Electrolytic composition in powder form for topical applications

Abstract

The invention relates to an electrolytic mineral composition in powder form for solution to be diluted for topical applications for use as a medicinal product and medical device, comprising a specific concentration of chloride (Cl), sodium (Na), sulfate (SO4), sulfur (S), magnesium (Mg), calcium (Ca), potassium (K), and bicarbonate (HCO3). This composition, combining pharmaceutical-grade salts, is dosable, reproducible, stable, well-tolerated, and can be used alone or in combination with other ingredients to inhibit inflammatory factors and / or promote wound healing and / or promote ciliary beat, particularly in the treatment and prevention of diseases associated with inflammatory disorders, and / or for wound healing purposes, and / or for mucociliary dysfunction.

Description

Title of the invention: Electrolytic composition in powder form for topical applications

[0001] The invention relates to an electrolytic mineral composition in powder form for solution to be diluted for topical applications for use as a medicinal product and medical device, comprising a specific concentration of chloride (Cl), sodium (Na), sulfate (SO4), sulfur (S), magnesium (Mg), calcium (Ca), potassium (K), and bicarbonate (HCO3). This composition, combining pharmaceutical-grade salts, is dosable, reproducible, stable, well-tolerated, and can be used alone or in combination with other ingredients to inhibit inflammatory factors and / or promote wound healing and / or promote ciliary beat, particularly in the treatment and prevention of diseases associated with inflammatory disorders, and / or for wound healing purposes, and / or for mucociliary dysfunction. Previous Art

[0002] In a number of chronic inflammatory pathologies involving the mucous membranes and / or the skin, a link is observed between the increase in oxidative stress (Mishra 2018), the alteration of the barrier function leading to microlesions and dysfunctions of local immune processes.

[0003] In ENT, in polyposis, the severity of oxidative stress is significantly correlated with the severity of nasal obstruction and congestion (Topai 2014).

[0004] Since permeability is a key factor in triggering inflammatory mechanisms, the importance of limiting oxidative stress and preserving or restoring the protective barrier function of mucous membranes is better understood.

[0005] The nasal mucosa plays a particularly important protective role. Mucociliary clearance is a defense mechanism involving the secretory cells of the epithelium, which produce respiratory mucus that traps inhaled airborne contaminants. Through the coordinated beating of the cilia of the epithelial ciliated cells, the mucus and the particles it contains are transported to the nasopharynx and then eliminated from the airways by swallowing, blowing the nose, or coughing.

[0006] It is known that the main components of air pollution can induce oxidative stress and inflammatory responses in nasal epithelial cells (Hong, 2016). Prolonged contact with air pollutants and allergens, or with respiratory pathogens, leads to pulmonary inflammation and damage to the respiratory epithelium.

[0007] It has also been shown that the ciliary beat frequency can be impacted by air pollutants (Hong 2016, Calderon 2001), by certain antibiotics (Hong 2016) or factors produced by bacteria found in the lungs, such as Pseudomonas aeruginosa, Streptococcus pneumoniae, or Haemophilus influenzae (Janson 1999; Read 1992; Steinfort 1989). Ciliary beat frequency is also altered in respiratory pathologies such as allergic rhinitis and asthma (Holmström 1992; Maurizi 1984; Mezey 1978; Ohashi 1985).

[0008] The repair of lesions as well as the regeneration of a mature and functional epithelium are crucial to restoring epithelial defense properties, particularly in terms of mucociliary clearance.

[0009] Saline solutions in nasal irrigation are commonly used as an adjunct treatment both in upper airway pathologies and in post-surgical treatments (Tomooka 2000). Numerous studies have demonstrated the benefits of these saline solutions in cases of acute rhinitis (Mezey 1978, Ohashi 1985, Tomooka 2000, Salpak 2008 and Tano 2004), allergic rhinitis (Gallant 2018, Hermelingmeier 2012, Roberts 2013, Anigier 2010, Chia-Ling 2019, Head 2018), acute sinusitis (Scadding 2017, Wang 2014, Wang 2009), chronic rhinosinusitis (Rosenfeld 2015, Fokkens 2012, Seppey 1996, Holmstrom 1997, Slapak 2008, Culig 2010, Hahn 2013, Salib 2013) or after endonasal surgery (Rosenfeld 2015). : • reduction of nasal symptoms including nasal obstruction, rhinorrhea, postnasal drip, itching, sneezing, loss of smell, dry nose (Seppey 1996-Holmstrom 1997, Slapak 2008, Culig 2010, Hahn 2013, Salib 2013, Tugrul 2015, Atar 2022) • improvement in quality of life (Culig 2010, Hahn 2013, Tugrul 2015) • the prevention or reduction of allergic reactions (Chen 2014) • improved healing after endonasal surgery (Salib 2013 Tugrul 2015) • the reduction of drug treatments (Seppey 1996, Slapak 2008) particularly in acute rhinitis.

[0010] In vitro, various studies show the role of certain electrolytes, in particular calcium on ciliary beat or magnesium in the mechanisms of inflammation.

[0011] In vitro, an experiment on the respiratory mucosa (Bonnomet 2016) demonstrated the benefits of seawater on ciliary beat frequency and the rate of wound repair of the nasal epithelium, suggesting a potential therapeutic role for electrolytes in respiratory pathologies and in post-surgical treatment. The seawater used was isotonic and obtained by two different manufacturing processes, one by electrodialysis, the other by dilution. A difference favoring the first method was shown in 14 subjects. This same study demonstrated the harmful impact of sodium chloride solutions.

[0012] A multicenter randomized post-surgical study demonstrated the clinical superiority of a solution containing sodium chloride, potassium, bicarbonates, calcium, and magnesium (vs. a sodium chloride solution alone). The addition of these minerals led to a postoperative reduction in crusting, a more rapid disappearance of secretions, and a decrease in epistaxis, particularly in subjects aged 60 years and older, smokers, and the most severely ill patients (de Gabory 2019).

