lesions of the oesophageal mucosa on endoscopy.

[0034] Only 50% of patients with NERD have a pathological exposure to oesophageal acid detected during 24-hour pH monitoring. NERD patients with physiological exposure to oesophageal acid and good temporal correlation of symptoms with reflux events are considered to have oesophageal hypersensitivity, while patients without symptomreflux correlation are considered to have functional heartburn (15).

[0035] It is possible, but uncommon, for NERD to progress to severe ERD or BE. Patients with NERD and pathological exposure to oesophageal acid have motor dysfunctions and acid reflux abnormalities similar to patients with ERD and BE, while NERD patients with physiological exposure to oesophageal acid have minimal abnormalities and are not very different from healthy controls at an endoscopic control.

[0036] The most indicative pathological feature of NERD is the presence of dilated intercellular spaces within the squamous epithelium, an ultrastructural abnormality easily identifiable with microscopic investigation performed on oesophageal biopsies (16).

[0037] Molecular mechanisms

[0038] In addition to the congenital causes of GERD, such as hiatal hernia, and causes related to increased intra-abdominal pressure (obesity), increased gastric acidity (gastric hyperacidity) or decreased buffering power of saliva (for example, in smokers), molecular mechanisms that may promote or counteract GERD have also been studied, also with the aim of developing new specific pharmacological therapies.

[0039] Among these mechanisms, the most investigated concerns the role of cannabinoid (CB) receptors. These receptors belong to the G-protein-coupled receptor superfamily (17), and exist in two subtypes: type 1 (CB1) and type 2 (CB2). In the gastrointestinal tract, the CB1 receptor is expressed in neurons of the enteric nervous system and in the sensory terminals of vagal and spinal neurons, and its functions include control of secretion, intestinal motility, and neurotransmitter release (18). CB2 receptors, on the other hand, are located mainly in gut-associated immune cells.

[0040] Expression of CB1 was also observed at non-neuronal sites, including adipocytes, endothelial cells, smooth muscle, and enterocytes. In colonic epithelial cell lines and primary colonic epithelial cells, stimulation of the CB1 receptor initiates several downstream signal transduction pathways including phosphorylation of ERK1 and ERK2 (19). Accordingly, it has been proposed that its physiological role includes enterocyte proliferation and epithelial wound healing.

[0041] Cannabinoid type 1 receptors also play a role in transient lower oesophageal sphincter relaxations (TLESRs), which occur in the absence of swallowing and are the main mechanism underlying reflux. CB1 receptors have been located in brain areas involved in the triggering of TLESRs and in the nodal ganglion from which vagal afferents originate (20) (21). A study in ferrets confirmed the involvement of CB1 receptors in the central regulation of LES relaxation and showed the presence of CB1 receptors in the brain centers involved in TLESR activation (21).

[0042] The molecular mechanisms that lead from oesophagitis to Barrett's oesophagus have also been studied but, even today, the understanding of the cellular and molecular mechanisms through which this metaplastic transformation occurs remains limited. However, metaplasia is thought to be a pathological condition that commonly occurs in the presence of chronic inflammation (22), associated with strong oxidative damage (23). Thus, there appears to be a strong association between GERD-induced reactive oxygen species (ROS) accumulation, acid insult-induced chronic inflammatory infiltration on the mucosa, and BE formation.

[0043] Giuseppe Antonio Malfa et al: “A standardized extract of Opuntia ficus-indica (L.) Mill and Olea europaea L. improves gastrointestinal discomfort: A double-blinded randomized-controlled study”, Physiotherapy research, John Wiley & Sons Ltd. Chichester, GB, vol.35, no.7, pages 3756-3768 discloses that a standardized extract of Opuntia ficus-indica (L.) Mill and Olea europaea L. (Mucosave) ameliorates gastrointestinal distress in a double-blind randomized controlled trial. The clinical trial was conducted in patients with gastrointestinal reflux disease (GERD).

[0044] IT 2020 0002 4973 Al discloses a composition for the treatment of gastroesophageal reflux comprising sodium alginate, sodium hyaluronate, chondroitin sulfate, Emblica officinale, calcium citrate, palmitoylethanolamide, medium chain triglycerides. The composition is in the form of a gelled emulsion, wherein at least the sodium hyaluronate, chondroitin sulphate and palmitoylethanolamide are in the form of a dry powder finely dispersed in the gelled emulsion. The composition may further comprise magnesium alginate, calcium alginate, aloe vera, vitamin B6, potassium bicarbonate, sodium bicarbonate, calcium carbonate, hydrolyzed keratin, sodium citrate, potassium citrate, aluminum hydroxide, magnesium hydroxide, Tamarindus indica L., Zingiber officinale Rose., simethicone, melatonin, Opuntia ficus- indica (L.) Mill., Musa paradisiaca L., Carum Carvi L., Glycyrrhiza Glabra L (see Claim 6). The application does not contain an extract of Olea Europea.

[0045] Goela R K et al: "Anti -ulcerogenic effect of banana powder (Musa sapzentum var. paradzszaca) and its effect on mucosal resistance" discloses the anti -ulcerogenic effect of banana powder in a model of gastric ulcer in rats. The article shows that banana powder increases the resistance of the gastric mucosa and promotes the healing of the mucosa, promoting cell proliferation. WO 2019 / 026047 Al discloses a composition comprising the combination of at least one antacid, an extract from the fruit of a plant of the genus Musa and at least one digestive protease enzyme. The compositions are in the form of a sachet and comprise Actinidain as an enzyme (from kiwi) and carbonate / bicarbonate as an antacid. The compositions are for the treatment of gastric ulcer and heartburn (reflux oesophagitis).

