Liquid composition for treating the mucous membranes of the oropharynx, esophagus and throat

Abstract

The present invention relates to an aqueous liquid composition or a hydroalcoholic liquid comprising a mixture and optional food and / or pharmaceutical grade additives and / or process excipients, wherein the mixture comprises or consists of a combination of aloe vera gel, hyaluronic acid and honey; the composition is used for the preventive and / or curative treatment of symptoms and conditions associated with gastroesophageal reflux (GERD) and / or laryngopharyngeal reflux (RLF) and diseases caused thereby, as an adjunct in the symptomatic treatment of gastroesophageal and / or laryngopharyngeal reflux diseases, or for the preventive and / or curative treatment of: (i) oral and pharyngeal-laryngological-esophageal lesions; (ii) mucositis; and / or (iii) aphthous and / or aphthous-like lesions.

Description

[0001] The present invention relates to an aqueous liquid composition or an aqueous alcoholic liquid for treating the mucosa of the gastroesophageal, laryngopharyngeal and / or oral tract, preferably for treating gastroesophageal reflux (GERD). The composition of the present invention comprises the following mixture and optional food and / or pharmaceutical grade additives and / or process excipients, the mixture comprising a combination of aloe vera gel, hyaluronic acid and honey, or consisting of a combination of aloe vera gel, hyaluronic acid and honey. The composition is used for the preventive and / or curative treatment of symptoms and conditions associated with gastroesophageal reflux and / or laryngopharyngeal reflux (LPR) and diseases caused thereby, as an adjuvant in the symptomatic treatment of gastroesophageal and / or laryngopharyngeal reflux diseases, or for the preventive and / or curative treatment of: (i) lesions of the oral cavity and pharyngopharyngeal esophageal tract; (ii) mucositis; and / or (iii) aphthous and / or aphthous-like lesions.

[0002] Gastroesophageal reflux, or GER, is a phenomenon characterized by the temporary upward flow of gastric contents into the esophagus, without necessarily regurgitating or vomiting. Reflux is primarily due to relaxation of the lower esophageal sphincter (LES), which may be caused by insufficient pressure at the LES relative to increased abdominal pressure or by a gradual loss of closing pressure.

[0003] Gastroesophageal reflux disease, abbreviated as GERD (or GORD, gastro-esophageal reflux disease), is a chronic disease of gastroenterology that is associated with the pathological complications of gastroesophageal reflux (GER) and lies in the damage of the esophageal mucosa caused by gastric acid.

[0004] The most common symptoms of GERD are burning in the gastroesophageal area (retrosternal burning or heartburn), acidic aftertaste, regurgitation, and less commonly cough, painful swallowing (dysphagia and odynophagia), angina-like chest pain, nausea, and increased salivation (drooling).

[0005] In addition to a deterioration in quality of life and difficulty ingesting food and drink, GERD can cause permanent damage to the esophagus, such as chronic inflammation and necrosis of the esophageal epithelium (esophagitis), ulcers, esophageal strictures, Barrett's esophagus (a form of metaplasia characterized by replacement of the typical squamous epithelium of the esophagus with columnar epithelium), and tumors. Subjects with persistent symptoms of GERD are considered to be at high risk for developing adenocarcinoma of the distal esophagus.

[0006] Evaluation of esophageal mucosal damage is usually performed by endoscopic examination, such as gastroscopy or pH testing.

[0007] The treatment of GERD is currently based on some basic hygiene and dietary rules (stop using tobacco and consuming alcoholic beverages) and the (long-term or short-term) administration of drugs belonging to the class of proton pump inhibitors (PPIs), which significantly inhibit the production of acid in the stomach and replace antihistamine (anti-H2) drugs. To relieve symptoms, antacids and alginates can also be used.

[0008] However, the administration of these drugs may be ineffective in some patients and, in the case of long-term treatment, may have side effects at the intestinal level (diarrhea, flatulence, abdominal pain), rash, palpitations and osteoporosis and increased bone fragility.

[0009] Laryngopharyngeal reflux (LPR) is a little known condition that is difficult to diagnose and does not cause significant problems when treated, but without adequate treatment it can prove to be a serious condition that is dangerous to the airway.

[0010] Laryngopharyngeal reflux involves the retrograde reflux of gastric juice that rises from the stomach through the esophagus and reaches the pharynx and larynx, the first upper airway. At this level, the mucosa is damaged and thus becomes inflamed due to the action of the gastric juice.

[0011] This pathology is caused by dysfunction of the upper esophageal sphincter, a group of muscles located in the initial part of the esophagus, which normally have the function of closing and opening the esophagus by contraction and expansion and preventing the esophageal contents from rising through the airway and preventing air from entering the stomach.

[0012] Unlike what happens in the better-known gastroesophageal reflux, gastric juices and gases rising from the stomach pass quickly through the esophagus in such quantities that people with LPR do not complain of ailments such as burning or acidity; in these cases, the patient is "reflux silent." In most cases, LPR manifests itself with symptoms that are unlikely to be reflux-related, making it difficult for doctors to diagnose. Typical symptoms are those of many common oral diseases:

[0013] Chronic sore throat, hoarseness, frequent need to clear the throat, chronic dry cough (lasting more than three weeks), nocturnal cough, postural and nocturnal regurgitation, dysphonia, thick and copious mucus, a sensation of something stuck in the throat, a so-called "throat mass," and, in some cases, a burning sensation behind the sternum.

[0014] These symptoms are due to direct damage to the outermost tissues of the pharynx and larynx by gas and fluid from the stomach.

[0015] This is why, in addition to the gastric acid resistant drugs traditionally used for the treatment of laryngopharyngeal reflux, dedicated medicines or medical devices based on hyaluronic acid are now also available, for example in the form of orally disintegrating tablets.

[0016] However, administration of these products may be ineffective in some patients and may cause side effects similar to those caused by drugs that counteract stomach acid.

[0017] Finally, there are some known liquid compositions on the market containing sodium chondroitin sulfate, sodium hyaluronate and bioadhesive polymers, such as those described in EP 2296670 B1, which is hereby incorporated by reference (see, for example, Examples 1 to 6), which are limited, for example, in terms of effectiveness.

[0018] To date, the following technical problem has not been solved: to provide an effective solution for treating or preventing symptoms associated with gastroesophageal reflux, symptoms of GERD and / or symptoms associated with laryngopharyngeal reflux, which can overcome the disadvantages of the prior art, in particular in terms of side effects.

[0019] More generally, the following technical problem has not been solved to date: to provide an effective solution for treating (i) lesions of the oral cavity and the pharynx-laryngology-esophagus, (ii) mucositis and / or (iii) aphthous and / or aphthous-like lesions without side effects.

