BR112020002106B1 - GEL COMPOSITION, PREPARATION METHOD AND USE - 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, wherein the gelatinous matrix comprises water, and cellulose derivatives. The invention also relates to a method for preparing the gels and the particular uses of the gels in the field of cosmetics for the oral cavity, hygiene, prevention of diseases of the oral cavity and treatment of said diseases.

Description

technical field

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

Background of the technique

[2] According to the World Health Organization (WHO), oral health is a state of being free from various 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 (gum) disease, tooth decay and tooth loss. Risk factors are unhealthy diet, 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.

[3] Oral tissues require maintenance of proper oral hygiene by toothbrushing, flossing, dentifrices, gels, mouthwashes, etc. In particular, mouthwashes are used in addition to conventional toothbrushing and to reduce plaque buildup. These mouthwashes are also used for patients.

[4] These oral care compositions are also used to treat bad breath, primarily 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 bacterial plaque and the activity of microorganisms, while being safe and respectful of gingival and dental tissues.

[5] With this objective, there are compositions for oral hygiene comprising chlorhexidine widely known and marketed. Chlorhexidine is, so far, the most commonly used oral antiseptic, acting as both bactericidal and bacteriostatic. It's a biguanide. Chlorhexidine (CHX) has some side effects, such as discoloration of the teeth and lingual mucosa with increased formation of supragingival calculus; in addition, taste disturbances have been reported, as well as discoloration of some restorative materials.

[6] 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 healing acute and chronic oral lesions, especially periodontal changes. HA forms a protective surface film on the oral mucosa. In vivo, the plaque growth inhibition activity of HA in 4-day plaque regrowth models is comparable to CHX. HA is also known as a mucoadhesive agent.

[7] Liquid compositions comprising both compounds are known. These are mouthwashes that aim to preserve oral hygiene. Examples of these compositions are commercially available and also described in 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 marketed mouthwash products EllaDent Perio 020 and CURASEPT®ADS Perio.

[8] Using rinses has the inconvenience that they need to be held in the mouth for a predetermined period to achieve the effect. Furthermore, they need to be used more than once a day and frequently to ensure their effectiveness in the case, for example, of gum wounds due to surgical intervention or due to a pathological process.

[9] Long-lasting active delivery compositions are formulated as gels with adequate consistency. The gels are applied to the gums and the actives are gradually released.

[10] Gels comprising only chlorhexidine include hydroxy ethyl cellulose, for example, as a gel-forming agent (for example: Curasept ADS 350 gingival gel; 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, mixing both types of gel in order to present a gel with the two active ingredients, chlorhexidine and hyaluronic acid or one of its salts, results in a gelatinous formulation with a chlorhexidine precipitate.

[11] However, prior art gels comprising both chlorhexidine and hyaluronic acid are described. An example is the gel for feminine hygiene 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 smooth, compact, filamentous, transparent, clean and colorless gel. The inventors of CH691030 propose the gel also for the disinfection of the oral cavity, although no specific example is given.

[12] 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 polyvinyl alcohol with sodium alginate as a gelling agent.

[13] Although the aforementioned gels have been publicized, 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 actives, or even liquid compositions with both compounds to be used in the oral cavity. A likely reason is, as stated, 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 prevent precipitation.

[14] Therefore, compositions with both ingredients are not stable for a long time. 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.

[15] 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 tissue adhesive properties are not good or are compromised, thus rendering them not useful.

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

[17] Therefore, it is evident that there is still a need in the field for alternative formulations that avoid the aforementioned drawbacks, while still being effective for oral hygiene.

Summary of the invention

[18] The inventors have determined that chlorhexidine, or a salt thereof, and hyaluronic acid, or a salt thereof, can be formulated together as a clear gel composition with good adhesion properties for the oral cavity (in particular, when tooth 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 show high moisturizing properties and are versatile in terms of that a wide range of chlorhexidine and hyaluronic acid concentrations can be incorporated into the gel.

[19] 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 percentage by weight comprised of 0.05 % w / w to 1.5 % w / w, based on 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.

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

[21] In this gel composition, hyaluronic acid and/or a pharmaceutically or cosmetically acceptable salt thereof also contributes to shaping the gel as 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 a mucus adhesive.

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

[23] Furthermore, the gel composition not only solves the problem of precipitation of chlorhexidine into 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). Furthermore and surprisingly, the gel composition maintains its consistency and transparency in the case of its colorless (which means that at least no precipitation of chlorhexidine 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.