[0046] Problems of the background art

[0047] Both pharmacological and non-pharmacological therapies for GERD have limitations.

[0048] PPI-based pharmacological therapy

[0049] For example, the most commonly used medications to treat these patients are proton pump inhibitors (PPIs) taken once a day, usually before the first meal of the day (30- 60 min before). In case of partial response, therapy is increased to twice per day. PPIs are used on monthly or bimonthly cycles, while PPI therapy becomes chronic for patients who continue to have symptoms and for those with erosive oesophagitis and Barrett's oesophagus.

[0050] It is estimated that for between 53% and 69% of patients PPI prescriptions concern inappropriate therapeutic indications, for which the benefits may not justify the risks (24). Recently, there has been increasing overprescription for trivial gastrointestinal symptoms without evidence-based indications, and abuse of PPIs among patients. Rather, PPIs should be prescribed at lower dosages and for the shortest possible period of time, in relation to the pathology treated, and not indefinitely without any re- evaluation of the cases, as unfortunately often happens. The reason lies not only in the unnecessary waste of resources, but in the onset of undesirable, sometimes even serious, effects that an inconsiderate administration of this category of medications can cause. Therefore, PPI treatment should be avoided in all those conditions in which there is no rationale for an inhibition of gastric acid secretion.

[0051] Chronic use of PPIs is associated with non-negligible side effects, such as an increased risk of bone fractures, electrolyte deficiencies and kidney failure. In particular, shortterm side effects are usually transient and reversible such as headache, diarrhoea, skin rash and anaphylactic reactions. In the long term, however, they can cause more severe and serious effects, such as poor absorption and consequent deficiencies in vitamin B 12, magnesium and calcium, useful for the proper functioning of the musculoskeletal system. In at-risk individuals, such as those suffering from osteoporosis, the risk of fractures may be increased. Antacids in gastric juice have been shown to inhibit phosphate absorption in the intestine. This process, in turn, can lead to hypophosphatemia and impairment of bone mineralization.

[0052] In addition, by changing the pH of the stomach, they can promote the development of intestinal infections, such as those caused by Helicobacter Pylori or Clostridium Difficile (as demonstrated by an extensive meta-analysis of 23 studies and about 270,000 patients, according to which the use of PPI is associated with a 69% increase in the relative risk of C. difficile infection). These infections are quite dangerous because they can lead to the appearance of tumors of the stomach or intestine (25). In this regard, it has been shown that PPIs are able to influence the composition of the intestinal microbiota and, consequently, modulate the immune response (26). In particular, by buffering the pH in the stomach, PPIs allow many more bacterial species to cross the intestinal barrier and colonize it. Furthermore, due to acidification of lysosomes, reactive toxic oxygen species (ROS) are released resulting in oxidative neutrophil explosion. Added to this is a modulation of Natural Killer (NK) cell activity. In fact, it has been shown that omeprazole and lansoprazole are able to reduce the cytotoxic activity of NK cells in a dose-dependent manner.

[0053] Finally, the alteration of the microbiota of the small intestine can lead to the onset of intestinal bacterial overgrowth, a syndrome called Small Intestinal Bacterial Overgrowth (SIBO), characterized by a hyperproliferation of anaerobic bacteria in the lumen of the small intestine. In particular, the term SIBO is used when a bacterial concentration of more than 100,000 CFU / ml is recorded in the aspirate. It has been shown that in patients taking full-dose PPIs for 1 year, the onset of SIBO occurred in 50% of cases and at all age groups. It can also affect up to 70-75% of patients after 5 years of continuous therapy, aggravating their symptoms. In the same study, rifaximin polymorph alfa, at a dose of 1,200 mg / day for a period of not less than 12 days, is recognized as an effective medication in the treatment of PPI-induced SIBO. Eradication of SIBO was achieved in 87% of patients taking PPIs. Treating SIBO with shorter periods resulted in markedly lower eradication rates: with a 7-day treatment, eradication was achieved in only 59-60% of cases (27). In randomized controlled clinical trials (RCTs), proton pump inhibitors are able to relieve symptoms in 50-80% of patients, and to induce healing of erosive forms in a percentage of patients that exceeds 85%. Up to 50% of patients taking PPIs for the treatment of non-erosive GERD are dissatisfied due to the unresolved and still persistent symptoms. In addition, among patients using PPI therapy increased to twice daily, nearly 40% increased their dosage due to persistent nocturnal symptoms. Poor compliance, combined with a narrow therapeutic window due to the short plasma halflife, or a short-term effect, can be a major cause of PPI failure in these cases (28). Added to this is the fact that many patients experience a relapse of symptoms after discontinuation of PPI treatment; therefore, lifelong therapy is necessary in these cases, with the possible risks of long-term side effects (29).

[0054] It is also important to pay attention to patients who take multiple medications at the same time, thus exposing themselves to an increased risk of pharmacological interactions. In this regard, the most well-known and discussed interaction of medications with PPIs is that related to clopidogrel, an antiplatelet medication. The debate is still open, due to conflicting results in the literature, but in the meantime the FDA recommends "avoiding concomitant use of esomeprazole / omeprazole and clopidogrel".

[0055] Among the different PPIs on the market, there are variations in the pharmacokinetic and pharmacodynamic profile. In particular, the metabolism of these medications causes the alteration of their plasma levels. In fact, it has been shown that genetic polymorphisms of the cytochrome P isoenzyme CYP2C19 (CYP) in the liver, an important metabolic pathway for the elimination of first-generation PPIs (80%), are able to influence the pharmacological levels of PPIs that depend on this cytochrome for metabolism. A patient having a rapidly metabolising CYP2C19 genotype (RMs) may have lower plasma levels of PPIs, thereby reducing their acid-suppressing action (30).

