BR112020002106A2 - gel comprising chlorhexidine - Google Patents

Abstract

The invention relates to a gel composition comprising chlorhexidine and / or a pharmaceutically acceptable salt thereof; hyaluronic acid and / or a pharmaceutically acceptable salt thereof; and a gelatinous matrix, in which the gelatinous matrix comprises water, and cellulose derivatives. The invention also relates to a method for preparing gels and the particular uses of gels in the field of cosmetics for the oral cavity, hygiene, prevention of diseases of the oral cavity and treatment of said diseases.

Description

GEL UNDERSTANDING CHLOREXIDINE

[1] This application claims the benefit of the European patent application EP 17382547.2 filed on August 4, 2017 and the Irish patent application 2017/0230 filed on November 2, 2017. Technical field

[2] The invention relates to the field of hygiene of the oral cavity and compositions with active ingredients and ingredients to preserve the health of the oral cavity. Therefore, this refers to compositions usable in the field of dentistry or dental dentistry. Background of the technique

[3] According to the World Health Organization (WHO), oral health is a state of being free from several disorders that affect the oral cavity, including chronic pain in the mouth and face, oral and throat cancer, mouth sores , birth defects such as cleft lip and palate, periodontal disease (gum), tooth decay and loss of teeth. Risk factors are unhealthy eating, tobacco, harmful use of alcohol and poor oral hygiene. It is widely recognized that oral health contributes to overall health and is an essential component of quality of life.

[4] Oral tissues require the maintenance of adequate oral hygiene by brushing teeth, floss, toothpaste, gels, mouthwashes, etc. In particular, mouthwashes are used in addition to conventional toothbrushing and to reduce the accumulation of plaque. These mouthwashes are also used for patients.

[5] These oral care compositions are also used to treat bad breath, mainly by controlling the growth of microorganisms in the oral cavity. For this reason, the compositions comprise compounds that make it possible to reduce the formation of plaque and the activity of microorganisms, while being safe and respectful for gingival and dental tissues.

[6] For this purpose, oral hygiene compositions comprising chlorhexidine are widely known and commercially available. Chlorhexidine is, until now, the most commonly used oral antiseptic, acting as a bactericide and bacteriostatic. It's a biguanide. Chlorhexidine (CHX) has some side effects, such as the coloring of teeth and lingual mucosa with an increase in the formation of supra-gingival stones; in addition, flavor disorders have been reported, as well as discoloration of some restorative materials.

[7] In addition, hyaluronic acid (HA) is the main component of the extracellular matrix of many tissues and is present in human saliva acting as a lubricant. HA has a role in curing acute and chronic oral lesions, especially periodontal changes. HA forms a protective surface film on the oral mucosa. In vivo, the growth inhibitory activity of HA plaque in 4-day plaque regrowth models is comparable to CHX. HA is also known as a mucus adhesive agent.

[8] Liquid compositions comprising both compounds are known. These are mouthwashes that aim to preserve oral hygiene. Examples of these compositions are marketed and also described in the patent literature, such as in PCT application WO 9852612, in which water-based antiseptic compositions comprising, among others, hyaluronic acid and chlorhexidine are reported. Other examples of said compositions are the commercial mouthwash products EllaDent Perio 020 and CURASEPT®ADS Perio.

[9] Using kidneys implies that they need to be held in the mouth for a predetermined period to achieve the effect. In addition, they need to be used more than once a day and often to guarantee their effectiveness in the case, for example, of gum sores due to surgical intervention or due to a pathological process.

[10] Long-lasting compositions for the distribution of assets are formulated as gels with adequate consistency. The gels are applied to the gums and the assets are gradually released.

[11] Gels comprising only chlorhexidine include hydroxy ethyl cellulose, for example, as a gel-forming agent (for example: gingival gel Curasept ADS 350; TrisDent dental gel and Oralsan gingival gel). On the other hand, sodium hyaluronate in gel formulations can be produced, for example, with carbopol (also called carbomer) (for example: Neutrogena Hydro Boost aqueous gel; Ultimate hydration gel; Bionect gel and Thealoz Duo gel). However, the mixture of both types of gel in order to present a gel with the two active ingredients, chlorhexidine and hyaluronic acid or one of its salts, provides, as a result, a gelatinous formulation with a precipitate of chlorhexidine.

[12] However, it is described in the state of the art geis comprising both chlorhexidine and hyaluronic acid. An example is the Swiss hygiene gel of the Swiss patent CH691030, in which sodium hyaluronate and chlorhexidine, among other ingredients, are ingredients of a mixture comprising carrageenan as a gel forming agent. Carrageenan is mentioned as a suitable gel forming agent which, together with hyaluronate, provides a sliding, compact, filamentary, transparent, clean and colorless gel. The inventors of CH691030 also propose the gel for disinfecting the oral cavity, although no specific example is provided.

[13] Another gel composition comprising chlorhexidine and hyaluronic acid is described in Russian patent RU2286764. The gel is particularly mentioned for use in the treatment of inflammatory diseases of the oral cavity and it comprises a combination of poly vinyl alcohol with sodium alginate as a gel forming agent.

[14] Although the aforementioned gels have been disclosed, dentists and surgeons still administer chlorhexidine solutions and hyaluronic acid compositions separately. This is mainly due to the fact that there are no commercially available gels with both assets, or even liquid compositions with both compounds to be used in the oral cavity. One likely reason is, as indicated, due to the fact that chlorhexidine and hyaluronic acid tend to precipitate when they are together. This may be due to the fact that chlorhexidine is a cationic preservative. Cationic preservatives and HA are incompatible, resulting in their conjugation and precipitation, as disclosed in PCT application WO 2008144185. In this PCT application, hyaluronic acid and another cationic preservative, in particular benzalkonium chloride, were finally mixed, first preparing separate solutions of HA and benzalkonium chloride and then combining them to avoid precipitation.

[15] Therefore, compositions with both ingredients are not stable for a long period. This is the reason why there are no gel compositions on the market with chlorhexidine and hyaluronic acid, although it is a request made by dentists and surgeons.

[16] On the other hand, some gels in which all the desired ingredients can be stably incorporated together in a gelatinous matrix have the disadvantage that their adhesive properties on the fabric are not good or are compromised, thus making them not useful.

[17] In addition, many of the gel-forming agents are pH sensitive and do not perform their functions at the desired final pH, in general, around 7 - 8, for oral compositions. In addition, some gel-forming agents can alter the final pH of compositions making them not useful for the treatment of the oral cavity.

[18] Therefore, it is evident that there is still a need in the field for alternative formulations that avoid the above mentioned drawbacks, although they are effective for oral hygiene. Summary of the invention

[19] The inventors have determined that chlorhexidine, or a salt thereof, and hyaluronic acid, or a salt thereof, can be formulated together as a transparent gel composition with good adhesion properties for the oral cavity (in particular, when dental enamel and gums) and also for skin surfaces, if a carboxy (C1-C3) alkyl cellulose and / or a salt thereof is used as a gel-forming agent in the gelatinous matrix that forms the gel. In addition, the compositions have high moisturizing properties and are versatile in terms of that a wide range of concentrations of chlorhexidine and hyaluronic acid can be incorporated into the gel.

[20] Thus, a first aspect of the invention is a gel composition comprising: - an effective amount of chlorhexidine (CHX) and / or a pharmaceutically or cosmetically acceptable salt thereof, said effective amount being a weight percentage comprised of 0.05 % w / w 1.5% w / w, in relation to the total weight of the gel composition; - an effective amount of hyaluronic acid (HA) and / or a pharmaceutically or cosmetically acceptable salt thereof; and - a gelatinous matrix comprising water, and a cellulose derivative, said cellulose derivative comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, together with pharmaceutically or cosmetically acceptable excipients and / or carriers.

[21] The carboxy (C1-C3) alkyl cellulose in the gelatinous matrix acts as a thickener or gel forming agent and forms, optionally with other excipients or carriers, a hydrophilic matrix that incorporates the active ingredients chlorhexidine and / or a pharmaceutically acceptable salt of and hyaluronic acid and / or a pharmaceutically acceptable salt thereof.

[22] In this gel composition, hyaluronic acid and / or a pharmaceutically or cosmetically acceptable salt thereof, it also contributes to shaping the gel because it is a polymeric compound that behaves in the same way when dissolved in the water of the gelatinous matrix. Therefore, it is also a thickening agent. In the particular case of the gel composition being used for hygiene of the oral cavity and / or treatment, this HA also acts as adhesive mucus.

[23] This gel composition assumes a need that is widely requested by doctors and citizens as a whole, as it allows the simultaneous administration of an antiseptic and a compound to cure any tissue damage (ie, to the oral cavity or other cavities lesions, including cavities containing mucosa).

[24] In addition, the gel composition not only solves the problem of precipitation of chlorhexidine in hyaluronic acid or both when they are together in gels, but also of maintaining the pH at desired values for oral use (namely, pH of 7 to 8). In addition, and surprisingly, the gel composition maintains its consistency and transparency in the case of its colorless (which means that at least no chlorhexidine precipitation is present) with a wide range of concentrations of chlorhexidine and hyaluronic acid. Therefore, no precipitation occurs. This opens up the option of preparing a wide variety of compositions with these active ingredients.

