Patent Description:
(II) a composition (C2) in form of tablet comprising:.

The present invention further regards a kit comprising said combination (C) for said use, wherein said kit comprises at least one housing in which the composition (C1) in form of eye wash is received and in which the composition (C2) in form of tablet is received.

In the context of the present invention, the expression "combination" is used to indicate two or more compositions together as defined in the context of the present invention.

In the context of the present invention, the expression "composition" is used to indicate a pharmaceutical composition or medical device composition according to the European regulation on medical devices [UE <NUM>/<NUM> -(MDR), Directive <NUM>/<NUM>/CEE -(MDD)] or dietary supplement product or a food product or a food for special medical purpose.

In the context of the present invention the following nosological entities are defined: gastroesophageal reflux, laryngopharyngeal reflux (alternatively defined extraoesophageal reflux) and non-erosive reflux.

Gastroesophageal reflux or the gastroesophageal reflux disease (abbreviated as GERD) is a para-physiological characterised by the backflow of the acid gastric content or acid gastric vapours from the stomach to the oesophagus (from now henceforth, simply, gastric content) for example comprising pepsin, hydrochloric acid, gastric juices, duodenal juices and acid gastric vapours.

The cardia is the anatomic communication region between the oesophagus and stomach, normally located in the abdomen between <NUM> and <NUM> below the diaphragm. In the cardia there occurs the transition between the oesophageal mucosa and the gastric mucosa.

Right upstream of the cardia, the circular muscle fibres of the oesophagus acquire a sphincter action, in the sense that they remain contracted in the rest condition, while they relax during eructation, the descent of the food into the stomach and its backflow when vomiting; in the other stages of the digestive process, instead, this functional sphincter should normally remain shut and contracted, so as to prevent the acid gastric content of the stomach from flowing back into the oesophagus, irritating the inner walls thereof. The sphincter we are talking about is known as the cardiac sphincter, gastroesophageal sphincter, lower oesophageal sphincter (LES) or cardia.

Cardia incapacity, more or less temporary, such to make the reverse movement of the gastric content possible, occurs in patients suffering from gastroesophageal reflux symptoms or diseases (GERD). In patients suffering from GERD, part of the gastric content flows back from the stomach to the oesophagus, which is not provided with systems for protection for example against hydrochloric acid or against gastric juices or against acid gastric vapours produced by the stomach. Gastric juice is a secretion produced by the internal mucosa of the stomach containing mucus, salts, water, digestive enzymes (such as for example pepsin) and hydrochloric acid. The pH of the gastric content or gastric juice is very low, but for example variable between <NUM> and <NUM> in any case.

Thus, in patients suffering from GERD, the backflow - even at very small amounts - of the gastric content from the stomach to the oesophagus causes the irritation of the epithelium of the oesophagus, which causes a burning feeling at the retrosternal position and pains upon deglutition, as well as an increase of caries (due to the corrosion of the teeth enamel caused by the gastric acids), retching after taking food, acidity feeling at the upper part of the oesophagus and in the pharynx (particularly frequent when one lies horizontally after eating, due to the fact that this facilitates the backflow process of the gastric content into the oesophagus).

Gastroesophageal reflux is very common, temporary at times, sometimes a symptom of a much more severe disease. The most common causes can be obesity, diabetes mellitus, conditions of increased gastric secretion, pregnancy, smoking, alcohol, hiatal hernia (congenital condition in which the position of the oesophagus hiatus, the opening of the oesophagus in the stomach, is in an unusual position that facilitates the backflow of the gastric content).

Laryngopharyngeal reflux (abbreviated as LPR from the English acronym Laryngopharyngeal Reflux) or laryngopharyngeal reflux disease or, alternatively, extraoesophageal reflux are the various terms used for identifying the symptoms or diseases caused by the backflow of gastric acid, for example the backflow of pepsin, hydrochloric acid, acid gastric vapours or gastric and/or duodenal juices, from the stomach to the extraoesophageal areas.

In the context of the present invention, the upper respiratory tract, the eyeball (or the eye), the periocular area, the lacrimal apparatus and the ear apparatus, the Eustachian tube and the middle ear are referred to as extraoesophageal areas.

In the context of the present invention, the nasal cavity, the paranasal sinuses, the oral cavity, the pharynx, the epiglottis and the larynx are referred to as upper respiratory tract.

In the context of the present invention, the region between the eye or regarding the eye contour, such as for example the conjunctiva and the lacrimal apparatus, are referred to as the periocular area.

The conjunctiva is a mucosa membrane, which covers the eyeball and the inner part of the eyelids.