[0056] For these reasons, it is essential to try to avoid the excessive use of this category of medication, in order to prevent the symptoms described above as much as possible, precisely because, to date, there is no 100% effective pharmacological treatment that does not have side effects, including serious ones, in the long term. Prokinetic agents, such as cisapride or metoclopramide, activate serotonin or dopamine receptors that can increase oesophageal or gastric peristalsis. On the other hand, these medications show a disadvantageously slow onset of action, a short duration and no curative effect. The same medications also have several side effects, such as tremors, dyskinesias, fatigue and increased adverse cardiac events, so their use is quite limited in the treatment of GERD.

[0057] Known therapies based on natural ingredients

[0058] As an alternative to pharmacological therapy, there are compositions based on nutritional ingredients, including various herbs, fibres and botanicals. Their enduring appeal is due to the desire and need for more natural approaches to health, so that the potential side effects of more traditional treatments, for example pharmacological treatments, can be mitigated.

[0059] For example, alginates are used for the symptomatic treatment of GERD. Alginates, like sodium alginate, are natural polysaccharides that, in contact with the gastric environment, precipitate forming a low-density gel in a few minutes. Bicarbonates and carbonates, almost always present in commercially available alginate formulations, release carbon dioxide, which is trapped in the alginate gel, able to float on the gastric content. The alginate gel is formed in the portion of the stomach near the gastroesophageal junction, right where the acidic pocket develops. In this way, the ascent of acid from the stomach to the oesophageal canal is blocked or greatly reduced. Although alginates are safer than PPIs, the combined use of alginates and carbonates / bicarbonates is not useful in the treatment of non-acidic oesophageal reflux.

[0060] Still, again by way of example, therapies are known that involve the combined use of extracts of plants of the genus Musa in association with at least one proteolytic digestive enzyme, including bromelain, papain, actnidaine. Such a combination is disclosed in the patent document W02019026047A1. The extracts of plants of the Musa genus are characterized by anti -ulcer and mucoprotective activity. According to the authors of the paper in question, proteolytic enzymes instead contribute to gastric emptying. However, it is noted that, as indicated by the authors of W02019026047A1, actnidain is characterized by instability due to oxidative phenomena. In light of the known therapies, there is a need to find a composition that is able to prevent and / or treat gastroesophageal reflux and / or related symptomatology, in particular to act promptly on inflammation or on the disorders or symptoms associated with it, mainly in the oesophageal and / or gastric tissue, consequently reducing or eliminating pain. At the same time, it would be important to promote a "barrier" effect against gastric acidity, a mucoprotective effect of the injured tissue, and acceleration of the gastric emptying phenomenon.

[0061] SUMMARY OF THE INVENTION

[0062] The Applicant has identified an oral composition comprising palmitoyl ethanol ami de, dry extract of musa paradisiaca, dry extract of Zingiber officinale, mixture containing a dry extract of Opuntia ficus-indica and a dry extract of Olea europaea, for use in the prevention and / or in the treatment of gastroesophageal reflux disease.

[0063] Advantages of the invention

[0064] The composition in question offers advantages because it makes it possible to act on several fronts, including:

[0065] - the anti-inflammatory action on the tissues of the oesophagus and stomach, resulting in a significant reduction in "pain". In fact, the main disorder or symptom associated with gastroesophageal reflux is the burning sensation (also called heartburn) felt in the upper abdomen (epigastrium) and behind the sternum. The composition boasts endocannabinoid-like actions, some of its components acting as mediators at the CB1 and CB2 endocannabinoid receptors. The CB1 and CB2 receptors all play a fundamental role in the maintenance of gastrointestinal homeostasis, such as the modulation of intestinal motility, gastric emptying and secretion, visceral hypersensitivity and inflammation, all mechanisms in turn involved in the genesis of "pain". In particular, the action of reducing inflammatory markers contributes to the management of heartburn, therefore to the management of this very impactful symptom;

[0066] - the action of accelerating gastric emptying. Slowed gastric emptying and food staying in the stomach longer than usual can lead to gastroesophageal reflux. This condition is often poorly managed, given the use of PPIs as almost the only therapeutic solution to reflux problems. Comprehensive management of GERD cannot neglect the phenomenon of reduced kinesis of the stomach, due to the complications that may occur. In fact, chronic gastroparesis (reduced gastric emptying) can lead to dehydration or loss of water and electrolytes due to persistent vomiting resulting in malnutrition and weakness; oesophagitis, pain and irritation of the oesophagus; the formation of bezoars, a small mass of food, fibre or other substances in the stomach that can lead to nausea, vomiting or interference with some medicines; changes in blood sugar. The composition of the invention has a strong prokinetic action that speeds up gastric emptying, contributing to the elimination of the hyperacid environment and its ascent towards the oesophagus;

[0067] - the mucoprotective and barrier action to counteract gastric acidity, protecting the mucous membranes of the oral cavity, pharynx and oesophagus. This limits the irritation generated by gastric juices on the mucous membranes, protecting against the discomfort of acid regurgitation.

[0068] DESCRIPTION OF THE FIGURES

[0069] Figures la, lb, 1c: Results of action on inflammatory markers of the preclinical text in Example 2.2, respectively for IL-6, IL-8 and IL-lbeta (Legend: Control - not stimulated with LPS; HC1 - positive control; PEA - PEA; MS - Mixture containing the dry extract of Opuntia ficus-indica and the dry extract of Olea europaea; MP - Musa Paradisiaca; ZNZ - Ginger).

[0070] Figure 2: GERD Health-Related Quality of Life Questionnaire (GERD-HRQL) questions.

[0071] Figure 3: Reflux Symptom Index (RSI) questionnaire questions.