[25] In addition, as will be shown in the examples below, the gel composition has the appropriate adhesive properties that allow its use for a long period of time. Thus, if the gel is well adhered to the gums and / or teeth or even other surfaces, such as topically or skin surfaces, then low numbers of daily applications are required to achieve the desired effect.

[26] In a second aspect, the invention encompasses a method for preparing a gel composition as defined in the first aspect and its modalities, the method comprising: (a) forming a homogenized aqueous dispersion, said dispersion comprising chlorhexidine and / or a pharmaceutically or cosmetically acceptable salt thereof, dispersed in a solvent selected from the group consisting of poly alkylene glycol, glycerin, propylene glycol and mixtures thereof; and hyaluronic acid and / or a pharmaceutically or cosmetically acceptable salt thereof, dissolved in water; and (b) adding to the homogenized aqueous dispersion of step (a), a cellulose derivative, said cellulose derivative comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, to obtain a gel composition.

[27] Therefore, the method comprises the gelatinization of the carboxy (C1-C3) alkyl cellulose and / or a salt thereof in a homogenized aqueous dispersion comprising hyaluronic acid and / or a pharmaceutically or cosmetically acceptable salt thereof, dissolved in water and chlorhexidine and / or a pharmaceutically or cosmetically acceptable salt thereof, dispersed in a solvent selected from the group consisting of poly alkylene glycol, glycerin, propylene glycol and mixtures thereof.

[28] For "gelatinization" of carboxy (C1-C3), alkyl cellulose must be understood that this ingredient is added in an aqueous solution and the formation of gel is promoted (or runs).

[29] Gel compositions, as defined above, allow the treatment of many of the diseases, injuries or disorders of the oral cavity, for which hyaluronic acid is effective and in which antiseptic conditions are required or desired. In addition, the gels of the invention are useful for maintaining good health of the oral cavity, in particular the gums, after brushing.

[30] Therefore, another aspect of the invention is a gel composition as defined above, for use as a medicament.

[31] The invention then also relates to the use of gel compositions as defined above, as topical pharmaceutical or cosmetic compositions. Therefore, gel compositions can be applied to any surface of the skin or mucosa, on which it remains for as long as necessary to allow all assets to perform their effects. In addition, said gels, as indicated above, are colorless and transparent within the stability test established in the cosmetic and pharmacological fields. As they are colorless, no precipitation of chlorhexidine and / or a salt thereof has occurred.

[32] Another aspect of the invention is the use of a gel composition as defined above, as a cosmetic care agent (or as simple as a cosmetic). This applies, in particular, when no disease is present, however, administration of the gel improves the appearance of the surface on which it is applied. For example, improvement in skin elasticity or appearance of the oral cavity, leading to a healthy appearance of gums and mucous membranes in the mouth. This cosmetic effect also helps to present an adequate condition of the tissue that prevents or minimizes the risk of diseases (in particular or of the oral cavity) and / or allows an improved cure in case of damage to the tissue for any reason (ie, extraction) .

[33] Yet, another aspect of the invention is the use of a gel composition as defined above, as a cosmetic oral hygiene agent for hydrating, strengthening and improving the appearance of oral mucous membranes and gums, where said gel comprises amounts cosmetically effective amounts of hyaluronic acid and / or a cosmetically acceptable salt thereof, and cosmetically effective amounts of chlorhexidine, said effective amount being a weight percentage of 0.05% w / w to 1.5% w / w, relative to the total weight of the composition gel. Thus, another aspect of the invention is a topical or cosmetic pharmaceutical composition, which comprises an effective amount of chlorhexidine and / or a salt thereof; hyaluronic acid and / or a salt thereof; and a gelatinous matrix comprising water and a cellulose derivative, said cellulose derivative comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, together with one or more suitable pharmaceutically or cosmetically acceptable top excipients or carriers.

[34] Yet, another aspect of the invention is the use of gel compositions comprising chlorhexidine, or a salt thereof, and hyaluronic acid, or a salt thereof, and a carboxy (C1-C3) alkyl cellulose in the gelatinous matrix, as an agent for the hygiene of the oral cavity. This aspect is more related to the cosmetic effect of the combination of active ingredients, which allow a healthy appearance of the gums and teeth. This aspect can also be formulated as a gel composition as defined above, for use as a cosmetic care agent for the oral cavity. Alternatively, for use of a gel composition as defined above, comprising chlorhexidine, or a salt thereof; hyaluronic acid, or a salt thereof; and a carboxy (C1-C3) alkyl cellulose in the gelatinous matrix, as a cosmetic agent in the oral cavity. The cosmetic use of the gel composition of the invention implies the use of cosmetically acceptable excipients or carriers that can be matched with pharmaceutically acceptable excipients or carriers.

[35] Yet another aspect of the invention is the use of carboxy (C1-C3) alkyl cellulose and / or a salt thereof as a suspending agent for chlorhexidine in hyaluronic acid containing compositions in the form of gels.

[36] Therefore, with the best knowledge of the inventors, a gel composition is proposed for the first time in which chlorhexidine is suspended (which means that no precipitation occurs) in a gel composition containing hyaluronic acid.

Brief description of the figures

[37] FIG. 1, related to Example 2, is a comparative graph of the levels of mucus adhesion of a gel of the invention over time, recorded by means of a gravimetric test on an inclined plane with controlled temperature treated with mucin. The error bars show the standard deviation for each data set. The percentage of adherence score (abbreviated as AS (%)) on the Y axis is indicated as a percentage of adherence. The X axis shows the time (T) in minutes (min). Each data set includes water data (first column of the set), water data on an inclined plane containing mucin (second column of the set), sample (third column of the set) and sample on an inclined plane containing mucin (fourth column of the set) set). Detailed description of the invention

[38] All terms used in this application, unless otherwise indicated, should be understood in their common meaning, as known in the art. Other more specific definitions for certain terms, as used in this application, are those set out below and are intended to apply uniformly throughout the specification and claims, unless a definition expressed otherwise provides a broader definition.

[39] A "gel-forming agent" (or gelling agent) is a thickening agent that forms a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure. A thickening or thickening agent is a substance which can increase the viscosity of a liquid without substantially modifying its other properties. Thickeners used in cosmetic, pharmaceutical or personal care products include various liquids such as polyethylene glycol, synthetic polymers such as carbomer (a brand name for poly acrylic acid) and vegetable gums. A gel is a solid gelatin-like material that can have properties ranging from soft and weak to hard and strong. The gels are defined as a substantially diluted lattice system, which does not exhibit flow when in the fixed state. By weight, gels are mostly liquids, although they behave as solids due to the three-dimensional lattice network within the liquid. It is the cross-linking within the fluid that provides a gel with its structure (hardness) and contributes to adhesiveness (adhesion). In this sense, gels are a dispersion of molecules of a liquid within a solid in which the solid is the continuous phase and the liquid is the discontinuous phase. The gel composition of the invention is also referred to herein as an aqueous gel.

[40] By "gelatinous matrix", it is to be understood, in the sense of the present invention, as a composition comprising a solvent; in particular water, and a gel forming agent. The gelatinous matrix keeps all solutes (active ingredients) completely dissolved or completely suspended in the solvent, all of them incorporated in the weakly cohesive internal structure formed by the gel forming agent.

[41] “Carboxy (C1-C3) alkyl cellulose” is a cellulose derivative with carboxy (C1-C3) alkyl (- (C1-C3) groups

alkyl COOH) attached to any of the hydroxyl groups of the glycopyranose monomers that make up the cellulose structure. It can be represented as in formula (I). A particular example is carboxy methyl cellulose. Carboxy (C1-C3) alkyl cellulose is often used as its sodium salt, just like carboxy methyl cellulose sodium.

(I) R = H or - (C1-C3) alkylCO2H

[42] Throughout the specification and claims, the term (C1-C3) alkyl must be interpreted as linear or branched.

[43] Depending on the weight percentage of the monomers of formula (I) and the degree / amount of substitution, which is proportional to the average number of carboxy methyl groups in a monomer unit, the properties of the cellulose derivative can be modulated. For example, by assuming that the concentration remains the same; adding more substitutions also increases viscosity.

[44] By "suspending agent", it is understood according to this specification, a compound that prevents the precipitation of other compounds in a particular matrix (for example, in a gelatinous matrix). In the present invention, carboxy (C1-C3) alkyl cellulose, in particular carboxy methyl cellulose, is used as a CHX suspending agent in the aqueous gel comprising hyaluronic acid or a salt thereof. Carboxy (C1-C3) alkyl cellulose is also used as a thickening agent or gel forming agent.

[45] The term “oral cavity” covers, according to this specification, the two regions of the mouth; the vestibule and the oral cavity itself. The vestibule is the area between the teeth, lips and cheeks. The oral cavity is connected on the sides and front by the alveolar process (containing the teeth) and on the bottom by the isthmus of the fauces. The upper part is formed by the hard and soft palate and the lower part is formed by the myohyoid muscles and is occupied mainly by the tongue. A membrane - the oral mucosa, aligns the sides and, under the surface of the tongue to the gums, aligns the internal aspect of the jaw bone (mandible). It receives secretions from the sub maxillary and sublingual salivary glands.