The lacrimal apparatus is the set of secretory system of the lacrimal film, which includes the lacrimal gland, and of the apparatus that allows the outflow thereof. The apparatus that allows the outflow thereof includes the lacrimal ways, consisting of: lacrimal points, lacrimal sac and lacrimal channels or lacrimal ducts or nasolacrimal duct.

In other words, when the gastric acid flows back from the stomach, irritative conditions that can involve, for example, the eyeball (or the eye) and the periocular area (e.g. the conjunctiva and the lacrimal apparatus) may occur at the extraoesophageal areas level.

In the context of the present invention, the terms "laryngopharyngeal reflux" (LPR) and "extraoesophageal reflux" will be used interchangeably to indicate what has been defined above.

The main symptoms of LPR (or extraoesophageal reflux) are, for example, dry cough, dysphonia, globus pharyngis, different from the classical GERD "heartburn". Contrary to what occurs in classical gastroesophageal reflux, where the reflux events mainly occur at night, in case of LPR it has been proven that the events occur throughout the <NUM> hrs.

Despite laryngopharyngeal reflux (LPR) or extraoesophageal reflux having been initially considered as an extension of the gastroesophageal reflux disease (GERD), today it is considered as an independent disease in that it is capable of locally determining disease forms.

The two diseases, GERD and LPR, can coexist or manifest themselves separately.

Should GERD and LPR coexist, patients with GERD, besides the diseases in the oesophagus region, may also suffer from diseases (for example ailment or non-severe illness) or symptoms (for example manifestation of a pathological condition or even a combination of events through which the disease is manifested) in one or more extraoesophageal areas.

Should GERD and LPR not coexist, diseases or symptoms felt in one or more extraoesophageal areas may also occur in subjects not affected by GERD, following the backflow of the gastric content from the stomach into the extraoesophageal area.

In light of the above, people suffering from LPR or extraoesophageal reflux can be affected, for example, from the lacrimal dysfunction syndrome (abbreviated as LDS or OSD (Ocular Surface Disease) alternatively defined as dry eye syndrome. As a matter of fact, there has been observed the presence of gastric acid content in the lacrimal secrete of subjects suffering from LPR (<NPL>;<NPL>). The lacrimal dysfunction syndrome (LDS) is an eye disease which consists in a quantity reduction and/or in a quality alteration of the lacrimal film, which mainly has a function of moistening and protecting the front surface of the eyeball. The lacrimal film has the task of carrying out crucial functions i) nutritional: the tears allow to guarantee a correct oxygen content and nutritional substances for an appropriate turnover of the cells of the ocular surface; ii) anti-microbial: the presence of antibodies and enzymes in the lacrimal film guarantees a defensive action against external attacks; iii) cleaning and iv) lubricating. Thus, the alteration in the quantity/quality of the lacrimal film entails exposing the eyeball to a greater friction (determined by the movement of the eye lids) and a greater risk of infections. The lacrimal dysfunction syndrome is among the most frequent diseases in ophthalmology and the impact thereof is high in the middle age and elderly population.

In the context of the present invention, the terms "lacrimal dysfunction syndrome" (LDS) and "dry eye syndrome" will be used interchangeably to indicate what has been defined above.

Another symptom or disease that may occur in subjects suffering from LPR or extraoesophageal reflux is the inflammation of the eyeball or the inflammation of the periocular area, in particular conjunctivitis, i.e. an inflammation that affects the conjunctiva, causing the reddening of the eyes. Conjunctivitis may affect adults, children and new-borns alike.

Lastly, in the context of the present invention there is defined the nosological entity of the non-erosive reflux or non-erosive reflux disease (abbreviated as NERD), characterised by the presence of gastroesophageal reflux or laryngopharyngeal reflux (LPR) in absence of endoscopic damage visible under gastroscopy, in that the reflux of stomach acid content does not cause oesophagitis.

Frequently, symptoms or diseases in extraoesophageal areas, such as the upper respiratory tract, the eyeball (or the eye), the periocular area (e.g. Conjunctiva and lacrimal apparatus) and the ear apparatus, are analysed, diagnosed and/or treated without considering a possible correlation with the backflow of the gastric acid content from the stomach to the extraoesophageal areas.

Hence, many of said symptoms or diseases in extraoesophageal areas, such as for example lacrimal dysfunction syndrome (LDS), conjunctivitis or ocular or periocular inflammation, are treated using products currently available in the market that do not curatively and/or preventively treat the phenomenon relating to the backflow of the gastric acid content from the stomach to the extraoesophageal areas; such as for example the eyeball and/or the periocular area.

The prior art document <CIT> reveals an oral composition comprising at least one alginic acid salt, hyaluronic acid, a natural molecule and thickening agents.

