IT202000031433A1 - COMPOSITIONS INCLUDING SUCROSE OCTASULPHATE FOR THE TREATMENT OF GASTRIC REFLUX - Google Patents

Description

DESCRIPTION of the invention entitled: ?Compositions comprising sucrose octasulphate for the treatment of gastric reflux?

The present invention relates to compositions comprising sucrose octasulfate (sucrosofate) or a salt thereof and to their 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 with consequent acid hypersecretion; which can? lead to pathological conditions such as gastroesophageal reflux disease or the formation of ulcers on the mucosa of the upper digestive tract.

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 acid environment or with the gastric mucosa they implement a protective action through physical mechanisms (for example a 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, faces and solves the aforementioned technical problem by providing an innovative composition, preferably for oral use, comprising a mixture M comprising or, alternatively, consisting of sucrosofate and at least one further active component selected from (a) alginic acid or a salt thereof (alginate), (b) a simethicone and/or dimethicone, (c) a vegetable polysaccharide selected from gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof, and mixtures thereof, preferably gellan gum; and mixtures thereof, 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, in virtue the presence of sucrosofate, exert an excellent mucoadhesive and muco-protective action with consequent ability? to protect the gastric mucosa and the esophageal mucosa from the corrosive-inflammatory action of the gastric juices rising during the reflux episode (anti-acid effect). In fact, sucrosofate has a high capacity? adhesive to the mucosa and ? thus able to form a highly effective mucoadhesive layer on the mucosa, for example the gastric mucosa.

Furthermore, the compositions or mixtures M of the present invention, by virtue of the presence of sucrosofato, exercise a high capacity? healing on the mucous membrane.

In addition, sucrosofate provides the composition or mixture M of the invention with an anti-inflammatory effect and an anti-inflammatory ability. of maintenance of? integrity? mucous membranes, preferably gastric and oesophageal mucosa.

Sucrosofate has the advantage over other sucrose derivatives, such as sucralfate, of not including aluminum and of having a palatability? best, and therefore the compositions or mixtures M of the invention can be used by a wide range of subjects.

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

The compositions or mixtures of the present invention have no significant side effects and are easy and cheap to produce.

Finally, the compositions or mixtures M of the present invention have further technical characteristics which make them particularly effective for the treatment of gastric reflux, according to the further or further components (or active components) present, such as (a) alginic acid or alginate, (b) a simethicone and/or dimethicone, (c) a vegetable polysaccharide and mixtures thereof, as illustrated below.

These aims and 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 represents the formation of the floating raft according to the experimental conditions reported in the experimental part.

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:

- sucrose octasulfate (called sucrosofate) or a salt thereof of acceptable pharmaceutical or food grade, preferably an alkali or alkaline earth metal salt, more preferably sucrose octasulphate potassium or sodium salt; And

- at least one further active component selected from the group consisting of:

(a) an alginic acid or salt (alginate) 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 vegetable gum, preferably selected from: gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof, and mixtures thereof; more preferably gellan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof, even more? preferably gellan gum, guar gum, carrageenan and mixtures thereof, for example gellan gum; and (d) a mixture thereof;

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

In one embodiment, the composition or blend M of the invention does not consist of sucrose octasulfate, or a salt thereof, and xanthan gum.

In one embodiment, the composition or mixture M of the invention does not consist of sucrose octasulfate, or a salt thereof, simethicone and xanthan gum.

Sucrosofate? sucrose octasulfate (SOS for short), IUPAC name acid [(2R,3R,4S,5S)-4-(sulfooxy)-2,5bis[(sulfooxy)methyl]-5-{[(2R,3R,4S,5R ,6R)-3,4,5-tris(sulfooxy)-6-[(sulfooxy)methyl]oxane-2-yl]oxy}oxolan-3-yl]oxidanesulfonic acid, molecular formula C12H22O35S8, example of Cas no. 57680-56-5.

The alkali metal sucrosulphate salts usable in the context of the present invention can be, for example, sucrose octasulphate potassium salt or potassium sucrosulphate (example of Cas No. 76578-81-9), sucrose octasulphate sodium salt or sodium sucrosulphate (example of Cas n. 74135-10-7).