[0013] However, the mechanisms of action which take place at the level of the mucosa are little known and the conclusions of the consensus are unanimous on the need to determine the composition of the saline solution in qualitative and quantitative terms (which minerals and in what quantity) according to the objective aimed at and in particular in order to restore more effectively the barrier function, by optimizing the action of the solutions at the level of the ciliary beat, in terms of healing, anti-inflammatory, and antioxidant.

[0014] The contact times of these solutions with the mucous membrane, in particular in daily, multiple daily or prolonged use, justify the search for electrolytic matrices adapted to the respiratory system.

[0015] The Applicant has surprisingly identified electrolytic compositions comprising mineral salts that inhibit 9 markers of inflammation, the interleukins IL8, IL6, IL18, IL5, IL13, IL4, the cytokines TSLP (Thymia Stromal LymphoPoietin), GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor), the chemokine CCL26 (CC Motif Chemokine Ligand 26), also called eotaxin-3.

[0016] These compositions can be used to reduce the inflammatory markers IL8, IL6, TSLP, GM-CSF, CCL26, IL18, IL5, or markers most often associated with allergic reactions, asthma, or atopic dermatitis, such as TSLP, CCL26, and IL-5. They could be advantageous in the treatment or prevention of all local inflammatory manifestations, rhinitis, pharyngitis, bronchitis, and dermatitis, but particularly nasal polyposis, allergic rhinitis, asthma, and atopic dermatitis. They can be used alone or in combination with other ingredients for the prevention, pretreatment, treatment, or monitoring of anti-inflammatory and anti-allergy medications such as corticosteroids, antihistamines, vasoconstrictors, vasodilators, and even antifibrotics or therapeutic antibodies.

[0017] These latter (corticosteroids, antihistamines, vasoconstrictors, vasodilators, therapeutic antibodies) are satisfactory but they have problematic side effects and adverse effects, especially with chronic, prolonged use, or in sensitive subjects such as children, pregnant women, breastfeeding women, the elderly or those taking multiple medications.

[0018] Advantageously, the applicant has also identified compositions which combine both anti-inflammatory properties as described above with healing properties highlighted by measuring the rate of tissue repair in pm2 / hour. Description of the invention

[0019] Thus, according to a first aspect, the invention relates to an electrolytic composition of minerals, in powder form for solution to be diluted, comprising: • a pH of 7.2 to 8.2; • a conductivity of 17.5 to 19; • an osmolarity of 280 to 330 mOsm / kg, preferably 290 to 320 mOsm / kg, and comprises the following content of the main constituents: • 2200 to 3500 mg / L of sodium (Na) • 5200 to 6700 mg / L of chloride (Cl) • 95 to 120 mg / L of bicarbonate (HCO3) • 1400 to 1900 mg / L of magnesium (Mg); • 450 to 750 mg / L of calcium (Ca); • 50 to 60 mg / L of potassium (K); • 1900 to 2600 mg / L of sulfate (SO4).

[0020] According to one embodiment, the composition further comprises: • 800 to 3000 mg / L of sulfur (S).

[0021] According to one embodiment, the composition according to the invention further comprises at least one of: zinc (Zn), copper (Cu), selenium (Se), manganese (Mn), iron (Fe).

[0022] Preferably, the pH of the composition is between 7.2 and 8.2.

[0023] According to one embodiment, the pH of the solution is 7.9.

[0024] According to one embodiment, the pH of the solution is 7.4.

[0025] According to one embodiment, the pH of the solution is 7.6.

[0026] Preferably, the composition has an osmolarity of 290 to 315 mOsm / kg.

[0027] According to one embodiment, the composition has an osmolarity of 314 mOsm / kg.

[0028] According to one embodiment, the composition has an osmolarity of 293 mOsm / kg.

[0029] According to one embodiment, the composition has an osmolarity of 306 mOsm / kg.

[0030] Preferably, the composition has a conductivity of 18 to 19 mS / cm.

[0031] According to one embodiment, the composition has a conductivity of 18.6 mS / cm

[0032] According to one embodiment, the composition has a conductivity of 18.4 mS / cm

[0033] According to one embodiment, the composition has a conductivity of 18.7 mS / cm

[0034] Preferably, the composition comprises 5400 to 6600 mg / L of chloride (Cl).

[0035] According to one embodiment, the composition comprises 6200 to 6600 mg / L of chloride (Cl), preferably 6478 mg / L.

[0036] According to one embodiment, the composition comprises 5300 to 5800 mg / L of chloride (Cl), preferably 5485 mg / L or 5672 mg / L.

[0037] Preferably, the composition comprises 2300 to 3400 mg / L of sodium (Na).

[0038] According to one embodiment, the composition comprises 2200 to 2500 mg / L of sodium (Na), preferably 2369 mg / L or 2463 mg / L.

[0039] According to one embodiment, the composition comprises 3100 to 3300 mg / L of sodium (Na), preferably 3211 mg / L.

[0040] Preferably, the composition comprises 95 to 120 mg / L of bicarbonate (HCO3), preferably between 95 and 100 mg / L, even more preferably 97 mg / L.

[0041] Preferably, the composition comprises 95 to 120 mg / L of bicarbonate (HCO3), preferably between 110 and 120 mg / L, even more preferably 113 mg / L or 117 mg / L.

[0042] Preferably, the composition comprises 1400 to 1900 mg / L of magnesium (Mg).

[0043] According to one embodiment, the composition comprises 1400 to 1500 mg / L of magnesium (Mg), more preferably 1483 mg / L.

[0044] According to one embodiment, the composition comprises 1700 to 1850 mg / L of magnesium (Mg), more preferably 1770 or 1799 mg / L.

[0045] Preferably, the composition comprises 450 to 650 mg / L of calcium (Ca).

[0046] According to one embodiment, the composition comprises 450 to 500 mg / L of calcium (Ca), preferably 473 mg / L.

[0047] According to one embodiment, the composition comprises 575 to 615 mg / L of calcium (Ca), preferably 595 or 604 mg / L.

[0048] Preferably, the composition comprises 51 to 58 mg / L of potassium (K).

[0049] According to one embodiment, the composition comprises 57, 51 or 55 mg / L of potassium (K).