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

[25] In a second aspect, the invention encompasses a method for preparing a gel composition as defined in the first aspect and its embodiments, 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 polyalkylene glycol, glycerine, 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.

[26] Thus, the method comprises gelatinizing 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 polyalkylene glycol, glycerine, propylene glycol and mixtures thereof.

[27] For "gelatinization" of carboxy (C1-C3) alkyl cellulose it should be understood that this ingredient is added into an aqueous solution and gel formation is promoted (or corrected).

[28] 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. Furthermore, the gels of the invention are useful for preserving the good health of the oral cavity, in particular the gums, after brushing.

[29] Thus, another aspect of the invention is a gel composition as defined above, for use as a medicine.

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

[31] 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 to which it is applied. For example, improvement in the elasticity of the skin or appearance of the oral cavity, leading to a healthy appearance of gums and oral mucosa. This cosmetic effect also helps to present a proper tissue condition that avoids or minimizes the risk of disease (in particular or of the oral cavity) and/or allows for improved healing in the event of tissue damage for any reason (i.e. tooth extraction). .

[32] Still, another aspect of the invention is the use of a gel composition as defined above, as a cosmetic oral hygiene agent for moisturizing, strengthening and improving the appearance of oral mucosa and gums, wherein said gel comprises cosmetically effective amounts of hyaluronic acid and/or a cosmetically acceptable salt thereof, and cosmetically effective amounts of chlorhexidine, said effective amount being a percentage by weight ranging from 0.05% w/w to 1.5% w/w, relative to the total weight of the composition in gel. Thus, another aspect of the invention is a topical pharmaceutical or cosmetic 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 topical excipients or carriers.

[33] 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 hygiene of the oral cavity. This aspect is more related to the cosmetic effect of the combination of active ingredients, which allow for a healthy appearance of gums and teeth. This aspect may also be formulated as a gel composition as defined above, for use as an oral cavity cosmetic care agent. Alternatively, for use 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 for the oral cavity. The cosmetic use of the gel composition of the invention implies the use of cosmetically acceptable excipients or carriers which can be coincident with pharmaceutically acceptable excipients or carriers.

[34] 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.

[35] Therefore, to 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 figures

[36] FIG. 1, related to Example 2, is a graph comparing the levels of mucus adhesion of a gel of the invention over time, recorded by means of a gravimetric test on a temperature-controlled inclined plane treated with mucin. Error bars show the standard deviation for each data set. The percentage of adherence score (abbreviated AS (%)) on the Y-axis is indicated as percentage of adherence. The X axis shows time (T) in minutes (min). Each dataset includes data from water (first column of the set), data from water 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

[37] All terms used herein in this application, unless otherwise noted, are to be understood in their common meaning as known in the art. Other more specific definitions for certain terms, as used in this application, are set forth below and are intended to apply uniformly throughout the specification and claims, unless an otherwise express definition provides a broader definition.

[38] A “gelling agent” (or gellant) 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 agent or thickener is a substance which can increase the viscosity of a liquid without substantially changing its other properties. Thickening agents used in cosmetic, pharmaceutical or personal care products include various liquids such as polyethylene glycol, synthetic polymers such as carbomer (a brand name for polyacrylic acid) and vegetable gums. A gel is a gelatin-like solid material that can exhibit properties ranging from soft and weak to hard and strong. Gels are defined as a substantially dilute crosslinked system which does not exhibit flow when in the fixed state. By weight, gels are mostly liquids, although they behave like solids due to the three-dimensional lattice within the liquid. It is crosslinking within the fluid that gives a gel its structure (hardness) and contributes to stickiness (adherence). 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.

[39] By "gelatinous matrix", it should be understood, in the sense of the present invention, as a composition comprising a solvent; in particular water, and a gelling agent. The gelatinous matrix keeps all solutes (active ingredients) either completely dissolved or completely suspended in the solvent, all of which are incorporated into the loosely cohesive internal structure formed by the gelling agent.

R= H ou -(Ci-C3)alquilCθ2H[40] “Carboxy (C1-C3) alkyl cellulose” is a cellulose derivative with carboxy (C1-C3) alkyl groups (-(C1-C3) alkyl COOH) attached to one of the hydroxyl groups of the glycopyranose monomers that make up the structure of cellulose. 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, as is sodium carboxy methyl cellulose.

