IT202000031409A1 - MULTICOMPONENT COMPOSITION INCLUDING GELLANUM GUM AND ITS USE FOR THE TREATMENT OF GASTRIC REFLUX - Google Patents

Description

DESCRIPTION of the invention entitled:

?Multicomponent composition comprising gellan gum and its use for the treatment of gastric reflux?

The present invention relates to a multicomponent composition comprising a gellan gum, its preparation and its use for the treatment of gastric reflux and of pathologies or symptoms deriving from it.

The parietal cells, located in the gastric mucosa and responsible for the secretion of hydrochloric acid, are able to release H<+ > ions in the gastric lumen by exchanging them with K<+ > ions through the action of the H<+>/K<+ pump >. Chemical and physical stimuli induce the release of numerous mediators (gastrin, histamine, prostaglandins, somatostasin) which finely regulate this secretion. In some cases, however, there is an imbalance of these regulations resulting in acid hypersecretion. This acid hypersecretion can lead to pathological conditions such as gastroesophageal reflux disease or pharyngolaryngeal (or extra-oesophageal) reflux disease or the formation of ulcers on the mucosa of the upper digestive tract.

Gastroesophageal reflux disease (GERD or GERD, gastroesophageal reflux disease) ? a clinical condition characterized by massive ascent of gastro-duodenal contents into the esophagus. The strongly acidic gastric contents and the bile contained therein in contact with the esophageal mucosa lead to inflammatory states that can result in heartburn or esophageal ulcers. The characteristic symptoms of this disorder can be divided into typical (e.g. acid regurgitation, heartburn), atypical (e.g. feeling of gastric fullness, epigastric pain, dyspepsia, nausea) and extra-oesophageal (e.g. chronic cough, bronchospasm, sore throat, laryngitis).

Pharyngolaryngeal reflux disease (RFL or LPR from English LaryngoPharyngeal Reflux) or extraesophageal reflux ? a clinical condition characterized by the ascent of gastro-duodenal contents from the stomach to extra-oesophageal regions such as the upper respiratory tract (the nasal cavity, the paranasal sinuses, the oral cavity, the pharynx, the epiglottis and the larynx), the periocular region (conjunctiva and the lacrimal apparatus) and the auricular apparatus (the Eustachian tube and the middle ear).

Acid hypersecretion, gastroesophageal, pharyngolaryngeal or extra-oesophageal reflux and ulcers in the gastric and oesophageal mucosa can be treated either by drug therapy (anti-H2 antihistamines, proton pump inhibitors, etc.) either through compounds or by contact with the gastric acid environment they implement a protective action through physical mechanisms (for example floating raft).

The technical problem that the present invention faces and solves? that of providing innovative therapeutic solutions with an anti-reflux action (treatment of gastric reflux and the pathologies and/or symptoms deriving from it) and highly effective gastroprotective, free from significant side effects, usable by a wide range of subjects having need, and economically advantageous.

The Applicant, following an extensive research and development program, tackles and solves the above technical problem by providing an innovative composition, preferably for oral use, comprising a mixture M of active components comprising or, alternatively, consisting of (a) an acid alginic acid or a salt thereof (alginate), (b) a simethicone and/or dimethicone, and (c) a gellan gum, as described below in the present invention (in short, composition(s) or mixture(s) M of the invention) .

The compositions or mixtures M of the present invention, according to any one of the described embodiments, exert an effective mechanical action for the treatment of gastric reflux, in order to reduce the pathologies and/or symptoms related to it. In addition, said compositions or mixtures M of the present invention exert an excellent mucoadhesive and mucoprotective action with consequent ability to protect the esophageal mucous membranes from the corrosive-inflammatory action of the gastric juices rising during the reflux episode, and the gastric mucosa (anti-acidity effect).

In particular, the compositions or mixtures M of the present invention, in virtue of the combination of the specific active components and/or their synergy, are able to: (i) increase the quality, in terms of greater resistance and greater elasticity, of the structure of the gel which forms in the stomach starting from the compositions of the The invention as a consequence of the acid pH conditions (gel with floating raft effect/action), (ii) to increase the rapidity? in the formation of said gel in the stomach, and/or (iii) exhibit a high capacity? gastro-protective or mucoprotective.

In fact, in an environment with an acid pH such as the stomach, alginate and gellan gum give rise to the formation of a floating gelatinous precipitate (floating raft) which prevents the gastric reflux from rising up to the cardia level and therefore to the esophagus and extra-oesophageal areas (e.g. pharynx, larynx, upper respiratory tract, lacrimal duct).

Advantageously, the gellan rubber allows to form, in combination with the alginate and the other components of the composition of the invention, a floating raft that is more resistant and long-lasting than those known in the art. In particular, gellan gum, in the presence of cations, able to form a gel. because in the gastric juice there are salts, gellan gum ? able to gel in situ and, therefore, to strengthen the volume of the raft.

Furthermore, said high gastroprotective or mucosal protective action of the composition or mixture M of the invention ? mainly due, but not only, to its ability? to form a highly effective mucoadhesive layer on a mucous membrane, for example the gastric mucosa, in particular thanks to the presence of gellan gum in the composition.

In addition, the compositions of the invention preferably do not include all or almost all sources of sodium.

These aims, and still others which will become clear from the detailed description which follows, are achieved by the mixtures and compositions of the present invention thanks to the technical characteristics claimed in the appended claims.

FIGURES

Figure 1: flow chart of the preparation process of a composition of the invention in aqueous liquid form of syrup.

Figure 2: formation of the floating raft according to the experimental conditions reported in the experimental part (I.A).

Figure 3a and 3b: respectively, residue after filtration and filtrate of acid solutions comprising gellan gum or xanthan gum.

Figure 4: Mucoadhesiveness Index Histogram of Formulation 1 comprising magnesium alginate and xanthan gum (comparative composition): comparison between the sum of the viscosity? of Samples 1 and 2 and of Sample 4.

Figure 5: Mucoadhesiveness Index histogram of Formulation 2 comprising magnesium alginate and gellan gum (composition according to the invention): comparison between the sum of the viscosity? of Samples 1 and 3 and of Sample 5.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a composition comprising (i) a mixture M of active components comprising or, alternatively, consisting of:

- (a) an alginic acid or salt thereof of acceptable pharmaceutical or food grade, preferably an alkali metal or alkaline earth metal (e.g. magnesium, sodium, potassium or calcium) or ammonium alginate;

- (b) a simethicone and/or dimethicone

- (c) a gellan gum;

and, optionally, said composition comprises (ii) at least one additive and/or excipient of pharmaceutical or food grade.

