AQUEOUS SALINE COMPOSITION, ITS MANUFACTURING PROCESS, AND ITS USES

Description

[0001] The subject of the present invention relates to an aqueous saline composition, its process for obtaining it, its use as a medicament, for example in the form of a spray for the prevention or adjunctive treatment of ear, nose and throat (ENT) conditions.

[0002] The nasal cavities act as a filter that helps protect against ear, nose and throat conditions, such as sinusitis, rhinitis, etc. However, various compositions based on salt water, such as sea water, are known for washing the nasal cavities, particularly in the context of such pathologies.

[0003] For example, such seawater-based compositions are generally intended to be isotonic. These compositions can be obtained by mixing seawater with purified water, or by extracting certain ions (sodium, potassium, chloride, etc. - for example by electrodialysis). These mixtures can be subjected to sterilization procedures, such as filtration (preferably), submission to UV radiation, before their packaging. The compositions finally obtained can also be radio-sterilized (beta or gamma radiation). The products are packaged in the form of aerosol sprays or mechanical sprays. Document FR 2 299 041 relates to such a composition. Document WO 2008 / 037938 describes a hypertonic saline aqueous solution based solely on seawater, and having a Na + < / Mg 2 + < ratio of less than 6.

[0004] In a completely separate therapeutic field, document EP 3 369 429 describes a saline composition comprising an oxytocin and a carboxyvinyl polymer, and an osmolality lower than that of physiological serum, i.e. lower than 286 mosmol / kg.

[0005] In a completely separate therapeutic area, WO 98 / 08500 describes an aqueous saline composition containing L-arginine for correcting cerebral ischemia and hypoxia in combinations of traumatic brain injury (TBI) and hemorrhage.

[0006] The present invention aims to improve the effectiveness of known compositions based on sea water. SUMMARY OF THE INVENTION

[0007] The subject of the present invention relates to an aqueous saline composition comprising a film-protective and / or hyperosmotic organic compound for use in the treatment and prevention of ear, nose and throat conditions, wherein the osmolarity of said composition is greater than 1000 mosmol / l at 20°C and less than 2000 mosmol / l at 20°C, wherein the film-protective and / or hyperosmotic organic compound is xylitol.

[0008] According to an exemplary embodiment, the osmolarity of said composition is greater than 1500 mosmol / l at 20°C.

[0009] The subject of the present invention also relates to a method for manufacturing an aqueous composition comprising a film-protective and / or hyperosmotic organic compound comprising a polyol derived from a saccharide compound, the saccharide compound in question, or a mixture thereof, and with an osmolarity greater than 1000 mosmol / l at 20°C, comprising the following steps: a) micro-filtration of sea water; b) addition of purified water, c) mixing d) while mixing, addition to the solution of step c) of the film-protective and / or hyper-osmotic organic compound; e) recovery of the mixture of step d); said process being characterized in that the quantity of sea water is greater than or equal to 10% by total mass of aqueous composition obtained in step e) and in that the quantity of film-protective and / or hyper-osmotic organic compound is greater than or equal to 5% by total mass of aqueous composition obtained in step e), and in which the film-protective and / or hyper-osmotic organic compound is xylitol.

[0010] According to one aspect, the quantity of seawater is greater than or equal to 15%, 20%, 30%, 40%, 50%, 60%, 70% or 80% by total mass of aqueous composition obtained in step e), and / or the quantity of film-protective and / or hyperosmotic organic compound is greater than or equal to 6%, 7%, 8%, 9%, 10%, 15%, 20%, preferably 11%, by total mass of aqueous composition obtained in step e).

[0011] Thus, the subject of the present invention relates to a composition capable of being obtained by the manufacturing process described above.

[0012] According to one aspect, the composition comprises: a chloride concentration of between 2 and 18 g / kg a sodium concentration of between 1 and 10 g / kg a sulfate concentration of between 0.3 and 2.4 g / kg a magnesium concentration of between 0.1 and 1.2 g / kg a calcium concentration of between 0.04 and 0.4 g / kg a potassium concentration of between 0.04 and 0.4 g / kg and / or it has a pH of between 4 and 10, preferably between 5 and 9, for example 7.