In the context of the present invention with the term ?sucrosofate? both sucrose octasulphate and its alkali or alkaline earth metal salts (e.g. potassium or sodium sucrosulphate) are meant.

Examples of sucrosophate usable in the context of the present invention, in association with at least one or more? among (a), (b) and (c) (according to any of the described embodiments), are sucrosophate potassium salt heptahydrate (molecular formula C12H14O35S8 8K 7H2O) and sucrosophate potassium salt anhydrous (molecular formula C12H14O35S8 8K) .

In one embodiment of the present invention, the mixture M of the composition of the invention comprises or alternatively consists of sucrosulfate, preferably sucrose octasulfate potassium salt, and (a) an alginic acid or a salt thereof, preferably magnesium alginate.

The mixture M of the composition of the invention can? comprise or alternatively consist of sucrose octasulfate potassium salt and magnesium alginate.

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 compositions or mixtures M of the present invention, thanks to the presence of alginic acid or an alginate, exert an effective mechanical action for the treatment of gastric reflux, in order to reduce the pathologies and/or symptoms related to it.

In fact, in an environment with an acidic pH such as the stomach, alginate d? result in the formation of a floating gelatinous precipitate (floating raft) capable of forming a mechanical barrier which prevents the ascent of gastric reflux at the level of the cardia and therefore to the esophagus and extra-esophageal areas (for example, pharynx, larynx, upper respiratory tract, lacrimal duct).

Advantageously, said (a) alginic acid or its salt, included in the composition or mixture M of the invention together with sucrosofate and, optionally, (b), (c), (e) and/or (f) (according to any of the described embodiments), ? 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 200 KDa to about 300 KDa, for example about 240 KDa (a Dalton (Da) is equivalent to a unified atomic mass unit (amu, from the English atomic mass unit)).

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

Examples of (a) an alginic acid or alginate usable in composition or mixture M of the invention together with sucrosofate and, optionally, (b), (c), (e) and/or (f) (according to any of the forms of construction described), are represented by:

- Alginic acid EP (CAS nr. 9005-32-7) in the form of a straw 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 nr. 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 nr. 37251-44-8) (composition: approx. 65-75% guluronic acid and approx. 25-35% mannuronic acid and a magnesium content of approx. 5.4-6.6) with a pH value of about 6-9.5, a viscosity? (CPS) (LV, 12RPM) 7.5% natural base solution 25?C of approximately 1.000-1.800.

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

According to a further aspect of the present invention, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrosulphate, preferably sucrose octasulphate potassium salt; and (c) a vegetable gum, preferably selected from: gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; more preferably gellan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulphate or a salt thereof; even more preferably gellan gum, guar gum, carrageenan and mixtures thereof, for example gellan gum.

For example, the mixture M of the composition of the invention can? comprise or alternatively consist of sucrose octasulfate potassium salt and gellan gum.

Advantageously, according to a further aspect of the present invention, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrosulphate, preferably sucrose octasulphate potassium salt; (a) an alginic acid or a salt thereof, preferably magnesium alginate (e.g. CAS no.

37251-44-8); and (c) a vegetable gum, preferably selected from: gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; preferably gellan gum (e.g. CAS nr. 71010-52-1).

The mixture M of the composition of the invention can? comprise or alternatively consist of sucrose octasulfate potassium salt, magnesium alginate and gellan gum.

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

Advantageously, said (c.i) gellan gum, included in the composition or mixture M of the invention together with the sucrosofate and, optionally, (a), (b), (e) and/or (f) (according to any of the embodiments described), has an average molecular weight in the range of about 50 kDa to about 2000 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.i) usable in the context of the present invention in conjunction with sucrosofate and, optionally, (a), (b), (e) and/or (f), ? gellan gum having CAS nr 71010-52-1 (example of commercial product: Gellan Gum Kelcogel CG-LA).

The gellan rubber, in combination or not in combination with the alginate in the composition or mixture M of the invention, allows to form a floating raft that is more resistant, more elastic, quick to form and long-lasting than those known in the art.

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.

Furthermore, the gellan gum gives the composition or mixture M of the invention a high gastroprotective or muco-protective action mainly due, but not only, to the ability? of the gellan gum to form a highly effective mucoadhesive layer on the mucous membrane, for example the gastric mucosa.