The mixture M of the composition of the present invention comprising (a), (b), (c) and, optionally (e) (according to any of the described embodiments) can? further comprising (d) a bicarbonate salt and/or a carbonate salt with an alkali or alkaline earth metal, preferably selected from the group comprising or alternatively consisting of sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate , sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and mixtures thereof.

An example of (and) potassium bicarbonate ? potassium bicarbonate E501 (acidity regulator), for example EINECS nr. 298-14-6 with Bulk density of about 0.99-1.12 g/cm<3 > and Tapped density of about 1.14-1.25 g/cm<3>.

The alginic acid? a natural, linear polysaccharide consisting of monomers of D-mannuronic acid and D-glucuronic acid joined by ?(1?4) glycosidic bonds; structural formula (C6H8O6)n. The presence along the chain of numerous carboxyl groups makes s? that in an acid pH environment, such as in the stomach, the alginate tends to form a low-density gel, able to float and accumulate near the stomach. of the gastroesophageal sphincter; this behavior leads to a decrease in the frequency and severity? of episodes of gastroesophageal reflux.

because the? alginic acid not ? particularly soluble in water, preferably in the composition of the invention ? there is an alginic acid salt, such as an alkali metal or alkaline earth metal alginate.

The alginate, at acid pH of the stomach, precipitates in the form of a gel. Simultaneously, the reaction between bicarbonate and/or carbonate, if present in the composition of the invention, and hydrochloric acid present in the stomach generates carbon dioxide which creeps into the meshes of the gel and increases its buoyancy.

Advantageously, said (a) alginic acid or its salt, included in the composition or mixture M of the invention together with (b), (c) and, optionally, (d) and/or (e), ? or is derived from an alginic acid having an average molecular weight in the range of from about 10 kDalton (kDa) to about 600 kDa; preferably from about 100 kDa to about 400 kDa or 500 kDa, more? preferably from about 200 kDa to about 300 kDa, for example about 240 kDa (a Dalton (Da) is equivalent to a unified atomic mass unit (amu, from English atomic mass unit).

Said (a) alginic acid or its salt, included in the composition or mixture M of the invention together with (b), (c) and, optionally, (d) and/or (e), can? be or derive from an alginic acid having an average molecular weight of about 200-300 kDa (e.g. 240 kDa) and/or be obtained from marine algae, such as, for example, a magnesium alginate (e.g. CAS n. 37251-44- 8) obtained from alginic acid with an average molecular weight of about 230-250 KDa. Preferably, said alginic acid or alginate (a) does not comprise sodium.

In a preferred embodiment, said active component (a) comprised in the composition or mixture M of the invention together with (b), (c) and, optionally, (d) and/or (e), according to any of the forms of realization described, ? a magnesium alginate (for example, CAS nr. 37251-44-8), preferably of an average molecular weight of about 200-300 kDa (e.g. 240 kDa) and/or obtained from marine algae.

Preferably (a) does not include sodium.

Examples of (a) an alginic acid or alginate usable in the composition or mixture M of the invention, according to any of the described embodiments, are represented by:

- Alginic acid EP (CAS No.? 9005-32-7) in the form of a pale yellow powder with an average particle size of about 80 mesh, a viscosity less than or equal to 50 cPs, an acidity index? greater than or equal to 230, carboxyl groups of about 19-25, a pH of about 2-3.5.

- Calcium alginate (CAS n.? 90005-35-0) with general formula (C6H7Ca1/2O6)n; unit? structural 195.16 (theoretical), 219 (average) and macromolecules: 10,000-600,000 (typical average).

- Magnesium alginate (CAS No. <o >37251-44-8) (composition: about 65-75% guluronic acid and about 25-35% mannuronic acid and a magnesium content of about 5.4-6.6 ) with a pH value of about 6-9.5, a viscosity? (CPS) (LV, 12RPM) of 7.5%, 25?C natural base solution of about 1.000-1.800.

- Potassium alginate (CAS n.? 90005-36-1), with general formula (C6H7KO6)n; unit? structural 214.22 (theoretical), 238 (average) and macromolecules: 10,000-600,000 (typical average).

- Composition: E401 sodium alginate and sucrose, with a viscosity? of about 550-750 mPas (1% sol.) and a pH of about 6-8.5 (1% sol.).

- Sodium alginate (CAS n.? 90005-38-3), with general formula (C6H7NaO6)n; unit? structural 198.11 (theoretical), 222 (average) and macromolecules: 10,000-600,000 (typical average).

The term ?simeticone? (example CAS 8050-81-5), alternatively referred to as activated dimethicone, refers to a polydimethylsiloxane (or dimethicone, example CAS 63148-62-9) activated with silica dioxide (synthetic polymer). The simethicone has a structural formula (C2H6OSi)n(SiO2)m with n and m variables (for example, n=6 and m=3).

Preferably, said active component (b), included in the composition or mixture M of the invention together with (a), (c) and, optionally, (d) and/or (e), ? simethicone, for example the compound with CAS no. 8050-81-5 called ?-(trimethylsilyl)-?-methylpoly[oxy(dimethylsilylene)] in admixture with silica dioxide.

Examples of simethicone or simethicone (b) usable in the compositions or mixtures M of the present invention, in association with (a), (c), and, optionally, (d) and/or (e), are represented by:

- Simethicone in the form of a water-dispersible simethicone (aqueous emulsion) with a? activity? defoamer of 15 seconds max. and an active content including (simeticone) from 29% to 32% by weight and a density? about 1 g/cm<3>;

- Simethicone as a compound consisting of a fluid polydimethylsiloxane (PDMS) and an airgel silica. Airgel silica activates the properties? defoamer of fluid silicone. This compound has a gravity specification at 25°C of about 0.1; a viscosity? at 25°C about 3000 cP; an efficiency of less than 15 seconds; a composition of PDMS of about 92.5-97.5% and silica of about 4-7%;

- Simethicone in the form of an emulsion with a solid content of about 31-34% by weight; an active ingredient (?Simethicone?, USP) of about 30% by weight, a density? at 25? C of about 1 g/ml, a viscosity? at 25°C of about 1500-5000 mPas, a pH at 25°C of about 3-5.

Alternatively, said active component (b), included in the composition or mixture M of the invention together with (a), (c) and, optionally, (d) and/or (e), can be forgetful.

Examples of dimethicone or dimethicone (b) usable in the compositions or mixtures M of the present invention, in association with (a), (c) and, optionally, (d) and/or (e), are represented by:

- Dimethicone CAS No.? 63148-62-9, in liquid form with a viscosity? kinematics at 25? C of about 332.5-367.5 mm2/s, a density? at 25°C of about 0.9660-0.9720 g/ml, a refractive index at 25°C of about 1.4025-1.4045, chemical name polydimethylsiloxane.