[46] The term "pharmaceutically acceptable excipients or carriers" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. They must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications proportional to a reasonable risk / benefit ratio. In the particular case where gels are used in the oral cavity, excipients are orally acceptable, meaning that they can be used without problems or complications if they are finally swallowed and reach the digestive tract.

[47] The term "therapeutically effective amount" as used herein, refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate, to some extent, one or more of the symptoms of the disease which this is addressed. The particular dose of the compound administered in accordance with this invention will, of course, be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated and similar considerations.

[48] The term “cosmetically acceptable” refers to those excipients or carriers suitable for use in contact with the mucosa of the oral cavity and the enamel without undue toxicity, incompatibility, instability, allergic response, among others. The term also refers to “dermatologically acceptable” including excipients or carriers suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, among others.

[49] As indicated, a first aspect of the invention is, briefly, a gel composition comprising chlorhexidine and / or a pharmaceutically acceptable salt thereof, hyaluronic acid and / or a pharmaceutically acceptable salt thereof, and a gelatinous matrix comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, together with pharmaceutically acceptable excipients and / or carriers.

[50] Chlorhexidine and / or a pharmaceutically acceptable salt thereof, hyaluronic acid and / or a pharmaceutically acceptable salt thereof are both in the gel composition in therapeutically effective or cosmetically effective amounts.

[51] In a particular embodiment of the first aspect of the invention, the carboxy (C1-C3) alkyl cellulose salts are selected from alkali metal salts, alkaline earth metal salts, quaternary ammonium salts and mixtures thereof. In a more particular modality, salts are alkali metal salts selected from sodium, potassium and mixtures thereof. In a particular embodiment of the gels of the first aspect, the carboxy (C1-C3) alkyl cellulose is carboxy methyl cellulose or a salt thereof. In a particular embodiment, the carboxy (C1-C3) alkyl cellulose salt is an alkali metal salt of carboxy methyl cellulose. In a particular embodiment, the carboxy (C1-C3) alkyl cellulose salt is sodium carboxy methyl cellulose. In another particular embodiment, the carboxy (C1-C3) alkyl cellulose salt is an alkaline earth metal salt of carboxy methyl cellulose.

[52] Carboxy methyl cellulose is known as a bioadhesive pharmaceutical carrier of US patent 5192802 or US patent

6117415. In these documents, carboxy methyl cellulose is used in combination with xanthan gum or sodium alginate to promote adhesion to mucous membranes and thus release pharmaceutical assets of interest in a controlled manner. In US 6117415, it is also mentioned that the degree and amount of the carboxy methyl cellulose can be adjusted in the toothpaste according to the desired viscosity of the paste.

[53] The gels of the invention are designed and aim to remain on the desired surface of the application for a period of time that allows the assets in the gel to be released and then to realize their effect. Carboxy methyl cellulose or carboxy (C1-C3) alkyl cellulose and salts thereof, provide the required adhesion to the gel of the invention and, surprisingly, result in an ingredient that allows the administration of two active ingredients that tend to precipitate when mixed together in the gelatinous matrices. In addition, with the presence of carboxy (C1-C3) alkyl cellulose in the gelatinous matrix, wide ranges of key ingredients are permitted, in particular, wide ranges of concentrations of hyaluronic acid or a salt thereof and chlorhexidine or a salt of the same.

[54] In one embodiment, the gel composition of the present invention is one in which the carboxy (C1-C3) alkyl cellulose has a content of the carboxy (C1-C3) alkyl portion of 15% to 30% by weight of the weight of the carboxy (C1-C3) alkyl cellulose; preferably from 19% to 24% by weight of the weight of the carboxy (C1-C3) alkyl cellulose. Measurements of the content of the carboxy (C1-C3) alkyl moieties can be performed by any method known in the art.

[55] In another particular embodiment, optionally, in combination with the above or below embodiments, the gel composition of the present invention is one in which the carboxy (C1-C3) alkyl cellulose, in particular the carboxy methyl cellulose, has a degree replacement value from 1.15 to 1.45 measured according to American standard ASTM D1439. In a particular embodiment, the carboxy (C1-C3) alkyl cellulose is Blanose 12M31P, a carboxy methyl cellulose.

[56] In another embodiment, the composition of the present invention is one in which the carboxy (C1-C3) alkyl cellulose has a viscosity of 1500 mPa.s to 6500 mPa.s; preferably from 3100 mPa.s to 6500 mPa.s. The term "viscosity" refers to the shear fluid resistance, also called dynamic viscosity or shear viscosity and defined mathematically as a quotient of the shear stress rate. Usually, viscosity is measured by the use of devices such as rotational viscometers or rheometers which measure the torque exerted on an axis in contact with the sample when it is rotated at a precisely controlled angular speed. The conversion of torque and speed to stress and shear rates, respectively, is direct by multiplying by calibration constants. In the present invention, viscosity measurements are performed using a Brookfield viscometer, axis # 2 (SP2), operating at 0.3 rpm).

[57] In another particular embodiment, the percentage by weight of carboxy (C1-C3) alkyl cellulose, relative to the total weight of the gel composition is 1.0% to 5.0%. More in particular, it is 1.0% to 4.0%. Even more in particular, it is 2.0% to 3.0%.

[58] In another particular embodiment of the first aspect of the invention, gel formulations comprise a pharmaceutically acceptable salt of chlorhexidine selected from the group consisting of chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine hydrochloride (or hydrochloride) and chlorhexidine base , and mixtures thereof. In a more particular embodiment, optionally in combination with any above or below embodiment, the pharmaceutically acceptable salt of chlorhexidine is chlorhexidine gluconate. Chlorhexidine gluconate is also known as chlorhexidine diglyconate (used interchangeably here).

[59] In another particular embodiment, optionally in combination with any of the above or below embodiments, chlorhexidine and / or its salts are in a weight percentage of 0.05 to 1.5%, relative to the total weight of the gel formulation. More in particular, it is 0.10% to 1.0% by weight. Also more in particular, it is from 0.1% to 0.5%, even more in particular from 0.1% to 0.3% by weight. Also more in particular, it is 0.10% to 0.25% by weight. Even more in particular, it is selected from 0.10%, 0.15%,

0.20%, 0.21%, 0.22%, 0.23%, 0.24% and 0.25%, all percentages by weight relative to the total weight of the gel formulation.

[60] As indicated above, hyaluronic acid is the main component of the extracellular matrix of many tissues and is present in human saliva that acts as a lubricant. Hyaluronic acid is also an adhesive mucus agent that acts as a healing agent in cases where tissues are injured due to surgical interventions or due to certain diseases. Therefore, hyaluronic acid is not only one of the active ingredients in the formulation when the tissue must be repaired, but it also promotes adhesion. In the present invention, adhesion to the mucosa and / or enamel is also achieved due to the presence of carboxy (C1-C3) alkyl cellulose, as set out above.

[61] In a particular embodiment of the gels of the invention, optionally in combination with any embodiment above or below, hyaluronic acid and / or one of its salts has a molecular weight of at least 1.3 MDa. More in particular, it is from 1.3 to 2.5 MDa.

[62] In yet another particular embodiment of the first aspect, the pharmaceutically acceptable salt of hyaluronic acid is selected from the group consisting of alkali metal salts, alkaline earth metal salts and combinations thereof. In a more particular embodiment, the salt is an alkali metal salt of hyaluronic acid. In yet another more particular embodiment, the gel composition comprises hyaluronic acid as the sodium salt (i.e., sodium hyaluronate).

[63] As indicated, due to the presence of carboxy (C1-C3) alkyl cellulose, both hyaluronic acid (or its salts) as well as chlorhexidine (or its salts) are stably incorporated into the gel composition without showing precipitation. This is achieved, surprisingly, within a wide range of hyaluronic acid concentrations. Thus, in another particular modality, the weight percentage of hyaluronic acid or a salt thereof, in relation to the total weight of the gel composition is

0.1 to 1.0%. More in particular, it is 0.1 to 0.8%, in particular 0.75%. In another particular modality, it is 0.1 to 0.5% and, even more in particular, it is 0.1 to 0.30%. More in particular, it is 0.10 to 0.25%. Even more in particular, this is selected from 0.10%, 0.15%, 0.20%,

0.21%, 0.22%, 0.23%, 0.24% and 0.25%.

[64] In a more particular embodiment, the gel composition according to the first aspect comprises: - a percentage by weight of chlorhexidine or a pharmaceutically or cosmetically acceptable salt thereof, in relation to the total weight of the gel composition of 0.05 % a

1.5%; - a percentage by weight of hyaluronic acid or a pharmaceutically or cosmetically acceptable salt thereof, based on the total weight of the composition, from 0.1% to

1.0%; and - a percentage by weight of carboxy (C1-C3) alkyl cellulose and / or a salt thereof, relative to the total weight of the composition, from 1.0% to 5.0%.

[65] This particular embodiment is a gel composition suitable to be an oral gel composition, more particularly for application to the oral cavity. Thus, it is a gel to be used in the oral cavity for the treatment of dysfunctions, diseases or any condition, such as promoting tissue repair or regeneration after tooth extraction (tooth extraction). The gel adheres widely to oral tissue (mainly gums and dental socket in the case of tooth extraction) and allows controlled distribution of both chlorhexidine and hyaluronic acid (or any of its salts), both of which are active compounds since they are not effective. precipitate in the gel composition.