[0050] Preferably, the composition comprises 1950 to 2500 mg / L of sulfate (SO4).

[0051] According to one embodiment, the composition comprises 1900 to 2100 mg / L of sulfate (SO4), preferably 2000 to 2050 mg / L of sulfate (SO4), even more preferably 2004 mg / L of sulfate (SO4).

[0052] According to one embodiment, the composition comprises 2350 to 2500 mg / L of sulfate (SO4), preferably 2400 to 2450 mg / L of sulfate (SO4), even more preferably 2417 or 2439 mg / L of sulfate (SO4).

[0053] According to one embodiment, the composition further comprises: • 800 to 900 mg / L of sulfur (S), preferably 839 mg / L.

[0054] According to one embodiment, the composition further comprises: • 2500 to 3000 mg / L of sulfur (S), preferably 2600 to 2700 mg / L, of even more preferred method 2621 mg / L.

[0055] According to one embodiment, the composition further comprises: • 2500 to 3000 mg / L of sulfur (S), preferably 2800 to 2900 mg / L, of even more preferred method 2833 mg / L.

[0056] According to one embodiment, the composition according to the invention is devoid of any preservative agent.

[0057] According to one embodiment, the composition according to the invention comprises: • 3211 mg / L of sodium (Na) • 6478 mg / L of chloride (Cl) • 117 mg / L of bicarbonate (HCO3) • 1483 mg / L of magnesium (Mg) • 473 mg / L of calcium (Ca) • 55 mg / L of potassium (K) • 2004 mg / L of sulfate (SO4) • 839 mg / L of sulfur (S).

[0058] According to one embodiment, the composition according to the invention comprises: • 2369 mg / L of sodium (Na) • 5485 mg / L of chloride (Cl) • 97 mg / L of bicarbonate (HCO3) • 1799 mg / L of magnesium (Mg) • 595 mg / L of calcium (Ca) • 51 mg / L of potassium (K) • 2439 mg / L of sulfate (SO4) • 2833 mg / L of sulfur (S).

[0059] According to another embodiment, the composition according to the invention comprises: • 2463 mg / L of sodium (Na); • 5672 mg / L of chloride (Cl); • 113 mg / L of bicarbonate (HCO3); • 1770 mg / L of magnesium (Mg); • 604 mg / L of calcium (Ca); • 57 mg / L of potassium (K); • 2417 mg / L of sulfate (SO4); • 2621 mg / L of sulfur (S).

[0060] According to another aspect, the invention relates to a composition as defined above, for use as a medicinal product.

[0061] According to one embodiment, said composition for use is administered topically, on the skin or mucous membranes.

[0062] Preferably, said topical application is carried out by local application, by installation, continuous spray, metered spray, spraying, misting, nebulizing, gargling, washing, inhalation, gel, cream, emulsion, ointment.

[0063] According to one embodiment, the composition for use according to the invention is used in the treatment or prevention of respiratory conditions aimed at an anti-inflammatory, or scarring action or on mucociliary clearance.

[0064] According to one embodiment, the composition for use according to the invention is used in the treatment or prevention of nasal polyposis, allergic rhinitis, asthma.

[0065] According to one embodiment, the composition for use according to the invention is used in the treatment or prevention of dermatological conditions aimed at an anti-inflammatory or scarring action.

[0066] According to one embodiment, the composition for use according to the invention is used in the treatment or prevention of skin reactions of allergic origin, and / or atopic dermatitis.

[0067] According to one embodiment, the composition for use according to the invention is used in the treatment or prevention of oropharyngeal conditions with an anti-inflammatory or scarring action.

[0068] According to one embodiment, the composition for use according to the invention is administered concomitantly with other treatments for nasal polyposis, allergic rhinitis, asthma, atopic dermatitis.

[0069] According to one embodiment, the composition for use according to the invention is administered alone, or in combination with other physiologically acceptable ingredients, or in combination concomitantly, in prevention, pretreatment, treatment or follow-up of inflammation and allergy drugs such as corticosteroids, antihistamines, vasoconstrictors, vasodilators, antifibrotics and / or therapeutic antibodies.

[0070] According to one embodiment, the composition for use according to the invention is associated in the same composition with local drugs such as corticosteroids, antihistamines, vasoconstrictors, vasodilators.

[0071] According to another aspect, the invention relates to the use of the composition according to the invention for the manufacture of a medical device intended for the administration of said composition to patients.

[0072] According to one embodiment, said medical device is used in the treatment or prevention of respiratory conditions in the event of an inflammatory, allergic state or in wound healing.

[0073] Preferably, said medical device is used in the treatment or prevention of nasal polyposis, allergic rhinitis, asthma.

[0074] Preferably, said medical device is used in the treatment or prevention of dermatological pathologies requiring an anti-inflammatory and / or healing effect, for example atopic dermatitis.

[0075] According to one embodiment, said medical device is used in the treatment or prevention of all oropharyngeal conditions requiring an anti-inflammatory and / or healing effect.

[0076] The compositions according to the invention are preferably free from, or contain in very small quantities of, any preservative or stabilizing agent. This latter advantage is of great importance. Indeed, the preservatives and / or stabilizing agents present in most synthetic electrolyte compositions cause side effects in the short or long term. However, according to the invention, the electrolyte composition is administered over periods of time ranging from one week to several months, or even for years.

[0077] The composition according to the invention has an anti-inflammatory and healing effect, as characterized in the example section.

[0078] The composition according to the invention has a favorable effect on ciliary beat, as characterized in the example section

[0079] This composition also has a much faster effect than usual treatments such as topical corticosteroids.