[0020] Additionally, there remains the unresolved problem of providing an effective solution that is both effective and anti-inflammatory and that effectively and rapidly promotes tissue re-epithelialization and the healing process to counteract damage to the oral-laryngeal-pharyngeal-esophageal mucosa caused by the upward flow of acidic and / or alkaline vapors from the stomach to the upper digestive system.

[0021] In order to overcome the technical problems, the present invention provides a composition comprising a substance of natural origin, which can effectively and quickly treat (prevent and / or cure) symptoms associated with gastroesophageal reflux and / or laryngopharyngeal reflux, as well as symptoms of diseases caused thereby, and in particular can exert an anti-inflammatory effect and promote tissue re-epithelialization and healing processes to counteract damage to the oral-throat-pharyngeal-esophageal duct mucosa. In addition, the present invention provides a composition that does not have the side effects present in the prior art treatments, is easy to prepare and is economically advantageous. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shown is the percentage of caffeine over time at pH=7 in a reconstructed human esophageal epithelial model treated with the investigated compositions.

[0023] Figure 2 Shown is the percentage of caffeine over time under acidic conditions (pH = 3.3) in a reconstructed human esophageal epithelium model treated with the investigated compositions.

[0024] Figure 3Histological analysis of reconstructed human esophageal epithelium (HOE2E / S / 5) involving damaged areas treated with the composition (B) of the present invention.

[0025] Figure 4 Histological analysis of HOE2E / S / 5 involving intact areas treated with the comparative composition (B).

[0026] Figure 5 Histological analysis of HOE2E / S / 5 involving damaged areas treated with the composition (A) of the invention.

[0027] Figure 6 Histological analysis of HOE2E / S / 5 involving intact areas treated with the comparative composition (A).

[0028] Figure 7 Histological analysis of HOE2E / S / 5 involving lesioned areas treated with an aloe vera:honey gel mixture (C).

[0029] Figure 8 Histological analysis of HOE2E / S / 5 involving intact areas treated with an aloe vera:honey gel mixture (C).

[0030] Fig. 9 Shown is the percentage of caffeine over time at pH=7 in a reconstructed human esophageal epithelial model treated with the investigated compositions.

[0031] Fig.10 Shown is the percentage of caffeine permeation over time under acidic conditions in a reconstructed human esophageal epithelium model treated with the investigated compositions.

[0032] The present invention relates to an aqueous liquid composition or a hydroalcoholic liquid (C) comprising the following mixture and optionally at least one excipient or additive suitable for pharmaceutical or food use, the mixture comprising or consisting of a combination of the following substances:

[0033] (a) Aloe vera gel (as defined herein); and

[0034] (b) hyaluronic acid or a salt thereof; and

[0035] (c) Honey, wherein the honey is not honey having non-peroxide antimicrobial activity and the honey is not clover honey filtered and processed at a temperature of 100°F to 140°F.

[0036] Honey with non-peroxide antibacterial activity refers to a substance with antibacterial activity that is visible in situ, whose antibacterial activity is not destroyed by catalase, and whose antibacterial activity is independent of the production or presence of hydrogen peroxide, such as described in patent application US 20110038945 A1, see for example paragraph

[0142] . Examples of types and sources of honey with substantial non-peroxide antibacterial activity are those described, for example, in patent application US 20110038945; see for example paragraphs

[0229] to

[0237] .

[0037] An example of clover honey filtered and processed at a temperature between 100°F and 140°F (degrees Fahrenheit) is clover honey from Montana or North Dakota, such as described in patent application US 2009 / 0208588 A1. The filtration and pasteurization process of the honey is a method known to those skilled in the art.

[0038] In a first embodiment, composition (C) is an aqueous liquid solution.

[0039] In a second embodiment, composition (C) is an aqueous alcoholic liquid solution. Advantageously, the aqueous alcoholic liquid composition comprises at least one alcohol in an amount of 0.01% to 3% by volume, preferably 0.05% to 2.5% by volume, more preferably 0.1% to 1.0% by volume, wherein the amount is relative to the total volume of composition (C).

[0040] Advantageously, the at least one alcohol is ethanol or any other alcohol suitable for forming an aqueous alcoholic solution which, besides being compatible with components (a) to (c) and optionally (d), can be administered to a human or animal subject.

[0041] In the context of the present invention, the term liquid composition (C) or the composition (C) of the present invention comprises an aqueous liquid composition, or an aqueous-alcoholic liquid composition.

[0042] The present invention relates to an aqueous liquid composition or hydroalcoholic liquid (C) according to the present invention for use as a medicament, comprising (a), (b), (c) and optionally (d) as defined herein above and below.

[0043] The present invention relates to an aqueous liquid composition or an aqueous alcoholic liquid (C) according to the present invention, comprising (a), (b), (c) and optionally (d) as defined herein above and below, for use in the treatment of gastroesophageal reflux and / or laryngopharyngeal reflux; as an adjunct in the symptomatic treatment of gastroesophageal reflux and / or laryngopharyngeal reflux diseases; or for preventive and / or curative treatment against: (i) lesions of the oral cavity (e.g. tongue and palate) and pharynx-laryngolaryngology-esophagus; (ii) mucositis; and / or (iii) aphthous ulcers and / or aphthous-like lesions.

[0044] The present invention relates to a method for the preventive and / or curative treatment of the following conditions: gastroesophageal reflux and / or laryngopharyngeal reflux, and / or: (i) lesions of the oral cavity (e.g., tongue and palate) and pharynx-laryngolaryngology-esophagus; (ii) mucositis; and / or (iii) aphthous ulcers and / or aphthous ulcer-like lesions; wherein the treatment method envisages administering an aqueous liquid composition or hydroalcoholic liquid (C) of the present invention to a subject in need thereof, wherein the composition or liquid (C) comprises (a), (b), (c) and optionally (d).

[0045] Furthermore, the present invention relates to a method of treatment, wherein the aqueous liquid composition of the present invention or the aqueous alcoholic liquid (C) comprising (a), (b), (c) and optionally (d) is administered to a subject in need thereof as an adjuvant in the treatment of the above-mentioned conditions or disorders to increase their effectiveness.

[0046] It has been found that the use of the composition (C) of the present invention can significantly reduce / reduce and / or eliminate the symptoms and diseases associated with gastroesophageal reflux and laryngopharyngeal reflux, thereby alleviating the impact of the disease itself. Advantageously, the liquid composition (C) of the present invention works along the esophagus and pharynx, and exerts an anti-inflammatory effect, promotes the process of tissue epithelial re-formation and healing effect, to counteract the mucosal damage caused by the upward flow of a mixture of steam and acidic substances or substances with acidic characteristics, and / or alkaline substances or substances with alkaline characteristics and / or alternative acid-base substances from the stomach to the esophagus and pharynx. In particular, the liquid composition (C) of the present invention can make the various components / materials contained in the mixture better contact with the oral-pharyngeal-throat-esophageal wall, and is conducive to its protection, lubrication and repair.

