Formulation comprising a mucoadhesive, washout-resistant and film- forming association

Abstract

The present patent application concerns a formulation comprising: a mucoadhesive, washout-resistant and film-forming association, consisting of: a first element consisting of at least one water-soluble cellulose derivative, a second element selected from the group consisting of: at least one plant food polysaccharide, at least one glycosaminoglycan, and combinations of the foregoing; suitable excipients and diluents, wherein the weight ratio between the amount of the first element and the amount of the second element is comprised between 1:0.05 and 1:0.8.

Description

[0001] TITLE: "Formulation comprising a mucoadhesive, washout-resistant and filmforming association "

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention falls within the field of technologies with mucoadhesive, washout-resistant and film-forming capabilities.

[0005] STATE OF THE ART

[0006] Mucous membranes are tissue structures that line the cavities of the body communicating with the outside, belonging to the respiratory, digestive and urogenital systems and have a unique environment characterized by moisture, movement and a mucus covering layer. The mucus layer acts as a protective barrier and carries out a crucial role in regulating interactions between the body and its external environment. The gastrointestinal tract is the main site of mucus production in the human body. However, mucus is also present in other mucous membranes of the body, differing mainly in the amount and type of mucins involved. It is important to note that mucus has a relatively short life cycle, with a washout period occurring within minutes or hours. The primary function of mucus is to protect the underlying epithelial cells from external pathogens and to maintain hydration, also acting as a lubricant.

[0007] The mucus layer consists of a dense gelatinous matrix containing a wide range of components, including inorganic salts, antimicrobial enzymes such as lysozyme, immunoglobulins, such as IgA, and glycoproteins, such as lactoferrin and mucins. Despite the complexity, the properties of mucus are strongly influenced by the structure of the mucins that carry out a crucial role in the protection and homoeostasis of mucous membranes, providing an adequate environment for the optimal functioning of biological tissues and protecting against external aggressions.

[0008] Specifically, the mucus layer consists of two distinct types of mucins:

[0009] 1. Secretory mucins: these mucins are produced by the submucosal glands and by goblet cells. They are characterized by their high molecular mass and the presence of high levels of oxygen-bound carbohydrates. Secretory mucins contribute to the formation of the gel-like mucus layer and provide protection to the underlying epithelial cells;

[0010] 2. Membrane-bound mucins: these mucins are found on the cell surface and form a layer called the glycocalyx. The glycocalyx is a gel-like layer covering the luminal surface of vascular endothelial cells. It consists of various components, including proteoglycans, glycosaminoglycan chains, glycoproteins and plasma proteins that adhere to the cell surface. Membrane-bound mucins are involved in cell protection and signalling processes, including the control of chemokine secretion.

[0011] Mucins are a family of proteins with high molecular mass and high glycosylation that allow them to form a gel-like structure and carry out essential functions such as lubrication and barrier formation. Their high molecular mass, typically greater than 1 million Daltons, contributes to the formation of a three-dimensional network that gives mucus its viscosity and cohesion. The hydrophilic glycoprotein nature of mucins positively influences their solubility in water and the ability to absorb and retain water itself, thus contributing to the lubrication of mucosal surfaces. The structure of the mucins is characterized by the presence of glycans that provide binding sites for protein-polysaccharide interactions which are crucial for both the formation of the mucosal gelatinous matrix and its ability to adhere to mucosal surfaces. The negative charge of mucins, attributed to the presence of surface groups such as sialic acid or sulphate, makes them able to interact with ions and other charged molecules present in the surrounding environment. These interactions can influence the viscosity and cohesiveness of the mucus layer, as well as play a role in the capture and elimination of foreign particles or pathogenic microorganisms. Furthermore, mucins can act as proton acceptors and donors in highly glycosylated regions and cysteine-rich areas, allowing them to interact with other molecules through hydrogen bonds and other chemical interactions. These chemical characteristics of mucins offer many possibilities for interactions with other compounds, such as polysaccharides or other proteins present in the mucosal environment, thus contributing to the versatility and functionality of the mucus layer. Mucoadhesion is an essential phenomenon concerning the ability of a substance or material to adhere to mucous membranes and interact with the mucus layer present in biological tissues.