[0080] The results presented as examples demonstrate a surprising activity identified with electrolyte compositions comprising mineral salts that inhibit nine markers of inflammation: the interleukins IL-8, IL-6, IL-18, IL-5, IL-13, and IL-4; the cytokines TSLP (Thymia Stromal Lymphopoietin), GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor), and the chemokine CCL26 (CC Motif Chemokine Ligand 26), also known as eotaxin-3, compared to a control of dexamethasone (a potent corticosteroid commonly used for its anti-inflammatory and immunosuppressive properties). The distinctive features of these results are the massive, even near-total, reduction in interleukin secretion obtained with these electrolyte solutions compared to a reference drug, the overall non-specific nature of the observed anti-inflammatory effects, and their rapidity (less than 24 hours). Figures

[0081] [Fig 1] Graph showing the quantities of inflammatory markers secreted by seawater-based solution in pg / mL after stimulation, for IL8, IL6, TSLP, IL4, IL5, IL13, GM-CSF, IL18, CCL26. Graph A shows IL8 secretion per solution. Graph B shows IL6 secretion per Graph C represents TSLP secretion per solution. Graph D represents IL-5 secretion per solution. Graph E represents CCL-26 secretion per solution (pg / mL). Graph F represents GMCSF secretion per solution (pg / mL). Graph G represents IL-18 secretion per solution (pg / mL).

[0082] [Fig.2] Graph showing the rate of repair of the nasal epithelium by solution vs. control and NaCl (pm2 / hour)

[0083] [Fig.3] Graph showing the ciliary beat frequency velocity by Solution vs. control and NaCl (Hz) Definitions

[0084] By "electrolytic composition" is meant a composition comprising ions, cations and / or anions, and which therefore includes in particular Sodium, Magnesium, Calcium, Potassium, Chloride, Sulfate, Bicarbonate.

[0085] The "dry matter content" of an electrolytic composition refers to the amount of non-volatile substances that remain after the evaporation of water in a solution containing ions. It is therefore the residual mass of solids, mainly composed of salts and minerals, that persists when all the water has been removed. In the case of an electrolytic solution, such as seawater, the dry matter would consist of dissolved ions (such as sodium, chloride, sulfate, etc.) which, after the evaporation of the water, are found in the form of solid salts.

[0086] The "resistivity" of an electrolytic composition is a physical property that describes the ability of an electrolytic solution to resist the flow of electric current. It depends on the concentration of ions present in the solution as well as the nature of these ions. The more ions a solution contains, the more capable it is of conducting electricity, and therefore, its resistivity is lower. Conversely, a solution with fewer ions will have a higher resistivity.

[0087] “Density” is understood to be the physical property describing the mass of a given volume of water. In the context of the invention, it is expressed in grams per cubic centimeter (g / cm3).

[0088] The osmolarity of an electrolytic composition is a measure of the total concentration of osmotically active particles (mainly ions) in a solution. It indicates how many moles of ions or molecules are dissolved in one liter of solution and reflects the solution's ability to generate osmotic pressure, that is, to attract water across a semi-permeable membrane. It is expressed in osmoles per liter (osm / L), where 1 osmole corresponds to 1 mole of dissolved particles that contribute to osmosis.

[0089] By "isoosmotic" is meant an electrolytic composition having the same osmolarity as body fluids.

[0090] By “hyperosmotic” is meant an electrolytic composition having a higher osmolarity than that of body fluids.

[0091] “Preservative agent” means a substance to prevent the growth of microorganisms and to prolong shelf life.

[0092] By "stabilizing agent" is meant a substance to maintain the stability of a composition or improve its consistency, or prevent undesirable changes in its physical or chemical properties.

[0093] Nasal spraying involves administering a medication or solution into the nasal passages using a spray. This method allows for rapid local application.

[0094] Nasal misting is the dispersion of a fine mist of solution into the nasal passages using a device. It promotes rapid and uniform absorption, often to treat nasal congestion or irritation.

[0095] By "treatment" or "treat" is meant the alleviation of symptoms associated with a specific disorder or condition and / or the elimination of said symptoms.

[0096] “Prevention” means the use of a composition or a drug to prevent the onset or progression of diseases.

[0097] Nasal polyposis is a condition in which noncancerous polyps form in the nasal cavities or sinuses, causing congestion, runny nose, and difficulty breathing. These polyps are swollen growths of the nasal mucosa, often associated with allergies or chronic infections.

[0098] Allergic rhinitis is an inflammation of the nasal mucous membranes caused by an allergic reaction to allergens such as pollen, dust mites, or animal dander. It manifests itself through symptoms such as congestion, runny nose, sneezing, and itching.

[0099] Atopic dermatitis is a chronic skin disease characterized by dry, red, itchy rashes. It is often linked to allergies and genetic factors, and can affect any part of the body.

[0100] Asthma is a chronic respiratory disease characterized by inflammation and constriction of the airways, causing symptoms such as coughing, wheezing, shortness of breath and chest tightness.

[0101] Ciliary beating is the rhythmic movement of cilia lining the nasal mucosa that play a crucial role in the nose's defense system. Their main function is to move mucus, which contains particles such as dust, allergens, microbes, and other impurities, to the back of the throat, where it can be swallowed or expelled. This constant movement helps keep the airways clear and prevent infections.

[0102] Nasal irrigation is a medical practice consisting of rinsing the nasal passages with a saline solution to clean the nasal cavities. This method helps to remove mucus, allergens, irritants, and other debris that accumulate in the nose.

[0103] The term “powder to be reconstituted” means a form of which is presented as a dry powder and which must be mixed with a liquid, usually water, before being consumed.

[0104] IL8, IL6, IL18, IL5, IL13, IL4 are the acronyms for interleukin 8, 6, 18, 5, 13 and 4.

[0105] TSLP stands for Thymic Stromal Lymphopoietin. It is a cytokine that plays a key role in the activation of immune cells, particularly in allergic-type inflammatory responses. TSLP is notably implicated in diseases such as asthma and atopic dermatitis.

[0106] The acronym GM-CSF stands for Granulocyte-Macrophage Colony-Stimulating Factor. It is a cytokine, that is, a protein involved in the developmental mechanisms of immune system cells. It plays a key role in the immune response and inflammation.

[0107] CCL26 stands for CC Motif Chemokine Ligand 26, also known as eotaxin-3. It is a chemokine, a small protein involved in guiding immune cells to areas of inflammation or infection. It plays an important role in diseases such as asthma or allergies.