- Dimethicone CAS No.? 63148-62-9, in liquid form with a refractive index of approximately 1.4030-1.4050, a density? at 25? C of about 0.95-0.97 g/ml and a viscosity? at 25?C of about 332-368 mm2/s.

- PEG-14 Dimethicone (components: PEG-14 Dimethicone 95% by weight and Propylene glycol 5% by weight) CAS No.? 68937-54-2, in liquid form with a refractive index of approximately 1.4500-1.4600, a density at 25? C of about 1.063-1.077 g/ml and a viscosity? at 25°C about 300-600 mPas; - Dimethicone (Component: Stearoxy Dimethicone 100%) CAS No? 68554-53-0, with a refractive index of approximately 1.4210-1.4270, a density? at 50?C of about 0.8600-0.9000 g/ml and a recrystallization of about 20-30?C.

Further examples of dimethicone usable in the context of the present invention are: cetyl dimethicone, stearyl dimethicone, stearoxy dimethicone, behenoxy dimethicone and all polymers belonging to the copolyol dimethicone group such as for example: dimethicone PEG-8 adipate, dimethicone PEG-8 benzoate, dimethicone PEG-7 phosphate, dimethicone PEG-10 phosphate, dimethicone PEG/PPG-20/23 benzoate, PEG/PG-7 dimethicone, PEG-10 dimethicone, PEG-9 dimethicone, PEG-10 dimethicone, PEG-12 dimethicone, PEG- 3 dimethicone, PEG-7 dimethicone, PEG-14 dimethicone, PEG/PPG-8/14 dimethicone, PEG/PPG-3/10 dimethicone, PEG/PPG-4/12 dimethicone, PEG/PPG-6/11 dimethicone, PEG /PPG-4 dimethicone, PEG/PPG-15/15 dimethicone, PEG/PPG-16/2 dimethicone, PEG/PPG-17/18 dimethicone, PEG/PPG-18/18 dimethicone, PEG/PPG-19/ PPG- 20/6 dimethicone, PEG/PPG-20/15 dimethicone, PEG/PPG-20/20 dimethicone, PEG/PPG-20/23 dimethicone, PEG/PPG-20/29 dimethicone, PEG/PPG-22/23 dimethicone, PEG/PPG-22/24 dimethicone, PEG/PP G-23/6 dimethicone, PEG/PPG-25/25 dimethicone and PEG/PPG-27/27 dimethicone.

Simethicones and dimethicones are inert and water-repellent silicone compounds capable of promoting gastric emptying.

Gellan gum (c) ? a linear polysaccharide consisting of units? tetrasaccharides formed by units? of glucose-rhamnose-glucose-glucuronic acid.

Advantageously, said (c) gellan gum, included in the composition or mixture M of the invention together with (a), (b) and, optionally, (d) and/or (e), has an average molecular weight in the range approximately 50 kDa to approximately 2000 kDa (e.g. 200 kDa, 300 kDa, 400 kDa, 500 kDa, 600 kDa, 800 kDa, 1000 kDa, 1200 kDa, 1400 kDa, 1600 kDa, or 1800 kDa); preferably from about 100 kDa to about 600 kDa, more? preferably from about 200 kDa to about 300 kDa. An example of gellan gum (c) usable in the context of the present invention in conjunction with (a), (b) and, optionally, (d) and/or (e), ? gellan gum having CAS n. 71010-52-1 (example of commercial product: Gellan Gum Kelcogel CG-LA).

For the compositions of the present invention ? been analyzed and observed that, in the acid pH environment similar to the pH of the stomach, the gellan gum ? capable of gelling by participating together with the alginate salt in the formation of a fluid gel (liquid gel), called a floating raft, when this gel forms in the stomach of the subject treated with the composition of the invention.

The ?fluid gels? or ?liquid gels? show a behavior analogous to that of strong gels when a slow and weak shear force is impressed on them, while they have a behavior analogous to that of viscous liquids if the shear force impressed ? strong and fast. The behavior of liquid gels can? be exploited to prevent the sedimentation of particles within a suspension.

The gelling of gellan gum in an acid pH environment? due to the passage of the polysaccharide from the random coil conformation to a double helix conformation; the double helices, formed in a neutral environment and with a low ionic strength, tend to repel each other due to the negatively charged carboxyl groups; by lowering the pH of the environment and increasing its ionic strength, these repulsions disappear, thus allowing the formation of junction zones between the polysaccharide chains and the consequent formation of a three-dimensional network.

Given the chemical characteristics of gellan gum, ? It is possible to hypothesize that in the acidic pH environment of the stomach the gelling of gellan together with the alginate salt is favored both by the formation of junction zones between the double helices and by their stabilization due to the ionic interaction of the latter with the cation ions ( e.g. of alkali or alkaline earth metal) released from the alginate salt.

Therefore, in the acidic pH environment of the stomach, the composition of the invention is capable of forming a floating gel (floating raft) that is more resistant and stable than the products currently known in the art, thanks to the interaction and/or synergy of gellan gum and alginate.

In addition, the gellan gum provides the composition or mixture M of the invention with a marked ability to mucoadhesive, as demonstrated in experimental part by the in vitro test with the use of mucins.

Preferably the mixture M included in the composition of the invention comprises or, alternatively, consists of: (a) alginate of an alkali or alkaline earth metal, preferably magnesium alginate, advantageously derived from an alginic acid having an average molecular weight about 200 kDa - 300 kDa, (b) simethicone (e.g., CAS No. 8050-81-5), (c) gellan gum (e.g., CAS No. 71010-52-1), and optionally, (d) bicarbonate of an alkali metal or alkaline earth, preferably potassium bicarbonate.

For example, the mixture M comprised in the composition of the invention comprises or alternatively consists of: (a) magnesium alginate, preferably having an average molecular weight of about 200 kDa - 300 kDa (e.g. CAS no. 37251-44- 8), (b) simethicone (e.g., CAS No. 8050-81-5), (c) gellan gum (e.g., CAS No. 71010-52-1), and optionally, (d) potassium bicarbonate.

In a further example, the mixture M comprised in the composition of the invention comprises or, alternatively, consists of: (a) magnesium alginate, preferably having an average molecular weight of about 200 kDa - 300 KDa, (b) simethicone, (c ) gellan gum, (d) potassium bicarbonate and (e) a magnesium salt, for example magnesium chloride or a similar salt.

The composition or mixture M of the present invention comprising (a), (b), (c) and, optionally, (d) (according to any of the disclosed embodiments), can further comprising (e) a salt of an alkali or alkaline earth metal, preferably wherein said alkali or alkaline earth metal ? the same as component (a) when said (a) ? in the form of alginate salt. Said (e) salt of an alkali or alkaline-earth metal can? be selected from magnesium salt, potassium salt, calcium salt or a mixture thereof, for example magnesium chloride, potassium chloride, calcium chloride; preferably magnesium chloride. Preferably (e) does not include sodium.