The prior art document <CIT> reveals a medical device in form of syrup containing silicone oils, magnesium alginate, carboxypolymethylene, re-epithelization compounds and sedative compounds.

The Applicant posed the technical problem of providing combinations, compositions, formulations, preparations or mixtures (in short, combinations) for methods for the preventive and/or curative treatment of symptoms or diseases manifested in at least one extraoesophageal area, relating to or deriving from extraoesophageal reflux or LPR, as defined in the context of the present invention, in subjects suffering from gastroesophageal reflux or in subjects not suffering from gastroesophageal reflux.

In particular, the Applicant posed the technical problem of providing combinations for use in methods for the preventive and/or curative treatment of symptoms or diseases of the eyeball and/or periocular area relating to or deriving from said extraoesophageal reflux, such as for example the lacrimal dysfunction syndrome (LDS), conjunctivitis or ocular or periocular inflammation.

Furthermore, the Applicant posed the technical problem of providing combinations for use in said treatment methods that are effective and avoid relapses, that are stable, east to take/apply and that, once administered, are well-tolerated by the majority of subjects and basically without adverse effects.

Lastly, the Applicant posed the technical problem of providing combinations for use in said treatment methods comprising compositions that do not contain steroidal substances and thus without the adverse effects typically observed in subjects treated using steroidal substances, such as for example the increase of the ocular pressure or risk of glaucoma when the combinations of the invention, in particular, for the treatment of symptoms or diseases of the eyeball and/or periocular area.

Following an extensive and deep research and development activity, the Applicant appropriately solved the technical problem outlined above.

The Applicant surprisingly found combinations of two compositions, without steroidal substances, for use in methods for the treatment of symptoms or diseases manifested in at least one extraoesophageal region (e.g. eyeball or periocular area), relating to or deriving from extraoesophageal reflux (or LPR), such as for example, the lacrimal dysfunction syndrome (LDS), conjunctivitis and/or ocular or periocular inflammation that are effective, stable, easy to take/apply, well tolerated by the majority of subjects to whom it is administered and basically without adverse effects.

Forming an object of the present invention is a combination of two compositions for use in a treatment method having the characteristics as defined in the attached claims.

Furthermore, forming an object of the present invention is a kit comprising said combination (C) for said use, wherein said kit comprises at least one housing in which the composition (C1) in form of eye wash is received and in which the composition (C2) in form of tablet is received, having the characteristics as defined in the attached claims.

Preferred embodiments of the present invention will be apparent from the detailed description below and they are indicated in the attached claims.

It is also disclosed a combination (C) comprising:(I) a composition (C1) comprising (i) a mixture (M1), as defined hereinafter, and, optionally, (ii) at least one technological additive and/or at least one pharmaceutical or food grade excipient; and (II) a composition (C2) comprising (iii) a mixture (M2), as defined hereinafter, and, optionally, (iv) at least one technological additive and/or at least one pharmaceutical or food grade excipient (in short the combination (C)); saic combination being for use in the preventive and/or curative treatment of symptoms or diseases of the eyeball and periocular area, relating to or deriving from extraoesophageal reflux, laryngopharyngeal reflux or, generally, from the backflow of the gastric content or acid gastric vapours from the stomach in at least one extraoesophageal area or in more than one extraoesophageal area.

It is also disclosed a combination (C) comprising: (I) a composition (C1) in form of eye wash comprising (i) a mixture (M1), as defined hereinafter, and, optionally, (ii) at least one technological additive and/or at least one pharmaceutical or food grade excipient; and (II) a composition (C2) in form of tablet comprising: (iii) a mixture (M2), as defined hereinafter, and, optionally, (iv) at least one technological additive and/or at least one pharmaceutical or food grade excipient (in short the combination (C));said combination (C) being for use in a method for the preventive and/or curative treatment of symptoms or diseases of the eyeball and periocular area, wherein said symptoms or diseases relating to or deriving from extraoesophageal reflux or laryngopharyngeal reflux (LPR) or from the backflow of the gastric content or of the acid gastric vapours from the stomach into said at least one extraoesophageal area.

Said (ii) and (iv), at least one technological additive and/or pharmaceutical or food grade excipient, can be selected - by way of non-limiting examples and irrespective of each other - from among a preservative, antioxidant, stabiliser, thickener, rheology modifier, biocide, dye, pH buffers and the like.

By way of non-limiting example, said (ii) and (iv) can be selected, irrespectively of each other, from among sorbitol, mannitol, calcium phosphate dibasic anhydrous, flavour, silicon dioxide, corn starch, vegetable magnesium stearate, sucralose, cellulose and derivatives and microcrystalline cellulose.