Xanthan gum (c.ii), or simply xanthan, ? a polysaccharide having the molecular formula (monomer) C35H49O29, example of CAS n. 11138-66-2, for food use European code E415.

Guar gum (c.iii) ? a polysaccharide whose main constituent ? a galactomannan, a trisaccharide formed by units? of mannose and galactose, specifically polymerized to form ?-D-mannopyranosyl chains joined by a ?-D-(1-4) glycosidic bond and with a molecular weight around 200-300 kDa or higher, to form a linear chain 1-4 with short lateral branches 1-6 of galactose. Molecular formula C18H30O15, example of CAS no. 9000-30-0, for food use European code E412.

Carrageenans (c.iv) are a family of linear sulphated polysaccharides. All carrageenans are high molecular weight polysaccharides made up of units repetitive levels of galactose and 3,6 anhydrogalactose (3,6-AG), both sulfated and unsulfated. The units? are joined by alternating ?-1,3 and ?-1,4 glycosidic bonds.

Hyaluronic acid or its salt (c.v) (for example of sodium or potassium) usable in the context of the present invention can be linear or cross-linked and have a weight average molecular weight in the range of 500 kDa to 2500 kDa (kDa short for kilodalton), e.g. 600 kDa, 800 kDa, 1000 kDa, 1200 kDa, 1400 kDa, 1600 kDa, 1800 kDa, 2000 kDa or 2200 kDa (example of CAS nr. 9004-61-9).

Chondroitin sulfate or its (c.vi) salt (e.g. sodium or potassium) usable in the context of the present invention can have a weight average molecular weight in the range of 50 kDa to 2000 kDa, e.g. 100 kDa, 200 kDa, 400 kDa, 600 kDa, 800 kDa, 1000 kDa, 1200 kDa, 1400 kDa, 1600 kDa, or 1800 kDa. Said chondroitin sulfate usable in the context of the present invention can be obtained from animal cartilage extracts, mainly from bovine and porcine tissue (for example: trachea, ear and nose) or chicken, or from shark, fish (for example ray) or bird cartilage.

According to a further aspect of the present invention, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrosulphate, preferably sucrose octasulphate potassium salt; and (b) simethicone and/or dimethicone; preferably simethicone.

The mixture M of the composition of the invention can? comprise or alternatively consist of: sucrosulfate, preferably sucrose octasulfate potassium salt; (b) simethicone and/or dimethicone; preferably simethicone (e.g. CAS 8050-81-5); and (a) an alginic acid or a salt thereof, preferably magnesium alginate (e.g. CAS No. 37251-44-8).

For example, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrose octasulfate potassium salt; (b) simethicone; and (a) magnesium alginate.

The mixture M of the composition of the invention can? comprise or alternatively consist of: sucrosulfate, preferably sucrose octasulfate potassium salt; (b) simethicone and/or dimethicone; preferably simethicone (e.g. CAS 8050-81-5); and (c) a vegetable gum, preferably selected from: gellan gum, xanthan gum, guar gum, carrageenan and mixtures thereof, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; more preferably gellan gum, xanthan gum, guar gum, carrageenan and mixtures thereof, for example gellan gum (e.g. CAS nr. 71010-52-1).

For example, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrose octasulphate potassium salt; (b) simethicone; and (c) gellan gum.

The mixture M of the composition of the invention can? comprise or alternatively consist of: sucrosulfate, preferably sucrose octasulfate potassium salt; (b) simethicone and/or dimethicone; preferably simethicone (e.g. CAS 8050-81-5); (a) an alginic acid or a salt thereof, preferably magnesium alginate (e.g. CAS No. 37251-44-8); and (c) a vegetable gum, preferably selected from: gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; preferably gellan gum (e.g. CAS nr. 71010-52-1).

For example, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrose octasulfate potassium salt; (b) simethicone; (a) magnesium alginate; and (c) gellan gum.

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 sucrosofate and optionally (a), (c), (e) and/or (f) according to any of the described embodiments, ? 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 sucrosofate and optionally (a), (c), (e) and/or (f) according to any of the described embodiments, are represented by:

- simethicone in the form of a water-dispersible simethicone (aqueous emulsion) with an 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 sucrosofate and optionally (a), (c), (e) and/or (f) according to any of the described embodiments, can ? be a moron.