[0013] In one aspect, the composition is presented in final dosage forms selected from the group consisting of nasal drops, liquid nasal sprays and nasal washes.

[0014] Furthermore, the subject matter of the present invention relates to a composition as described herein as a medicament having a therapeutic effect. It relates to such a composition for its use in the treatment of nasal mucosal disorders of viral, bacterial or allergic origin.

[0015] In one aspect, the composition comprises seawater.

[0016] More specifically, the subject of the present invention relates to a composition as described herein, intended for its use in the treatment and prevention of otolaryngological conditions, in particular for the prevention of otitis media.

[0017] Finally, the subject of the present invention relates to a nasal administration device, such as a sprayer, characterized in that it comprises a composition according to the present invention. DEFINITIONS

[0018] The term "film-protective organic compound" is understood within the scope of the present invention to mean a compound having the property of protecting the biological surface to which said compound is applied. In this case, this compound protects the epithelium of the nasal cavities and improves the functioning of the cilia. This compound comprises at least one "CH" entity, where "C" represents a carbon atom and "H" represents a hydrogen atom. This compound may in particular be a polyol. It is a derivative of a saccharide compound. In particular, the compound may be a monosaccharide. The monosaccharide may be a pentose. According to certain examples, the film-protective organic compound is xylitol. This film-protective organic compound may also, or alternatively, be combined with or replaced by the corresponding saccharide. In particular, with regard to xylitol, it could be combined with or replaced by xylose.The organic film-protective compound can be obtained by synthesis, or by extraction from a natural product.

[0019] For the purposes of the invention, the term "tonicity" of a solution refers to the salt concentration in the solution relative to human blood. Thus, "isotonic" refers to a solution whose solute concentration is equal to that contained in the blood. "Hypotonic" refers to a solution whose solute concentration is lower than that contained in the blood. "Hypertonic" refers to a solution whose solute concentration is higher than that contained in the blood.

[0020] The term "hyper-osmotic compound" is understood within the scope of the present invention to mean a compound having high osmotic power or which results from very rapid osmosis, or which causes it. Osmosis is a phenomenon of diffusion of matter, evidenced when solvent molecules cross a semi-permeable membrane separating two solutions with different solute concentrations. The overall transfer of solvent then takes place from the less concentrated solution to the more concentrated solution until equilibrium is reached. This compound is organic, that is to say it comprises at least one "CH" entity, where "C" represents a carbon atom and "H" represents a hydrogen atom. This compound is in particular a polyol. It is a compound derived from a saccharide compound. The saccharide compound is a monosaccharide. The monosaccharide is a pentose. The compound is xylitol.This film-protective organic compound may also, or alternatively, be combined with or replaced by the corresponding saccharide. In particular, with regard to xylitol, it could be combined with or replaced by xylose. The hyperosmotic organic compound may be obtained by synthesis, or by extraction from a natural product. In order to determine whether a compound is hyperosmotic according to the present invention, a test may be carried out using an osmometer. For example, osmolarity is measured using a cryoscopic osmometer, by measuring the freezing point, by reference to that of distilled water. Other osmometry technologies are known, which may be calibrated to obtain results similar to cryoscopic osmometers.

[0021] By "aqueous saline composition" is understood within the scope of the present invention a composition comprising water and salt. If the aqueous saline composition is preferably a composition based on seawater, any type of salt having the same properties as the salts found in seawater, once dissolved in water, can be used. Preferably, by "aqueous saline composition" is understood a composition comprising water and at least one salt found in seawater. Preferably, the salt is NaCl. Seawater may also comprise other elements, such as for example sulfate, magnesium, calcium, potassium, copper, iron and zinc.