[0108] By "physiologically acceptable medium" is meant a medium compatible with oral, nasal, or parenteral administration. In other words, the medium used contains compounds that prevent the degradation of d-xylose or its derivatives, and presents no risk to the patient or consumer that might deter them from using this composition, or any risk that could cause adverse side effects.

[0109] In the description and the following examples, unless otherwise stated, percentages are percentages by weight, and value ranges expressed as "between ... and ..." include the specified lower and upper bounds. The following examples are provided by way of illustration and are not intended to limit the scope of the invention. Examples

[0110] Example 1: In vitro comparison of the healing and anti-inflammatory capacities of several electrolytic solutions containing mineral salts, on the nasal mucosa. [YES] MATERIALS AND METHODS

[0112] Experimental solutions:

[0113] Seven experimental solutions were defined with:

[0114] an isotonic osmolality oscillating between 270 to 310 mOsm / L, + / - 10%;

[0115] modulations of composition at the qualitative and quantitative level.

[0116] Isotonic solutions were deliberately chosen for their tolerance and efficacy profile in the literature, and to avoid any osmotic movement that could cause bias.

[0117] Hypotonic solutions are not marketed for nasal irrigation, and are prohibited in practice as they may promote aqueous flows inside cells and create swelling and risk of edema.

[0118] The literature is conflicting on the benefits of hypertonic vs. isotonic solutions. While they show better results specifically for nasal congestion, particularly in allergies, overall assessments do not show a significant difference.

[0119] Three control solutions: • SI / A: le milieu de culture des cellules (BEGM) *BEGM™ Bronchial Epithelial Cell Growth Medium BulletKit™ : Culture System containing BEBMTM Bronchial Epithelial Cell Growth Basal Medium (CC-3171) and BEGMTM Bronchial Epithelial Cell Growth Medium SingleQuotsTM Suppléments and Growth Factors (CC-4175) https: / / bioscience.lonza.com • S2 / B: the cell culture medium and the corticosteroid, dexamethasone. Dexamethasone is a potent corticosteroid, commonly used for its anti-inflammatory and immunosuppressive properties. It is used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, ulcerative colitis, and Crohn's disease. In the lungs, dexamethasone is used for severe allergies, severe asthma attacks, the treatment of chronic obstructive pulmonary disease (COPD), and in the treatment of COVID-19 to reduce excessive inflammation due to the body's immune response to the virus. • S3 / C: a 0.9% sodium chloride solution (physiological saline). This is a widely used comparator for daily nasal hygiene in infants, available with or without a tampon for nasal irrigation under brands such as Neilmed, Simply Saline, Fess, Arm & Hammer, and Simply Saline.

[0120] Solutions studied

[0121] Five powders containing pharmaceutical-grade salts, namely sodium chloride and various electrolytes at different concentrations allowing for the reconstitution of electrolyte solutions • S4 / D: Powder of 6 minerals: chlorides, sodium, magnesium, calcium, bicarbonates, and potassium. This is the comparator marketed under the brand name "Respimer®". All the salts used in this composition are chlorides. • S6 / F: Powder of 8 minerals: Chlorides, sodium, sulfates, magnesium, sulfur, calcium, bicarbonates, and potassium. Two major components of seawater have been added: sulfur and sulfates, in the form of magnesium sulfate. Magnesium sulfate exhibits bronchodilator activity. It is used as an adjunct to local treatment (nebulization) of COPD exacerbations (Ni H, et al. 2022) and asthma (Rovsing AH et al. 2023). • S7 / G: Boosted 8-mineral powder. Qualitative S6 composition with varying dosages of: chlorides, sulfur, sulfates, sodium, magnesium, calcium, bicarbonates, and potassium. Electrolyte modulation was achieved with magnesium sulfate and sodium thiosulfate (Tang SM et al. 2024). • S8 / H: Qualitative composition S7. Boosted 8 mineral powder + trace elements: zinc, copper and selenium supplied by sodium selenite, copper sulfate and zinc sulfate. • S9 / I: Hypotonic NaCl powder of 8 minerals. Qualitative composition S6 with varying dosages: sodium chloride, sulfates, magnesium, sodium, sulfur, calcium, bicarbonates, and potassium. Electrolyte modulation was achieved with potassium lactate and potassium bicarbonate.

[0122] Composition of solutions [Tables 1] Content (mg / L) S3 S4 S6 S7 S8 S9 Physiological Serum Control (9 g / L NaCl) Comparator R espimer® 6 Minerals Experimental 8 Minerals Experimental 8 Boosted Minerals Experimental 8 Boosted Minerals + Trace Elements Experimental 1 8 Minerals Hypothalamic NaCl Chlorides 5490 8100 6478 5485 5672 3891 Sodium 3510 1920 3211 2369 2463 1576 Sulfates <LQ 2004 2439 2417 2952 Magnesium 1247 1483 1799 1770 2020 Sulfur <LQ 839 2833 2621 1215 Calcium 401 473 595 604 725 Potassium 65 55 51 57 54 Bicarbonates 140 117 97 113 113 Zinc <LQ NR NR 0,067 NR Cuivre 0,00026 NR NR 0,196 NR Sélénium <LQ NR NR <LQ NR Osmolarité - 314 314 293 306 294 Conductivité (mS / cm) - 18,9 18,6 18,4 18,7 15,1 PH - 8,0 7,9 7,4 7,6 8,00

[0123] Design

[0124] Randomized, blinded ex vivo study vs. control and reference specialties as comparator.

[0125] Parameters studied

[0126] The experimental solutions produced were studied on various validated functional parameters of the human nasal epithelium. • the rate of repair of epithelial lesions (pm / h) • the frequency of ciliary beats (Hz) • the secretion of pro-inflammatory cytokines (pg / mL).

[0127] Protocol

[0128] The experiments were performed with cells from nasal polyps of subjects over 50 years of age with stage III or IV polyposis (chronic rhinosinusitis with polyps) resistant to well-conducted medical treatment and with an indication for surgery (EPOS 2020). Tissues and cells from 39 different patients were used. The nasal polyps were provided by the ENT surgery department of the Bordeaux University Hospital (Dr. Ludovic de Gabory). The samples were processed and transported to the Inserm UMR-S 1250 laboratory in accordance with current regulations.