R= H or -(C1-C3)alkylCθ2H

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

[42] Depending on the percentage by weight 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 monomeric 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 the viscosity.

[43] By “suspending agent” is to be 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 suspending agent for CHX in an aqueous gel comprising hyaluronic acid or a salt thereof. Carboxy (C1-C3) alkyl cellulose is also used as a thickening agent or gelling agent.

[44] The term “oral cavity” encompasses, according to this specification, both 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 at the sides and front by the alveolar process (containing the teeth) and at 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 mylohyoid muscles and is mainly occupied by the tongue. A membrane - the oral mucosa, lines the sides and, under the surface of the tongue to the gums, lines the inner aspect of the jawbone (jaw). It receives secretions from the submaxillary and sublingual salivary glands.

[45] The expression “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 human and animal tissue or organs without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable risk/benefit ratio. In the particular case where the gels are used in the oral cavity, the excipients are orally acceptable, which means that they can be used without problems or complications if they are finally swallowed and reach the digestive tract.

[46] The term "therapeutically effective amount" as used herein, refers to that amount of a compound which, 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.

[47] The term “cosmetically acceptable” refers to those excipients or carriers suitable for use in contact with the oral cavity mucosa and 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.

[48] 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.

[49] 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.

[50] 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 embodiment, the 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.

[51] Carboxy methyl cellulose is known as a bioadhesive pharmaceutical carrier from US patent US 5192802 or US patent US 6117415. In these documents, carboxy methyl cellulose is used in combination with xanthan gum or sodium alginate to promote adhesion to adhesives. mucous membranes and thus release pharmaceutical actives of interest in a controlled manner. In US 6117415, it is also mentioned that the degree and amount of carboxy methyl cellulose can be adjusted in the toothpaste according to the desired viscosity of the paste.

[52] The gels of the invention are designed and intended to remain on the desired surface of the application for a period of time that allows the actives in the gel to be released and then perform their effect. Carboxy methyl cellulose or carboxy (C1-C3) alkyl cellulose and its salts provide the required adhesion to the gel of the invention and, surprisingly, result in an ingredient that allows to join 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.

[53] In one embodiment, the gel composition of the present invention is one in which the carboxy (C1-C3) alkyl cellulose has a carboxy (C1-C3) alkyl moiety content 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 carboxy (C1-C3) alkyl cellulose. Measurements of the content of carboxy(C1-C3)alkyl moieties can be performed by any method known in the art.

[54] 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 of from 1.15 to 1.45 measured in accordance with American Standard ASTM D1439. In a particular embodiment, the carboxy (C1-C3) alkyl cellulose is Blanose 12M31P, a carboxy methyl cellulose.

[55] 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 fluid resistance to shear, also called dynamic viscosity or shear viscosity and defined mathematically as a quotient of the shear stress ratio. Usually, viscosity is measured by the use of devices such as rotational viscometers or rheometers which measure the torque exerted on a shaft in contact with the sample when it is rotated at a precisely controlled angular velocity. Conversion of torque and speed to stress and shear rate, respectively, is straightforward by multiplication by calibration constants. In the present invention, viscosity measurements are performed using a Brookfield viscometer, spindle #2 (SP2), operating at 0.3 rpm).

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

[57] In another particular embodiment of the first aspect of the invention, the 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 embodiment above or below, the pharmaceutically acceptable salt of chlorhexidine is chlorhexidine gluconate. Chlorhexidine gluconate is also known as chlorhexidine digluconate (used interchangeably herein).

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

[59] As indicated above, hyaluronic acid is the main component of the extracellular matrix of many tissues and is present in human saliva which acts as a lubricant. Hyaluronic acid is also a mucoadhesive 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 tissue must be repaired, 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 exposed above.

[60] 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 1.3 to 2.5 MDa.

[61] 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).

[62] 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 in the gel composition without showing precipitation. This is surprisingly achieved within a wide range of hyaluronic acid concentrations. Thus, in another particular embodiment, the weight percentage of hyaluronic acid or a salt thereof, in relation to the total weight of the gel composition is from 0.1 to 1.0%. More specifically, it is from 0.1 to 0.8%, in particular 0.75%. In another particular embodiment, it is from 0.1 to 0.5% and, even more in particular, it is from 0.1 to 0.30%. More particularly, it is from 0.10 to 0.25%. Even more particularly, this is selected from 0.10%, 0.15%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24% and 0.25%.