The presence in the composition of the invention of a certain quantity? of the component (e) salt of an alkali or alkaline-earth metal, for example a magnesium salt such as magnesium chloride, favors the formation of the liquid gel, in particular when the composition? formulated in water-based liquid form (e.g. syrup).

? It has been hypothesized, on the basis of the chemical characteristics of gellan gum, that in an acid environment gelling of gellan gum is favored both by the formation of junction zones between the double helices and by their stabilization due to the ionic interaction of the latter, in an acid environment , with the alkali or alkaline earth metal released from the alginate (a) and, if present, the alkali or alkaline earth metal salt (e).

The compositions of the present invention, comprising said (i) mixture M comprising (a), (b), (c) and, optionally, (d) and/or (e), may comprise (ii) at least one additive and/or acceptable pharmaceutical or food grade excipient, cio? a substance without activity? therapeutic suitable for pharmaceutical or food use. In the context of the present invention, the additives and/or excipients acceptable for pharmaceutical or food use include all the auxiliary substances known to the person skilled in the art for the preparation of compositions in solid, semi-solid or liquid form, such as, for example, diluents, solvents (including water), solubilizers, acidifiers, thickeners, sweeteners, flavourings, colors, sweeteners, lubricants, surfactants, preservatives, stabilizers, pH stabilizing buffers, and mixtures thereof.

Preferably, the composition or mixture M of the present invention, comprising (a), (b), (c) and, optionally, (d) and/or (e) according to any of the disclosed embodiments, does not comprise an antagonist of histamine H2 receptors (H2 antagonists), such as for example ranitidine, famotidine or cimetidine.

The compositions or mixtures M object of the present invention, according to any of the forms described, can be in a liquid form, such as a solution, dispersion or suspension of a solid in a liquid, in a semi-solid form, such as a gel, cream or foam, or in solid form, such as powder, granules, microgranules, flakes, tablets or capsules.

Preferably, the compositions or mixtures M of the invention are formulated in a form suitable for oral administration, for example in liquid form, in solid form.

The compositions or mixtures M of the invention can be formulated in solid form, preferably in the form of granules, powder or flakes for suspension or oral dispersion on an aqueous basis (aqueous formulation). For example, the composition of the invention in said solid form is administered to treated subjects in an aqueous formulation by dispersing or suspending the solid composition of the invention in an aqueous medium or water prior to administration.

Alternatively, the composition of the invention ? preferably formulated in water-based liquid form (aqueous formulation), for example in the form of a suspension or dispersion such as a water-based syrup.

The composition of the invention in the form of an aqueous formulation (for example in the form of a solid dispersed or suspended in an aqueous medium, or in the form of a syrup or the like) demonstrates high stability? (>= 30 months), homogeneity? and absence of precipitate formation.

Said aqueous formulation of the composition of the invention, such as a suspension of a solid in an aqueous medium or a syrup, exhibits thixotropic characteristics, which make it considerably more effective. compliant for the treated subject. Furthermore, during swallowing by the treated subject, the composition of the invention adheres in a highly effective way to the pharyngeal and esophageal mucosa with consequent greater attenuation of the pharyngolaryngeal and esophageal irritation phenomena caused by gastric reflux.

Advantageously, the composition of the present invention in liquid form on an aqueous basis (for example a syrup) comprises the active components in the following percentages by weight with respect to the total weight of the composition:

- water in a percentage between 40% and 90% (for example 50%, 60%, 65%, 70%, 75%, 80%, or 85%); preferably from 55% to 80%, pi? preferably from 60% to 75%;

- said (a) alginic acid or a salt thereof, preferably magnesium alginate, in a percentage included in the range from 0.5% to 15% (for example 1%, 2%, 3%, 4%, 5%, 8%, 10%, 12%, or 14%); preferably from 1% to 10%, pi? preferably 1% to 5% (e.g. about 2.5% magnesium alginate, such as CAS No. 37251-44-8);

- said (b) simethicone and/or dimethicone, preferably simethicone, in a percentage ranging from 0.05% to 15%; preferably from 0.1% to 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9%), plus? preferably from 0.5% to 5% (e.g. about 1.5% simethicone, such as CAS No. 8050-81-5);

- said (c) gellan gum in a percentage ranging from 0.05% to 10% (for example 0.1%, 0.5%, 1%, 2%, 4%, 6%, or 8% ); preferably from 0.1% to 5%, more? preferably 0.1% to 2% (e.g. about 0.2% or 0.3% or 0.4% or 0.5% gellan gum, such as CAS No.

71010-52-1); and, optionally,

- said (d) bicarbonate and/or carbonate salt of an alkali metal or of an alkaline earth metal, if present, in a percentage included in the range from 0.1% to 10% (for example 1%, 2%, 3 %, 4%, 5%, 6%, 7%, 8%, or 9%); preferably from 0.5% to 5%, more? preferably from 0.5% to 2.5% (e.g. about 1% potassium bicarbonate).

Preferably, in the mixture M of the composition of the invention the weight ratio between the components (a) alginate (e.g. magnesium alginate) and (b) simethicone and (c) gellan gum ((a):(b):(c) ) ? ranging from about 10:10:5 to about 10:2:1, preferably from about 10:8:5 to 10:3:1, for example about 10:5,6:1,3.

In the context of the present invention, with the term ?composition? means a pharmaceutical composition and/or a composition for a medical device and/or food supplement or a composition for a food supplement or food.

The present invention relates to the compositions and mixtures M of the present invention (comprising (a), (b), (c) and, optionally, (d) and/or (e), according to any of the described embodiments) for use as a medicine.

The present invention relates to the compositions and mixtures M of the present invention (comprising (a), (b), (c) and optionally (d) and/or (e), according to any of the described embodiments) for use in a method of treatment, preventive and/or curative, of gastric reflux or gastroesophageal reflux disease or laryngopharyngeal or extra-oesophageal reflux disease, and/or a disease, disorder or symptom associated with said gastric reflux in a person needing 2, wherein said method of treatment provides for the administration to said subject of a therapeutically effective dose of one of said compositions or mixtures M object of the present invention.

These pathologies, disorders or symptoms associated with gastric reflux are chosen from among: laryngopharyngeal or extra-oesophageal reflux disease, oesophagitis (acute or chronic inflammation of the oesophageal mucosa), oesophageal ulcers, de-epithelialization of the oesophageal mucosa, acid regurgitation, heartburn stomach pain, feeling of gastric fullness, epigastric pain, dyspepsia, nausea, chronic cough, bronchospasm, sore throat, laryngitis, sensation of a hypopharyngeal globe or bolus, heartburn, dysphonia, nasopharyngeal inflammation, and all disorders that have as main cause or contributing cause gastric reflux.