Examples of dimethicone or dimethicone (b) usable in the compositions or mixtures M of the present invention, in association with sucrosofate and, optionally, (a), (c), (e) and/or (f) (according to any of the forms of construction described), are represented by:

- dimethicone CAS n. 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 n. 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 n. 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.

The mixture M of the composition of the present invention comprising sucrosofate and at least one of (a), (b) and (c) or a mixture thereof, according to any of the disclosed embodiments, can further comprising (e) a bicarbonate salt and/or a carbonate salt with an alkali or alkaline earth metal, preferably selected from sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, sodium carbonate, potassium carbonate , magnesium carbonate, calcium carbonate and mixtures thereof; preferably potassium bicarbonate.

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>.

Advantageously, the mixture M of the composition of the invention comprises or, alternatively, consists of: sucrosofate, preferably sucrosofate potassium salt; (e) an alkali or alkaline earth metal bicarbonate or carbonate; preferably potassium bicarbonate; and at least one further active component selected from (a) alginic acid or a salt thereof, preferably magnesium alginate; (b) a simethicone and/or dimethicone; preferably simethicone; (c) a vegetable polysaccharide selected from: gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; preferably gellan gum.

The composition or mixture M of the present invention comprising sucrosofate and at least one or more? between (a), (b) and (c) and, optionally, (e) (according to any of the described embodiments), pu? further comprising (f) 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 (f) 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 (f) does not include sodium.

The presence in the composition of the invention of a certain quantity? of component (f) 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, from the alkali or alkaline earth metal salt (f).

For example, the mixture M of the composition of the invention comprises or alternatively consists of: sucrosofate, preferably sucrosofate potassium salt, (a) magnesium alginate; (c) gellan gum or xanthan gum; (e) potassium bicarbonate; (f) magnesium chloride, and optionally additives and/or excipients.

The compositions of the present invention, comprising said (i) mixture M comprising sucrosofate and at least one of (a), (b), (c) or a mixture thereof and, optionally, (e) and/or (f), may comprise (ii) at least one additive and/or excipient of acceptable pharmaceutical or food grade, i.e. 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 does not comprise a histamine H2 receptor antagonist (H2 antagonist), 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 or 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, when is it? in 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) it shows 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 syrup) comprises:

- water in a percentage between 40% and 90%; preferably from 55% to 80%, pi? preferably from 60% to 75%; And

- sucrosofate, preferably sucrosofate potassium salt, in a percentage by weight with respect to the total weight of the composition in the range from 0.1% to 20% (for example, 0.5%, 1%, 1.5%, 2 %, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, or 18%); preferably from 0.1% to 10%, more? preferably from 0.1% to 5%.

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 subject of the present invention are the compositions and mixtures M of the present invention (comprising sucrosofate and at least one of (a), (b) and (c) or a mixture thereof and, optionally, (e) and/or (f), according to any of the described embodiments) for use as a medicament.

The subject of the present invention are the compositions and mixtures M of the present invention (comprising sucrosofate and at least one of (a), (b) and (c) or a mixture thereof and, optionally, (e) and/or (f), according to any of the described embodiments) for use in a method of treatment, preventive and/or curative, of a gastric reflux or gastroesophageal reflux disease or laryngopharyngeal reflux disease or extra-oesophageal reflux, and/or a disease, disturbance or symptom associated with said gastric reflux, in a subject having need, 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 selected from: laryngopharyngeal or extra-esophageal reflux disease, esophagitis (acute or chronic inflammation of the esophageal mucosa), esophageal ulcers, de-epithelization of the esophageal 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 sucrosofate and at least one of (a), (b) and (c) or a mixture thereof, according to any of the disclosed embodiments, are for use in re-epithelialization treatments , as a single treatment or as adjuvants for further treatments

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 sucrosofate and at least one of (a), (b), (c ), and optionally (e) and/or (f), according to any one of the described embodiments).

The present invention relates to the non-therapeutic use of the compositions and mixtures M of the present invention (comprising sucrosofate and at least one of (a), (b), (c), and optionally (e) and/or (f), according to any of the 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.

For clarity, to achieve the object of the present invention, the components (or active components) sucrosofate, (a), (b), and/or (c) of the composition of the invention can be administered simultaneously or separately (preferably in a range 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. pet animals such as dogs, 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 1-3.