[0022] For the purposes of this invention, "osmolality" means the number of osmoles of solute per kilogram of solvent. For the purposes of this invention, "osmolarity" means the number of osmoles of solute per liter of solution. One osmole is equal to the number of moles of particles that can be osmotically active in an ideal solution. DETAILED DESCRIPTION

[0023] Method for manufacturing an aqueous composition according to the invention

[0024] The subject of the present invention therefore relates to a method for manufacturing an aqueous composition as described above.

[0025] According to one embodiment, the manufacturing method comprises the following steps: a) micro-filtration of sea water; b) addition of purified water; c) mixing; d) while mixing, addition to the solution of step b) of the film-protective and / or hyper-osmotic organic compound; e) recovery of the mixture of step d).

[0026] Preferably, the method for manufacturing an aqueous composition according to the present invention may be characterized in that the amount of seawater is greater than or equal to 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70% or 80% by total mass of aqueous composition obtained in step e), and / or that the amount of film-protective and / or hyperosmotic organic compound is greater than or equal to 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, preferably 11%, by total mass of aqueous composition obtained in step e).

[0027] The process for manufacturing an aqueous composition according to the present invention is characterized in that the film-protective and / or hyperosmotic organic compound is a polyol, in particular derived from a saccharide.

[0028] The process for manufacturing an aqueous composition according to the present invention is characterized in that the film-protective and / or hyperosmotic organic compound is a monosaccharide and / or a polyol derived from this monosaccharide, or a mixture thereof.

[0029] The method for manufacturing an aqueous composition according to the present invention is characterized in that the film-protective and / or hyperosmotic organic compound is xylitol, or even a mixture of xylitol with a compound chosen from maltitol, mannitol, sorbitol, lactitol, galactitol, erythritol, arabitol and ribitol. This / these film-protective organic compound(s) may also, or alternatively, be associated with or replaced by the corresponding saccharide(s). In particular, with regard to xylitol, it could be associated with or replaced by xylose.

[0030] In a particular embodiment, the method for manufacturing an aqueous composition according to the present invention can be characterized in that step a) is carried out by filtration of seawater through a 0.2 µm filter, or even through a 0.1 µm sterilizing filter. Composition

[0031] The subject of the present invention relates to an aqueous saline composition as described above, that is to say characterizable for example by its osmolarity. A particular embodiment relates to an aqueous saline composition capable of being obtained by the method described above. Indeed, one of the embodiments according to the present invention relates to the use of seawater, which may comprise a variety of potentially active chemical species.

[0032] Thus, in a particular embodiment, the aqueous composition according to the present invention can be characterized in that said composition comprises: a chloride concentration between 2 and 18 g / kg a sodium concentration between 1 and 10 g / kg a sulfate concentration between 0.3 and 2.4 g / kg a magnesium concentration between 0.1 and 1.2 g / kg a calcium concentration between 0.04 and 0.4 g / kg a potassium concentration between 0.04 and 0.4 g / kg and / or that it has a pH between 4 and 10, preferably between 5 and 9, for example 7.

[0033] The aqueous composition may also include copper. The aqueous composition may also include zinc.

[0034] Preferably, the aqueous composition according to the present invention can be characterized in that said composition comprises sea water.

[0035] Preferably, the aqueous composition according to the present invention can be characterized in that it can form final dosage forms selected from the group consisting of nasal drops, nasal sprays, and nasal washes.

[0036] In a particular embodiment, the aqueous composition according to the present invention may be characterized in that the film-protective and / or hyperosmotic organic compound is xylitol. This film-protective organic compound may also, or alternatively, be associated with or replaced by the corresponding saccharide. In particular, with regard to xylitol, it could be associated with or replaced by xylose.

[0037] Preferably, the aqueous composition according to the present invention can be characterized in that the film-protective and / or hyperosmotic organic compound is included at a concentration greater than or equal to 5% by mass, preferably between 10 and 20% by mass relative to the total mass of the composition, in particular a composition of 11% by mass.

[0038] According to an exemplary embodiment, no chemical preservative has been added to the chemical composition.