These pathologies, disorders or symptoms associated with gastric reflux may be present even in the absence of a diagnosis of gastroesophageal reflux disease.

Furthermore, the compositions and blends M of the present invention, comprising (a), (b), (c) and optionally (d) and/or (e) and/or additives/excipients, according to any of the described embodiments , are for use in re-epithelialization treatments, as a sole therapy or as adjuvants to further therapies.

The object of the present invention is a method of preventive and/or curative treatment of gastric reflux or gastroesophageal reflux disease or laryngopharyngeal or extra-oesophageal reflux disease, and/or of a pathology or symptom associated with said gastric reflux in a subject having a need, wherein said treatment method provides for the administration to said subject of a therapeutically effective dose of one of said compositions or mixtures M object of the present invention (comprising (a), (b), (c) and optionally (d ) and/or (e), according to any one of the described embodiments).

The object of the present invention is the non-therapeutic use of the compositions and mixtures M of the present invention (comprising (a), (b), (c) and optionally (d) and/or (e), according to any of the forms of described embodiments) for gastric or gastroesophageal or laryngopharyngeal or extra-esophageal disorders in a healthy subject, wherein said use provides for the administration to said subject of one of said compositions or mixtures M object of the present invention.

The object of the present invention is a process for the preparation of the composition or mixture M of the present invention formulated in liquid form on an aqueous basis (e.g. syrup), in which said process comprises the steps of:

1. arrange the quantity? amount of prescribed water and divide it into a first aliquot (aliquot 1), equal to approximately 20%-60% v/v (e.g. 25%, 35%, 45%, 50%, or 55%), preferably 30 %-40% v/v, with respect to the total water volume, and in a second aliquot (aliquot 2) for the remainder; followed by

2. add to said aliquot 2 of water said (d) bicarbonate salt and/or carbonate of alkali or alkaline earth metal (e.g. potassium bicarbonate); followed by 3. adding to said aliquot 2 of water also (a) alginic acid or a salt thereof (e.g. magnesium alginate), (b) simethicone and/or dimethicone (e.g. simethicone or simethicone CAS nr. 8050-81-5) , and the remaining raw materials (e.g. bicarbonate or carbonate of alkali or alkaline earth metal, preferably potassium bicarbonate), with the exception of (c) gellan gum and, if present, of said (e) salt of alkali or alkaline earth metal ( e.g. magnesium chloride), and stir to obtain a mixture A; followed by or in parallel with said steps 2-3;

4. heat aliquot 1 of water to a temperature of 60?C-90?C, preferably 70?C-80?C, plus? preferably about 75°C, add (c) gellan gum (e.g. gellan gum CAS nr. 71010-52-1) and stir to obtain a suspension B after step 4; optionally followed by step 5 of

5. add said (e) alkali or alkaline earth metal salt (e.g. magnesium chloride) and stir for a few minutes to obtain a suspension B after step 5; stage 4 or stage 5 followed by

6. adding said suspension B after phase 4 or after phase 5 to the mixture A obtained from phase 3 to obtain suspension C; followed by

7. stir the suspension C until it becomes homogeneous, then leave it to cool to obtain a compact and weak gel; followed by

8. put again the gel obtained in phase 7 under stirring obtaining a viscous and homogeneous suspension.

An example of the preparation process of the composition of the invention in aqueous syrup formulation? shown in Figure 1.

For clarity, to achieve the object of the present invention, the components (or active components) (a), (b) and (c) of the composition of the invention can be administered simultaneously or separately (preferably in a time interval from 5 minutes to 30 minutes) and in any order; preferably, the active components are administered to a subject simultaneously, even more preferably in a single composition to obtain a more? quick and for ease? of administration. When the active components of the invention are administered in a single composition, said single composition corresponds to the composition of the present invention.

With the term ?subject/s? within the scope of the present invention human subjects or animal subjects are indicated, preferably mammals (e.g. pets such as dogs and cats, horses, sheep or cattle). Preferably, the compositions of the invention are for use in human treatment methods.

Unless otherwise specified, the expression composition or mixture or other which includes a component in an amount? ?in the range from x to y? do you mean that this component can? be present in the composition or mixture or other in all quantities? present in said range, even if not explicit, including extremes of the range.

Unless otherwise specified, the content of a component in a composition or mixture refers to the % by weight of that component with respect to the total weight of said composition or mixture.

Unless otherwise specified, an indication that a composition or mixture or other ?comprises? one or more components means that other components may be present in addition to the one or those specifically indicated and the indication that a composition or mixture or other ?consists? of certain components means that ? excluding the presence of other components.

The term ?quantity? therapeutically effective? does it refer to the quantity? of active compound and/or strain of bacteria that elicits biological or medicinal response in a tissue, system, mammal or human being that is researched and defined by an individual, researcher, veterinarian, physician or other clinician or health care practitioner.

The term ?medical device? in the context of the present invention ? in accordance with the European regulation on medical devices [e.g. EU 2017/745 ?(MDR), Directive 93/42/EEC ?(MDD)].

EXAMPLES

Examples of the composition of the present invention in liquid form on an aqueous basis (aqueous formulation, for example syrup) are reported in Tables 1-4.

Substances % w/w Demineralized water 60-75 Magnesium Alginate 1-5 Simethicone 0,5-5 Gellan Gum 0,1-2 Potassium Bicarbonate 0,5-2,5 Magnesium Chloride (optional) 0,001-0,01 additives and excipients to taste to 100 Table 1

Substances % w/w Demineralized water 62-70 Magnesium Alginate 2.0-4.5 Simethicone 0.9-3.0 Gellan Gum 0.1-1.5 Potassium Bicarbonate 1.0-2.5 additives and excipients q.b. to 100 Table 2

Substances % w/w Demineralized water 67.5-74.6 Magnesium Alginate 0.5-2.5 Simethicone 1.2-4.5 Gellan Gum 0.3-1.5 Potassium Bicarbonate 0.7-1.2 Magnesium Chloride 0.005-0.01 additives and excipients q.b. to 100 Table 3

EXPERIMENTAL PART

(I) TRAINING of the floating raft

(I.A) Formation and permanence of the floating raft in an acid environment of a composition comprising magnesium alginate and gellan gum

1. Materials and tools

- 0.1 M hydrochloric acid solution

- pHenomenal electrode pH meter (VWR)

- product under analysis (see point 2.)

2. Preparation of the product under analysis

Using the preparation process of the invention, 300 g of composition according to the invention (hereinafter, product) containing magnesium alginate and gellan gum were prepared having the formulation described in Table 4.