[0047] The composition (C) of the present invention (aqueous or aqueous alcohol) may be in the form of a clear solution (without precipitate) or a suspension (i.e. a liquid phase showing visible milky solids suspended in a liquid or semi-liquid substance or precipitates that can be suspended by shaking), and it may be a thick and viscous liquid (such as caramel) or a fluid, flowable substance (such as water) or it may be a two-phase liquid / liquid system. The composition (C) of the present invention is preferably not an emulsion.

[0048] In a preferred embodiment, the composition of the present invention is in the form of a syrup, which has a viscosity of about 1.2 to 1.3 kg / dm at 20°C. 3 A composition having a specific gravity of about 200 to 205 mPa.s at 20° C., comprising water and at least one food or pharmaceutical grade ingredient or additive and / or process excipient.

[0049] In the context of the present invention, "treatment" is meant to include intervention by administering a substance or mixture of substances or a combination thereof with the purpose of eliminating, reducing / lowering or preventing a condition or disease and its symptoms or disorders.

[0050] Unless otherwise specified, the content of a component or substance in a composition refers to the weight percentage of the component or substance relative to the total weight of the composition.

[0051] Unless otherwise stated, a composition "comprising" one or more components or materials means that additional components or materials may be present in addition to the specifically named one or more components or materials.

[0052] Compositions according to the invention are to be understood as compositions for human or veterinary use, ie as preparations for administration to animals in the uses and methods known to those skilled in the art.

[0053] In the context of the present invention, and according to its ordinary meaning, as defined in Italian Legislative Decree No. 179 of May 21, 2004 (replacing Decree 2001 / 110 / EC) on the production and sale of honey, the term "honey" refers to a sweet natural product produced by bees (e.g., Apis mellifera) from the nectar of one or more plant species of any type or from secretions originating from the living parts of plants or from substances secreted by piercing insects found on the living parts of plants, which is collected, transformed, stored in the form of honeycombs and prevented from growing and maturing by combining it with its own specific substances, sediments, dehydrates. Said honey can be obtained by standard methods known to those skilled in the art (for example, including extraction, separation, decanting, filtering, induced crystallization and similar operations). In the context of the present invention, the term "honey" also includes products that can be obtained from natural honey, including products for industrial use, such as products obtained by refining processes or heat treatments such as pasteurization.

[0054] In the context of the present invention, the term "honey" refers to the honey as described above, wherein the honey is not honey with non-peroxide antimicrobial activity (as defined above), and the honey is not clover honey (as defined above) filtered and processed at a temperature of 100°F to 140°F.

[0055] It is known to use honey having a peroxide activity greater than 5 mg hydrogen peroxide / g honey in combination with crude dietary fiber, such as wheat bran, to produce a composition for combating diseases such as gastroesophageal reflux.

[0056] As a non-limiting example, the honey that can be used in the composition of the present invention may have a pH of 3.5 to 4.5, a drying loss of 18% (by weight relative to the total weight of the honey), and a reducing sugar content in the dry product of 70% (by weight relative to the total weight of the honey).

[0057] In the context of the present invention, "aloe vera gel" refers to a usually colorless mucilaginous gel obtained from the parenchyma tissue of the leaves of Aloe vera (L) Burm. F. or Aloe barbadensis Mill. Aloe vera gel has no use as a food substance or fiber and must not be confused with the juice (aloe juice) obtained by cutting and drying the same plant. In the monograph on aloe vera gel in "WHO monographs on selected medicinal plants" (Vol. 1, World Health Organization, Geneva, 1999, pp. 43-49), it is pointed out that its main components, in addition to water, are polysaccharides (pectin, hemicellulose, glucomannan, acetomorphan and mannose derivatives), and it is not shown that the application of aloe vera gel has any significant therapeutic effect (p. 45).

[0058] Furthermore, the term "aloe gel" in the context of the present invention should not be confused with the general term "aloe" since aloe gel is a mucilaginous gel obtained from a specific part of the aloe plant, namely from the parenchymal tissue of the leaves of Aloe barbadensis or Aloe barbadensis.

[0059] In contrast, the inventors have discovered that, according to the present invention, oral administration of aloe vera gel in combination with honey and hyaluronic acid can effectively and rapidly significantly reduce or completely eliminate symptoms and disorders associated with gastroesophageal reflux and laryngopharyngeal reflux, and can treat (i) lesions of the oral cavity (such as the tongue and palate) and the pharynx-laryngolaryngology-esophageal tract; (ii) mucositis; and / or (iii) aphthous ulcers and / or aphthous-like lesions, if the honey is not a honey having non-peroxide antimicrobial activity (as defined above) and the honey is not clover honey (as defined above) filtered and processed at a temperature of 100°F to 140°F.

[0060] In composition (C) of the present invention, the aloe vera gel is preferably freeze-dried inner leaf gel, more preferably from Barbados Aloe vera.

[0061] As a non-limiting example, the pH of the aloe vera gel used in the present invention may be 3 to 6, preferably 3.5 to 5.5, or 3.7 to 4.2, and the content of aloin is less than 1 ppm.

[0062] The aloe vera gel of the present invention is obtained by a standard preparation method. An example of a preparation method is as follows: Aloe vera gel is obtained by the following steps: selecting leaves of adult aloe vera plants; removing the outer part, where the spines and glands that secrete anthraquinones (these substances are particularly known for their laxative effect) are concentrated; pressing the aloe vera pulp, thereby obtaining a gel, leaving a fibrous residue; stabilizing the gel with specific additives to protect the active ingredients from chemical oxidation; purifying the gel; packaging in dark or opaque sealed containers, because aloe vera gel is easily degraded if exposed to oxygen and direct light; storing in a cool place (4°C to 20°C), because aloe vera gel is severely damaged by temperature increases. As an alternative, aloe vera gel can be prepared as a freeze-dried aloe vera inner leaf gel according to methods known to those skilled in the art.

[0063] Hyaluronic acid is a non-sulfated glycosaminoglycan with an unbranched polysaccharide chain derived from the condensation of disaccharide units formed in turn by residues of glucuronic acid and N-acetylglucosamine linked together by alternating glycosidic bonds β1→4 and β1→3 (CAS number 9004-61-9).

[0064] Hyaluronic acid is also widely used in the form of salts such as the sodium salt by injection in cosmetic surgery and dermatology, otology, ophthalmology and arthrology. In addition, hyaluronic acid is widely used for topical application against inflammatory or ulcerative lesions of the oral cavity and as a filler for skin applications in face and body care products.