[0012] The mucoadhesion mechanism of some polymers involves a series of complex chemical and physical interactions. These interactions are fundamental to ensure an effective adhesion of the polymers to the mucosal surface, a property also called "bioadhesion", and can vary depending on the specific properties of the polymers and the characteristics of the target mucosa.

[0013] Accordingly, both the chemical and physical characteristics of the polymers must be carefully considered in the design of mucoadhesive systems. The chemical properties depend on the presence of functional groups, including hydroxyl (-OH), carboxyl (- COOH), or amino (-NH2) groups, which favour weak non-covalent chemical interactions (hydrogen bonds, electrostatic interactions, and van der Waals forces) with mucin. The physical characteristics relate to interpenetration, viscosity, cohesion and the ability to form a protective barrier on the mucosal surface.

[0014] Developing effective and safe mucoadhesive systems therefore requires a thorough understanding of polymer-mucin interactions and targeted polymer design to maximize treatment adhesion, persistence and efficacy without compromising the safety or integrity of mucosal tissues.

[0015] WO2006131262 describes mucoadhesive and controlled-release formulations consisting of aqueous solutions containing 0.05% to 5% by weight of a purified natural polymer having a xyloglucan structure and 10% to 70% by weight of glycerol. The presence of glycerol increases the mucoadhesion of xyloglucan. These formulations are suitable for application to human mucous membranes, such as nasal, oral, and vaginal mucous membranes, as moisturising and softening agents, or as pharmaceutical delivery systems for local and / or systemic use. The formulations can have active ingredients and excipients added which are known to the person skilled in the art and suitable for making pharmaceutical preparations or medical devices for administration to humans. The pharmaceutical preparations and medical devices can be in the form of, for example, solutions, gels, ovules, sprays, mouthwashes, creams, ointments, salves, washes and any other administration system acceptable for the indicated use.

[0016] EP3067042 describes a two-layer mucoadhesive buoyant tablet designed to obtain a controlled release in the gastric tract. This formulation uses mucoadhesiveness to adhere to the gastric mucosa, improving treatment stability and efficacy. It is particularly useful for treating gastric disorders, as it guarantees a prolonged release of the active agent and reduces the need for frequent dosing. The tablet composition includes various ingredients, such as buffer salts (particularly sodium bicarbonate as an effervescent agent and potassium citrate), chitosan, and fucoidan to promote mucoadhesion and mucosal relief, along with a modified cellulose-based polymer (such as hydroxypropylmethyl cellulose or derivatives), and carbovinyl polymers (such as Carbopol®) to generate buoyancy. The modified cellulose, such as hydroxypropylcellulose, is in a lower amount than that of chitosan, as reported in embodiment examples 1 and 3. In the patent document in question, the mucoadhesion capacity is demonstrated.

[0017] Problems of the background art

[0018] The low mucoadhesion of a formulation can create several known problems that influence treatment effectiveness: i. product dilution: if the product does not interact with the mucosa of the treatment area, it could lose the concentration necessary to possibly exert an effective biological, therapeutic or protective effect on the spot; ii. poor persistence: if the product is removed from the mucosal surface before completing its therapeutic effect, its effectiveness could be impaired or reduced;

[0019] Hi. mucosal clearance: the physiological mechanisms of the body, such as mucus production or ciliary movement, can remove the product from the mucous membranes before it has had time to act completely, thus limiting its therapeutic potential.

[0020] In summary, low mucoadhesion can hamper the effectiveness of treatment due to dilution, poor persistence, and mucosal clearance, negatively affecting the overall patient experience and treatment outcome. Therefore, there is a need to develop a formulation comprising an association of substances capable of favouring not only the appearance of mucoadhesion in a synergistic manner, but also of guaranteeing: resistance to washout mechanisms, whether physiological or deriving from the outside, and film-forming or barrier capacity.