In particular, the composition (C1) may comprise at least one technological additive and/or excipient known to the man skilled in the art and useable in ophthalmic formulations or for topical ocular use, wherein said formulations can be liquid, semi-solid or solid.

The combination (C) for use according to the attached claims can be for use in human subjects or for veterinarian use, by way of non-limiting example, in pets such as dogs or cats, or in other mammals. Preferably, the combination (C) according to the present invention is for use in humans.

The combination (C) for use according to the attached claims is for use both in diseased subjects (patients who have been diagnosed with a disease) and in healthy subjects (non-diseased subjects).

The combination (C) for use according to the attached claims is for use both in subjects suffering from gastroesophageal reflux disease (GERD), i.e. patients suffering from GERD or in subjects with the typical symptoms and problems relating to GERD, or in subjects not suffering from GERD, i.e. in subjects who have not been diagnosed with GERD or who show the typical symptoms and problems relating to GERD.

Preferably, the combination (C) is for use in subjects suffering from gastroesophageal reflux disease (GERD).

In an embodiment, the combination (C) for use according to the attached claims is for use in the preventive and/or curative treatment of diseases or symptoms that are manifested in the or diseases of the eyeball or periocular area.

In a preferred embodiment, the combination (C) for use according to the attached claims is for use in the preventive and/or curative treatment of symptoms or diseases relating to or deriving from the lacrimal dysfunction syndrome or dry eye syndrome, conjunctivitis of the conjunctiva, conjunctivitis of the cornea, ocular inflammation or periocular inflammation.

In a preferred embodiment, the combination (C) for use according to the attached claims is for use in the simultaneously preventive or curative treatment of one or more first symptoms or disease relating to or deriving from extraoesophageal reflux and, simultaneously, of one or more second symptoms or disease relating to or deriving from extraoesophageal reflux, wherein said one or more first symptoms or diseases are symptoms manifested in the or diseases of the eyeball, of the periocular area and/or of the lacrimal apparatus, and wherein said one or more second symptoms or diseases are not symptoms manifested in the or diseases of the eyeball, of the periocular area and/or of the lacrimal apparatus.

Advantageously, for example, the use of the combination (C) allows the simultaneous preventive or curative treatment of diseases of the eye area (eyeball, periocular area and lacrimal apparatus), such as for example, lacrimal dysfunction syndrome or dry eye syndrome, conjunctivitis of the conjunctiva, conjunctivitis of the cornea, ocular inflammation or periocular inflammation as well as diseases of the upper respiratory tract, such as for example irritations or inflammations of the upper respiratory tract mucosae, relating to or deriving from the extraoesophageal reflux or laryngopharyngeal reflux.

Hence, according to an advantageous aspect, the combination (C) for use according to the attached claims allows the treatment of diseases closest to the main causes (the extraoesophageal reflux or laryngopharyngeal reflux or the backflow of the gastric content or of the gastric acid gastric vapours from the stomach) of such diseases that develop in a subject in a further position with respect to, and due to, such main cause.

To express such concept in an even more concise manner, the combination (C) for use according to the attached claims allows the treatment of a subject both in proximity of the cause or of the source of disease as well as the symptoms triggered by such cause that are manifested in relatively remote extraoesophageal areas (for example at the eye and ear).

Advantageously, the combination (C) for use according to the attached claims allows to carry out said simultaneous treatment of said one or more first symptoms or diseases using smaller doses of at least one, or both, from among the composition (C1) and the composition (C2) of the present invention with respect to the utilised doses of the composition (C1) and/or of the composition (C2) when used singularly. The use of smaller dose of one or both compositions (C1) and (C2) allows, advantageously, to reduce the risk of occurrence of adverse effects.

Alternatively, the combination (C) for use according to the attached claims allows to carry out said simultaneous treatment of said one or more first symptoms or diseases and said one or more second symptoms or diseases using the same doses of the composition (C1) and the composition (C2) of the present invention with respect to the doses used when (C1) and (C2) are used singularly, but offering a treatment of at least one among said first or second symptoms or diseases more effective with respect to when obtained using (C1) and (C2) singularly.

In a preferred embodiment, the combination (C) for use according to the attached claims is for use as coadjuvant for the re-epithelialization processes of a mucosa in at least one extraoesophageal area, preferably of the mucosa of the eyeball or periocular area.

In a preferred embodiment, the combination (C) for use according to the attached claims is for use in subjects with Reflux Symptom Index greater than <NUM>.

There are various methods for the diagnosis of laryngopharyngeal reflux (LPR), both anamnestic and objective or instrumental. Among them, recognised and accepted at international level is the use of a symptom severity score called Reflux Symptom Index (abbreviated as RSI), a symptomatology score which, despite its simplicity, allows an accurate diagnosis of the presence/absence of the laryngopharyngeal reflux disease and the severity of the symptoms.