[0072] Figure 4: Clinical test results of Example 3 relative to GERD-HRQL.

[0073] Figure 5: Clinical test results of Example 3 relative to RSI. DETAILED DESCRIPTION OF THE INVENTION

[0074] In the following, the invention and preferred embodiments thereof are described in more detail.

[0075] Oral composition

[0076] As already mentioned, the subject of the present invention is an oral composition comprising or consisting of palmitoyl ethanol ami de, dry extract of musa paradisiaca, dry extract of Zingiber officinale, mixture containing the dry extract of Opuntia ficus-indica and the dry extract of Olea europaea, preferably, suitable excipients and / or diluents. for use in the prevention and / or in the treatment of gastroesophageal reflux disease.

[0077] Note that palmitoylethanolamide, Musa paradisiaca dry extract, Zingiber officinale dry extract, mixture containing Opuntia ficus-indica dry extract and Olea europaea dry extract constitute the active agents included in the composition.

[0078] Extracts generally refer to products of natural origin that are obtained from medicinal plants and herbs of different types. Many different parts of the plant can be used to obtain these products: leaves, flowers, fruits (pulp and / or peel), seeds, roots, rhizomes, bark, etc. They can be preparations in liquid form (fluid extracts), solid (dry extracts) or of intermediate consistency (soft extracts), obtained by suitable extraction processes; the latter include the use of appropriate solvents and the use of maceration or percolation, or other suitable processes.

[0079] A dry extract is a solid preparation obtained by an extraction process that involves the extraction of the active agents contained in the extract itself, and subsequent evaporation of the solvent. Generally, the dry extract is characterized by a dry residue of not less than 90% by mass and has a moisture content of generally less than or equal to 5% by mass. It should be noted that, although not experimentally proven at present, the Applicant believes that the oral solid composition of the invention may be synergistic in the prevention and / or treatment of gastroesophageal reflux disease and / or in the treatment of the symptomatology and / or disorders associated with gastroesophageal reflux.

[0080] Palmitoylethanolamide

[0081] Palmitoylethanolamide (PEA) is a non-endocannabinoid lipid mediator belonging to the N-acyl-ethanolamine (NAE) family of fatty acid amides and was initially isolated from soybean lecithin, egg yolk and peanut flour (39).

[0082] PEA was identified in the 1950s as an active anti-inflammatory agent in chicken egg yolk. In mammals, PEA is produced on demand from the lipid bilayer and is ubiquitous.

[0083] Its pleiotropic effects comprise anti-inflammatory, analgesic, anticonvulsant, antimicrobial, antipyretic, antiepileptic, immunomodulatory, and neuroprotective activities (40). The varying effects of PEA are due to its unique mechanisms of action that affect multiple signaling pathways in different cell types (41).

[0084] Preclinical and clinical studies suggest that PEA could potentially be useful in a wide range of therapeutic areas, including eczema, pain and neurodegeneration and at the same time appears to be substantially free of undesirable effects in humans.

[0085] PEA has anti-inflammatory properties, mediated mainly by peroxisome proliferator- activated receptor a (PPAR-a), resulting in inhibition of NF-kB and thus reduction of downstream release of pro-inflammatory cytokines (42) (43).

[0086] Given the anti-inflammatory properties of PEA, an interesting hypothesis is that it plays a role both in the pathogenesis of inflammatory disorders (where a relative deficiency fails to control inflammation), and as a response to the disorder to mitigate the level of inflammation (42).

[0087] Preferably, palmitoylethanolamide is comprised in a quantity between 0.1% and 3% by weight, preferably between 0.1% and 2.5% by weight, preferably between 0.2% and 2% by weight, preferably between 0.2% and 1.5% by weight, preferably between 0.2% and 1% by weight, preferably between 0.2% and 0.6% by weight, preferably between 0.3% and 0.6% by weight, preferably equal to about 0.5% by weight, of the total weight of the composition.

[0088] Preferably, for the purposes of the invention, the PEA is in a water-dispersible form, preferably in the form of a fine powder with a particle size comprised > 10 and < 50 pm, preferably > 20 and < 50 pm. This shape ensures greater ease for liquid formulations or to be dissolved in water, and better bioavailability.

[0089] Preferably, for the purposes of the invention, the PEA is not in ultra-micronized form. Said ultra-micronization size is preferably a size < 10 pm, preferably < 6 pm.

[0090] Dry extract of musa paradisiaca

[0091] Musa paradisiaca (Linnaeus classification) and other related species of the Musa genus are commonly called "banana" in English, "Kela" in Indian languages and are members of the Musaceae family (33). The Musa paradisiaca is distributed in tropical and subtropical regions around the world. In traditional medicine, extracts of Musa paradisiaca leaves and peel were used for the treatment of diarrhoea, dysentery, intestinal lesions in ulcerative colitis, diabetes, nephritis, gout, hypertension and heart disease (34) (35). Given the importance of Musa paradisiaca in traditional oriental medicines, many studies have investigated the existence of scientifically assessable therapeutic properties. From the point of view of the composition of the plant and its extracts, the components characterized are both organic and inorganic. These include vitamins, lutein, carotene, potassium and magnesium (36) (37), but also phytochemical substances such as flavonoids, tryptophan, indole, tannins, and triterpenes (34) (35). The antimicrobial activities of the plant, tested against various bacterial species of the genus Pseudomonas, Staphylococcus aureus, Escherichia coli and Proteus mirabilis, are attributed to these latter components (36). In aspirin-treated rats and histamine- treated guinea pigs (38), an anti -ulcerogenic effect and protection of the gastric mucosa from aspirin-induced erosion was demonstrated. From this, it was seen that the preparation based on banana powder not only increased the thickness of the mucosa, protecting it from the erosive action of aspirin, but also significantly increased the incorporation of thymine into the DNA of the mucosa, indicating an increased regenerative activity. In fact, treatment with banana powder strengthens mucosal resistance against ulcerogens and promotes cell proliferation (38). The Musa paradisiaca therefore has a function of controlling gastric acidity, and a digestive function.