[63] 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, relative to the total weight of the gel composition of 0.05 % to 1.5%; - a percentage by weight of hyaluronic acid or a pharmaceutically or cosmetically acceptable salt thereof, relative to 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%.

[64] 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 (exodontia). The gel adheres widely to oral tissue (mainly gums and tooth socket in the case of tooth extraction) and allows the controlled distribution of both chlorhexidine and hyaluronic acid (or any of its salts), both active compounds being effective since they do not precipitate in the gel composition.

[65] 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.

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

[67] In the gel composition according to the first aspect of the invention, the gelatinous matrix with carboxy (C1C3) alkyl cellulose or a salt thereof, but also hyaluronic acid or a salt thereof, contribute to the gel consistency of the composition, mainly due to its polymeric nature and behavior in water.

[68] 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 gelling 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, gum tragacanth, xanthan gum and mixtures thereof.

[69] Then, in another particular embodiment, optionally in combination with any modality 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 the same, said effective amount being a percentage by weight comprised of 0.05% w/w to 1.5% w/w, relative 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 polyalkylene glycol, glycerine, propylene glycol and mixtures thereof.

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

[71] The inventors have observed that, with the use of a solvent of polyol nature 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 carboxy (C1-C3) alkyl cellulose or a salt thereof allowed for 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 surfaces to which the gel composition is applied. In particular, it improves adhesion to the animal's skin and to 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.

[72] Although carboxy(C1-C3) alkyl cellulose or a salt thereof is also present as a gelling agent in the gelatinous matrix, no precipitation is observed, the gel composition comprises, in a particular embodiment, additional compounds that help to avoid precipitation when gel compositions comprise a large amount of ingredients. Thus, 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 in a percentage by weight relative to the total weight of the gel composition from 0.05% to 1%. More particularly, it is from 0.1% to 0.40%. More particularly, it is from 0.1% to 0.20%. More particularly, the chelating compound is ethylene diamine tetraacetic 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 sodium gluconate. In a more particular embodiment, the compound gluconate or sodium gluconate is comprised in 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 in a percentage by weight of 0.1% to 1.0%.

[73] These chelating compounds, also called chelating agents, chelating agents, or sequestering agents, are polydentate molecules that establish coordinate bonds with metal ions. 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 gelling agent.

[74] 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 carboxy (C1-C3) alkyl cellulose, an antimicrobial agent, an aqueous vehicle (i.e., water) and mixtures thereof.

[75] 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, peppermint oil , cinnamon leaf oil, clover leaf oil, tea tree oil and origanum oil.

[76] While chlorhexidine or one of its salts acts as an antimicrobial agent by itself, in another particular embodiment of the first aspect, optionally in combination with any embodiment above or below, 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, benzalkonium, octenidine (as one of its salts), and mixtures thereof.

[77] 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 gelling agent does not change its pH, which means that, at the proper pH, no precipitation of chlorhexidine and/or one of its salts will occur.

[78] 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 thereof, 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.

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

[80] 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.

[81] Then, in a particular embodiment, 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 polyol nature , more in particular with propylene glycol, glycerin or a mixture of both, said polyol acts as a dispersant for chlorhexidine or a salt thereof. Optionally, said aqueous premix is, in another particular embodiment, derivatized with polyalkylene glycols, said polyalkylene glycols soluble in water and having a molecular weight of 50 to 200 Da. The solvent is, in another particular embodiment, optionally derivatized with oils. Examples of oils to add to the premix include castor oil.

[82] This premix is further completed with carboxy (C1-C3) alkyl cellulose and/or a salt thereof, which evolves to a gel consistency once it comes into contact with the aqueous premix.

[83] 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 its salts to be stably suspended in the aqueous gel .

[84] The gel composition of the first aspect is for use as a medicine. In a more particular embodiment it is for use in the treatment of diseases, disorders or conditions of the oral cavity selected from the group consisting of plaque and calculus, decay, gingivitis, periodontitis, mucositis, oral ulcers, tooth 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 medicament 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, tooth sensitivity and combinations thereof. The present invention also relates to a method for treating or preventing diseases, disorders or conditions of the oral cavity, selected from the group consisting of plaque and calculus, decay, gingivitis, periodontitis, mucositis, oral ulcers, tooth sensitivity, and combinations thereof comprising administering a pharmaceutically effective amount of the compound from the gel, as defined above, together with pharmaceutically acceptable excipients or carriers, to a subject in need thereof, including a human.