Sucrosofate<(a) >0.1-2.5

Potassium Bicarbonate 0.5-2.5

Magnesium Chloride (optional) 0.001-0.01

additives and excipients q.s. to 100

Table 1. <(a)>Sucrosofate: for example Sucrose K octasulfate (anhydrous or heptahydrate)

Substances % w/w

Demineralised water 62-70

Magnesium Alginate 2.0-4.5

Simethicone 0.9-3.0

Gellan gum 0.1-1.5

Sucrosofate<(a) >0.1-2.5

Potassium Bicarbonate 1.0-2.5

additives and excipients q.s. to 100

Table 2

Substances % w/w

Demineralised water 67.5-74.6

Magnesium Alginate 0.5-2.5

Simethicone 1.2-4.5

Gellan gum 0.3-1.5

Sucrosofate<(a) >2.5-5

Potassium Bicarbonate 0.7-1.2

Magnesium Chloride 0.005-0.01

additives and excipients q.s. to 100

Table 3

EXPERIMENTAL PART

TRAINING of the floating raft

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? 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.

Claims (10)

1. A composition comprising (i) a mixture M comprising or alternatively consisting of: - sucrose octasulfate, called sucrosofate, or a pharmaceutical or food grade salt thereof, and - at least one further active component selected from the group consisting of: (a) a pharmaceutically acceptable alginic acid or alginate salt, (b) a simethicone and/or dimethicone; (c) at least one polysaccharide selected from the group consisting of: gellan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; And (d) a mixture thereof; And 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 comprises or, alternatively, consists of: sucrose octasulfate or a salt thereof, preferably sucrose octasulfate potassium salt, e (a) a pharmaceutically acceptable alginic acid or alginate salt, preferably an alkali metal or alkaline earth metal alginate selected from the group consisting of: magnesium alginate, potassium alginate, calcium alginate, and a mixture thereof; more preferably magnesium alginate. 3. The composition according to claim 1, wherein said mixture M comprises or, alternatively, consists of: sucrose octasulfate or a salt thereof, preferably sucrose octasulfate potassium salt, e (c) at least one polysaccharide selected from the group consisting of: gellan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; preferably gellan gum. 4. The composition according to any one of claims 1-3, wherein said mixture M comprises or, alternatively, consists of: sucrose octasulphate or a salt thereof, preferably sucrose octasulphate potassium salt; (a) a pharmaceutically acceptable alginic acid or alginate salt, preferably an alkali metal or alkaline earth metal alginate selected from the group consisting of: magnesium alginate, potassium alginate, calcium alginate, and a mixture thereof; more preferably magnesium alginate; And (c) at least one polysaccharide selected from the group consisting of: gellan gum, xanthan gum, guar gum, carrageenan, hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof; preferably gellan gum. 5. The composition according to claim 1, wherein said mixture M comprises or, alternatively, consists of: sucrose octasulfate or a salt thereof, preferably sucrose octasulfate potassium salt, e (b) a simethicone and/or dimethicone; preferably simethicone. 6. The composition according to claim 1 or 2 or 5, wherein said mixture M comprises or, alternatively, consists of: sucrose octasulphate or a salt thereof, preferably sucrose octasulphate potassium salt; (a) a pharmaceutically acceptable alginic acid or alginate salt, preferably an alkali metal or alkaline earth metal alginate selected from the group consisting of: magnesium alginate, potassium alginate, calcium alginate, and a mixture thereof; more preferably magnesium alginate; And (b) a simethicone and/or dimethicone; preferably simethicone. 7. The composition according to any one of claims 1-6, wherein said composition is formulated for oral use; preferably in solid form of powder or granules to be suspended or dispersed in an aqueous medium or, alternatively, in liquid form of suspension or dispersion in an aqueous medium; preferably syrup. 8. The composition according to any one of claims 1-7 for use as a medicament. The composition according to any one of claims 1-7 for use in a method of treatment, preventive and/or curative, of a gastric reflux or 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. 10. The composition according to any one of claims 1-7 for use in a method of treatment, preventive and/or curative, of: oesophagitis or acute or chronic inflammation of the oesophageal mucosa, oesophageal ulcers, de-epithelialization 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.