Substances % w/w

Demineralised water 67.0-70.5

Magnesium Alginate 1.5-3.1

Simethicone 0.8-2.0

Gellan gum 0.1-0.6

Potassium hydroxide 0.05-0.4

Potassium Bicarbonate 0.5-1.2

Magnesium Chloride 0.005-0.01

additives and excipients q.s. to 100

Table 4

3. Formation of the floating raft

In order to determine the formation of the floating raft, approximately 50 ml of 0.1 M hydrochloric acid solution were taken and transferred to a 50 ml conical flask. Using a common measuring spoon of the capacity? of about 15 g. The product containing magnesium alginate and gellan gum ? been poured into the acid solution.

The contents of the flask? observed for 24 hours without moving or shaking it.

4. Results and discussion

4.1 pH measurement

Using an electrode pH meter, the recorded pH of the 0.1 M hydrochloric acid solution? found to be equal to 1.02.

4.2. Floating raft observation

? It has been observed that the product containing magnesium alginate and gellan gum ? able to form a gel immediately after contact with the acid solution. After a few moments this gel tends to float, positioning itself on the surface of the solution; as shown in Figure 2. After 24 hours, taking care not to move the system at all and avoiding any disturbance, ? the presence of the gel formed on the surface of the solution was still observed.

5. Conclusions

Based on your observations? Is it possible to state that the product under examination (composition according to the invention), containing magnesium alginate and gellan gum, in contact with an acid solution at pH 1.02? able to form a gel able to float on the solution; such gel ? able to persist for at least 24 hours.

(I.B). Comparison in the formation and permanence of the floating raft in an acid environment of a composition comprising gellan gum and of a composition comprising xanthan gum.

Purpose of the study

The capacity? of floating raft training ? been tested in vitro by putting in contact with hydrochloric acid (0.1 M):

- a gellan gum suspension (sGG for short), or - a xanthan gum suspension (sGX for short).

Products under analysis

Preparation of the polymeric suspensions - Gellan gum (sGG) suspension: 0.30 g of gellan gum were transferred to a beaker containing 99.70 g of demineralised water. The system ? was placed under magnetic stirring until it had a homogeneous appearance, obtaining a suspension of gellan gum in water at a concentration of 0.3% w/w.

- Xanthan gum suspension (sGX): using a procedure similar to that described for sGG ? a suspension of xanthan gum in water at a concentration of 0.25% w/w (0.25 g of xanthan gum and 99.75 g of demineralized water) was obtained.

In both suspensions ? been added a minimum amount? of erythrosine, in order to make the suspensions colored and evaluate in a more? efficient gel formation.

Method

In order to determine the capacity? of gelation of the polysaccharides under examination (sGG and sGX) two aliquots of a 0.1 M hydrochloric acid solution of about 40 ml each were taken and transferred into two 50 ml flasks. Approximately 15 mL of sGG and 15 mL of sGX were poured into each flask, respectively. Using an electrode pH meter, the recorded pH of the 0.1 M hydrochloric acid solution? found to be equal to 1.02.

The capacity? of gelling? been evaluated through a visual analysis of the two systems obtained; also each rate ? been filtered using filter paper; finally, both filtrates and filters were observed.

Results

After having poured the two polysaccharide suspensions (sGG and sGX) into the respective flasks containing the 0.1 M hydrochloric acid solution? It has been observed that gellan gum immediately forms a compact gel which floats in solution while xanthan gum is totally dispersed (figures omitted). The two acid solutions were then filtered with filter paper in order to determine the effective formation of the gel. What about the gellan gum on the filter paper? Was a compact gel collected and the filtrate ? turned out to be totally colourless, an indication of the fact that the instantaneous gelation of the polysaccharide did not allow the diffusion of the dye molecule in the acid solution (Figures 3a and 3b right). The xanthan gum filter paper, on the other hand, did not retain anything and the filtered solution is coloured, as it does not ? formed any gel and the dye molecule ? diffused in the acid solution (Figures 3a and 3b left).

These results demonstrate how gellan gum, unlike xanthan gum, possesses the ability of gelling in an acid environment. On the basis of what has been described, it follows that the raft resulting from the cooperative and/or synergistic magnesium alginate/gellan rubber action is more? compact and long-lasting compared to a magnesium alginate/xanthan gum combination.

(II). CAPACITY MUCOADESIVE

The capacity? mucoadhesive of a substance ? closely related to the interaction of the test substance with the mucins present on the outer layer of the mucosa of interest (e.g. oesophageal mucosa).

Based on this principle, in order to evaluate the functional differences in the use of gellan gum compared to xanthan gum in formulations containing magnesium alginate, ? been evaluated the mucoadhesiveness? of - a formulation 1 comprising magnesium alginate and gellan gum e

- a formulation 2 comprising magnesium alginate and xanthan gum

measuring the? increase in viscosity? of a suspension deriving from the interaction of said formulations under examination with mucins.

1. Introduction to mucoadhesiveness and viscosity?

The mucoadhesive can? be defined as the capacity? of a substance or a group of substances to adhere to a biological tissue for a prolonged period of time. There are several hypotheses that lay the theoretical foundations for the explanation of this phenomenon; one of these? diffusion theory; which states that, in mucoadhesive polymers, this property? is consequent to the diffusion of the polymeric chains within the layer of glycoproteins present on the surface of the mucous membranes, and of the glycoproteins within the polymeric material; the diffusion of one layer into the other leads to the formation of semi-permanent bonds and interactions. The glycoproteins that contribute to the mucoadhesion phenomenon are defined as mucins, they are molecules with very high molecular weight; with water, electrolytes and a small amount of fat, they form the protective mucus layer that covers the mucous membranes.

The viscosity? of a suspension made up of mucins? given by the conformation of each molecule and by the intermolecular interaction forces that lead to chain entanglement. The presence of mucoadhesive polymers in the mucin suspension leads to an increase in interactions and chain entanglement such that the viscosity? total suspension? described by the following equation (equation 1).

Equation 1

Where: vt = viscosity? total; vm= viscosity? due to mucins; vp = viscosity? due from the polymer; vb = component of the viscosity? due to mucoadhesion.

So, ? is it possible to determine the capacity? mucoadhesive of a polymer or a set of polymers by measuring the viscosity? of solutions containing equal concentrations of polymers in the presence or absence of mucins (Hassen et al. ?Pharmaceutical Research?, 7(5), 1990; Gar?a et al. ?Pharmaceutics?, 10, 1-16, 2018).

2. Materials

- Gellan gum (CAS nr. 71010-52-1)

- Xanthan Gum 200 MESH

- Magnesium alginate (CAS n.<o >37251-44-8)

- Type II porcine stomach mucins (Sigma Aldrich)

- Ubbelohde viscometers.