[0092] For the purpose of the invention, the dry extract of Musa paradisiaca is obtained from the fruit.

[0093] Preferably, the dry extract of Musa paradisiaca is in a quantity comprised between 0.2% and 4% by weight, preferably between 0.2% and 3.5% by weight, preferably between 0.5% and 3% by weight, preferably between 0.5% and 2.5% by weight, preferably between 0.5% and 2% by weight, preferably between 1% and 2% by weight, preferably equal to 1.5% by weight, of the total weight of the composition.

[0094] Dry extract of Zingiber officinale

[0095] Ginger (Zingiber officinale Roscoe) is a rhizome of a plant belonging to the family Zingiberaceae and the genus Zingiber.

[0096] It has long been commonly consumed both as a spice and as a medicinal herb in the East (44). Ginger root is used to attenuate and treat several common diseases, such as headache, cold, nausea, and emesis. Many bioactive compounds have been identified in ginger, such as phenolic and terpene compounds, including gingerols. In recent years, ginger has been found to possess interesting biological activities, such as antioxidant and anti-inflammatory activity. In general, ginger and its active compounds have been shown to be effective in relieving inflammation, especially in inflammatory bowel diseases. The anti-inflammatory mechanisms of ginger are probably associated with inhibition of Akt and NF-KB activation also on enterocytes (45).

[0097] Generally, ginger extract has a digestive function, regulates gastrointestinal motility and gas elimination. It acts as an antinausea agent. It also regulates the function of the cardiovascular system; it promotes normal blood circulation and joint function. Finally, it is able to counteract localised states of tension and menstrual cycle disorders.

[0098] Note that the dry extract of Zingiber officinale imparts a gastric emptying effect, as it acts as a prokinetic. Preferably, the dry extract of Zingiber officinale is in a quantity comprised between 0.01% and 1% by weight, preferably between 0.01% and 0.5% by weight, preferably between 0.01% and 0.05% by weight, preferably between 0.01% and 0.03% by weight, preferably between 0.02% and 0.03% by weight, preferably equal to about 0.025% by weight, of the total weight of the composition.

[0099] Preferably, the dry extract of Zingiber officinale comprises gingerols in a quantity comprised between 10% to 25% by weight, preferably comprised between 15% to 20% by weight, preferably equal to 20% by weight, of the total weight of the extract.

[0100] Mixture containing the dry extract o f Opuntia ficus-indica and the dry extract o f Olea europaea

[0101] Preferably, the composition comprises a mixture (hereinafter also referred to as "mixture") which in turn contains or consists of a dry extract of Opuntia ficus-indica, preferably an extract obtained from the leaves or cladodes, a dry extract of Olea europaea, preferably an extract obtained from the leaves.

[0102] Generally, Opuntia ficus-indica dry extract is able to rebalance body weight; modulate / limit the absorption of nutrients; and regulate intestinal transit. In addition, it serves as an emollient and soothing agent in the digestive system.

[0103] Generally, the dry extract of Olea europaea helps the metabolism of carbohydrates and lipids, in addition to promoting normal blood circulation, to regulate blood pressure. Finally, it serves as an antioxidant.

[0104] Preferably, the mixture comprises the dry extract of Olea europaea in a quantity ranging from 23% to 25% by weight of the weight of the mixture.

[0105] Preferably, the mixture comprises the dry extract of Opuntia ficus-indica in a weight ranging between 32% and 35% of the weight of the mixture.

[0106] The mixture preferably comprises the two plant extracts containing polysaccharides from cladodes of Opuntia ficus indica and polyphenols from leaves of Olea europaea.

[0107] Preferably, the polysaccharide content of the cladodes is comprised between 15% and 30%, preferably between 17% and 29% by weight, of the total weight of the mixture. Preferably, the content of polyphenols is comprised between 3% and 5%, preferably between 3.5% and 4.5% by weight, of the total weight of the mixture.

[0108] The Opuntia ficus-indica extract, preferably the polysaccharide extract obtainable from Opuntia cladodes in the form of mucilage, can be obtained by squeezing the cladodes or by treatment with water at room temperature. Alternatively, the cladodes are pressed, the juice thus obtained is centrifuged, and the supernatant liquid is subjected to ultrafiltration, thereby obtaining an aqueous solution enriched in polysaccharides. Afterwards, the aqueous solution can be concentrated and dried. The content of polysaccharides in the extract of cladodes of Opuntia ficus-indica generally varies from 1 to 70% by weight on the weight of the extract.

[0109] Olea europaea extract can be obtained by subjecting the leaves to extraction with aqueous or hydroalcoholic solvents (10-80% ethanol) at room temperature or heated to 60-70°C, or by treatment with microwaves, ultrasound or extraction with superheated liquids. The hydroalcoholic extraction process can be repeated multiple times to achieve a biophenol enrichment. Once the extraction is finished, the aqueous or hydroalcoholic solvent is removed under vacuum at 40°C. Further enrichment in biophenols can be obtained by loading the dry extract onto styrenic resins and eluting with a 50:50 ethanol / water solution.

[0110] The prickly pear is the most widespread cactus in the Mediterranean countries and, to survive in a dry climate, the plant uses its "leaves", called cladodes, to save and accumulate water. Beneath the thorny surface, the cladodes contain a juicy gel very rich in polysaccharides. In folk medicine, cladodes are used for their healing activities and find use in the treatment of mucous membranes.