[0039] The addition of one or more excipients is entirely possible, such as aqueous extracts of cosmetic or aromatic plants. Therapeutic application

[0040] The composition according to the present invention can therefore be used as a medicament. The composition according to the present invention can be intended for use in the prevention or adjunctive treatment of ear, nose and throat (ENT) conditions. The composition can also be intended for the prevention of middle ear infections.

[0041] More specifically, the composition according to the present invention may be intended for use in the treatment of conditions of the nasal mucous membranes of viral, bacterial or allergic origin, such as sinusitis, rhinitis, nasal polyps, cystic fibrosis, etc.

[0042] The composition according to the present invention may also be intended for use in the prevention of otitis media. Preferably, the aqueous composition according to the present invention may be characterized in that the bacterial infection is due to at least one of the pathogens chosen from the group consisting mainly of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus.

[0043] Without wishing to be limited by theory, the inventors have surprisingly observed that the composition which is the subject of the invention presents a synergy between the different beneficial effects going beyond the individual effects provided by each of the elements, namely: . a deep mechanical cleaning by seawater, which will carry with it viral and allergenic particles, protect the epithelium of the nasal cavities, and improve the functioning of the vibrating cilia, . a protective effect provided by certain components of seawater, as described in more detail below, . and a barrier effect against the progression of bacteria towards the Eustachian tube provided by the film-protective compound.

[0044] Trace elements in seawater (such as zinc, copper, and magnesium) contribute to better defenses against bacterial and viral attacks and reduce the risk of lower respiratory infections. Six studies were conducted to examine the effects of zinc supplementation in preventing pneumonia in Bangladesh, India, Peru, and South Africa. 5,193 children aged 2 to 59 months were followed. Zinc supplementation was significantly associated with a reduction in the incidence and prevalence of pneumonia in children aged 2 to 59 months.

[0045] The film-protective compound xylitol / xylose provides a barrier effect against the progression of bacteria to the Eustachian tube, thus providing protection against otitis media. Maltitol, mannitol, sorbitol, lactitol, galactitol, erythritol, arabitol, or ribitol may have similar effects to xylitol / xylose. Administration device

[0046] The subject of the present invention finally relates to a nasal administration device, such as a sprayer, characterized in that it comprises a composition according to the present invention.

[0047] Any type of nasal delivery device can be used. For example, a mechanical pump or an aerosol sprayer, with or without a bag valve, is considered. Preferably, an aerosol sprayer with a bag valve is used.

[0048] Advantageously, the pocket is under pressure, for example greater than or equal to 1.5 bars, 2 bars, 3 bars, 4 bars, 5 bars or even 10 bars.

[0049] The aerosol spray delivery devices with a bag valve are designed to limit and avoid any risk of retrocontamination. This property has been verified by appropriate tests. EXAMPLES

[0050] The examples given below are a simple illustration of the present invention which is not limited to these particular embodiments.

[0051] Several compositions were made, and their osmolarity measured, as shown in Table 1 below. [Tables 1] Compositions A B C D Xylitol 11% 11% - Sea water 21% 68% 30% 80% Purified water 68% 21% 70% 20% Average osmolarity (mosmol / l) 1100 1700 300 800 The quantities of matter are given in % m / m at 20°C. The average osmolarity corresponds to the average of the osmolalities measured for different samples of each composition.

[0052] Compositions A and B correspond to embodiments of the present invention. Composition C is an isotonic solution of seawater and composition D is a hypertonic solution of seawater.

[0053] Solution A, although hypotonic, has an osmolarity much higher than that of blood.

[0054] Solution B, hypertonic, has an osmolarity much higher than that of blood (almost 6 times higher).

[0055] Tests were conducted, during which the compositions were administered by nasal spray to test subjects at different application dosages.

[0056] Composition C has cleansing, purifying, and healing effects.

[0057] Composition D has a nasal decongestion effect.

[0058] Composition A is effective in protecting patients against otitis media. The presence of seawater extends the protective effect to the entire ENT sphere. Seawater has a cleansing, purifying, and healing effect on the nasal mucosa.