3. Preparation of the Formulations

In order to evaluate the mucoadhesiveness of the two anti-reflux syrups under examination, two different formulations were prepared (Formulations 1 and 2) containing only the polysaccharides and the pH correctors foreseen in the respective products (Tables 5 and 6).

- Formulation 1: Suspension containing magnesium alginate and xanthan gum

Substance % w/w

Demineralised water 93.00-97.80

Sodium Hydroxide 0.06-0.12

Sodium Bicarbonate 0.30-1.00

Magnesium Alginate 1.70-2.90

Xanthan Gum 0.10-0.50

Table 5

- Formulation 2: Suspension containing magnesium alginate and gellan gum

Substance % w/w

Demineralised water 94.00-98.50

Potassium Hydrate 0.09-0.20

Sodium Bicarbonate 0.50-1.20

Magnesium Alginate 1.90-3.10

Gellan gum 0.15-0.55

Table 6

4. Preparation of the mucin suspension

Using the analytical balance, 20 g of mucins were weighed; the latter were then transferred to a beaker containing 180 g of demineralised water. The system ? was placed under vigorous magnetic stirring for about 2 hours, in order to optimally hydrate the mucins. Using the method described ? a suspension of mucins in demineralized water was obtained at a concentration of 10% w/w.

5. Preparation of magnesium alginate suspensions

because different concentrations of magnesium alginate are used in the formulations under examination, in order to determine the contribution to the mucoadhesiveness? of the polysaccharide the following suspensions were prepared:

- Suspension 1: Magnesium Alginate 2.1% w/w

2.10 g of magnesium alginate (polysaccharide) were dispersed in 97.90 g of demineralised water. The system ? was placed under magnetic stirring until it was completely homogeneous.

- Suspension 2: Magnesium Alginate 2.3% w/w

Similarly, 2.30 g of magnesium alginate were dispersed in 97.70 g of demineralized water.

Four control solutions were prepared using suspensions 1 and 2:

- Control 1: Suspension 1 diluted 1:2

50 g of Suspension 1 were transferred to a beaker containing 50 g of demineralised water.

- Control 2: Suspension 2 diluted 1:2

50 g of Suspension 2 were transferred to a beaker containing 50 g of demineralised water.

- Check 3: Suspension 1 Mucins 5 %

50 g of Suspension 1 were diluted 1:2 with the 10% Mucine suspension.

- Check 4: Suspension 2 Mucins 5%

50 g of Suspension 2 were diluted 1:2 with the 10% Mucine suspension.

6. Sample preparation

- Sample 1: Mucin suspension 5% w/w

50 g of the 10% mucin suspension? been diluted 1:2 by adding 50 g of demineralised water; thus obtaining a suspension of mucins at a concentration of 5% w/w.

- Sample 2: Formulation 1 diluted 1:2

50 g of Formulation 1 (paragraph 8.1.) and were transferred into a beaker containing 50 g of demineralised water.

- Sample 3: Formulation 2 diluted 1:2

Using the same method described above also Formulation 2 ? was diluted 1:2 with demineralised water.

- Sample 4: Formulation 1 Mucins 5% w/w

50 g of Formulation 1 were transferred into a beaker containing 50 g of the Mucine suspension at 10% w/w.

- Sample 5: Formulation 2 Mucins 5% w/w

50 g of Formulation 2 were transferred into a beaker containing 50 g of Mucine 10% w/w.

The dilutions performed allow that in each sample there are the same concentrations of the substances to be examined (Table 7). After the various additions, each sample? was placed under magnetic stirring, at room temperature, for 2 hours.

Sample 2 1.05 0.125 - -Sample 3 1.15 - 0.15 -Sample 4 1.05 0.125 - 5 Sample 5 1.15 - 0.15 5 Table 7 Composition of the samples under examination

7. Measurement of viscosity? and assessment of mucoadhesion

Using the appropriate Ubbelohde viscosimeter, the viscosities were measured of each sample. The viscosity Were they analyzed at room temperature, measuring the travel time of the suspensions inside the capillary of the viscosimeter, and applying the formula described below? been calculated the viscosity? (v) of the sample (equation 2). Equation 2: v=kt

in which,

k = characteristic constant of each viscosimeter t = time (expressed in seconds) of travel of the product in the capillary.

For each sample ? been calculated the viscosity? of three rates.

The evaluation of mucoadhesion ? was calculated using the mucoadhesion index (?%) (Equation 3)

Equation 3 (F. C. Carvalho et al., ?Brazilian Journal of Pharmaceutical Sciences?, 46, 1-17, 2010)

in which:

vt = viscosity? average of the system made up of polysaccharides and mucins

vm= viscosity? average of the suspension of mucins 5% w/w vp= viscosity? average of the formulations diluted 1:2.

8. Results and discussion

8.1. Control Solutions

These solutions were analyzed with the aim of evaluating the contribution of the magnesium alginate in the interaction with the mucins at the two different expected concentrations. The results obtained are shown in Table 8.

Table 8

Using Equation 3 (Section 7) the following mucoadhesion indices were obtained:

Suspension 1: ?% = 100

Suspension 2: ?% = 130

It is clear that a higher concentration of magnesium alginate leads to a higher mucoadhesion index, however the difference between the two suspensions does not appear to be high.

8.2. Sample Solutions

From the analyzes carried out and from the times obtained, the viscosity was calculated? shown in Table 9.

Table 9

To determine the mucoadhesiveness? of xanthan gum and gellan gum have been compared, respectively, the viscosity? of samples 1; 2; 4 and of samples 1; 3; 5.

From the data reported in Table 9 it is clear that both in Formulation 1 and in Formulation 2 (paragraph 3) there is a considerable increase in viscosity? in the presence of mucins; an indication of the fact that in both cases there are phenomena of interaction between the polysaccharides and the mucins themselves (Figures 4 and 5).

On the basis of the data obtained and using Equation 3 (paragraph 7) ? the mucoadhesion index of the two formulations was calculated:

- Formulation 1: ?% = 204

- Formulation 2: ?% = 375

The mucoadhesion index indicates how Formulation 2 (according to the present invention), comprising magnesium alginate and gellan gum, is considerably more? mucoadhesive compared to Formulation 1 (comparative), containing magnesium alginate and xanthan gum.

9. Conclusions

The study performed had the aim of evaluating the functional differences between the formulations containing xanthan gum or gellan gum in association with magnesium alginate for the treatment of gastroesophageal reflux disease and associated pathologies or symptoms.

because the mucoadhesiveness? of a given substance? in close correlation to the interaction of the substance itself with the mucins present on the outer layer of the mucosa (e.g. oesophageal mucosa), ? been evaluated? increase in viscosity? of the suspensions deriving from the formulations under examination in the presence of mucins.