[0111] Olea europaea is also a tree species found in the Mediterranean basin. The phenolic compounds present in olive leaves are associated with antioxidant and soothing activity.

[0112] This mixture is useful for the treatment of mucous membranes and to counteract the main symptoms caused by gastrointestinal disorders.

[0113] The mixture has a strong mucoadhesive capacity thanks to the polysaccharides of the prickly pear tree and a soothing effect due to the biophenols of the olive tree to protect the sensitised mucous membranes. In fact, this natural compound can improve gastrointestinal disorders and counteract gastroesophageal reflux.

[0114] Preferably, the mixture containing the dry extract of Opuntia ficus-indica and the dry extract of Olea europaea is in a quantity comprised between 0.5% to 5% by weight, preferably 0.5% to 4% by weight, preferably 1% to 4% by weight, preferably 1% to 3% by weight, preferably equal to 2% by weight, of the total weight of the composition.

[0115] The mixture may preferably also contain maltodextrins.

[0116] Additional ingredients

[0117] The composition of the invention may preferably comprise at least one filming agent and / or at least one antacid agent.

[0118] Filming agent means an ingredient which, once it has reached the gastric cavity, comes into contact with the hydrochloric acid contained in the gastric juices and an acid-base reaction occurs, is able to form a film / coating or a gel layer on the gastric walls. Examples of the filming agent are alginic acid derivatives.

[0119] An antacid agent means an ingredient capable of neutralizing gastric acid. Examples of antacid agents are bicarbonate and / or carbonate salts.

[0120] In this way, the composition promotes a buffering action and neutralizes gastric hyperacidity.

[0121] The mucoprotective and barrier action are due to the formation of a "floating" coating on the gastric content so that, in the event of regurgitation, it comes up primarily into the oesophagus, reducing the impact of the acidic material on the mucosa, and also promoting the inactivation of pepsin. In addition, the direct anchoring of the components of the composition to the walls of the throat and oesophagus induces the formation of a protective film on more than 60% of the oesophageal surface which, added to the floating phase, optimises the anti-lesive effect.

[0122] Preferably, at least one filming agent and / or one antacid agent in a quantity comprised between 0.5% and 8% by weight, preferably between 1% and 6% by weight, preferably between 1% and 5% by weight, preferably between 1% and 4% by weight, preferably equal to 1.5% or 2.5% or 4% by weight, of the total weight of the composition. The composition of the invention can preferably comprise alginic acid derivatives, preferably sodium alginate, and / or bicarbonate and / or carbonate salts, preferably sodium or potassium salts.

[0123] Preferably, the alginic acid derivative, preferably sodium alginate, is in a quantity comprised between 1% and 3.5% by weight, preferably between 1.5% and 3% by weight, preferably equal to 2.5% by weight, of the total weight of the composition.

[0124] Note that, in addition to filming and coating capacity, the role of alginic acid derivatives is also that of a sequestrant of pepsin, which normally irritates the oesophageal mucosa.

[0125] Preferably, the salt of bicarbonate or carbonate, preferably sodium bicarbonate, is in a quantity comprised between 0.5% to 2.5% by weight, preferably 1% to 2.5% by weight, preferably 1% to 2% by weight, preferably equal to 1.5% by weight, of the total weight of the composition.

[0126] Still preferably, the composition comprises a total quantity of active agents comprised between 3% and 15% by weight, preferably between 4% and 10% by weight, preferably between 6% and 9% by weight, preferably between 7% and 8.5% by weight, of the total weight of the composition.

[0127] Preferred embodiment

[0128] According to a preferred embodiment, the oral composition comprises the following active ingredients palmitoyl ethanol ami de, dry extract of musa paradisiaca, dry extract of Zingiber officinale, the mixture containing a dry extract of Opuntia ficus-indica and a dry extract of Olea europaea, sodium bicarbonate, sodium alginate, suitable excipients and / or diluents. Note that the ranges and quantitative point values for each of the above actives are similar to those already described in the previous sections.

[0129] It should be noted that the composition of the invention may also comprise excipients and / or diluents selected from the group consisting of: solvents, flavours, preservatives, thickeners, stabilizers, pH regulators, antioxidants, and combinations of the foregoing.

[0130] According to a preferred form, the oral composition comprises excipients and / or diluents selected from the group consisting of: water, glycerol, sucralose, flavour(s), potassium sorbate, sodium benzoate, and combinations of the foregoing.

[0131] Form and use of the composition

[0132] The composition of the invention is preferably in the form of a medicament, food supplement, or nutraceutical.

[0133] Medicament means a preparation used for therapeutic purposes in the medical field.

[0134] Food supplement means a formulation falling within the definition underlying the Directive 2002 / 46 / EC as amended. In this regulation, food supplements are defined as: "foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients, such as vitamins and minerals, or other substances with a nutritional or physiological effect, including, but not limited to, amino acids, essential fatty acids, fibre and various plants and herbal extracts, both single- and multi-compound, in pre-dosed forms".

[0135] Nutraceutical means a food, or part of a food, with beneficial and protective effects on both the physical and psychological health of the individual.

[0136] Preferably, the oral composition is in liquid form.

[0137] The composition of the invention is preferably in the form of a stick or unit dose sachets.

[0138] For the purposes of the present invention, stick means a package in the form a small cylinder, preferably suitable for containing a liquid preparation.

[0139] For the purposes of the present invention, a single-dose sachet means a package in the form of an envelope, intended to be consumed on a single occasion, preferably suitable for containing a liquid preparation. The composition of the invention is preferably to be administered at least once per day, preferably one to two times per day.

[0140] Preferably, the composition can be administered for at least two weeks.