In a preferred embodiment, the combination (C) for use according to the attached claims is for use in subjects with Reflux Symptom Index greater than <NUM> and Ocular Surface Disease Index greater than <NUM>, preferably with Ocular Surface Disease Index greater than <NUM>, more preferably with Ocular Surface Disease Index greater than <NUM>.

There are various methods for the diagnosis of lacrimal dysfunction syndrome (LDS), both anamnestic and objective or instrumental. Among them, recognised and accepted at international level is the use of a symptom severity score called Ocular Surface Disease Index (abbreviated as OSDI), which allows an accurate diagnosis, and staging of the lacrimal dysfunction syndrome.

In an embodiment, the composition (C1) of the present invention is administered topically and wherein the composition (C2) is administered enterally.

In other words, the composition (C1) comprising (i) the mixture (M1) as described hereinafter and, optionally, (ii) the at least one technological additive and/or at least one pharmaceutical or food grade excipient, is administered topically. The composition (C2) comprising (iii) the mixture (M2) as described hereinafter and, optionally, (iv) at least one technological additive and/or at least one pharmaceutical or food grade excipient, is administered enterally.

Preferably, the composition (C1) is administered in an ocular topical manner, for example on an eyeball and/or periocular area surface, and the composition (C2) is administered enterally, such as for example orally (or gastrointestinal means), rectally and sublingually (or buccal).

Preferably, the composition (C1) is administered topically in the eyeball and/or periocular area surface (ocular topically) and the composition (C2) is administered orally.

In an embodiment, the composition (C1) is administered topically in the eyeball and/or periocular area surface (ocular topically) and the composition (C2) is administered orally.

It should be observed that forming an object of the present invention the combination (C) for use according to the attached claims is for use in the preventive and/or curative treatment of symptoms or diseases relating to or deriving from extraoesophageal reflux or laryngopharyngeal reflux or, generally, from the backflow of the gastric content or acid gastric vapours from the stomach in at least one extraoesophageal region, both when the composition (C1) and the composition (C2) are administered to a subject in any order, both when the composition (C1) and (C2) are administered to a subject in a close sequence over time or in a non-close sequence, both when (C1) and (C2) are administered to a subject with the same frequency or with different frequencies.

According to an embodiment, the composition C1 in form of eye wash could be administered from one to four times (preferably from two to three times) per day, at an amount comprised between one to three drops per eye for each administration. According to another embodiment, the composition C2 in form of tablet could be administered from one to four times (preferably from two to three times) per day, at an amount of one tablet or two tablets for each administration.

Advantageously, the composition (C) according to the present invention allows the curative and/or preventive treatment of the symptoms and the diseases caused by gastroesophageal reflux and that are manifested in the eye and/or in the periocular area without administering substances of the steroidal type, that could cause adverse effects, even severe, and they can deteriorate the gastroesophageal reflux disease, besides causing the increase of ocular pressure and increasing the risk of glaucoma.

Preferably, the composition (C1) according to the present invention does not contain active ingredients of the steroidal type.

The mixture (M1) of the present invention comprises or, alternatively, consists of:.

In a first embodiment, the mixture (M1) consists of: (i-a) an alginic acid, or a salt thereof, and (i-b) a hyaluronic acid or a salt thereof, and the composition (C1) does not contain active ingredients besides those present in said mixture (M1).

In a second embodiment, the mixture (M1) comprises, besides (i-a) an alginic acid, or a salt thereof, and (i-b) a hyaluronic acid or a salt thereof, at least another compound or active ingredient; preferably, said at least another compound or active ingredient is selected from among:.

Preferably, both in case of the first embodiment and the second embodiment, the composition (C1) comprises (i-a) and (i-b) in the following percentages by weight with respect to the total weight of the composition (C1):.

Preferably, both in the case of the first embodiment and in the second embodiment, the mixture (M1) comprises (i-a) an alginic acid (<NPL>), a colloidal and hydrophilic polysaccharide, having an (average) molecular weight comprised between about <NUM> kDalton (kDa) and about <NUM> kDa; preferably comprised between about <NUM> kDa and about <NUM> kDa; even more preferably comprised between about <NUM> kDa and about <NUM> kDa, preferably at about <NUM> kDa, wherein kDalton (kDa) corresponds to <NUM> Dalton (Da) and <NUM> Dalton corresponding to <NUM> unified atomic mass unit (u). Preferably, (i-a) is obtained from marine algae. Preferably, (i-a) it is an alginate salt, more preferably magnesium alginate.

The mixture (M1) according to the present invention comprises (i-b) a hyaluronic acid (<NPL>) in acid or salified form, for example such as sodium salt.