[0129] 1) Study of ciliary beat frequency

[0130] Upon receipt, the polyps are examined by inverted microscopy to determine the presence of ciliated epithelium. The ciliated borders are then cut with a scalpel and fractionated into expiants of approximately 1 mm². The expiants are seeded into 12-well plate culture wells previously coated with collagen IV (Sigma). Aldrich) in BEGM medium (Lonza). Several expiants are loaded per well. After several days of culture, cell growth develops around the expiants, containing ciliated cells.

[0131] Each well is then rinsed with one of the solutions to be tested and incubated for 30 minutes with the same solution. Each well is then analyzed by videomicroscopy. For each condition, at least 10 areas containing hair cells are filmed for 10 seconds each at an acquisition rate of 50 frames / second at 32x magnification. An ImageJ plug-in developed in the laboratory will determine the ciliary beat frequency, which will be expressed in Hertz. The expiants from 20 different patients are thus analyzed.

[0132] 2) Study of the rate of repair of the nasal epithelium

[0133] Epithelial cells are isolated from tissues by enzymatic treatment with pronase E (Sigma Aldrich). The cells are seeded in 24-well plates (BD Falcon) previously coated with type IV collagen (Sigma Aldrich) in CnT17 culture medium (CELLnTEC). At 90% confluence, the cells are transferred to BEGM medium (Lonza).

[0134] At total confluence, the cells are rinsed with PBS (Gibco) and then pre-incubated with each of the 12 solutions to be tested for 4 hours at 37°C. A linear wound is then made in each well using a 100pL pipette tip. Each well is rinsed with PBS and then re-incubated with the corresponding pre-incubation solution. A technical duplicate is prepared for each solution (2 wells per solution).

[0135] Each wound is then studied by videomicroscopy (at least 3 different positions along the wound) at xlO magnification, at a rate of one image every 10 minutes, for 24 hours. An ImageJ plug-in developed in the laboratory allows the rate of lesion repair to be determined in pm2 / hour.

[0136] At the end of the experiment, the wells are rinsed in PBS and the plates are stored at -80°C for a potential subsequent study of gene expression in the cells.

[0137] Cell cultures from 39 different patients were thus analyzed.

[0138] 3) Study of the secretion of pro-inflammatory cytokines

[0139] Epithelial cells isolated from tissues are seeded in 48-well plates (BD Falcon) previously coated with type IV collagen (Sigma Aldrich) in CnT17 culture medium (CELLnTEC). At 90% confluence, the cells are transferred to BEGM medium (Lonza).

[0140] At total confluence, the cells are rinsed with PBS (Gibco) and then pre-incubated for 12 to 24 hours with BEGM culture medium or with a mixture of pro-inflammatory cytokines (IL-β, TNFα, IFNγ) known to inflame respiratory epithelial cells (22). The cells are then incubated for 12 to 24 hours with each of the 12 solutions to be tested. A technical duplicate is prepared for each condition (2 wells for each incubation combination). One of the solutions (S2) contains a known anti-inflammatory (dexamethasone) used as a positive control.

[0141] Following the various incubations, the culture medium from each well is collected. A multiplex analysis of its cytokine content is performed.

[0142] The remainder of the culture medium is frozen for potential later use. The plates still containing the cells are also stored at -80°C for potential future study of gene or protein expression in the cells.

[0143] The following cytokines are analyzed: IL-4, IL-5, IL-6, IL-8, IL-13, IL-25, IL-33, TSLP, GM-CSF, TNFa, eotaxin-3 (CCL26).

[0144] Cell cultures from 39 different patients were thus analyzed.

[0145] Results

[0146] At the inflammatory level and secretions of interleukins and other substances inflammatory:

[0147] Figure 1 shows the quantities of inflammation markers secreted per solution in pg / mL after stimulation, for IL8, IL6, TSLP, IL5, CCL26, GM-CSF and IL18.

[0148] TSLP, IL5 and CC26, often associated with allergic reactions or asthma or atopic dermatitis, have been grouped together.

[0149] Interleukins IL 25, 33, 13 and 4 were not shown due to the absence or very low amounts secreted.

[0150] [Table 2] Variation in interleukin secretion vs. control (SI) per solution after stimulation in % expressed as median: SI S2 S3 S4 S6 S7 S8 S9 With st imulati on N=39 N=39 N=39 N=39 N=39 N=39 N=39 N=39 IL8 6 804 -4% -96% -75% -79% -81% -82% -92% IL6 154 28% -99% -93% -93% -94% -95% -99% TSLP 89 17% -99% -95% -96% -98% -97% -98% GMCSF 38 9% -99% -93% -92% -94% -93% -96% CCL26 22 -1% -100 % -57% -55% -61% -57% -76% IL 18 20 -15% -86% -82% -72% -81% -90% -54% IL5 11 -7% -100% -88% -88% -92% -93% -95% IL13 3 -13% -100% -100% -100% -100% -100% -100% IL4 0.3 0% -100% -100% -100% -100% -100% -100% IL25 - IL33 - -81% to -100% -61% to -80% -41 to -60% -1% to -20% >0%

[0151] We chose to study a wide range of interleukins (IL) and molecules involved as mediators of the inflammatory and immune response, and in particular TSLP, CCL26, IL-4, IL-5, IL-13 which are specifically involved in the Th2 type immune response, and the allergic and asthmatic response.

[0152] We also studied less specific interleukins of inflammation and immunity such as IL8.

[0153] The Bronchial Epithelial Cell Growth Medium (BEGM) does not show anti-inflammatory activity, which is not surprising.

[0154] Unexpectedly, the control (S2) containing a potent corticosteroid, dexamethasone, showed no reduction in interleukin production; our hypothesis is that the initial effects of nasal corticosteroid therapy are often modest. The full and optimal effect may take 1 to 2 weeks of regular use. To be effective, nasal corticosteroid therapy requires good adherence and non-sporadic use.

[0155] All experimental solutions tested show a dramatic decrease in interleukin secretions vs. control (SI) and (S2) containing dexamethasone.