[0141] Preferably, the composition is for use in the treatment of the symptomatology and / or disorders associated with gastroesophageal reflux.

[0142] Symptomatology and / or disorders associated with gastroesophageal reflux are those signs or symptoms that occur in conjunction with a condition of gastroesophageal reflux.

[0143] Preferably the symptomatology and / or the disorders are selected from the group consisting of: heartburn; chest and / or retrosternal pain; digestion difficulties; swallowing difficulties; regurgitation; hoarseness and / or dysphonia; cough; breathing difficulties; mucosal hypersecretion or phlegm; nausea; belching; hiccup; mucosal lesions; and combinations of the foregoing.

[0144] According to a preferred embodiment the composition for use in the treatment of the symptomatology and / or of the disorders associated with gastroesophageal reflux, preferably the symptomatology and / or the disorders are selected from the group consisting of: heartburn; chest and / or retrosternal pain; digestion difficulties; swallowing difficulties; regurgitation; mucosal lesions; and combinations of the foregoing.

[0145] By acting on the symptomatology and / or disorders associated with gastroesophageal reflux, the composition for use according to the invention is intended to improve the quality of life of subjects suffering from such disorders or symptoms.

[0146] Preferably, the sublingual composition may also be for use as an adjunct to pharmacological therapies in the treatment of gastroesophageal reflux.

[0147] Adjuvant means a substance or composition of substances which, in combination with a medication or a pharmacological therapy, is capable of reinforcing or completing its action.

[0148] Preferably, the composition of the invention does not comprise any proteolytic digestive enzymes, preferably does not comprise bromelain, papain and / or actnidain. EXAMPLES

[0149] Example 1: Liquid oral composition in stick form.

[0150] Recommended dose: 1 stick / day Example 2: Preclinical study to evaluate the effects on inflammation.

[0151] The purpose is to verify the effects of the composition of the invention, in order to validate its ability to effectively counteract mucosal damage from GERD. The study worked on in vitro models of oesophageal mucosal damage that can mimic, in some way, that which occurs in vivo following or in conjunction with gastroesophageal reflux disease (GERD).

[0152] In particular, the oesophageal cell line CP-B, derived from oesophageal mucosa with Barrett's oesophagus, was used in the study. Responses to inflammatory stimuli, such as exposure to the bacterial toxin lipopolysaccharide (LPS) and exposure to an acidic environment (pH=4.5), were examined, as the oesophageal cell line CP-B is pathophysiologically representative of what happens in GERD.

[0153] Continuous variables are expressed as the average ± SD. Statistical differences between treatments were determined by bidirectional analysis of variance (two-way ANOVA). GraphPad Prism 6 (GraphPad Software Inc., San Diego, CA, USA) was used for calculations of p. Differences were considered significant at p<0.05.

[0154] In order to better study the anti-inflammatory effects, it was decided to proceed with the analyses on the individual actives and on the sum of the actives, using the lowest concentrations tested for each active in comparison, since they have all been shown to be active in reducing the secretion of at least one cytokine in at least one of the inflammation models.

[0155] It was decided to study the acid stimulation model, as it was closer to the objective of the project which was to study compounds with possible GERD activity, characterized by the presence of mucosal damage mainly due to the aggressive acid and proteolytic insult.

[0156] The individual substances demonstrate specificity of anti-inflammatory action on different cytokines and on the two different models of inflammation chosen.

[0157] In vivo, where mucosal damage due to the presence of pathological gastroesophageal reflux is complex and follows different metabolic pathways (46), the composition is overall much more effective than the individual actives.

[0158] The composition comprising PEA, MS, MP and ZNZ is, in fact, able to simultaneously inhibit the pathways of IL-6, IL-8 and IL-lb, significantly increasing the migration of oesophageal cells, which is essential to accelerate the repair of erosions and other mucosal damage caused by all forms of GERD.

[0159] In particular, with regard to the stimulation of inflammation by acidification of the culture medium, some natural compounds added to the medium had statistically significant effects on the decrease in the concentration of IL-6, resulting in a reduction in inflammation. In fact, a p-value of 0.028 is obtained for PEA L, of 0.038 for Musa paradisiaca L, all evaluated compared to the acid control. For ginger, on the other hand, no statistically significant results are found at the minimum concentration L.

[0160] With stimulation of inflammation by addition of LPS (control), it can be seen that treatments with PEA, MS and MP have no significant effect on IL-6 secretion, whereas ginger has a significant, albeit limited, effect on decreasing IL-6 concentration compared to control of LPS alone (L, p=0.029).

[0161] For IL-8, measurable values are observed with acid stimulation. In fact, a p-value of 0.022 for PEA L is obtained, respectively, of 0.018 for Musa paradisiaca. Ginger also proves effective with a p=0.020 for ZN-L. Induction of inflammation with LPS instead leads to much higher IL-8 concentrations, which reach values above the reading ability of the standard curve.

[0162] With regard to the concentration of IL-lb, a p-value of 0.044 is obtained for MS L. Ginger does not reveal statistically significant results. With the stimulation of inflammation by the addition of LPS it can be seen that none of the treatments had a significant effect.

[0163] Example 3: Clinical study to evaluate the effects on the symptomatology associated with gastroesophageal reflux.

[0164] The composition that is the object of the clinical study is that of Example 1 (hereinafter "composition").

[0165] Objective

[0166] The objective of the study was to evaluate the effect of the composition in NERD patients who had not taken PPIs in the month prior to enrollment. The use of PPIs will not be granted throughout the duration of the study to avoid confounding effects with those of the nutraceutical.