[85] 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.

[86] 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 teeth, in front of teeth, behind teeth, on 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 bacterial degradation of fermentable sugar - and periodontal problems such as gingivitis and periodontitis; therefore, it is important to stop the mass of bacteria and remove it. Plaque control and removal can be achieved with proper daily or twice-daily brushing 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 the teeth (also known as tooth decay) or hardening into dental calculus.

[87] Tooth decay or decay, also known as caries or tooth decay, is a breakage of teeth due to acids produced by bacteria. The cavities can have many different colors, from yellow to black. Symptoms can include pain and difficulty eating. Complications can include inflammation of the tissue around the tooth, tooth loss, infection or abscess formation. The main cause of caries is acid from bacteria, which dissolves the hard tissues of the teeth (enamel, dentin and cementum). Acid is produced from food residue or sugar on the surface of the tooth. The simple sugars in food are the main source of energy for these bacteria, and therefore 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. Medications that decrease saliva production include antihistamines and antidepressants. Caries is also associated with poverty, poor cleaning of the mouth, and receding gums, resulting in exposed tooth roots.

[88] Gingivitis (“inflammation of the 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, 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.

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

[90] Mucositis is painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere in the gastrointestinal (GI) tract, however, oral mucositis refers to 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 nearly all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with head and neck malignancies receiving radiotherapy, and a wide range of patients who receive chemotherapy.

[91] 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 a variety of mechanisms, but there is usually no serious underlying cause. The two most common causes of oral ulceration are local trauma (eg, friction from a sharp edge on a broken filling) and aphthous stomatitis (“thrush”), a condition characterized by the recurrent formation of oral ulcers for largely unknown reasons. Mouth ulcers often cause pain and discomfort, and may change a person's food choices as they heal (for example, avoiding acidic or spicy foods and drinks).

[92] Tooth sensitivity or dentin hypersensitivity (abbreviated DH or DHS, and also called sensitive dentin, dentin sensitivity, cervical sensitivity, and cervical hypersensitivity) is an acute, short-lived toothache resulting from exposed tooth surfaces. 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 usually not felt with everyday 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 more accurate. The main cause of HD is gingival recession (removing gums), with exposure of root surfaces, loss of cementum layer and residual layer, and tooth wear. Receding gums can be a sign of long-term trauma from excessive or heavy brushing, or brushing with an abrasive toothpaste (dental abrasion) or a sign of chronic periodontitis (gum disease).

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

[94] A tooth extraction (also called a tooth extraction, tooth extraction, tooth extraction, or, informally, tooth extraction) 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, particularly when associated with toothache. Sometimes wisdom teeth are impacted (stuck and unable to grow normally in the mouth) and can cause recurrent gum infections (pericoronitis). In orthodontics, if the teeth are crowded together, the sound teeth can be extracted (usually bicuspid) to create space for the rest of the teeth to be straightened.

[95] 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, stitches are used to replace the gum in its normal position. However, tooth extraction is a surgical act performed in the oral cavity, producing tissue damage. The postoperative period in tooth extraction is a challenging process, affecting the patient's quality of life due to pain and inflammation in the area associated with healing events. In this way, after a tooth extraction, a blood clot is formed in the tooth socket and tissue regeneration and recovery. Early healing processes include formation of granulocyte tissue in the tooth socket which is progressively replaced by new bone tissue.

[96] 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.

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

[98] 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 relates 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.

[99] The gel is used as a cosmetic oral hygiene agent for moisturizing, 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 of the same and cosmetically effective amounts of chlorhexidine and/or a cosmetically acceptable salt thereof, said effective amount of the chlorhexidine or salt being a percentage by weight comprised of 0.05% w/w to 1.5% w/w, relative to the total weight of the gel composition.

[100] A more particular modality of the use of the gel as a cosmetic agent for oral hygiene is for daily cosmetic care and for the protection of the mucosa and gums.

[101] 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 gel consistency, it remains for an adequate time on the surface and thus allows the absorption of any of the actives that the gel contains.

[102] Thus, topical cosmetic gel compositions as defined above are also used as a skin care agent, wherein the skin care comprises improvement of at least one of the following symptoms: roughness, scaling, dehydration , stiffness, cracking, reduced scarring and lack of elasticity.

[103] 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, yet low enough to avoid serious side effects (with a risk ratio / reasonable benefit), within the scope of good medical sense. 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.