[0156] A particular feature of these results is that they are observed rapidly, between 12 and 24 hours. The advantage of a composition containing corticosteroids within one of the experimental solutions rich in electrolytes is evident, as it provides an immediate effect before the corticosteroids take effect and improves adherence to these treatments and their efficacy.

[0157] The almost imperceptible results on physiological saline (S3) and (S9) may reflect apoptosis of epithelial cells: without minerals or in contact with a hypotonic NaCl solution, respiratory epithelial cells undergo paralysis or cell death. These two solutions should be avoided for respiratory use.

[0158] Minerals and trace elements play a crucial role in the body's antioxidant system, helping to neutralize free radicals and prevent cellular damage, in particular magnesium and sulfur

[0159] A particular feature of these results is their overall non-specific anti-inflammatory nature. An effect is observed on 7 of the 11 inflammation markers tested: IL8, IL6, TSLP, GM-CSF, eotaxin-3, IL18, IL5.

[0160] All interleukins showed dramatic decreases or even suppressions compared to the control (medium), regardless of the solution, and particularly interestingly, TSLP, CCL26, and IL-5. These interleukins are often associated with allergic reactions and asthma. IL-5, -4, and -13 are not produced by epithelial cells but primarily by immune cells, which may explain why they were expressed at low or no levels.

[0161] IL-8 is the most widely secreted interleukin by nasal cells in pg / mL; dramatic reductions are observed compared to SI and S2 dexamethasone. IL-8 plays an important role in acute immune responses to bacterial and viral infections. Excessive IL-8 production may contribute to chronic inflammation and tissue damage in diseases such as rheumatoid arthritis, Crohn's disease, and chronic obstructive pulmonary disease (COPD).

[0162] The solutions show dramatic reductions in IL6, TSLP, GM-CSF, eotaxin-3, IL18, IL5 ([Fig 1])

[0163] IL-6 is involved in the regulation of inflammation, immunity, and metabolism. It is found in many chronic inflammatory and autoimmune diseases, and some cancers. Therapies targeting IL-6 or its receptor (IL-6R) have been developed; for example, tocilizumab, a monoclonal antibody that inhibits IL-6R, is used to treat rheumatoid arthritis and other inflammatory diseases.

[0164] TSLP is highly expressed in the upper respiratory tract (allergic rhinitis, where it contributes to nasal inflammation) and in the lower respiratory tract in asthmatic patients. It plays a key role in the initiation and maintenance of allergic inflammation in asthma. It is also implicated in atopic dermatitis, where it is overexpressed in the skin, contributing to chronic inflammation and increased sensitivity to allergens. Its expression can be increased in response to viral infections or environmental irritants, thus amplifying Inflammation. It is a target for the development of new treatments for allergic and inflammatory diseases. For example, monoclonal antibodies targeting TSLP, such as tezepelumab, to treat conditions like severe asthma or mepolizumab (AstraZeneca) in polyposis.

[0165] GM-CSF is implicated in the pathology of rheumatoid arthritis (RA), where it contributes to inflammation and joint destruction, and in certain inflammatory lung diseases, such as interstitial pneumonia and pulmonary alveolar proteinosis, where it is essential for maintaining alveolar macrophages, which clear the lungs of cellular debris. While beneficial for fighting infections and supporting the immune system, it may also contribute to chronic inflammatory and autoimmune conditions.

[0166] CCL26 (eotaxin-3) is a chemokine primarily involved in the recruitment of eosinophils to sites of inflammation, particularly in allergic and inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis.

[0167] IL-5 is a cytokine involved in the regulation of eosinophils and in immune responses against parasites and in allergic diseases, such as asthma and allergic rhinitis. Several treatments targeting IL-5 have been developed. For example, mepolizumab and reslizumab are monoclonal antibodies that neutralize IL-5, thereby reducing the number of eosinophils and alleviating symptoms in patients with severe eosinophilic asthma.

[0168] The results presented allow us to consider using these solutions alone or with other drugs for any condition involving a form of inflammation or allergy, separately or in the same composition for synergistic purposes. The results presented allow us to consider using these solutions alone or with other ingredients for any condition involving a form of inflammation or allergy, separately or in the same composition for synergistic purposes.

[0169] Rate of nasal epithelium repair (scarring):

[0170] Fig. 2 shows the rate of repair of the nasal epithelium by solution vs. control (SI) and NaCl (S3)(pm2 / hour)

[0171] Solution (S3), which is 0.9% physiological saline NaCl, shows results significantly lower than all the other solutions. The phenomenon of apothosis is confirmed by videomicroscopy.

[0172] The results of solution (S9) compared to (S3) demonstrate a less marked difference, showing the limitations of hypotonic NaCl solutions.

[0173] Unexpected differences are visible in this figure with regard to healing.

[0174] The BEGM (SI) culture medium gives superior results to all others solutions.

[0175] Solutions (S7), (S6) and (S8) then demonstrate superior efficiency vs. the comparator product on the market (S4).

[0176] No difference is observed between (S7), (S6) and (S8).

[0177] Solution (S4) demonstrates lower efficiency than solutions (S7), (S6), and (S8). The particularly significant difference between (S4) and (S6) is noteworthy.

[0178] In general, (S6) is superior to the comparator. Magnesium sulfate improves wound healing performance when added to the 6 basic minerals (chlorides, sodium, magnesium, calcium, bicarbonates, and potassium). Ciliary beat frequency

[0179] Figure [Fig. 3] shows the ciliary beat frequency velocity per solution vs. control (SI) and NaCl (S3) (Hz)

[0180] Solution (S3), which is physiological saline NaCl 0.9%, has results that are very significantly lower than all the solutions.

[0181] The BEGM (SI) culture medium gives superior results to all other solutions.

[0182] Solutions (S6), (S8) and (S4) in trend order have similar results showing good tolerance.

[0183] (S6) shows significantly greater activity on the ciliary beat than (S7) and (S9)

[0184] Summary and Discussion

[0185] The various experiments carried out above made it possible to identify the effectiveness of the compositions studied in anti-inflammatory indications, in wound healing and the frequency of ciliary beat.