[66] So, in a particular embodiment, the gel is a topical gel composition for the oral cavity comprising orally, pharmaceutically or cosmetically acceptable excipients and / or carriers.

[67] Throughout the specification, quantities are mainly indicated as percentages (%) by weight relative to the total weight of the composition, if not stated otherwise. This percentage by weight is also indicated with the abbreviation “w / w”.

[68] In the gel composition according to the first aspect of the invention, the gelatinous matrix with carboxy (C1-C3) alkyl cellulose or a salt thereof, but also hyaluronic acid or a salt thereof, contribute to the consistency of composition gel, mainly due to its polymeric nature and behavior in water.

[69] In another particular embodiment of the first aspect of the invention, the gelatinous matrix comprises, in addition to water and the cellulose derivative comprising carboxy (C1-C3) alkyl cellulose or a salt thereof as a gel forming agent, in particular carboxy methyl cellulose, additional gel forming agents selected from the group consisting of propylene glycol, carbomers (such as Carbopol®), other cellulose derivatives (such as ethyl cellulose, methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose), magnesium aluminum silicate (such as Veegum®), polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum and mixtures thereof.

[70] Then, in another particular embodiment, optionally in combination with any embodiment above or below, the gel composition according to the invention comprises: - an effective amount of chlorhexidine (CHX) and / or a pharmaceutically or cosmetically acceptable salt of same, said effective amount being a weight percentage comprised of 0.05% w / w and 1.5% w / w, in relation to the total weight of the gel composition; - and effective amount of hyaluronic acid (HA) and / or a pharmaceutically or cosmetically acceptable salt thereof; and - a gelatinous matrix comprising water, and a cellulose derivative, said cellulose derivative comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, together with pharmaceutically or cosmetically acceptable excipients and / or carriers; said gelatinous matrix comprising, in addition, a compound selected from the group consisting of poly alkylene glycol, glycerin, propylene glycol and mixtures thereof.

[71] This compound selected from the group consisting of poly alkylene glycol, glycerin, propylene glycol and mixtures thereof is, in fact, a solvent, so it acts as a solvent for the other ingredients. Thus, in another particular embodiment of the first aspect of the invention, the gel further comprises a solvent selected from the group consisting of poly alkylene glycol, glycerin, propylene glycol and mixtures thereof.

[72] The inventors have observed that, with the use of a polyol solvent selected from the group consisting of propylene glycol, glycerin and mixtures thereof, chlorhexidine or one of its salts can be dispersed and mixed with an aqueous solution of hyaluronic acid or its salts, preventing the precipitation of chlorhexidine. The additional presence in the composition of the carboxy (C1-C3) alkyl cellulose or a salt of the same allowed highly stable gel compositions in which both chlorhexidine and hyaluronic acid are suspended and no precipitation occurs. In addition, the presence of carboxy (C1-C3) alkyl cellulose or a salt thereof improves adhesion to the surfaces on which the gel composition is applied. In particular, it improves adhesion on the animal's skin and the tissues of the oral cavity (tooth enamel and gums). Thus, the gel composition is a highly stable topical gel composition for the skin and tissues of the oral cavity.

[73] Although carboxy (C1-C3) alkyl cellulose or a salt thereof is also a gel-forming agent in the gelatinous matrix, no precipitation is observed, the gel composition comprises, in a particular embodiment, additional compounds that assist avoid precipitation when gel compositions comprise a large amount of ingredients. Therefore, in a particular embodiment, the gel compositions of the first aspect comprise chelating compounds selected from the group consisting of EDTA, phosphonate compounds, gluconate compounds, citrate compounds and combinations thereof. In a particular embodiment, optionally in combination with any embodiment above or below, the chelating compound is comprised of a percentage by weight relative to the total weight of the gel composition from 0.05% to 1%. More in particular, it is 0.1% to 0.40%. More in particular, it is

0.1% to 0.20%. More in particular, the chelating compound is ethylene diamine tetra acetic acid (EDTA) or a salt thereof, such as disodium EDTA. Even more in particular, EDTA or its sodium salt, are comprised in a percentage by weight of 0.1% to 0.20%. In another particular embodiment, the chelating compound is a gluconate compound or a salt thereof; in particular, it is an alkali metal salt, more in particular, it is a sodium gluconate. In a more particular embodiment, the compound gluconate or sodium gluconate is comprised of a percentage by weight of 0.2% to 0.40%. In yet another particular embodiment, the chelating compound is a citrate compound or a salt thereof; in particular, it is an alkali metal salt, more in particular, it is sodium citrate. In a more particular embodiment, the citrate compound or sodium citrate is comprised of a weight percentage of 0.1% to

1.0%.

[74] These chelating compounds, also called chelating agents, chelating agents or sequestering agents are poly dentate molecules that establish coordinated bonds with metal ions. The chelation of metal ions improves their stability within the solvent in which they are dissolved. In the present case, in the solvent incorporated in the gel forming agent. More particularly, in the water incorporated in the gel forming agent.

[75] In another particular embodiment, the gel compositions of the present invention further comprise one or more compounds selected from the group consisting of an essential oil, a preservative, a flavoring agent, a humectant, an emulsifier, a chelating agent and an of additional gel formation in addition to the carboxy (C1-C3) alkyl cellulose, an antimicrobial agent, an aqueous vehicle (i.e., water) and mixtures thereof.

[76] Among the essential oils, the gel composition of the first aspect of the invention comprises, in a particular embodiment, oil selected from the group consisting of thyme oil, eugenol, eucalyptus oil, rosemary oil, mint oil , cinnamon leaf oil,

clover leaf oil, tea tree oil and Origanum oil.

[77] Although chlorhexidine or one of its salts acts on its own as an antimicrobial agent, in another particular embodiment of the first aspect, optionally in combination with any above or below modality, the gel composition comprises an additional antimicrobial agent. In a more particular embodiment, the additional antimicrobial agent is selected from the group consisting of salicylic acid or an ester or salt thereof, such as methyl salicylate, alexidine, triclosan, cetyl pyridinium chloride, delmopinol, amyl metacresol, chloride benzalkonium, octenidine (in the form of one of its salts), and mixtures thereof.

[78] In another particular embodiment, optionally in combination with any of the above or below embodiments, the gel composition has a pH of 7.0 to 8.0. In this pH range, the gel is suitable for particular use in the oral cavity, as indicated above. In addition and advantageously, the carboxy (C1-C3) alkyl cellulose gel forming agent does not change its pH, which means that, at the appropriate pH, no precipitation of chlorhexidine and / or one of its salts will occur.

[79] The invention also encompasses a method for preparing a gel composition as defined above, and comprising the steps of: (a) forming a homogenized aqueous dispersion, said dispersion comprising chlorhexidine and / or a pharmaceutically or cosmetically salt acceptable, dispersed in a solvent selected from the group consisting of polyalkylene glycol, glycerin, propylene glycol and mixtures thereof; and hyaluronic acid and / or a pharmaceutically acceptable salt thereof, dissolved in water; and (b) adding to the homogenized aqueous dispersion of step (a), a cellulose derivative, said cellulose derivative comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, to obtain a gel composition.

[80] In a particular embodiment of this method, the solvent in which chlorhexidine and / or a salt thereof is dispersed, is selected from the polyols propylene glycol, glycerin and mixtures thereof. In another particular embodiment, optionally in combination with any above or below embodiment, the solvent is selected from the polyethylene glycol polyethers, polypropylene glycol and mixtures thereof, which are also referred to in this specification as polyalkylene glycols. In yet another particular embodiment, the solvents in which chlorhexidine and / or a salt thereof is dispersed is a mixture of one or more polyols and one or more poly alkylene glycols. More in particular, the solvent is a mixture of polypropylene glycol and polyethylene glycol.

[81] In another particular embodiment, optionally in combination with any embodiment above or below, hyaluronic acid and / or a pharmaceutically or cosmetically acceptable salt thereof is dissolved in deionized water.

[82] Then, in a particular modality, and in order to improve the dissolution of chlorhexidine, or a salt thereof, and hyaluronic acid, or a salt thereof, a premix can be prepared with a solvent of a polyol nature , more particularly with propylene glycol, glycerin or a mixture of both, said polyol acts as a dispersant of chlorhexidine or a salt thereof. Optionally, said aqueous premix is, in another particular embodiment, derivatized with polyalkylene glycols, said water-soluble polyalkylene glycols and with a molecular weight of 50 to 200 Da. The solvent is, in another particular embodiment, optionally derivatized with oils . Examples of oils to be added to the premix include castor oil.

[83] This pre-mixture is also supplemented with carboxy (C1-C3) alkyl cellulose and / or a salt thereof, which evolves to a gel consistency once it comes in contact with the aqueous pre-mixture.

[84] As indicated above, this carboxy (C1-C3) alkyl cellulose and / or a salt thereof, in particular carboxy methyl cellulose, allows chlorhexidine and hyaluronic acid and / or their salts to be stably suspended in the aqueous gel .