[0059] Composition B combines the beneficial effects of the presence of a polyol (ensuring protection against middle ear infections) with a high concentration of seawater. The synergistic effects are multiplied and unexpected. Hyperosmolarity explains the extraordinary decongestant effects observed during tests carried out with pilot batches. Indeed, a single spray in each nostril with solution B allows the nose to be decongested for a relatively long time, depending on the physiological state of the patient (from one to several hours). There are many applications for solution B. Among them, solution B can be used to replace, in a beneficial and natural way, purely chemically formulated decongestant products such as corticosteroids or vasoconstrictors, known for their short- or longer-term side effects (tachycardia, high blood pressure, hormonal imbalances, addiction).In a completely different way to purely chemical products, solution B contributes to an improvement in respiratory function in the short and especially long term, with a preventive action on oro-rhino-laryngological conditions, and without side effects. A spray in each nostril before bedtime allows for lasting decongestion of the nose and better sleep thanks to more fluid breathing. An application in the reduction of snoring and sleep apnea is perfectly conceivable, with as a corollary a better lifestyle and an overall reduction in blood pressure, thanks to better quality sleep.

Claims

1. The aqueous saline composition comprising an organic film-protective and / or hyperosmotic, for its use in the treatment and prevention of ear, nose and throat (ENT) conditions wherein the osmolarity of said composition is higher than 1,000 mosmol / l at 20°C, particularly higher than 1,500 mosmol / l at 20°C and, less than 2,000 mosmol / l at 20°C, wherein the organic film-protective and / or hyperosmotic compound is xylitol.

2. The manufacturing process of an aqueous composition comprising an organic film-protective and / or hyperosmotic compound and having an osmolarity greater than 1,000 mosmol / l at 20°C, comprising the following steps: a) microfiltration of seawater; b) addition of purified water; c) mixing; d) while mixing, addition to the solution from step c) of the organic film-protective and / or hyperosmotic compound ; e) recovery of the mixture from step d) ; said process being characterised in that the quantity of seawater is higher than or equal to 10% of the total mass of the aqueous composition obtained in step e) and in that the quantity of organic film-protective and / or hyperosmotic compound is higher than or equal to 5% of the total mass of the aqueous composition obtained in step e), and wherein the organic film-protective and / or hyperosmotic compound is xylitol.

3. The manufacturing process of an aqueous composition according to claim 2, characterised in that the quantity of seawater is higher than or equal to 15%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the total mass of the aqueous composition obtained in step e) and / or the quantity of organic film-protective and / or hyperosmotic compound is higher than or equal to 6%, 7%, 8%, 9%, 10%, 15%, 20%, preferentially 11%, of the total mass of the aqueous composition obtained in step e).

4. Composition obtainable by any one of claims 2 or 3.

5. Composition according to claims 1 or 4 characterised in that said composition comprises: - a chloride concentration between 2 and 18 g / kg - a sodium concentration between 1 and 10 g / kg - a sulphate concentration between 0.3 and 2.4 g / kg - a magnesium concentration between 0.1 and 1.2 g / kg - a calcium concentration between 0.04 and 0.4 g / kg - a potassium concentration between 0.04 and 0.4 g / kg - and / or a pH between 4 and 10 preferably between 5 and 9, for example 7.

6. Composition according to claims 1, 4 or 5, characterised in that it is in final dosage forms selected from the group consisting of nasal drops, liquid nasal sprays and nasal washes.

7. Composition according to any one of claims 1, or 4 to 6, for its use in the treatment of nasal mucosal conditions of viral, bacterial or allergic origin.

8. Composition according to any one of claims 1, or 4 to 6, for its use in the prevention of otitis media.

9. Composition according to any one of claims 1, or 4 to 8, characterised in that the composition comprises seawater.

10. Nasal administration device, such as a spray device, characterised in that it comprises a composition according to any one of claims 1, or 4 to 9.