[0065] In the context of the present invention, the hyaluronic acid may be in the form of an acid or a salt, such as a sodium salt; the hyaluronic acid is preferably in linear form.

[0066] The mixture contained in the composition (C) of the present invention may contain hyaluronic acid or its salt having different origins and different molecular weight ranges.

[0067] The hyaluronic acid or its salt used in the mixture with substances (a) and (c) and optionally (d) contained in the composition (C) of the invention is linear or branched; the hyaluronic acid is preferably in linear form.

[0068] The mixture comprised in said composition (C) of the present invention comprising (a), (b), (c) and optionally (d) preferably comprises linear or branched hyaluronic acid or a salt thereof having a molecular weight of 400 kDa to 900 kDa, preferably 600 kDa to 800 kDa; the hyaluronic acid is preferably in linear form.

[0069] More preferably, the mixture comprised in said composition (C) of the present invention comprises sodium hyaluronate (CAS No. 9067-32-7) having a molecular weight of 600 kDa to 800 kDa.

[0070] In a preferred embodiment, the composition (C) of the present invention comprising (a), (b) and (c) further comprises at least one other glycosaminoglycan (GAG) or a salt thereof in addition to hyaluronic acid; more preferably, the GAG ​​is a salt of chondroitin; even more preferably, the GAG ​​is substance (d) chondroitin sulfate.

[0071] The chain of chondroitin or its derivatives such as sulfate esters is an unbranched polysaccharide of variable length containing two alternating monosaccharides: D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc), wherein the residue of GlcA can be epimerized to L-iduronic acid (the resulting disaccharide is called dermatan sulfate).

[0072] It is known from the Merck Index (14th edition) that chondroitin sulfate is a general term for a polymer having an average molecular weight of about 50,000 Da.

[0073] There are various forms of chondroitin sulfate, such as 4-sulfate chondroitin A [CAS No. 24967-93-9], its sodium salt [CAS No. 39455-18-0] or its disodium salt [CAS No. 9082-07-9]. There is also a form of 6-sulfate chondroitin (chondroitin sulfate C), CAS No. 25322-46-7.

[0074] In the context of the present invention, it is envisaged that one of the above-mentioned forms of chondroitin sulfate (d) is used in combination with substances (a), (b) and (c), and that the chondroitin (d) is chicken chondroitin.

[0075] Preferably, the average molecular weight of the chondroitin sulfate (optionally in the form of the sodium salt) in the composition for use according to the invention depends on the specific form of chondroitin used.

[0076] It has been found that administration of the liquid composition (C) of the present invention further comprising chondroitin sulfate has the effect of further alleviating symptoms associated with gastroesophageal reflux and / or laryngopharyngeal reflux with virtually no adverse effects.

[0077] The chondroitin sulfate in the composition (C) of the present invention is preferably derived from chicken, fish (e.g., shark chondroitin sulfate, CAS No. 9082-07-9), cattle or pig, or is of plant origin; more preferably, the chondroitin sulfate or its salt used in the composition of the present invention is derived from chicken. As a non-limiting example, the chondroitin sulfate in the composition of the present invention can be chicken chondroitin sulfate sodium salt, and relative to the total weight of the composition, it contains at least 91.5% by weight and no more than 8.5% by weight of chondroitin sulfate sodium salt; in addition, it can have a protein content of no more than 6% by weight and a pH of 5.5 to 7.5 and / or a specific rotation of 10° to 20° (e.g., measured by the method of European Pharmacopoeia 7.0).

[0078] In a preferred embodiment, the liquid composition (C) of the present invention comprises:

[0079] - (a) aloe vera gel in an amount of 0.01% to 5%, preferably 0.1% to 0.5%;

[0080] - (b) hyaluronic acid in an amount of 0.01% to 5%, preferably 0.1% to 0.5%;

[0081] - (c) honey in an amount of 5% to 50%, preferably 10% to 40%; and

[0082] - (d) a salt of chondroitin sulfate, preferably the sodium salt, if present, in an amount of 0.1% to 10%, preferably 1% to 4%; wherein all amounts are by weight relative to the total weight of (C).

[0083] In a preferred embodiment, the liquid composition (C) of the present invention, based on 100 ml of (C), comprises:

[0084] - (a) aloe vera gel in an amount of 100 mg to 500 mg, preferably 150 mg to 300 mg;

[0085] - (b) hyaluronic acid in an amount of 100 mg to 500 mg, preferably 100 mg to 300 mg;

[0086] - (c) honey in an amount of 10 g to 50 g, preferably 20 g to 30 g; and optionally

[0087] - (d) a salt of chondroitin sulfate in an amount of 1 to 5 g, preferably 2 to 3 g.

[0088] In a more preferred embodiment, the liquid composition (C), based on 100 ml of (C), comprises:

[0089] (a) freeze-dried aloe vera gel, 0.25 g;

[0090] (b) hyaluronic acid, 0.2 g;

[0091] (c) Honey, 25 g.

[0092] In another more preferred embodiment, the liquid composition (C), based on 100 ml of (C), comprises:

[0093] (a) freeze-dried aloe vera gel, 0.25 g;

[0094] (b) hyaluronic acid, 0.2 g;

[0095] (c) honey, 25 g;

[0096] (d) Chondroitin, preferably a salt of chondroitin sulfate, 2.5 g.

[0097] In addition to components (a) to (c) and optionally (d), the liquid composition (C) according to the invention may also comprise other active ingredients, such as, as non-limiting examples, anti-inflammatory agents, oral disinfectants, antacids, products for the treatment of gastroesophageal reflux and / or laryngopharyngeal reflux (e.g. prokinetic agents, alginates) and mixtures thereof.

[0098] The composition (C) as defined above comprising (a), (b), (c) and optionally (d) may further comprise at least one excipient or additive, ie a substance suitable for pharmaceutical or food use which has no therapeutic activity.

[0099] In the context of the present invention, acceptable ingredients for pharmaceutical or food use include all auxiliary substances known to those skilled in the art and suitable for preparing liquid forms for oral administration, such as diluents, solvents (including water, glycerol, ethanol), solubilizers, thickeners, sweeteners, flavoring agents, coloring agents, lubricants, surfactants, antimicrobial agents, antioxidants, preservatives, pH stabilizing buffers and mixtures thereof as non-limiting examples. Non-limiting examples of these materials are maltodextrin, phosphate buffers, alkalis such as sodium hydroxide, xanthan gum, guar gum, fructose and natural or artificial flavoring agents.

[0100] In the context of the present invention, composition(s) is intended to include pharmaceutical compositions, compositions for medical devices and compositions for dietary supplements.