[85] The gel composition of the first aspect is for use as a medicine. In a more particular modality it is for use in the treatment of diseases, dysfunctions or conditions of the oral cavity selected from the group consisting of plaque and calculus, decay, gingivitis, periodontitis, mucositis, oral ulcers, dental sensitivity and combinations thereof. This aspect can also be formulated as the use of the gel composition as defined above, for the manufacture of a medicine for the treatment or prevention of a disease, dysfunction or condition of the oral cavity selected from the group consisting of plaque and calculus , decay, gingivitis, periodontitis, mucositis, oral ulcers, dental sensitivity and combinations thereof. The present invention also relates to a method for the treatment or prevention of diseases, disorders or conditions of the oral cavity, selected from the group consisting of plaque and calculus, decay, gingivitis, periodontitis, mucositis, oral ulcers, dental sensitivity, and combinations thereof comprising administering a pharmaceutically effective amount of the gel compound, as defined above, together with pharmaceutically acceptable excipients or carriers, to an individual in need thereof, including a human.

[86] Thus, the invention relates in particular to the use of the gel composition in the treatment of diseases of the oral cavity that affect the gums and / or teeth and / or the oral mucosa.

[87] Dental plaque is a biofilm or mass of bacteria that grows on surfaces inside the mouth. It is a colorless, sticky deposit at first, but when it forms tartar (also known as calculus), it is usually brown or pale yellow. It is commonly found between the teeth, in front of the teeth, behind the teeth, on the chewing surfaces, along the gum line or below the cervical margins of the gum line. Dental plaque is also known as microbial plaque, oral biofilm, dental biofilm, dental plaque biofilm or bacterial plaque biofilm. The progression and formation of dental plaque can lead to tooth decay - the localized destruction of tooth tissues by acid produced from the bacterial degradation of fermentable sugar - and periodontal problems such as gingivitis and periodontitis; therefore, it is important to disrupt the bacteria mass and remove it. Plaque control and removal can be achieved with the correct daily brushing or twice a day and the use of interdental aids, such as dental floss and interdental brushes. Oral hygiene is important, as dental biofilms can become acidic, causing demineralization of teeth (also known as tooth decay) or hardening in dental calculus.

[88] Decay or decay of teeth, also known as tooth decay or tooth decay, is a tooth break due to acids produced by bacteria. The cavities can have several different colors, from yellow to black. Symptoms can include pain and difficulty eating. Complications can include inflammation of the tissue around the tooth, loss of teeth, infection, or abscess formation. The main cause of tooth decay is the acid from bacteria, which dissolves the hard tissues of the teeth (enamel, dentin and cement). The acid is produced from food residues or sugar on the tooth surface. Simple sugars in food are the main source of energy for these bacteria, so a diet high in simple sugar is a risk factor. Risk factors include conditions that result in less saliva, such as diabetes mellitus, Sjogren's syndrome and some medications. Medicines that decrease saliva production include antihistamines and antidepressants. Caries is also associated with poverty, poor cleaning of the mouth and gingival retraction, resulting in the exposure of the roots of the teeth.

[89] Gingivitis ("inflammation of gum tissue") is a non-destructive disease that occurs around the teeth. The most common form of gingivitis, and the most common form of periodontal disease in general, is a response to bacterial biofilms (also called plaque) that are attached to tooth surfaces, called plaque-induced gingivitis. Although some cases of gingivitis never progress to periodontitis, the data indicate that periodontitis is always preceded by gingivitis. Gingivitis is reversible with good oral hygiene; however, without treatment, gingivitis can progress to periodontitis, in which inflammation of the gums results in tissue destruction and bone resorption around the teeth. Periodontitis can lead to tooth loss.

[90] Periodontitis, also known as gum disease and worsening, refers to a set of inflammatory diseases that affect the tissues around the teeth. Periodontitis involves progressive loss of alveolar bone around the teeth and, if left untreated, can lead to loosening and subsequent loss of teeth. Periodontitis is caused by microorganisms that adhere to and grow on tooth surfaces, along with an overly aggressive immune response against these microorganisms. A periodontitis diagnosis is established by inspecting the soft gingival tissues around the teeth with a probe (ie, a clinical examination) and evaluating the patient's radiographs (ie, a radiographic examination), to determine the amount of bone loss around of the teeth.

[91] Mucositis is painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy for cancer. Mucositis can occur anywhere in the gastrointestinal tract (GIT), however, oral mucositis refers to the specific inflammation and ulceration that occur in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment. Oral and gastrointestinal (GI) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignant diseases of the head and neck receiving radiotherapy and a wide range of patients receiving chemotherapy.

[92] Oral ulcers or mouth ulcers are ulcers that occur on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and through different mechanisms, but there is usually no serious underlying cause. The two most common causes of oral ulceration are local trauma (for example, friction of a sharp edge on a broken pad) and aphthous stomatitis ("thrush"), a condition characterized by the recurrent formation of oral ulcers for reasons largely unknown. Mouth ulcers often cause pain and discomfort, and can alter a person's choice of food during healing (for example, avoiding acidic or spicy foods and drinks).

[93] Dental sensitivity or dentin hypersensitivity (abbreviated to DH or DHS, and also called sensitive dentin, dentin sensitivity, cervical sensitivity and cervical hypersensitivity) is a short-lived, acute dental pain, resulting from exposed surfaces of the dentin in response to stimuli, usually thermal, evaporative, tactile, osmotic, chemical or electrical; and that cannot be attributed to any other dental disease. A degree of dentin sensitivity is normal, but pain is not usually felt in daily activities, such as drinking a cold drink. Therefore, although the terms dentin sensitivity and sensitive dentin are used interchangeably to refer to tooth hypersensitivity, the latter term is the most accurate. The main cause of HD is gingival recession (receding gums), with exposure of root surfaces, loss of cement and residual layer, and wear of teeth. Receding gums can be a sign of long-term trauma due to excessive or strong brushing, or brushing with an abrasive toothpaste (dental abrasion) or a sign of chronic periodontitis (gum disease).

[94] The gels of the invention are, in another particular embodiment, for use in the treatment of tissues of the oral cavity after an extraction process. In particular, said tissues of the oral cavity include the gums.

[95] A tooth extraction (also called tooth extraction, tooth extraction, tooth extraction or, informally, tooth pulling) is the removal of teeth from the tooth socket (cavity) of the alveolar bone. Extractions are performed for a wide variety of reasons, but most commonly to remove teeth that have become impassable due to tooth decay, periodontal disease or dental trauma, especially when associated with toothache. Sometimes wisdom teeth are impacted (stuck and unable to grow normally in the mouth) and can cause recurrent gum infections (perichoronitis). In orthodontics, if the teeth are stacked together, the healthy teeth can be extracted (usually bicuspid) to make room for the rest of the teeth to be fixed.

[96] Tooth extraction is generally relatively straightforward, and the vast majority can be performed quickly, while the individual is awake, using local anesthetic injections to eliminate painful sensations. After the tooth is removed, the stitches are used to replace the gum in the normal position. However, extraction is a surgical procedure performed in the oral cavity, producing tissue damage. The postoperative period in extraction is a challenging process, affecting the patient's quality of life due to pain and inflammation in the area associated with healing events. Thus, after a tooth extraction, a blood clot is formed in the tooth socket and in tissue regeneration and recovery. Early healing processes include granulocyte tissue formation in the tooth socket that is progressively replaced by new bone tissue.

[97] On the other hand, the gels defined above, comprising chlorhexidine (or a salt thereof), hyaluronic acid (or a salt thereof) and a gelatinous matrix with carboxy (C1-C3) alkyl cellulose are, according to another aspect, for use as cosmetic care of the oral cavity. This means that they are, in particular, for use in improving the appearance of gums and teeth.

[98] Therefore, the gel compositions of the invention are used as a cosmetic care agent. More in particular, they are used as topical cosmetic compositions.

[99] The gel composition, as defined above, is used, according to another aspect of the invention, as a cosmetic care agent in the oral cavity. Therefore, the invention also refers to gel compositions for use in cosmetics. These cosmetic gel compositions comprise an effective amount of chlorhexidine and / or a salt thereof; hyaluronic acid and / or a salt thereof; and a gelatinous matrix comprising water and a cellulose derivative, said cellulose derivative comprising carboxy (C1-C3) alkyl cellulose and / or a salt thereof, together with suitable cosmetically and orally acceptable excipients and / or carriers.

[100] The gel is used as a cosmetic oral hygiene agent for hydrating, strengthening and improving the appearance of oral mucous membranes and gums, said gel comprising, as indicated above, cosmetically effective amounts of hyaluronic acid and / or a cosmetically acceptable salt thereof and cosmetically effective amounts of chlorhexidine and / or a cosmetically acceptable salt thereof, said effective amount of chlorhexidine or salt being a weight percentage comprised of 0.05% w / w and 1.5% w / w, relative to the total weight of the gel composition.

[101] In a more particular way of using the gel as a cosmetic oral hygiene agent, it is for daily cosmetic care and for the protection of the mucosa and gums.

[102] This cosmetic effect is achieved in any of the tissues of the oral cavity, in particular, in gums, teeth and oral mucosa, however, the cosmetic gel compositions of the invention can also be applied to the skin, since, due to the consistency in gel, it remains on the surface for an adequate time and thus allows the absorption of any of the assets that the gel contains.