[104] 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 (C3C6 hydroxyl cellulose), hydroxy propyl methyl cellulose and mixtures thereof , wherein the excipient(s) optionally replace carboxy (C1-C3) alkyl cellulose and/or a salt thereof.

[105] Throughout the specification and claims, the word "comprises", and variations of the word, are not intended to exclude other technical features, additives, components or steps. Also, 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 practice of the invention. The following examples are provided for purposes of illustration and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

Examples Example 1 - Aqueous gel formulations for topical use

[106] 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.

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

Tabela 3 - Fórmula para composição em gel incolor compreendendo 1.0 % em peso de ácido hialurônico. Composição para 100 g

Tabela 4 - Fórmula para composição em gel incolor compreendendo 0.75 % em peso de ácido hialurônico. Composição para 100 g

Tabela 5 - Fórmula para composição em gel incolor compreendendo 0.50 % em peso de ácido hialurônico. Composição para 100 g

[108] Table 2 below shows the appearance and consistency of various gel compositions comprising chlorhexidine and hyaluronic acid. The presence of carboxy methyl cellulose provided adequate gel consistency (colorless or white), but no precipitation was observed. Table 2 - Other gel compositions of the invention.

Table 3 - Formula for colorless gel composition comprising 1.0% by weight of hyaluronic acid. Composition for 100 g

Table 4 - Formula for colorless gel composition comprising 0.75% by weight of hyaluronic acid. Composition for 100 g

Table 5 - Formula for colorless gel composition comprising 0.50% by weight of hyaluronic acid. Composition for 100 g

[109] 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 were supplemented with a sweetener (sucralose) in order 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 for the evaluation of the mucoadhesive properties of a topical product

[110] The colorless gel of Example 1 (Table 1; gel composition with 0.24% hyaluronic acid) was tested in order to evaluate the mucoadhesive properties through gravimetric testing on a temperature-controlled inclined plane treated with mucin.

[111] The purpose of the test is to evaluate the mucoadhesive properties of a topical product by analyzing the kinetic release 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 sample sliding and plane detachment caused by mucin.

[112] The steel plane was positioned horizontally and the temperature control was set 60 minutes in advance. 4 ml of the analyzed sample or deionized water were positioned at the predefined running distance and left to settle for 2 minutes - To start the running, the plane was set at a 45° incline. The amount of sample detached 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. Timed recording of the measurement was controlled directly by the balance software

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

[114] The plan was precisely cleaned and prepared before each race. For mucin pellicle runs, the flat was precoated with an 8% suspension in water of porcine gastric mucin type II (Sigma Aldrich) spread to make a uniform pellicle.

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

[116] Temperature: 36°C

[117] Steel plane inclination: 45°

[118] Running surface length: 10cm

[119] Race duration: 60 seconds.

[120] To determine a mucus adherence value, the average of the 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 construct a graph of adherence versus time.

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

[122] In order to exhibit mucoadhesive properties, a sample must exhibit a significantly higher percentage of adhesion versus the control without mucin (p < 0.05) than that exhibited by water, which interacts with the protein only through the hygroscopic absorption.

[123] Results are reported below in Table 6 as percent adherence over time ± standard deviation. Table 6

[124] As can be deduced from this Table 6, the example 1 sample showed a mucus adhesion of 46.1% when stabilized versus a percentage of deionized water equal to 12.33%. The percentage corresponding to adherence 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 sample tested (Example 1) showed mucus adhesion properties.

[125] Data is 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 a temperature-controlled inclined plane treated with mucin. Error bars show the standard deviation for each data set. The adherence score (%) on the Y-axis is indicated as percentage of adherence. The X axis shows time in minutes (min). Each dataset includes data from water (first column of the set), data from water 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).

[126] All these data allow to conclude on the one hand that, using the particular carboxy (C1-C3) alkyl cellulose and/or a salt thereof, the mixture comprising sodium hyaluronate and chlorhexidine gluconate showed a gel consistency in which neither Chlorhexidine precipitation was observed. Soon, it was a colorless gel composition. On the other hand, the gel showed mucoadhesive properties, thus being able to be applied topically on any surface, such as the skin or even mucin-containing surfaces such as the gums of the oral cavity. These adhesive properties allow any active contained in the gel, for example, sodium hyaluronate and chlorhexidine, among other actives, 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

[127] The gel from example 1 (Table 1) was tested in order to see if the gel with both actives 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 scarring (or degree of cure, used synonymously with scarring) were evaluated. Secondary aspects that were evaluated included the ease of application and handling of the gel, its consistency and taste, as well as whether there was any effect on biofilm formation.