The hyaluronic acid is a non-sulphated glycosaminoglycan having a non-branched polysaccharide chain deriving from the condensation of disaccharide units in turn formed by residues of glucuronic acid and N-acetylglucosamine bonded to each other, alternatively, by β1→<NUM> and β <NUM>→<NUM> glycosidic bonds.

Preferably, both in the case of the first embodiment and in the second embodiment, the mixture (M1) may comprise (i-b) a hyaluronic acid, or the salts thereof, having a different origin and various molecular weight ranges and it can be linear or branched.

Preferably, the mixture (M1) comprises (i-b) a linear or branched hyaluronic acid, or salts thereof, for example sodium salt, with a (average) molecular weight comprised between <NUM> kDa and <NUM> kDa; more preferably it is comprised between <NUM> kDa and <NUM> kDa; even more preferably it is comprised between <NUM> kDa and <NUM> kDa.

In a preferred embodiment, the combination (C) comprises the composition (C1) comprising the mixture (M1 a) comprising, or alternatively, consisting of:.

It should be observed that, it is also disclosed the use of (i-a) and (i-b), as defined above, in the treatment of symptoms or diseases relating to or deriving from extraoesophageal reflux, preferably symptoms or diseases manifested in or diseases of the eyeball and/or periocular area, both when (i-a) and (i-b) are administered simultaneously, i.e. Mixed in the same composition (C1), and when (i-a) and (i-b) are administered to a subject separately by means of two separate compositions (C1- a) and (C1-b), in close sequence over time (and for example at the <NUM>-minute time interval) and in any order.

The composition (C1) according to the present invention is in form of eye wash.

In an embodiment, the composition (C1) according to the present invention is in form of ophthalmic solution, namely eye wash, comprising boric acid and/or sodium tetraborate preferably, irrespective of each other, at an amount comprised between <NUM> and <NUM>% by weight on the total weight of the pharmaceutical composition or medical device.

In a particularly preferred embodiment, the combination (C) comprises the composition (C1) in form of ophthalmic solution (. eye wash) wherein (C1) comprises in by weight % per <NUM> of total weight of composition (C1):.

The composition (C2) of the present invention comprises a mixture (M2) comprising or, alternatively, consisting of:.

In the mixture (M2) of the present invention it is observed that:.

In the composition (C2) of the present invention it is observed that:.

Advantageously, the composition (C2) of the present invention comprises the mixture (M2) of the present invention at a ratio by weight comprised between <NUM>:<NUM> [mixture (M2): composition (C2)] and <NUM> :<NUM> [mixture (M2): composition (C2)]; preferably at a ratio by weight of about <NUM> :<NUM> [mixture (M2): composition (C2)] or at a ratio by weight of about <NUM> :<NUM> [mixture (M2): composition (C2)].

Preferably, in said mixture (M2) said (iii-a) alginic acid is preferably an alginic acid having an average molecular weight comprised between about <NUM> kDalton (KDa) and about <NUM> kDa; more preferably comprised between about <NUM> kDa and about <NUM> kDa; more preferably comprised between about <NUM> kDa and about <NUM> kDa; more preferably comprised between about <NUM> kDa and about <NUM> kDa; wherein kDalton (kDa) corresponds to <NUM> Dalton (Da) and <NUM> Dalton corresponds to <NUM> unified atomic mass unit (u).

Preferably, (iii-a) is an alginic acid or an alginic acid salt having an average molecular weight of about <NUM> Dalton (unified atomic mass unit, u), i.e. <NUM> kDa, and (iii-a) is obtained from marine algae.

The alginic acid (iii-a) comprised in the mixture (M2) is in form of an alginate salt of an alkaline metal or of an alkaline earth metal; more preferably, in said mixture (M2) said alginate salt is selected from among the group comprising or, alternatively, consisting of: sodium alginate, potassium alginate, calcium alginate or magnesium alginate. Alginic acid is a polysaccharide consisting of two types of uronic acid: Mannuronic acid unit (M) and Guluronic acid unit (G), which form two types of polymeric segment blocks: M blocks with M-M bonds only; G blocks with G-G bonds only; M&G random blocks with M-G random bonds.

Examples of (iii-a) alginic acid and alginates used in the present invention together with (iii-b) and (iii-c) are represented by:.

Preferably, in the mixture (M2) (iii-a) there is the alginic acid having <NPL>.

The mixture (M2) of the present invention comprises, combined with said alginic acid (iii-a), (iii-b) a bicarbonate salt of an alkaline metal or of an alkaline earth metal (b) selected from among the group comprising or, alternatively, consisting of: sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate and calcium bicarbonate; and/or (iii-b) a carbonate salt of an alkaline metal or of an alkaline earth metal (b) selected from among the group comprising or, alternatively, consisting of; sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate.