[0186] [Table 3] Performance of solutions according to observed parameters IL8, IL6, TSLP, IL5, GM-CSF, IL18, eotaxin-3 Ciliary beat frequency (Hz) Wound healing rate (pm2 / hour) SI XX S3 S4 XX S6 XXX S7 XX S8 XXX S9

[0187] The effect on IL8, IL6, TSLP, IL5, GM-CSF, IL18, eotaxin-3 is comparable between (S6), (S7), (S8) and (S4); no significant difference is seen.

[0188] The favorable effect on the frequency of the ciliary beat is comparable between (S6), (S8) and (S4).

[0189] The favorable effect on the speed of healing is comparable between (S6), (S7) and (S8).

[0190] Composition (S6) and (S8) demonstrate efficacy in anti-inflammatory indications and in wound healing.

[0191] Composition (S6) shows statistically much superior results in healing speed vs. (S4)

[0192] This study reveals a dual activity: scar-reducing and anti-inflammatory beyond the traditional markers IL 8 and IL6, for composition (S6).

[0193] This composition has an anti-inflammatory action on 7 of the tested markers of inflammation: IL8, IL6, TSLP, IL5, GM-CSF, IL18, eotaxin-3.

[0194] This anti-inflammatory activity is observed on markers involved in allergy and chronic respiratory diseases such as polyposis or asthma: TSLP, IL 5

[0195] These effects are significant compared to the corticosteroid dexamethasone and, a fortiori, to corticosteroids sharing the same mode of action

[0196] These effects are rapid and have been observed within 12 to 24 hours.

[0197] Dramatic decreases in inflammation markers are observed

[0198] The properties of irrigation in the prevention of colds open the way to prophylactic applications on all respiratory pathologies in particular in the context of allergies, asthma, air pollution and the chronicity of diseases.

[0199] Use in combination or as an adjunct is possible, with corticosteroids or monoclonal antibodies, particularly those used in polyposis which act on the reduction of IL 5

[0200] Furthermore, these results suggest use in immune diseases impacting lung health such as rheumatoid arthritis, in combination with or as an adjunct to antifibrotics in pulmonary fibrosis, in therapies or prevention of lower respiratory tract diseases such as acute bronchitis, acute pneumonia, asthma, chronic pneumonia, COPD, superinfections of chronic obstructive bronchitis, occupational lung diseases, or GERD

[0201] These results also suggest applications in nebulization in COPD, bronchitis, asthma.

[0202] The results presented demonstrate that in the powdered solution (S6), the influential electrolytes are chloride, sodium, potassium, bicarbonates, calcium, magnesium, sulfates, and / or sulfur in the form of chlorides or sulfates, in particular magnesium sulfate. References

[0203] Mishra V, Banga J, Silveyra P. Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets. Pharmacol Ther. 2018 Jan;181:169-182.

[0204] Topai O, Kulaksizoglu S, Erbek SS. Oxidative stress and nasal polyposis: does it affect the severity of the disease? Am J Rhinol Allergy. 2014 Jan-Feb;28.

[0205] Hong Z, Guo Z, Zhang R, Xu J, Dong W, Zhuang G, Deng C. Airbome Fine Particulate Matter Induces Oxidative Stress and Inflammation in Human Nasal Epithelial Cells. Tohoku J Exp Med. 2016 Jun;239(2): 117-25.

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[0236] Culig 2010

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[0238] Salib 2013

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[0240] Atar 2022

[0241] Chen 2014

Claims

Demands

1. Electrolytic mineral composition, in powder form for solution to be diluted, having: • a pH of 7.2 to 8.2; • a conductivity of 17.5 to 19 mS / cm; • an osmolarity of 280 to 330 mOsm / kg, preferably 290 to 320 mOsm / kg, and comprising the following content of the principal constituents: • 2200 to 3500 mg / L of sodium (Na) • 5200 to 6700 mg / L of chloride (Cl) • 95 to 120 mg / L of bicarbonate (HCO3) • 1400 to 1900 mg / L of magnesium (Mg); • 450 to 750 mg / L of calcium (Ca); • 50 to 60 mg / L of potassium (K); • 1900 to 2600 mg / L of sulfate (SO4).

2. Composition according to the preceding claim, further comprises: • 800 to 3000 mg / L of sulfur (S).

3. Composition according to any one of the preceding claims, further comprises at least one of: zinc (Zn), copper (Cu), selenium (Se), manganese (Mn), iron (Fe).

4. Composition according to any one of the preceding claims, which is devoid of any preservative agent.

5. Composition according to any one of the preceding claims, comprising: • 2369 mg / L of sodium (Na); • 5485 mg / L of chloride (Cl); • 97 mg / L of bicarbonate (HCO3) • 1799 mg / L of magnesium (Mg); • 595 mg / L of calcium (Ca); • 51 mg / L of potassium (K); • 2439 mg / L of sulfate (SO4); • 2833 mg / L of sulfur (S).

6. Composition according to any one of claims 1 to 4, comprising: 3211 mg / L of sodium (Na) • 6478 mg / L of chloride (Cl) • 117 mg / L of bicarbonate (HCO3) • 1483 mg / L of magnesium (Mg) • 473 mg / L of calcium (Ca) • 55 mg / L of potassium (K) • 2004 mg / L of sulfate (SO4) • 839 mg / L of sulfur (S).

7. Composition according to any one of claims 1 to 6, for use in the treatment or prevention of respiratory conditions in cases of inflammatory, allergic or wound healing, preferably nasal polyposis, allergic rhinitis, asthma, or in dermatological conditions requiring an anti-inflammatory and / or wound healing effect.

8. Composition according to any one of claims 1 to 6, for use as a medicament, preferably: • in the treatment or prevention of nasal polyposis, allergic rhinitis, asthma; or • in the treatment or prevention of dermatological conditions with an anti-inflammatory or scarring effect; or • in the treatment or prevention of skin reactions of allergic origin, and / or atopic dermatitis; • in the treatment or prevention of oropharyngeal conditions with an anti-inflammatory or scarring effect.

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