[103] Thus, topical cosmetic gel compositions, as defined above, are also used as a skin care agent, in which skin care comprises improvement of at least one of the following symptoms: roughness, flaking, dehydration , stiffness, cracks, scar reduction and lack of elasticity.

[104] The term “safe and effective amounts” is defined as any amount sufficient to significantly improve the cosmetic appearance of the skin and / or tissues of the oral cavity without substantial irritation, but low enough to avoid serious side effects (with a risk ratio / reasonable benefit), within the scope of good medical judgment. The safe and effective amount of chlorhexidine and / or a salt thereof and hyaluronic acid and / or a salt thereof will vary with the age and physical condition of the consumer, the condition of the oral mucosa or skin, the duration of treatment, the nature of any concurrent treatment, the specific combination of active ingredients employed, the particular cosmetically acceptable carrier used and similar factors as factors in the knowledge and expertise of any responsible physician.

[105] The invention also relates to gel compositions comprising chlorhexidine and / or a pharmaceutically acceptable salt thereof, hyaluronic acid and / or a pharmaceutically acceptable salt thereof, and carboxy (C1-C3) alkyl cellulose and / or a salt thereof, together with pharmaceutically acceptable excipients and / or carriers, wherein the excipients and / or carriers comprise a cellulose derivative selected from the group consisting of hydroxy propyl cellulose (hydroxyl C3-C6 cellulose), hydroxy propyl methyl cellulose and mixtures thereof, wherein the excipient (s) optionally substitute the (C1-C3) alkyl cellulose carboxy and / or a salt thereof.

[106] Throughout the specification and the claims, the word "comprises", and variations of the word, are not intended to exclude other technical characteristics, additives, components or stages. In addition, the word "comprises" covers the case of "consisting of". Additional objects, advantages and features of the invention will become apparent to a person skilled in the art when examining the specification or can be taught by practicing the invention. The following examples are provided for purposes of illustration and they are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of particular and preferred embodiments described herein. Examples Example 1 - Aqueous gel formulations for topical use

[107] Table 1 below shows a particular gel composition of the invention with chlorhexidine gluconate and sodium hyaluronate.

Table 1 - Formula for colorless gel composition, comprising 0.24% by weight of hyaluronic acid.

Composition for 100 g and 5000 g

100 g 5000 g

Chlorhexidine digliconate at 1.065 g 53.250 g 20% Hyaluronic acid (0.24 g salt 12.000 g sodium) Essential oil 0.05 g 2.500 g rosemary Sodium methylparaben (Nipagin M 0.40 g 20.000 g sodium) Sodium ethylparaben (Nipagin A 0.04 g 2.000 g sodium) Propylene glycol 50.00 g grade 2500.000 g pharmacological Blanose 12M31P (Carboxy methyl 3.00 g 150.000 g sodium cellulose) Castor oil 0.20 g 10,000 g PEG- 40 disodium EDTA 0.10 g 5,000 g

Optamint flavor 0.27 g 13,500 g E7171 / 266165 Menthol 0.05 g 2,500 g crystallized Eugenol 0.010 g 0.500 g Methyl salicylate 0.07 g 3,500 g Citric acid q.s.p. pH 7.0 - 0.13 g 7.56 g 8.0 Purified water q.s.p. 100 g

[108] This composition did not show any precipitate of chlorhexidine and / or hyaluronic acid.

[109] Table 2 below shows the appearance and consistency of several gel compositions comprising chlorhexidine and hyaluronic acid. The presence of carboxy methyl cellulose provided adequate gel consistency (colorless or white), but without observed precipitation. Table 2 - Other gel compositions of the invention.

1701G 1702G Transparent Gel with Transparent Gel 1608G 1609G aspect and aspect and Transparent Gel Transparent Gel with consistency with aspect and aspect and adequate. appropriate. consistency consistency initially initially suitable suitable whitish due to whitish air bubbles that disappear due to air bubbles that disappear 1.065 g 1.065 g 1.50 g 1.50 g chlorhexidine 20% hyaluronic acid 0.24 g 0.24 g 0.50 g 0.50 g (sodium salt) Oil 0.05 g 0.05 g 0.05 g 0.05 g rosemary essential Sodium methylparaben 0.40 g 0.40 g 0.40 g 0, 40 g (Nipagin M sodium) Castor oil PEG-40 0.20 g 0.20 g 0.20 g 1.00 g

Optamint flavor 0.27 g 0.27 g 0.27 g 0.27 g E7171 / 266165 Menthol 0.05 g 0.05 g 0.05 g 0.05 g crystallized Eugenol 0.01 g 0.01 g 0, 01 g 0.01 g Methyl 0.07 g 0.07 g 0.07 g 0.07 g salicylate Citric acid 0.14 g 0.13 g ND 0.12 g qsp pH 7.0 - 8.0 Water (for 100 g)

Disodium EDTA 0.10 g 0.10 g 0.10 g 0.10 g 50.00 g propylene glycol 50.00 g 50.00 g 50.00 g pharmacological grade Sodium ethylparaben 0.04 g 0.04 g 0.04 g 0.04 g (Nipagin A sodium) Blanose 12M31P 3.00 g 3.00 g 3.00 g 3.00 g (Carboxy methyl sodium cellulose) Sodium citrate Glycerin

1704G 1705G 1706G Transparent Gel with Transparent Gel with Transparent Gel 1703G aspect and aspect and with aspect and transparent Gel consistency consistency consistency with aspect and suitable. appropriate. appropriate. consistency Initially Initially Initially suitable whitish due to whitish due to whitish air bubbles that to air bubbles that disappear due to bubbles disappear disappearing air Diglytonate 1.065 g 1.50 g 2.50 g 5.00 g 20% chlorhexidine Acid hyaluronic 0.24 g 0.50 g 1.00 g 1.00 g (sodium salt) 0.05 g essential oil 0.05 g 0.05 g 0.05 g rosemary Sodium methylparaben 0.40 g 0 , 40 g 0.40 g 0.40 g (Nipagin M sodium) Castor oil PEG-40 0.20 g 0.20 g 0.20 g 0.20 g

Aroma 0.27 g 0.27 g 0.27 g 0.27 g Optamint

E7171 / 266165 Crystallized menthol 0.05 g 0.05 g 0.05 g 0.05 g Eugenol 0.01 g 0.01 g 0.01 g 0.01 g Methyl 0.07 g 0.07 g 0.07 g 0.07 g salicylate Citric acid qsp pH 7.0 0.18 g 0.16 g 0.17 g 0.14 g - 8.0 Water (for 100 g)

EDTA 0.10 g 0.10 g 0.10 g 0.10 g disodium 50.00 g propylene glycol 50.00 g 50.00 g 50.00 g pharmacological grade

Sodium ethylparaben 0.04 g 0.04 g 0.04 g 0.04 g (Nipagin A sodium) Blanose 12M31P (Carboxy 3.00 g 3.00 g 3.00 g 3.00 g methyl sodium cellulose) Citrate sodium glycerin

1707G 1714G 1715G Transparent gel Transparent gel with white gel with adequate appearance and consistency and consistency. suitable suitable Initially whitish due to air bubbles disappearing 5.00 g 1.0650 g 1.0650 g 20% chlorhexidine Hyaluronic acid 1.00 g 0.24 g 0.24 g (sodium salt) Essential oil 0.05 g 0.05 g 0.05 g rosemary Methylparaben 0.40 g 0.40 g 0.40 g sodium (Nipagin M sodium) 1.00 g 0.20 g 0.20 g castor oil PEG -40 Aroma Optamint 0.05 g 0.27 g 0.27 g E7171 / 266165 Menthol 0.07 g 0.05 g 0.05 g crystallized Eugenol 0.01 g 0.01 g 0.01 g Methyl 0.07 g 0.07 g 0.07 g salicylate Citric acid qsp pH 7.0 0.12 g 0.14 g 0.10 g - 8.0 Water (for 100 g)

EDTA 0.10 g * 0.10 g disodium 50.00 g propylene glycol 50.00 g * pharmacological grade Sodium ethylparaben 0.04 g 0.04 g 0.04 g (Nipagin A sodium) Blanose 12M31P (Carboxy 3 , 00 g 3.00 g 3.00 g methyl sodium cellulose) 1.00 g sodium citrate

Glycerin 50.00 g

Table 3 - Formula for colorless gel composition comprising 1.0% by weight of hyaluronic acid.

Composition for 100 g

100 g

1.065 g digliconate 20% chlorhexidine Hyaluronic acid (1.0 g sodium salt) Rosemary essential oil 0.05 g Sodium methylparaben 0.40 g (Nipagin M sodium) Sodium ethylparaben 0.04 g (Nipagin A sodium ) Propylene glycol grade 50.00 g pharmacological Blanose 12M31P (Carboxy 3.00 g methyl sodium cellulose) Sucralose 0.05 g Castor oil PEG-40 0.50 g EDTA disodium 0.10 g Aroma Optamint 0.243 g E7171 / 266165 Menthol crystallized 0.045 g Eugenol 0.009 g Methyl salicylate 0.06 g Citric acid g qsp pH 7.0 - 8.0 Purified water 43.44 g q.s.p. 100 g Table 4 - Formula for colorless gel composition comprising 0.75% by weight of hyaluronic acid.