An example of potassium bicarbonate (b) is (E501 ii) with general formula HKCO<NUM>, molecular weight <NUM>, <NUM> and EINECS n. ° <NUM>-<NUM>-<NUM> and a Bulk density of about <NUM>-<NUM>/cm3 and a Tapped density of about <NUM>-<NUM>/cm<NUM>.

The mixture (M2) of the present invention comprises, in association with said (iii-a) alginic acid, or a salt thereof, and said (iii-b) bicarbonate salt and/or said (iii-b) carbonate salt, (iii-c) a simethicone compound, or (iii-c) a dimethicone compound, or (iii-c) a simethicone compound and a dimethicone compound together. Examples of (iii-c) simeticone to be used in association with (iii-a) and (iii-b), are represented by:.

Preferably, said (iii-c) simethicone is the simethicone having <NPL>; or it is a simethicone belonging to the following classes of simethicone: Simethicone <NUM>, Simethicone Emulsion <NUM>%, Simethicone Emulsion, Antifoam C <NUM>, Antifoam <NUM> PD, Antifoam PD30 S, Antifoam <NUM>.

Examples of (iii-c) of dimethicone are represented by:.

Preferred examples of (iii-c) dimethicone are: Cetyl dimethicone, Stearyl dimethicone, Stearoxy dimethicone, Behenoxy dimethicone and all polymers belonging to the group of dimethicone copolyols. Non-limiting examples of Copolyol dimethicone are: Dimethicone PEG-<NUM> Adipate, Dimethicone PEG-<NUM> Benzoate, Dimethicone PEG-<NUM> Phosphate, Dimethicone PEG-<NUM> Phosphate, Dimethicone PEG / PPG- <NUM>/<NUM> Benzoate, Dimethicone PEG / PG-<NUM> Dimethicone, PEG-<NUM> Dimethicone, PEG-<NUM> Dimethicone, PEG- <NUM> Dimethicone, PEG-<NUM> Dimethicone, PEG-<NUM> Dimethicone, PEG-<NUM> Dimethicone, PEG- <NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/<NUM> Dimethicone, PEG/PPG-<NUM>/ PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone, PEG/PPG-<NUM>/<NUM> dimethicone and PEG/PPG-<NUM>/<NUM> dimethicone.

It is also disclosed the use of (iii-a), (iii-b) and (iii-c), as defined above, in the treatment of symptoms or diseases relating to or deriving from extraoesophageal reflux, preferably symptoms manifested in or diseases of the eyeball and/or periocular area, both when (iii-a), (iii-b) and (iii-c) are administered simultaneously, i.e. mixed in the same composition (C2), and when (iii-a), (iii-b) and (iii-c) are administered to a subject separately by means of two separate compositions (C2-a), (C2-b) and (C2-c), in close sequence over time (and for example at the <NUM>-minute time interval) and in any order.

In a preferred embodiment, the mixture (M2) comprises (iii-c) simethicone having <NPL>.

In a preferred embodiment, the composition (C2) comprises the mixture (M2a) consists of:.

In a preferred embodiment, the composition (C2), in form of tablet, has the following composition by weight per <NUM> of (C2):.

It is also disclosed the combination (C) comprises the composition (C1) comprising the aforementioned mixture (M1a) and, furthermore, the combination (C) comprises the composition (C2) comprising the aforementioned mixture (M2a),
wherein said combination (C) is for use in a method for the preventive and/or curative treatment of symptoms or diseases relating to or deriving from lacrimal dysfunction syndrome (LDS) or dry eye syndrome, and wherein said combination (C) is for use in a method for treatment in subjects with Reflux Symptom Index (RSI) greater than <NUM>.

It is also disclosed the combination (C) comprises the composition (C1) comprising the aforementioned mixture (M1a) and, furthermore, the combination (C) comprises the composition (C2) comprising the aforementioned mixture (M2a),
wherein said combination (C) is for use in a method for the preventive and/or curative treatment of symptoms or diseases relating to or deriving from lacrimal dysfunction syndrome (LDS) or dry eye syndrome, and wherein said combination (C) is for use in a method for treatment in subjects with Reflux Symptom Index (RSI) greater than <NUM> and Ocular Surface Disease Index (OSDI) greater than <NUM>; preferably with Ocular Surface Disease Index (OSDI) greater than <NUM>; more preferably with Ocular Surface Disease Index (OSDI) greater than <NUM>.

In a preferred embodiment, the combination (C) comprises:.

(I) the composition (C1 ) in form of ophthalmic solution (eye wash) having the following composition in by weight % <NUM> of total weight of composition (C1 ):.