[0167] Sample

[0168] 50 patients diagnosed with NERD were enrolled. Patients with the following inclusion criteria will be enrolled in the study:

[0169] - non-erosive reflux disease with typical reflux symptoms for at least 3 months and at least three times per week in the month before the study screening visit;

[0170] - of both sexes and aged between 18 and 75 years;

[0171] - who have not taken PPI in the month prior to enrolment;

[0172] - with relevant symptomatology that need an intervention to feel better;

[0173] - poor quality of life identified by a low score on the quality of life questionnaire.

[0174] Gender of subjects enrolled: 54% female, 46% male.

[0175] Age of subjects enrolled: 53.79 (± 14.96).

[0176] Reflux duration (in months): 16.98 (± 9.29). The diagnosis of NERD was ascertained on the basis of recurrent symptomatology associated with gastroesophageal reflux and on the positivity of a validated questionnaire (Reflux Disease Questionnaire, RDQ), identified by an RDQ Score > 10. Note that the RDQ coincides with the RSI questionnaire in Figure 3.

[0177] Methods

[0178] The study is an interventional, prospective, single arm study.

[0179] Patients eligible for the study gave informed, written consent.

[0180] For the evaluation of the effect of treatment with the composition, each patient completed the questionnaires at the following experimental times: at baseline (TO), at the end of the first 2 weeks (Tl) and at the end of the study, after a further 2 weeks (T2).

[0181] At the TO visit, patients were instructed to take 1 stick of the composition of Example

[0182] 1, one hour after breakfast and 1 stick of the same composition before bedtime, or both sticks in the evening before going to sleep, depending on when the symptomatology occurs, for a treatment period of 4 weeks.

[0183] Primary objective: To evaluate the effect of the composition in terms of improvement of Quality of Life (QoL) and reflux symptoms.

[0184] Secondary objectives: to evaluate the tolerability of the nutraceutical and any dropout, both in terms of frequency and cause.

[0185] Questionnaires administered to patients

[0186] The questionnaires administered to enrolled patients for monitoring the symptomatology were:

[0187] - GERD-HRQOL (GERD-Health Related Quality of Life Questionnaire) - see Figure

[0188] 2,

[0189] - RSI (Reflux Symptom Index) - see Figure 3.

[0190] Statistical data analysis

[0191] Firstly, the descriptive statistics of all the variables were calculated: for the qualitative variables the number and percentages will be reported, for the quantitative variables the main indices (mean, median, quartiles, minimum, maximum and standard deviation).

[0192] Then, for each questionnaire, the total variables at the 3 times were constructed.

[0193] As for the variables measured at times TO, T1 and T2, based on the final sample number, the Friedman test was used to verify whether the distribution of the variable in the three times is similar or not.

[0194] In case of significance, Dunn's post hoc test was carried out, to see where the differences are, or the repeated measures ANOVA test, to check whether the average of the variables in the three times is similar or not.

[0195] In case of significance, post hoc tests (t-tests) were observed to see where the differences are.

[0196] For all tests, the level of significance considered was p<0.05.

[0197] Analyses will be carried out with IBM SPSS Statistics v.28 software.

[0198] Results

[0199] Regarding the GERD-HRQOL (Figure 4), it is observed that the change in the score from TO to T1 (+15 days) decreased by 72.27%, which is a statistically significant change (p<0.001).

[0200] The change in score between T1 and T2 decreased by about 21%, a significant result (p=0.006).

[0201] The change in score between TO and T2 is -78.34% and is statistically significant (p<0.001).

[0202] Regarding the RSI (Figure 5), it is observed that the change in the score from TO to T1 (+15 days) decreased by 49.28%, which is a statistically significant change (p<0.001).

[0203] The change in score from T1 to T2 (-65.54%) is also statistically significant (p<0.001).

[0204] The change in score between TO and T2 is -82.52% and is statistically significant (p<0.001). REFERENCES

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Claims

CLAIMS1. Oral composition comprising palmitoyl ethanol ami de, a dry extract of Musa paradisiaca, a dry extract of Zingiber officinale, a mixture containing a dry extract of Opuntia ficus-indica and a dry extract of Olea europaea, for use in the prevention and / or in the treatment of gastroesophageal reflux disease.

2. Composition for use according to claim 1, wherein the palmitoylethanolamide is in a quantity comprised between 0.1% and 3% by weight on the total weight of the composition.

3. Composition for use according to claim 1 or 2, wherein the dry extract of Musa paradisiaca is in a quantity comprised between 0.2% and 4% by weight on the total weight of the composition.

4. Composition for use according to any one of claims from 1 to 3, wherein the dry extract of Zingiber officinale is in a quantity comprised between 0.01% and 1% by weight on the total weight of the composition.

5. Composition for use according to any one of claims from 1 to 4, wherein the mixture containing the dry extract of Opuntia ficus-indica and the dry extract of Olea europaea is in a quantity comprised between 0.5% and 5% by weight on the total weight of the composition.

6. Composition for use according to any one of claims from 1 to 5, further comprising at least one filming agent and / or at least one antacid agent.

7. Composition for use according to any one of claims from 1 to 6, in the form of a medicine, food or nutraceutical supplement.

8. Composition for use according to any one of claims from 1 to 7, in the form of a single-dose stick or sachets.

9. Composition for use according to any one of claims from 1 to 8, to be administered at least once a day.

10. Composition according to any one of claims from 1 to 9, for use in the treatment of the symptomatology and / or of the disorders associated with gastroesophageal reflux, preferably the symptomatology and / or the disorders are selected from the group consisting of: heartburn; chest and / or retrosternal pain; digestion difficulties; swallowing difficulties; regurgitation; hoarseness and / or dysphonia; cough; breathing difficulties; mucosal hypersecretion or phlegm; nausea; belching; hiccup; mucosal lesions; and combinations of the foregoing.

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