Composition for 100 g

100 g

Chlorhexidine digliconate 1.065 g 20% Hyaluronic acid (0.75 g sodium salt) Rosemary essential oil 0.05 g Sodium methylparaben 0.40 g (Nipagin M sodium) Sodium ethylparaben 0.04 g (Nipagin A sodium) Propylene glycol 50.00 g pharmacological Blanose 12M31P (Carboxy 3.00 g methyl sodium cellulose) Sucralose 0.05 g Castor oil PEG-40 0.50 g EDTA disodium 0.10 g Aroma Optamint 0.243 g E7171 / 266165 Crystallized menthol 0.045 g Eugenol 0.009 g Methyl salicylate 0.06 g Citric acid g qsp pH 7.0 - 8.0 Purified water 43.69 g q.s.p. 100 g Table 5 - Formula for colorless gel composition comprising 0.50% by weight of hyaluronic acid.

Composition for 100 g 100 g Chlorhexidine digliconate 1.065 g 20% Hyaluronic acid (0.50 g sodium salt) Rosemary essential oil 0.05 g Sodium methylparaben 0.40 g (Nipagin M sodium) Sodium ethylparaben 0.04 g (Nipagin A sodium) Propylene glycol 50.00 g pharmacological grade Blanose 12M31P (Carboxy 3.00 g methyl sodium cellulose) Sucralose 0.05 g Castor oil PEG-40 0.50 g EDTA disodium 0.10 g Aroma Optamint 0.243 g E7171 / 266165 Crystallized menthol 0.045 g Eugenol 0.009 g Methyl salicylate 0.06 g Citric acid g qsp pH 7.0 - 8.0 Purified water 43.94 g q.s.p. 100 g

[110] These other particular examples of compositions with higher amounts of hyaluronic acid (0.50%, 0.75% and 1.0% relative to the total weight of the gel composition) did not show any precipitate of chlorhexidine and / or hyaluronic acid. They have been supplemented with a sweetener (sucralose) to mask the bitter taste of hyaluronic acid. The addition of the sweetener did not change the consistency and transparency of the gel. Example 2 - Test to evaluate the mucus adhesive properties of a topical product

[111] The colorless gel of Example 1 (Table 1; gel composition with 0.24% hyaluronic acid) was tested in order to evaluate the mucus adhesive properties by gravimetric testing on an inclined plane with controlled temperature treated with mucin.

[112] The purpose of the test is to evaluate the mucus adhesive properties of a topical product by analyzing the kinetic shedding of the sample from an inclined steel plane, with and without a mucin biofilm. The true mucus adhesion of the sample is determined from a delay in sliding the sample and in the detachment of the plane caused by the mucin.

[113] The steel plane was positioned horizontally and the temperature control was adjusted 60 minutes in advance. 4 ml of the analyzed sample or deionized water were placed at the predefined running distance and left to settle for 2 minutes - To start the run, the plane was adjusted at a 45º inclination. The amount of sample dropped from the plane fell into a petri dish and was automatically weighed every 60 seconds. For gravimetric measurements, an Ohaus Explorer Pro analytical balance equipped with a thermal printer was used. The timed recording of the measurement was directly controlled by the scale software

[114] The sample was tested without dilution. Each run was carried out in three replicates and the runs carried out included: deionized water without mucin; deionized water with mucin; sample analyzed without mucin and sample analyzed with mucin.

[115] The plan was precisely cleaned and prepared before each race. For runs with the mucin film, the plane was pre-coated with a suspension of 8% in water of swine gastric mucin type II (Sigma Aldrich) spread to make a uniform film.

[116] The test conditions for the sample were as follows:

[117] Temperature: 36 ºC

[118] Inclination of the steel plane: 45º

[119] Running surface length: 10 cm

[120] Running time: 60 seconds.

[121] To determine a mucus adhesion value, the average weight recorded in each unit of time was considered, along with its standard deviation. Each value was also compared with the total weight of the applied sample, in order to build a graph of adherence versus time.

[122] The percentage of adhesion was calculated according to the following formula: Adhesion% = (P0-Pt) / P0 * 100 Where: P0 is the weight of the sample applied in the plane at T = 0; Pt is the weight of the sample detached from the steel plane at each end time t.

[123] In order to exhibit mucus adhesive properties, a sample must have a significantly higher percentage of adhesion versus mucin-free control (p <0.05) than that exhibited by water, which interacts with the protein only through hygroscopic absorption.

[124] The results are reported below in Table 6 as the percentage of adherence over time ± standard deviation.

Table 6 Time 1 2 3 4 5 10 15 20 25 30 35 40 45 50 (min) Water 13.17% 12.33% 12.33% 12.33% 12.33% 12.33% 12.33% 12 , 33% 12.33% 12.33% 12.33% 12.33% 12.33% 12.33% (%) Deviation 4.37% 2.65% 2.60% 3.05% 2.65% 3.05% 3.13% 3.61% 3.28 % 3.13% 2.60% 2.18% 3.51% 3.01% (±%) Water + Mucine 18.83% 18.17% 18.67% 19.00% 19.17% 19.50% 20.17% 20.83% 20.83% 21.33% 21.00% 21.00% 20.50% 20.17% (%) Deviation 3.51% 2.79% 2.65% 2.30% 2.30% 1, 50% 1.00% 0.50% 1.00% 2.30% 2.50% 3.01% 3.01% 4.28% (±%) Sample 99.91% 94.17% 55.78 % 48.41% 43.44% 26.31% 26.22% 22.37% 22.37% 22.37% 22.37% 22.37% 22.37% 22.37% (%) Deviation 0 , 29% 19.20% 17.44% 9.65% 14.40% 9.44% 8.85% 6.76% 6.03% 6.53% 6.51% 6.50% 7.02 % 6.25% (±%) Water + 98.83% 99.91% 98.37% 77.89% 65.21% 46.70% 45.42% 45.76% 45.67% 46.02 % 46.02% 46.27% 45.93% 46.27% Mucine

(%) Deviation 0.58% 0.29% 5.06% 38.43% 10.54% 0.76% 5.06% 5.22% 5.22% 5.39% 5.58% 5, 77% 5.89% 6.11% (±%)

[125] As can be deduced from this Table 6, the sample in example 1 showed a mucus adhesion of 46.1% when stabilized versus a percentage of deionized water equal to 12.33%. The percentage corresponding to the adhesion of the sample without mucin was 22.37%. As the differential adhesion versus the negative control was statistically significant (p <0.0001), it can be concluded that the tested sample (Example 1) showed mucus adhesion properties.

[126] The data are also derived from FIG. 1, in which there is a comparative graph of the levels of mucus adhesion of a gel of the invention over time, recorded by means of a gravimetric test on an inclined plane with controlled temperature treated with mucin. The error bars show the standard deviation for each data set. The adherence score (%) on the Y axis is indicated as a percentage of adherence. The X axis shows the time in minutes (min). Each data set includes water data (first column of the set), water data on an inclined plane containing mucin (second column of the set), sample (third column of the set) and sample on an inclined plane containing mucin (fourth column of the set) set).

[127] All these data allow us to conclude on the one hand that, using the carboxy (C1-C3) alkyl cellulose and / or a salt thereof, the mixture comprising sodium hyaluronate and chlorhexidine gluconate showed a gel consistency in which none chlorhexidine precipitation was observed. Therefore, it was a colorless gel composition. On the other hand, the gel showed mucus adhesive properties, therefore, being able to be topically applied to any surface, such as skin or even mucin-containing surfaces such as the gums of the oral cavity. These adhesive properties allow any asset contained in the gel, for example, sodium hyaluronate and chlorhexidine, among other assets, to remain on the surface long enough to provide its effects. Example 3 - Clinical trial of the effectiveness of the gel of the invention comprising chlorhexidine and hyaluronic acid

[128] The gel in Example 1 (Table 1) was tested to see if the gel with both assets could be used together in dental practice after tooth extraction. The evolution of the degree of pain and inflammation after extraction, as well as the degree of healing (or degree of healing, used as a synonym for healing) were evaluated. The secondary aspects that were evaluated included the ease of application and handling of the gel, its consistency and flavor, as well as whether there was any effect on the formation of the biofilm. Materials and methods

[129] A prospective double-blind clinical trial was conducted with 30 patients. The experimental group (or the test group) included 15 patients who received the gel of Example 1. The control group also included 15 patients, who received as a placebo a gel without hyaluronic acid and chlorhexidine. Volunteer patients from the Center for Implantology and Oral Surgery (Madrid, Spain) with a need for extraction were properly informed of the trial and all gave mandatory authorization. Patients were recruited according to the inclusion parameters (age 18 - 39; dental extraction of parts 15 - 25 35 - 45 due to decay or periodontal disease without any infection; people in good health; no drug use). The trial was authorized by the ethical committee of Hospital Clínico San Carlos de Madrid (Spain) under code 18 / 129RX.

[130] Regarding the degree of healing, the distance measured in millimeters (mm) at the time of extraction was determined. The measurement was the middle end of the tongue or the middle palatal vestibular end of the tooth socket, which was determined again after 24, 48 and 72 hours after tooth extraction.

[131] Regarding the pain felt and the inflammation, a visual analog scale was used to question the patients about the severity of the pain: painless (rating 0), mild (rating 1 to 2), moderate (rating 3 to 7) and intense (rating from 8 to 9).