Materials and methods

[128] 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 a gel without hyaluronic acid and chlorhexidine as a placebo. Volunteer patients from the Center for Implantology and Oral Surgery (Madrid, Spain) with a need for tooth extraction were duly informed of the trial and all gave the mandatory authorization. Patients were recruited according to the inclusion parameters (age 18 - 39; tooth extraction 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 the Hospital Clínico San Carlos de Madrid (Spain) under code 18/129RX.

[129] Regarding the degree of scarring, the distance measured in millimeters (mm) at the time of extraction was determined. The measurement was the middle extremity of the tongue or the midpalatal buccal extremity of the tooth socket, which was determined again after 24, 48 and 72 hours after tooth extraction.

[130] Regarding perceived pain and inflammation, a visual analogue scale was used to ask patients about the severity of pain: no pain (score 0), mild (score 1 to 2), moderate (score 3 to 7) and intense (rating 8 to 9).

Tabela 8 - Dor no grupo controle

Tabela 9 - Cicatrização do grupo teste

Tabela 10 - Dor no grupo teste

[131] The results are shown in Tables 7 to 10 below. Table 7 - Control group healing

Table 8 - Pain in the control group

Table 9 - Healing of the test group

Table 10 - Pain in the test group

[132] In view of the results obtained, the exposition of descriptive statistics was made.

[133] Regarding the degree of healing variable, an average initial post-extraction exposure of 5.6 mm was observed in the control group (patients 1 to 15), similar to 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 translated into the 48 h group assessment, which was 1.4 mm and 0.5 mm 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 in the measure of the week. The control group presented values of 0.5 mm and 0.13 mm at those moments, respectively, which could be partly influenced by the presence of alveolar osteitis in the volunteers in the control group.

[134] Regarding pain after extraction, the control group had mean values of 3.2 - 2 - 1 and 0.6 according to the observed times of 24h - 48h - 72h and after one week of extraction. 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 observation stages in the experimental group, when compared to the control.

[135] It should be noted that some patients in the control group developed an 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 case of adverse reaction (allergy) was detected.

[136] Based on the results, the following conclusions were reached. 1. The degree of healing evaluated 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 mean values, seems to have lower values at all times questioned in the experimental group compared 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 dental extraction (healing).

Example 4 - Cosmetic use of the gel of the invention

[137] An oral gel composition as described in Example 1 (Table 1), was tested on a group of volunteers of different ages who did not suffer from any oral disease (healthy). 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.

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

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

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

[141] Based on surveys carried out by dermatologists and endocrinologists / diabetologists, individual assessments of individuals and interviews collected, it was found that: 1. The cosmetic formulation does not cause any symptoms that could demonstrate its harm, ie allergic or toxic effects - irritants to the mucous membranes, membranes or gums. The people involved in the tests did not report any serious symptoms, ie itching, contradiction or others that could suggest a negative impact of the tested product on the skin. 2. Such an opinion does not apply to participants with an allergy to any component of the evaluated formulation. 3. Tests carried out during use, as well as observations by dermatologists, have confirmed that the oral gel is a cosmetic product that can be recommended for the daily care and protection of mucous membranes and gums for people of all ages. 4. The tested products used in accordance with the recommendations, due to the good composition of the active principles, have beneficial and multidirectional effects in order to improve the condition of the mucous membranes and the oral cavity. 5. Each application contributes to the improvement of 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 long-lasting feeling of freshness. 8. The gel was characterized by: the right consistency, the pleasant taste, the high efficiency in use, the adequate durability of the effect, which does not change during application and which encourages the regular use of the preparation.