[0101] In a preferred aspect, the composition (C) of the present invention is a pharmaceutical composition, a composition for a medical device, or a composition for a dietary supplement.

[0102] In the context of the present invention, the term "medical device" is used with the meaning provided for in Italian Legislative Decree No. 46 of February 24, 1997, i.e. it indicates a substance or another product, whether used alone or in combination, which is intended by the manufacturer for use in humans for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease and which is not capable of achieving its main intended action in or on the human body by pharmacological, immunological or metabolic means, but which can assist its function in such a way.

[0103] As a non-limiting example, the composition (C) of the present invention, for example in the form of a medical device or a medicament or a dietary supplement, can be in the form of a syrup, a liquid or semi-solid preparation, a gel, a suspension, a solution, a two-phase liquid system and equivalent forms of medicine. However, it should be understood that the composition of the present invention is not in the form of an oil-water microemulsion.

[0104] The composition (C) of the present invention is preferably in the form of a water-based syrup.

[0105] The present invention relates to a composition comprising the following mixture and optionally pharmaceutical and / or food grade additives and / or excipients, the mixture comprising or consisting of:

[0106] (a) Aloe vera gel;

[0107] (b) hyaluronic acid; and

[0108] (c) honey, wherein the honey is not honey having non-peroxide antimicrobial activity and the honey is not clover honey filtered and processed at a temperature of 100°F to 140°F; and optionally

[0109] (d) chondroitin sulfate or a salt thereof, preferably a sodium salt;

[0110] The composition is used to treat and / or prevent gastroesophageal reflux and / or laryngopharyngeal reflux disease, as an adjuvant in the symptomatic treatment of gastroesophageal reflux and / or laryngopharyngeal reflux disease; or for the preventive and / or curative treatment of: (i) lesions of the oral cavity (e.g., tongue and palate) and pharynx-laryngolaryngology-esophagus; (ii) mucositis; and / or (iii) aphthous ulcers and / or aphthous-like lesions.

[0111] For the sake of clarity, for the purposes of the present invention, (a), (b), (c) and optionally (d) may also be administered separately and in any order, but preferably, (a), (b), (c) and optionally (d) are administered to the subject simultaneously, even more preferably in a single composition, in order to obtain a more rapid effect and facilitate administration.

[0112] When (a), (b), (c) and optionally (d) are applied in a single composition, said single composition corresponds to composition (C) according to the invention in liquid, preferably aqueous form.

[0113] The composition of the present invention preferably further comprises a salt of chondroitin, preferably a salt of chondroitin sulfate, such as sodium salt of chondroitin sulfate. The source of chondroitin is preferably chicken.

[0114] The following examples are provided to illustrate some embodiments of the present invention and are not intended to limit the scope thereof.

[0115] In the following examples, component (c) honey is as defined herein, i.e., honey provided that the honey is not honey having non-peroxide antimicrobial activity and the honey is not clover honey filtered and processed at a temperature of 100°F to 140°F as described above.

[0116] Example 1

[0117] The composition (C) of the present invention is prepared in the form of a syrup (total volume of 100 ml) comprising the following ingredients:

[0118]

[0119] Example 2

[0120] The composition (C) of the present invention is prepared in the form of a syrup (total volume of 100 ml) comprising the following ingredients:

[0121]

[0122] Example 3

[0123] The composition (C) of the present invention is prepared in the form of a syrup (total weight 100 g) comprising the following ingredients:

[0124]

[0125] The compositions of Examples 1, 2 and 3 were orally administered to subjects affected by gastroesophageal reflux disease (GERD) diagnosed by endoscopic analysis.

[0126] All subjects reported improvements in GERD-related symptoms without inducing significant side effects.

[0127] In the formulation in question (liquid composition (C), preferably aqueous), the above invention is suitable for use in subjects of all ages, from newborns to the elderly.

[0128] The liquid composition (C) of the present invention (which comprises a mixture, the mixture comprising (a), (b), (c) and optionally (d), or consisting of (a), (b), (c) and optionally (d)): preferably a combination (mixture) of chondroitin sulfate, hyaluronic acid, aloe vera gel and honey, and imparts the following properties:

[0129] Hydration, moisturizing, lubrication, viscosity enhancement, film formation and protection, barrier effect due to the formation of a sticky layer covering the esophageal mucosa by adhesion to it ("adhesion" effect), thus exerting a barrier effect for preventing the mucosa itself from contact with external agents and helping to alleviate irritation states, thus facilitating proper nutrition and appropriate functionality. Due to these effects, the above invention is able to exert nutritional, anti-inflammatory, analgesic (pain relief), repair (healing), restorative and re-epithelialization (which facilitates tissue regeneration) effects;

[0130] · Preferentially moisturizing and soothing effects on the epithelium and oral-pharyngeal-throat and esophageal mucosa, for relieving the most common symptoms of GERD and / or laryngopharyngeal reflux and stopping coughing and other related symptoms. Due to these effects, the above invention can exert refreshing, analgesic, sedative and antitussive effects;

[0131] It protects damaged tissues of the gastroesophageal and pharyngeal tracts and promotes the regeneration of damaged mucosa, and can be used to prevent damage caused by irritation, particularly due to contact with refluxed substances in the gastroesophageal tract. Due to these effects, the above invention can exert a gastroprotective effect.

[0132] The liquid composition (C) comprises a mixture comprising (a), (b), (c) and optionally (d), or consisting of (a), (b), (c) and optionally (d), in the form of a solution or syrup or a soluble sachet, and enables the individual components / substances to better contact with the oral-pharyngeal-throat-esophageal wall, facilitating its protection, lubrication and repair:

[0133] Chondroitin sulfate adheres to the gastroesophageal mucosa and protects the gastroesophageal mucosa by effectively isolating it from the invasion of gastric juice;

[0134] Hyaluronic acid combined with the adhesive properties of chondroitin sulfate protects damaged gastric tissue and promotes its regeneration;

[0135] Honey has a soothing, hydrating and protective effect due to the formation of a film covering the esophageal mucosa, acting as a barrier, protecting the irritated mucosa and hydrating it, thus reducing the sensation of pain. In addition, honey relieves throat irritation caused by reflux acidity by acting at the level of the oropharyngeal mucosa;

[0136] · Aloe vera gel, together with the properties of honey, exerts a refreshing, soothing and protective effect on the esophageal mucosa, providing a barrier effect. In fact, aloe vera has gastroprotective properties due to its mucopolysaccharide content, since by distributing itself on the gastric mucosa, it forms a membrane that protects the entire gastric tract from acids or irritants that could alter its proper functioning.