[132] The results are shown in Tables 7 to 10 below. Table 7 - Healing of the control group Parts Patient 0 h 24 h 48 h 72 h Week extracted 1 5 2 1 0 0 11 2 7 4 2 1 0 14 3 3 1 0 0 0 22 4 6 4 2 1 0 33 5 3 1 0 0 0 12 6 4 2 1 0 0 22 7 7 5 2 1 0 23

FASHION 7 (4) 3 (4) 2 (7) 0 (8) 0 (14) AVERAGE 84 48 22 8 2 Table 8 - Pain in the control group Pieces Patient 24 h 48 h 72 h Week extracted 1 2 1 0 0 11 2 4 3 0 0 14 3 0 0 0 0 22 4 3 2 0 0 33 5 2 0 0 0 12 6 3 1 0 0 22 7 4 4 3 1 23 8 5 5 3 1 14 9 3 1 0 0 21 10 5 2 0 0 14 11 5 3 1 0 24 12 2 0 0 0 12 13 3 1 0 0 21 14 5 6 8 8 14 15 3 1 0 0 24 FASHION 3 (5) 1 (5) 0 (11) 0 (12 )

AVERAGE 49 30 15 10 Table 9 - Healing of the test group Pieces Patient 0 h 24 h 48 h 72 h Week extracted 16 8 3 1 0 0 33 17 4 1 0 0 0 31 18 5 2 0 0 0 21 19 6 2 1 0 0 44 20 6 3 1 0 0 34 21 7 3 1 0 0 33 22 5 2 0 0 0 21 23 4 1 0 0 0 22 24 6 3 1 0 0 35 25 8 3 1 0 0 14 26 7 3 1 0 0 13 27 1 1 0 0 0 22 28 4 1 0 0 0 12 29 7 3 1 0 0 35 30 1 1 0 0 0 31 AVERAGE 79 32 8 0 0 FASHION 6 (3) 3 (7) 1 (8) 0 ( 15) 0 (15) Table 10 - Pain in the test group Pieces Patient 24 h 48 h 72 h Week extracted 16 3 1 0 0 33 17 0 0 0 0 31 18 0 0 0 0 21 19 2 0 0 0 44 20 4 2 0 0 34

FASHION 29 16 6 2 AVERAGE 0 (6) 0 (7) 12 (0) 0 (13)

[133] In view of the results obtained, the descriptive statistics were exposed.

[134] Regarding the variable of the degree of healing, a mean initial exposure after extraction of 5.6 mm was observed in the control group (patients 1 to 15), similar to the 5.2 mm in the experimental group. At 48 h, in the control group, the closure extended to a marginal space of 3.2 mm and, in the test, it was 2.13 mm, showing an improvement close to 1 mm in the test group. Similarly, it was translated into the evaluation of the groups at 48 h, which was 1.4 mm and 0.5 mm of mean values in both control and experimental groups, respectively. It is noteworthy that the experimental group at 72 h had a complete closure also maintained throughout the week. The control group showed values of 0.5 mm and 0.13 mm at those times, respectively, which could be influenced in part by the presence of alveolar osteitis in the volunteers in the control group.

[135] Regarding pain after extraction, the control group showed mean values of 3.2 - 2 - 1 and 0.6 according to the observed times of 24h - 48h - 72h and one week after the extraction. The values in the experimental group were 1.9 - 1 - 0.4 and 0.13 at the same determination times. Therefore, the results regarding pain were also lower in all stages of observation in the experimental group, when compared to the control.

[136] It should be noted that some patients in the control group developed alveolar osteitis, as mentioned above. This type of inflammation, which is a postoperative complication of tooth extraction, was not detected in any of the patients in the experimental group. In addition, no adverse reaction (allergy) was detected.

[137] Based on the results, the following conclusions have been reached.

1. The degree of healing assessed in the experimental group resulted in an improvement in the experimental group compared to the control group, especially in the first 24 - 72 h.

2. The pain felt by the patient, also in average values, seems to present lower values at all times questioned in the experimental group in relation to the control group.

3. The results obtained show that the product of Example 1 (Table 1), based on chlorhexidine and hyaluronic acid, has satisfactory properties in relation to the perception of the level of pain and the degree of healing after tooth extraction (healing).

Example 4 - Cosmetic use of the inventive gel

[138] An oral gel composition, as described in Example 1 (Table 1), was tested on a group of volunteers of varying ages and who did not suffer from any (healthy) oral disease. The objective was to evaluate the cosmetic (aesthetic) effect of the oral gel composition in terms of the appearance of the gums, mainly due to hydration linked to the presence of hyaluronic acid and strengthening of the gums.

[139] The study was conducted in accordance with European Parliament Regulation and Council Regulation (EC) No. 1223/2009 of 30 November 2009 for cosmetics.

[140] The volunteers included 30 people who participated in the study (informed not to use any type of antihistamines or pharmacological agents). They received an oral gel pack containing hyaluronic acid and were required to use it regularly for 3 weeks by: spreading it over clean gums with circular massage movements; the non-use of other products with the same or similar purpose, the immediate cession in case of any side effects in the tested area and reports to the dermatologist, observation and record of the observations.

[141] The parameters evaluated included: irritation of the membranes and gums; improvement of the appearance and condition of the gums and mucous membranes; protection of gums and membranes; maintenance of the oral mucosa in good condition; strengthening of gums; intensive hydration of membranes; use to improve the appearance of gums.

[142] Based on research by dermatologists and endocrinologists / diabetologists, individual assessments of individuals and collected interviews, it was found that:

1. The cosmetic formulation does not cause any symptoms that could demonstrate its harm, that is, allergic or toxic effects - irritating to the mucosa, membranes or gums. The people involved in the tests did not report any serious symptoms, that is, itching, contradiction or others that may suggest a negative impact of the tested product on the skin.

2. This opinion does not apply to participants with an allergy to any component of the evaluated formulation.

3. Tests performed during use, as well as observations by dermatologists confirmed that the oral gel is a cosmetic product that can be recommended for the daily care and protection of mucous membranes and gums of people of all ages.

4. The tested products used according to the recommendations, due to the good composition of the active ingredients, have beneficial and multidirectional effects in order to improve the condition of the mucous membranes and the oral cavity.

5. Each application contributes to improving the hydration of the oral mucosa, which brings relief and restores the feeling of comfort.

6. People who participate in evaluating the effectiveness of the tested product confirm that, during its use, there is a noticeable improvement in the condition of the mucous membranes and gums.

7. Based on the opinion of the participants, it was confirmed that the product tested during its application brings a feeling of long-lasting freshness.

8. The gel was characterized by: the right consistency, pleasant taste, high efficiency in use, adequate durability of the effect, which does not change during application and which encourages the regular use of the preparation.

[143] In addition, people who participated in the study indicated that the product tested had an adequate consistency, acceptable aesthetic color and fragrance. In addition, the well-composed active substances contained in the product evaluated with each application ensure proper care of the mucous membranes and gums of people of different ages. List of Citations

[144] Patent literature

[145] WO 9852612

[146] CH 691030

[147] RU 2286764

[148] WO 2008144185

[149] US 5192802

[150] US 6117415

Claims (6)

1. Classification box CHARACTERIZED by the fact that it contains a housing (10) comprising: a pair of side plates (11) perpendicular to the wide (W) direction of the housing (10) and located on the opposite sides of the housing (10) in the width direction (W); a feed inlet (12) formed on one side of the housing (10) in a height direction (H) that is perpendicular to the width direction (W); a discharge end (13) formed on the other side of the housing (10) in the height direction (H); an air inlet (14) formed on one side of the housing (10) in a length direction (L) perpendicular to the width direction (W) and the height direction (H); and an air outlet (15) formed on the other side of the housing (10) in the long direction (L) and opposite the air inlet (14); and a plurality of rupture rods (20) fixed horizontally between the pair of side plates (11), wherein the rupture rods (20) included in the two rows of rupture rods (20) adjacent in the height direction (H) they are arranged in a staggered manner; wherein the plurality of rupture rods (20) are located on the side of the housing that is closest to the feed inlet (12) in the height direction (H), and are located on the side of the housing (10) that is closest of the air inlet (14) in the length direction (L). 2. Classification box, according to claim 1, CHARACTERIZED by the fact that it additionally comprises a supply line (30). The supply line (30) is a straight pipe with one end connected to the supply port (12); the supply line (30) is perpendicular to the wide direction and inclined towards the side of the air inlet (14). 3. Classification box, according to claim 2, CHARACTERIZED by the fact that the length of the supply line (30) in the height direction (H) is 2 to 5 meters, and the angle between the supply line ( 30) and the length direction (L) is 40 to 60 degrees. 4. Classification box, according to claim 3, CHARACTERIZED by the fact that the cross section of the air outlet (15) along the length direction (L) is greater than the cross section of the air inlet (14) along the length direction (L). 5. Classification box, according to claim 1, CHARACTERIZED by the fact that the cross section of the housing (10) is gradually reduced in the height direction (H) towards the discharge end (13). 6. Classification box according to claim 1, CHARACTERIZED by the fact that it additionally comprises a plurality of pairs of mounting brackets (40), in which each pair of mounting brackets (40) is respectively located on both sides side plates (11) in the wide direction (W).