From the results obtained, it is clear that in both formulations (Formulation 1 and 2) there is a considerable capacity of mucoadhesion, in fact the viscosity? obtained from suspensions with polysaccharides and mucins are much higher than the sum of suspensions with mucins and with polysaccharides alone (rubber alginate). Specifically, the differences found are equal to 44.4 cSt and 125.3 cSt, respectively for Formulation 1 and Formulation 2.

Furthermore, calculating the mucoadhesive indices? been found as the latter? is considerably more? high for Formulation 2 (according to the invention with gellan gum), compared to Formulation 1 (comparison with xanthan gum).

? therefore it is possible to hypothesize that the magnesium alginate and the gellan gum interact in a synergistic way and considerably more? profound with mucins compared to the combination of magnesium alginate and xanthan gum. The great interaction with the mucins therefore translates into a greater property? mucoadhesive of Formulation 2 (according to the invention with gellan gum); this ability? would allow the relative product to remain adhered to the surfaces of the oesophageal mucous membranes for a longer time, protecting this organ from the corrosive-inflammatory action of the gastric juices rising during the reflux episode.

In conclusion, from what has been said, the product containing the association of magnesium alginate and gellan gum shows, in addition to the beneficial effect of the floating raft in the gastric environment, also an effect on the oesophageal and/or pharyngeal mucosa being able to form a mucoadhesive layer of mucosal protection.

(III). Chemical-physical characteristics and stability of a composition according to the invention

A composition according to the invention formulated in water-based liquid form (i.e. syrup)? was prepared using the raw materials reported in Table 4 and the process of the invention according to phases 1-8, including phase 5 and operating phase 3 at 75°C.

The obtained composition according to the invention (subsequently, product) appears as a viscous liquid, free of lumps and of an intense pink colour. The product appears to be stable, not showing the formation of any precipitate.

The pH of the product ? between 8.1 and 9.0, with a density? ranging from 1.063 g/ml to 1.200 g/ml. The viscosity?, evaluated by Brookfield rotational viscometer? ranging from 1500 cps to 1550 cps (R3; 60 rpm; 90%).

From the data obtained it is clear that the product has characteristics suitable for being easily administered orally.

The stability tests? carried out show that the product maintains its chemical-physical and microbiological characteristics for 30 months.

Claims (10)

1. A composition comprising (i) a mixture M comprising or alternatively consisting of: - (a) an alginic acid or salt thereof of acceptable pharmaceutical or food grade, - (b) a simethicone and/or dimethicone; - (c) a gellan gum; and, optionally, said composition comprises (ii) at least one additive and/or excipient of pharmaceutical or food grade. 2. The composition according to claim 1, wherein said mixture M further comprises (d) a salt of bicarbonate and/or carbonate with an alkali or alkaline-earth metal, preferably selected from the group comprising or, alternatively, consisting of bicarbonate of potassium, magnesium bicarbonate, calcium bicarbonate, potassium carbonate, magnesium carbonate, calcium carbonate and mixtures thereof; preferably potassium bicarbonate. The composition according to claim 1 or 2, wherein said mixture M further comprises (e) a salt of an alkali or alkaline earth metal; preferably selected from the group comprising or, alternatively, consisting of: potassium chloride, magnesium chloride, calcium chloride and mixtures thereof; more preferably magnesium chloride. 4. The composition according to any one of claims 1-3, wherein said (a) algic acid or salt thereof consists of or is derived from an alginic acid having an average molecular weight in the range from 10 kDa to 600 kDa; preferably from 100 kDa to 500 kDa, more? preferably from 200 kDa to 300 kDa. 5. The composition according to any one of claims 1-4, wherein said mixture M comprises or, alternatively, consists of: (a) an alkali metal or alkaline earth metal alginate selected from the group comprising or alternatively consisting of: magnesium alginate, potassium alginate, calcium alginate, and a mixture thereof; preferably magnesium alginate and/or an alginate having an average molecular weight in the range of 200 kDa to 300 kDa; - (b) a simethicone; - (c) a gellan gum; - (d) a bicarbonate salt with an alkali or alkaline earth metal, preferably potassium bicarbonate; And - (e) a salt of an alkali or alkaline earth metal; preferably magnesium chloride. 6. The composition according to any one of claims 1-5, wherein said composition is formulated for oral use; preferably in the solid form of powder or granules to be suspended or dispersed in an aqueous medium or, alternatively, in the liquid form of suspension or dispersion in an aqueous medium, preferably in the form of a syrup. 7. The composition according to any one of claims 1-6 for use as a medicament. The composition according to any one of claims 1-6 for use in a method of treatment, preventive and/or curative, of a gastric reflux, gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease (RFL) or extraesophageal reflux, or of pathologies and/or symptoms associated with said gastric reflux, in a subject having need. 9. The composition according to any one of claims 1-6 for use in a treatment method, preventive and/or curative, of: oesophagitis or acute or chronic inflammation of the oesophageal mucosa, oesophageal ulcers, de-epithelization of the oesophageal mucosa, acid regurgitation , heartburn, sensation of gastric fullness, epigastric pain, dyspepsia, nausea, chronic cough, bronchospasm, sore throat, laryngitis, hypopharyngeal globe or bolus sensation, heartburn, dysphonia, and/or nasopharyngeal inflammation. 10. A process for the preparation of the composition or mixture M according to any one of claims 1-6, wherein the composition or mixture M is in liquid form of suspension or dispersion in an aqueous medium, wherein said process comprises the steps of: 1. arrange a quantity? amount of water prescribed and divide it into two aliquots to give aliquot 1 and aliquot 2; 2. add to said aliquot 2 of water said (d) bicarbonate and/or carbonate salt of alkali or alkaline earth metal, preferably potassium bicarbonate, to give an aliquot of phase 2 water; 3. add to said aliquot of phase 2 water further said (a) alginic acid or a salt thereof, preferably magnesium alginate, said (b) simethicone and/or dimethicone, preferably simethicone, and, optionally, (e) salt of alkali or alkaline earth metal, preferably magnesium chloride, and stir to obtain a mixture A; 4. in parallel with said steps 2-3, heating said aliquot 1 of water to a temperature of between 60°C and 90°C, preferably between 70°C and 80°C, plus? preferably about 75°C, add said (c) gellan gum and leave under stirring to obtain a suspension B after step 4; optionally followed by step 5 of 5. add said (e) alkali or alkaline earth metal salt, preferably magnesium chloride, and stir for a few minutes to obtain a suspension B after step 5; 6. adding said suspension B after phase 4 or after phase 5 to the mixture A obtained from phase 3 to obtain suspension C; 7. stir the suspension C until the suspension appears homogeneous and let it cool to obtain a compact and weak phase 7 gel; 8. Stir the phase 7 gel again to obtain a viscous and homogeneous suspension.