[0137] The preferred intended use of the above-mentioned liquid composition (C) comprising the following mixture is: as an adjuvant in the symptomatic treatment of gastroesophageal reflux and / or laryngopharyngeal reflux disease; or for the preventive and / or curative treatment of: (i) lesions of the oral cavity (e.g., tongue and palate) and pharynx-laryngolaryngology-esophagus; (ii) mucositis; and / or (iii) aphthous ulcers and / or aphthous-like lesions, wherein the mixture comprises (a), (b), (c) and optionally (d), or consists of (a), (b), (c) and optionally (d).

[0138] The properties of the liquid composition (C) of the present invention are revealed by the experimental results given below. In particular, compared with the compositions existing on the market and the mixture of aloe vera gel and honey, the liquid composition (C) of the present invention exhibits a better film-forming / mucoadhesive / protective effect, as demonstrated in the in vitro test (Test I) described below. At the same time, the liquid composition (C) of the present invention has a neutral effect on the integrity of the barrier. In addition, the liquid composition (C) of the present invention effectively exerts an epithelial re-formation / repair effect in long-term treatment by promoting the re-proliferation of the damaged area and promoting the late stage of tissue re-epithelialization (proliferation phase after the migration phase), as demonstrated in the in vitro test (Test II) described below.

[0139] Embodiments of the present invention (FRn) are described as follows:

[0140] FR1. An aqueous liquid or aqueous alcoholic liquid composition (C) comprising the following mixture and optionally a pharmaceutical or food grade additive or excipient, the mixture comprising or consisting of:

[0141] (a) Aloe vera gel;

[0142] (b) hyaluronic acid or a salt thereof; and

[0143] (c) Honey, wherein the honey is not honey having non-peroxide antimicrobial activity and the honey is not clover honey filtered and processed at a temperature of 100°F to 140°F.

[0144] FR2. A composition (C) according to embodiment FR1, wherein the aqueous alcoholic liquid solution comprises at least one alcohol in an amount of 0.01% to 3% by volume, preferably 0.05% to 2.5% by volume, more preferably 0.1% to 1.0% by volume, wherein the amount is relative to the total volume of the composition (C), and wherein the at least one alcohol is preferably ethanol.

[0145] FR3. The composition (C) according to any one of the preceding embodiments FR, wherein the molecular weight of the hyaluronic acid is from 400 kDa to 900 kDa, preferably from 600 kDa to 800 kDa.

[0146] FR4. The composition (C) according to any one of the preceding embodiments FR, wherein the mixture further comprises:

[0147] (d) A salt of chondroitin, preferably a salt of chondroitin sulfate, more preferably a sodium salt of chondroitin sulfate.

[0148] FR5. Composition (C) according to any one of the preceding embodiments FR, wherein the aloe vera gel is freeze-dried inner leaf gel.

[0149] FR6. Composition (C) according to embodiment FR5, wherein the aloe vera gel is from Barbados Aloe vera.

[0150] FR7. A composition (C) according to any one of the preceding embodiments FR, wherein the components (a), (b), (c) and, if present, (d) are present in the following amounts:

[0151] The amount of (a) is 0.01% to 5%, preferably 0.1% to 0.5%;

[0152] (b) in an amount of 0.01% to 5%, preferably 0.1% to 0.5%;

[0153] (c) in an amount of 5% to 50%, preferably 10% to 40%; and

[0154] (d) if present, in an amount of 0.1% to 10%, preferably 1% to 4%;

[0155] All amounts are by weight relative to the total weight of (C).

[0156] FR8. A composition (C) according to any one of the preceding embodiments FR, comprising, based on 100 ml of (C):

[0157] - (a) in an amount of 100 mg to 500 mg, preferably 150 mg to 300 mg;

[0158] - (b) in an amount of 100 mg to 500 mg, preferably 100 mg to 300 mg;

[0159] - (c) in an amount of 10 g to 50 g, preferably 20 g to 30 g; optionally

[0160] - (d) in an amount of 1 to 5 g, preferably 2 to 3 g.

[0161] FR9. A composition (C) according to any one of the preceding embodiments FR, wherein the composition:

[0162] - for the treatment and / or prevention of gastroesophageal reflux and / or laryngopharyngeal reflux disease, or

[0163] - as an adjunct in the symptomatic treatment of gastroesophageal reflux disease; or

[0164] - For the prophylactic and / or curative treatment of: (i) oral (e.g. tongue and palate) and pharyngeal-laryngeal-esophageal lesions; (ii) mucositis; and / or (iii) aphthous and / or aphthous-like lesions; wherein the use comprises administering (a), (b), (c) and / or (d) to the subject in any order or simultaneously.

[0165] Experimental procedures

[0166] In vitro testing

[0167] The model used is Lyons (F) produced reconstructed human esophageal epithelium (HOE2E / S / 5).

[0168] aI) Film formation / mucosal adhesion / protective effect

[0169] aI-i) Compositions and controls studied

[0170] · Comparative composition (A),

[0171] The composition (B) of the present invention,

[0172] Comparative aloe vera-honey mixture (C),

[0173] Negative control: saline solution (NC),

[0174] Positive control: petrolatum (V).

[0175] Comparative composition ( One) is a prior art composition comprising sodium hyaluronate, sodium chondroitin sulfate and a bioadhesive polymer such as poloxamer or a A copolymer of ethylene oxide and propylene oxide, such as Lutrol F127, and / or polyvinylpyrrolidone, and other components (as specified in Table 1). In particular, the comparative composition (A) corresponds to the composition described in Example 1 of patent EP 2296670 B1.

[0176] Table 1

[0177] Deionized water 74.015 8882mg Sodium Hyaluronate 1％ 120mg Chondroitin Sulfate Sodium 2.5％ 300mg Xylitol C 18％ 2160mg LUTROL F127 2％ 240mg Polyvinylpyrrolidone Kw 24-32 2％ 240mg Sodium Benzoate 0.067％ 8mg Potassium Sorbate 0.2％ 24mg Flavoring + Coloring 0.22％ 26mg

[0178] The liquid composition (B) of the present invention (GERDOFF ) is the composition specified in Table 2. The composition has a pH value of 6.5 to 7.5 and a density value of 1.19 to 1.21 g / ml (measured in a collection container at 25°C using a hydrometer).

[0179] Table 2

[0180]

[0181] Aloe-honey mixture (C) is a 100:1 ratio freeze-dried aloe vera gel (Barbados Aloe):honey mixture, based on a volume of 100 ml, having the following composition:

[0182] Purified water 78.79%

[0183] Honey 21.00%

[0184] Aloe vera gel 0.21%

[0185] Neither the honey present in composition (B) nor in mixture (C) is honey having non-peroxide antimicrobial activity nor is it clover honey filtered and processed at a temperature between 100°F and 140°F.