(II) the composition (C2) having the following formula per <NUM> of (C2):.

Furthermore, forming an object of the present invention is a kit comprising said combination (C) for use according to the attached claims, wherein said kit comprises at least one housing in which the composition (C1) in form of eye wash is received and in which the composition (C2) in form of tablet is received.

Preferably, the kit comprises or, alternatively, consists of a secondary packaging receiving the composition (Cl) and the composition (C2). More preferably, the composition (C1) and the composition (C2) are each received in a separate primary packaging - directly at contact with the composition (C1) and with the composition (C2) - the two primary packagings being received in the secondary packaging.

According to an embodiment, the kit comprises a single housing in which the composition (C1) in form of eye wash is received and in which the composition (C2) in form of tablet is received, preferably in which the two packagings are received.

According to another embodiment, the kit comprises:.

Unless specified otherwise, the indication that a composition "comprises" one or more components means that other components besides the one, or the ones, indicated specifically, are present even though not necessarily indicated, meaning that the composition can also exclusively contain such components, and the indication that a composition "consists" of determined components means that the presence of other composition is excluded.

In the present invention, the expression "treatment" of a symptom or disease is used to indicate the therapy aimed at restoring a subject's health conditions, maintaining the current conditions and/or preventing the deterioration of said health conditions.

In the present invention, the expression "prevention" of a disease is used to indicate a therapy aimed at hindering the occurrence of such symptom or disease in a subject, including but not exclusively complication or effect of a pre-existing disease.

Unless indicated otherwise, in the present invention the percentages and amounts of a component in a mixture shall be deemed to refer to the weight of such component with respect to the total weight of the mixture.

Unless indicated otherwise, in the present invention, as regards the value intervals of numerical values for a given characteristic, the indication "from X to Y" comprises the extremities, i.e. X and Y, as well as all possible intermediate numerical values.

The expression "medical device" in the context of the present invention is used according to the meaning laid down by the Italian Legislative Decree n° <NUM>, dated <NUM> February <NUM>, corresponding to the definition provided by the World Health Organisation and available at http://www. int/medical_devices/full_deffinition/en/, i.e. it indicates a substance or another product, used alone or in combination, designated by the manufacturer to be used in humans for diagnosis, prevention, control, therapy or disease attenuation purposes, the product not exercising the main action, in or on the human body, for which it is designated, neither with pharmacological or immunology means nor by means of a metabolic process but the function thereof can be assisted by such means.

Both the mixtures and the compositions subject of the present invention are prepared using techniques, methods and equipment known to the man skilled in the art.

It was observed that through the combination according to the invention it is possible to obtain a synergic effect of the composition (C1) with the composition (C2) for the preventive and/or curative treatment of symptoms or diseases directly or indirectly relating to or deriving from extraoesophageal reflux or laryngopharyngeal reflux or, generally, from the backflow of the gastric content or acid gastric vapours from the stomach in at least one extraoesophageal area, in subjects suffering from gastroesophageal reflux or in subjects not suffering from gastroesophageal reflux, preferably in subjects suffering from gastroesophageal reflux.

The following examples provide practical embodiments of the invention, without limiting the scope of protection thereof in any manner whatsoever.

COMPOSITION <NUM>, ophthalmic solution (eye wash) comprising in by weight % per <NUM> of total weight:.

COMPOSITION <NUM>, for oral administration (tablet) having the following formula for <NUM>:.

Claim 1:
A combination (C) comprising:
(I) a composition (C1) in form of eye wash comprising:
(i) a mixture (M1) comprising, or alternatively, consisting of:
(i-a) an alginic acid, or a salt thereof,
(i-b) a hyaluronic acid, or a salt thereof, and, optionally,
(ii) at least one technological additive and/or at least one pharmaceutical or food grade excipient; and
(II) a composition (C2) in form of tablet comprising:
(iii) a mixture (M2) comprising, or alternatively, consisting of:
(iii-a) an alginic acid or a salt thereof of an alkaline metal or of an alkaline earth metal;
(iii-b) a bicarbonate salt of an alkaline metal or alkaline earth and/or a carbonate salt of an alkaline metal or alkaline earth;
(iii-c) a simethicone and/or dimethicone; and, optionally,
(iv) at least one technological additive and/or at least one pharmaceutical or food grade excipient;
said combination (C) being for use in a method for the preventive or curative treatment of symptoms or diseases of the eyeball and periocular area, wherein said symptoms or diseases relate to, or derive from, extraoesophageal reflux or laryngopharyngeal reflux (LPR) or from the backflow of the gastric content or of the acid gastric vapours from the stomach into at least one extraoesophageal area.