[142] In addition, people who participated in the study indicated that the tested product 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

[143] Patent literature

[144] WO 9852612

[145] CH 691030

[146] RU 2286764

[147] WO 2008144185

[148] US 5192802

[149] US 6117415

Claims (16)

1. Gel composition CHARACTERIZED in that it comprises: - an effective amount of chlorhexidine and/or a pharmaceutically or cosmetically acceptable salt thereof, said effective amount being a percentage by weight ranging from 0.05% w/w to 1.5% w/w , relative to the total weight of the gel composition; - an effective amount of hyaluronic acid 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. 2. Gel composition, according to claim 1, CHARACTERIZED by the fact that the carboxy (C1-C3) alkyl cellulose is carboxy methyl cellulose or a salt thereof. 3. Gel, according to claim 1 or 2, CHARACTERIZED in that the pharmaceutically or cosmetically acceptable salt of chlorhexidine is selected from the group consisting of chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine hydrochloride and mixtures thereof. 4. Gel composition, according to any one of claims 1 to 3, characterized by the fact that the pharmaceutically or cosmetically acceptable salt of hyaluronic acid is selected from the group consisting of salts of alkali metals, salts of alkaline earth metals , and mixtures thereof. 5. Gel composition, according to claim 4, CHARACTERIZED by the fact that the pharmaceutically or cosmetically acceptable salt of hyaluronic acid is the alkaline metal salt sodium hyaluronate. 6. Gel composition, according to any one of claims 1 to 5, characterized by the fact that it further comprises a solvent selected from the group consisting of polyalkylene glycol, glycerin, propylene glycol and mixtures thereof. 7. Gel composition, according to any one of claims 1 to 6, characterized by the fact that it further comprises one or more compounds selected from the group consisting of an essential oil, a preservative, a flavoring agent, a humectant, a emulsifier, a chelating agent and additional gelling agent in addition to carboxy (C1-C3) alkyl cellulose, an antimicrobial agent, an aqueous vehicle and mixtures thereof. 8. Gel composition, according to any one of claims 1 to 7, CHARACTERIZED by the fact that the percentage by weight of hyaluronic acid or a pharmaceutically or cosmetically acceptable salt thereof, in relation to the total weight of the composition is of 0.1% to 1.0%. 9. Gel composition, according to any one of claims 1 to 8, CHARACTERIZED by the fact that the percentage by weight of carboxy (C1-C3) alkyl cellulose and / or a salt thereof, in relation to the total weight of the composition is from 1.0% to 5.0%. 10. Gel composition, according to any one of claims 1 to 9, characterized by the fact that: - the percentage by weight of chlorhexidine or a pharmaceutically or cosmetically acceptable salt thereof, in relation to the total weight of the gel composition is from 0.05% to 1.5%; - the weight percentage of hyaluronic acid or a pharmaceutically or cosmetically acceptable salt thereof, in relation to the total weight of the composition is from 0.1% to 1.0%; and - the weight percentage of carboxy (C1-C3) alkyl cellulose and/or a salt thereof, in relation to the total weight of the composition is from 1.0% to 5.0%. 11. Gel composition, according to any one of claims 1 to 10, CHARACTERIZED by the fact that the pH is 7.0 to 8.0. 12. Gel composition, according to any one of claims 1 to 11, characterized by the fact that it is a topical gel composition for the oral cavity comprising orally, pharmaceutically or cosmetically acceptable excipients and/or carriers. 13. Method for preparing a gel composition, as defined in any one of claims 1 to 12, characterized by the fact that it comprises: (a) forming a homogenized aqueous dispersion, said dispersion comprising chlorhexidine and / or a pharmaceutically acceptable salt or cosmetically acceptable thereof, dispersed in a solvent selected from the group consisting of polyalkylene glycol, glycerine, propylene glycol and mixtures thereof; and hyaluronic acid and/or a pharmaceutically acceptable salt thereof, dissolved in water, in which the amount of chlorhexidine is such that the percentage by weight is comprised from 0.05% w/w to 1.5% w/w, in relation to the total weight the gel composition; 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. 14. Use of the gel composition, as defined in any one of claims 1 to 12, CHARACTERIZED by the fact that it is to prepare a medicine for the treatment of plaque and calculus, decay, gingivitis, periodontitis, mucositis, oral ulcers, tooth sensitivity and combinations thereof. 15. Use of the gel composition, as defined in any one of claims 1 to 12, characterized by the fact that it is to prepare a medicine for the treatment of tissues of the oral cavity after an extraction process. 16. Use of a gel composition, as defined in any one of claims 1 to 12, CARAC TERIZED because it is as a cosmetic agent for oral hygiene for hydration, strengthening and improvement of the appearance of oral mucous membranes and gums, preferably the cosmetic agent for oral hygiene is for the daily cosmetic care of the mucosa and gums; wherein said gel comprises 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 the chlorhexidine or salt being a percentage by weight comprised from 0.05% w/w to 1.5% w/w, based on the total weight of the gel composition.

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