[0186] aI-ii) Study design and results

[0187] The above compositions A, B and C (point aIi) were tested for their film-forming properties on reconstructed human esophageal epithelium (HO2E / S / 5) as a biological model under the following different pH conditions: standard = pH 7.0, acidic conditions = pH 3.3.

[0188] In vitro reconstructed human epithelial models approximate human tissue in vivo in terms of morphology (multilayered or epithelial) and biochemical and physiological properties and currently represent the most promising animal (ex vivo) alternative for evaluating administered topical products (Gordon et al., 2015, Zuog V. 2016).

[0189] In particular, the following items were evaluated:

[0190] Caffeine permeation kinetics (film-forming effect) induced by products A, B and C and they were compared with the negative control (NC) and the positive control (V).

[0191] program

[0192] Use 0.5cm 2 Reconstructed human esophageal epithelium (HOE2E / S / 5) was removed from the nutrient agar solution under a sterile laminar airflow chamber. The insert was transferred to a 6-well plate pre-filled with maintenance medium (1 ml / well) at room temperature and incubated overnight at 37°C, 5% CO2 and saturated humidity.

[0193] The next day, the maintenance medium was replaced and HO2E / S / 5 was pre-wetted with 15 μL of saline solution. After 15 minutes, 30 μL of NC, V, A, B, or C was applied for 15 minutes at room temperature. After 15 minutes of application, 100 μL of 0.5% caffeine solution (CAFFEINE 1 mg / cm 2 ) is applied topically, directly and evenly to the epithelium as a standard solution at pH = 7 or an acidic solution at pH = 3.3 at room temperature over 2 hours.

[0194] Caffeine penetration kinetics (film-forming effectiveness):

[0195] At 15 minutes, 1 hour and 2 hours after administration, the receiver fluid (1 ml of saline solution) was collected in test tubes (stored at 2 to 8°C for analysis) and analyzed for caffeine content using HPLC technique.

[0196] Controls and combinations were evaluated on three biological replicates.

[0197] The caffeine penetration was completely inhibited as expected by the reference product petrolatum (V) (not shown in Table 1). The effectiveness of compositions A, B and C was quantified as % of caffeine, considering the 100% dose quantified in the negative control (NC); the results are summarized in Tables 3 and Figure 1 and 2 middle( Figure 1 and 2 Samples D to F in are not samples of the present invention).

[0198] Table 3

[0199]

[0200] result

[0201] The greatest reduction in caffeine passage was observed with the composition of the invention (B) under both test conditions (pH 7 and pH 3.3). Overall, a 60% reduction was observed compared to the negative control (NC). The most significant difference was observed in the first hour of treatment.

[0202] II) Epithelial re-formation / repair

[0203] II-i) Compositions studied and controls

[0204] The re-epithelialization properties of the following (A), (B) and (C) having the composition as indicated in point ii) were tested on reconstructed human esophageal epithelium (HO2E / S / 5, as described in point 1):

[0205] -Comparative composition (A)

[0206] - Composition (B) of the present invention

[0207] -Comparative aloe vera:honey mixture (C)

[0208] Reproducible physical injury was generated in the reconstructed human esophageal epithelium as described in the present study.

[0209] This model allows the study of processes associated with the mechanisms of re-epithelialization and the evaluation of the effectiveness of products in:

[0210] - undamaged tissue treated with saline solution (negative control - NC),

[0211] - Injured tissue treated with saline solution and petrolatum (V) (positive control - INJ).

[0212] In particular, membrane integrity and inflammatory response were evaluated at the end of treatment (24 h) by histomorphometric analysis with H&E (Hematoxylin & Eosin) staining.

[0213] program

[0214] Use 0.5cm 2 Reconstructed human esophageal epithelium (HOE2E / S / 5) was removed from the nutrient agar solution under a sterile laminar airflow chamber. The insert was transferred to a 6-well plate pre-filled with maintenance medium (1 ml / well) at room temperature and incubated overnight at 37°C, 5% CO2 and saturated humidity.

[0215] The next day, for the negative control, the undamaged HOE2E / S / 5 was pre-wetted with 15 μL of saline solution; after 15 minutes, 30 μL of saline solution was applied for 24 hours; for the positive control and the studied compounds, the HOE2E / S / 5 was damaged and pre-wetted with 15 μL of saline solution for 15 minutes; then 30 μL of saline solution, V, A, B or C was topically, directly and evenly applied to the damaged tissue and treated in an incubator at 37°C and RH90% in CO2 for 24 hours.

[0216] After 24 hours of treatment (T=24 hours), HO2E / S / 5 were collected for histological analysis (H&E).

[0217] The control and the above combinations were evaluated in three biological replicates.

[0218] Histological analysis (H&E staining)

[0219] Histological evaluation can be used to gain a more thorough understanding of the type of interaction between the composition under investigation (A, B, or C) and living tissue.

[0220] At the end of treatment (T=24 hours), the tissues were rinsed with saline solution and fixed in an appropriate fixative. The tissues were sectioned (5 μm), stained with hematoxylin and eosin and analyzed under a microscope.

[0221] For the positive control (injured tissue treated with saline solution), H&E results of the injured area showed the presence of necrotic cells on the epithelial surface, flattened transitional cells and restored surface squamous layer integrity. In the intact area, no significant changes were observed compared to the negative control (injured tissue treated with saline solution).

[0222] For the composition (B) of the present invention, the H&E results of the damaged area ( Figure 3 ) shows a very high proliferation stimulus for repopulating the damaged area. In the undamaged area ( Figure 4 ), the tissue showed structural changes with greater thickness associated with greater production of ECM matrix. This mechanism may be related to the healing potential in the late stage of tissue re-epithelialization (proliferation phase after the migration phase) and indicates the potential effectiveness of product (B) after long-term treatment.

[0223] Figure 3 , the damaged area treated with (B) shows:

[0224] -Necrotic cells: few on the epithelial surface.

[0225] - Flattened transitional cells: absent except in the deepest layers.

[0226] -Surface integrity (scaly): Partially restored.

[0227] - Extracellular matrix: Due to the high proliferation of tissues and the production of ECM around the injured area, it is not possible to draw any precise conclusions regarding ECM alterations.

[0228] Figure 4 , the undamaged area treated with (B) shows:

[0229] - Basal cells: cells surrounded by an altered ECM.

[0230] -Intermediate layer: reduced integrity of cell-cell interactions and large amounts of ECM. Very few pyknotic nuclei.

[0231] -Surface layer (squamous): unchanged.

[0232] - Extracellular matrix: The entire tissue showed an altered structure in all layers, indicating a high proliferation rate in the basal layer to repair the injury. This mechanism may be related to the healing potential of the late stage of tissue re-epithelialization (proliferative phase after the migration phase).

[0233] -Thickness 97.40 μm.

[0234] H&E results of the lesioned area for the comparative composition (A) and the aloe vera:honey mixture (C) ( Figure 5 and Figure 7 ) confirmed the loss of integrity of the surface layer. Figure 6 and Figure 8 ), no significant changes were observed compared to the negative control in the basal layer, but a significant reduction in cell junctions was evident, with a loss of organizational structure in the intermediate layer.

[0235] Figure 5 , the damaged area treated with (A) shows:

[0236] -Necrotic cells: There are some remnants on the epithelial surface.

[0237] - Flattened transitional cells: Not observed.

[0238] -Surface integrity (scaly): Loss.

[0239] -Extracellular matrix: There is a loss of tissue and extracellular matrix adjacent to the lesion.

[0240] Figure 6 , the undamaged area treated with (A) shows:

[0241] -Basal cells: no significant changes.

[0242] -Intermediate layer: partial loss of tissue structure; significant reduction in cell-cell connections.

[0243] - Surface layer (scaly): Not applicable due to reduced thickness.

[0244] - Extracellular matrix: There is a significant decrease in tissue thickness and a reduction in the matrix surrounding intercellular junctions.

[0245] -Thickness 65.23 μm.

[0246] Experimental process (b)

[0247] The Applicant conducted in vitro studies to evaluate the film-forming effect (film-forming / mucoadhesion / protective effect) of the composition of the invention on a human esophageal epithelial model and compared it with a commercial product according to the procedure described in point (aI-ii) of experimental procedure (a).

[0248] bi) Compositions studied and controls

[0249] - Negative control: saline solution (NC);

[0250] - Positive control: white petrolatum (V);

[0251] - Composition A: Commercially available product one (liquid), the comparative composition specified in Table 1;

[0252] - Composition B: Commercially available product Protection (liquid), a composition of the invention specified in Table 2;

[0253] - Aloe vera:honey mixtures, products specified in point (aIi);

[0254] - Composition D: Commercially available product NEOBIANACID TM (solid), a comparative composition as described below;

[0255] - Composition E: Commercially available product GEL (liquid), a comparative composition as described below.

[0256] Composition D contains the following ingredients as functional substances:

[0257] A complex of polysaccharides (from aloe vera, Malva Sylvestris and Althea officinalis) and minerals (limestone and soda ash);

[0258] - Flavonoid fractions (obtained from chamomile (Matricaria recutita) and liquorice (Glycyrrhiza glabra)).

[0259] Composition E comprises: (hyaluronic acid, hydrolyzed keratin, tara gum, xanthan gum, purified water), magnesium alginate, sucralose, potassium sorbate, sodium benzoate, ε-polylysine, flavoring, purified water.

[0260] b-ii) Results

[0261] The reference product petrolatum (V) almost completely inhibited caffeine penetration as expected. The effectiveness of compositions A, B, C, D and E was quantified as % of caffeine (with the dose quantified as 100% of the negative control (NC); the results are summarized in Tables 4 and 5 and Fig. 9 and 10 middle.

[0262] Under both test conditions (pH 7 and pH 3.3), the liquid composition of the present invention, composition B ( Protection) observed the greatest reduction in caffeine passage. In particular, under standard pH conditions, the one 50.8%), C (aloe vera: honey mixture, 71.0%), D (Neobianacid TM , 83.2%) and E( Gel, 89.4%) compared to composition B ( Protection) showed the greatest overall effectiveness in reducing caffeine passage (effective passage rate was 34.8% after 2 hours), see Tables 4 and Fig. 9 In addition, under acidic pH conditions, one 47.0%), C (aloe vera: honey mixture, 70.3%), D (Neobianacid TM , 75.3%) and E( Gel, 83.5%) compared to composition B ( Protection) showed the greatest overall effectiveness in reducing caffeine passage (effective passage rate of 40.5% after 2 hours), see Tables 5 and Fig.10 .

[0263] Table 4

[0264]

[0265] Table 5

[0266]

Claims

1. Use of an aqueous liquid composition (C) in the preparation of a medicament for reducing and / or eliminating symptoms and conditions associated with laryngopharyngeal reflux, thereby alleviating the effects of the disease itself, wherein the composition (C) comprises: (I) A mixture consisting of: (a) Aloe vera gel; (b) hyaluronic acid or its salts; (c) honey, wherein The honey is not honey having non-peroxide antimicrobial activity and the honey is not clover honey that has been filtered and processed at a temperature between 100°F and 140°F; and (d) chondroitin sulfate, and optionally (II) pharmaceutical or food grade additives or excipients, The composition (C) has a pH value of 6.5 to 7.5 and a density value of 1.19 to 1.21 g / ml. Wherein, components (a), (b), (c), and (d) are present in the following amounts: (a) in an amount of 0.01% to 5%; (b) in an amount of 0.01% to 5%; (c) in an amount of 5% to 50%; and (d) in an amount of 0.1% to 10%; Herein, all the amounts % are weight ratios relative to the total weight of the composition (C).

2. The use according to claim 1, wherein: The molecular weight of the hyaluronic acid is 400 kDa to 900 kDa.

3. The use according to claim 1, wherein: The molecular weight of the hyaluronic acid is 600 kDa to 800 kDa.

4. The use according to claim 1, wherein: The chondroitin sulfate is chondroitin sulfate sodium salt.

5. The use according to claim 1, wherein: The aloe vera gel is freeze-dried aloe vera inner leaf gel.

6. The use according to claim 5, wherein: The aloe vera gel is a gel obtained from Barbados aloe (Aloe barbadensis Miller).

7. The use according to claim 1, wherein: Components (a), (b), (c) and (d) are present in the following amounts: (a) in an amount of 0.1% to 0.5%; (b) in an amount of 0.1% to 0.5%; (c) in an amount of 10% to 40%; and (d) in an amount of 1% to 4%; Herein, all the amounts % are weight ratios relative to the total weight of the composition (C).

8. The use according to claim 1, wherein: Based on 100 ml of (C), the composition (C) comprises: - (a) in an amount of 100 mg to 500 mg by weight; - (b) in an amount of 100 mg to 500 mg by weight; - a weight content of 10 g to 50 g of (c); and - (d) in an amount of 1 g to 5 g by weight.

9. The use according to claim 1, wherein: Based on 100 ml of (C), the composition (C) comprises: - (a) in an amount of 150 mg to 300 mg by weight; - (b) in an amount of 100 mg to 300 mg by weight; - a weight content of 20 g to 30 g of (c); and - (d) in an amount of 2 to 3 g by weight.

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