[0021] SUMMARY OF THE INVENTION

[0022] A first object of the invention is a formulation comprising an association consisting of

[0023] - a first element consisting of at least one water-soluble cellulose derivative,

[0024] - a second element selected from the group consisting of:

[0025] - at least one plant food polysaccharide,

[0026] - at least one glycosaminoglycan,

[0027] - and combinations of the foregoing, suitable excipients and / or diluents, wherein the weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8.

[0028] Advantages of the invention

[0029] The formulation comprising the association developed by the Applicant, and which balances both qualitative and quantitative choices, shows considerable synergistic properties and adhesive capabilities. It has been designed for the protection and wellbeing of mucous membranes.

[0030] Unlike the prior art, the association comprised in the formulation is also resistant to washout / washing.

[0031] As a film-forming association, it also forms a physical barrier or a protective film at the level of a mucosal layer of a body district.

[0032] Therefore, the association comprised in the formulation of the invention, shows a synergistic effect, and has been designed to be applied on human mucous membranes and other areas of the body. The main objective of the developed technology is to improve the mucoadhesiveness, as well as the resistance of the products to washing mechanisms, with the consequence of prolonging the adhesion and persistence of the product at the site of application and promoting the filming property. This, in turn, helps to increase the effectiveness and duration of treatment in the target areas, improving the protection and well-being of the mucous membranes.

[0033] It should further be noted that the association of the invention consists of components of natural origin / natural derivation. This represents an advantage from an eco- sustainability perspective, since in the state-of-the-art there are mucoadhesive / gel matrices that nevertheless envisage the use of at least one synthetic or non-naturally occurring component.

[0034] DESCRIPTION OF THE FIGURES

[0035] Figure 1 graph relating to the mucoadhesion values and the relative intermediate combinations of ingredients with reference to Example 2.

[0036] Figure 2 graph relating to the mucoadhesion values and the relative intermediate combinations of ingredients with reference to Example 3.

[0037] Figure 3 graph relating to the mucoadhesion values and the relative intermediate combinations of ingredients with reference to Example 4.

[0038] Figure 4 graph relating to the mucoadhesion values and the relative intermediate combinations of ingredients with reference to Example 5.

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] In the following, the invention and preferred embodiments thereof are described in more detail. It should be noted that, although the structure has been organised into paragraphs and sub-paragraphs, the information contained in each paragraph or subparagraph is not isolated, and is possibly combinable with that contained in other paragraphs or, more generally, with other information contained in the text of the patent application.

[0041] The expression "at least" means the presence of one, or two or three elements, up to n elements. Mucoadhesive, washout-resistant and film-forming association

[0042] The mucoadhesive, washout-resistant and film-forming association is, for the sake of brevity, also referred to as "association".

[0043] The mucoadhesive, washout-resistant and film-forming association consists of

[0044] - a first element consisting of at least one water-soluble cellulose derivative,

[0045] - a second element selected from the group consisting of

[0046] - at least one plant food polysaccharide, preferably extracted from plants, algae or fungi, preferably extracted from fruits, algae or fungi,

[0047] - at least one glycosaminoglycan, preferably one glycosaminoglycan,

[0048] - and combinations of the foregoing, wherein the weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8.

[0049] Preferably, the first element and the second element are in solid form, preferably in powder form. Preferably, the association is in powder form.

[0050] It should be noted that preferably the association of the invention can be a binary association, in the sense that it can consist of two elements.

[0051] Preferably, the formulation does not comprise exclusively synthetic polymers. For the purposes of the invention, synthetic polymers are understood as substances that are obtained exclusively by means of chemical synthesis, starting from compounds that do not exist in nature as such. This represents an advantage in terms of choice of natural ingredients (or of natural origin) or naturally derived ingredients.

[0052] Preferably, the elements forming the mucoadhesive, washout-resistant and filmforming association are of natural origin or of natural derivation.

[0053] For the purposes of the present invention, "natural ingredient" or "of natural origin" means an ingredient obtained exclusively from plants, animals, microorganisms or minerals, by means of: physical processes (for example, distillation); other preparation processes, including traditional ones (for example, solvent extraction) without intentional chemical modifications. For the purposes of the present invention, "derived natural ingredient" (or of natural derivation) means an ingredient which is obtained by chemical and / or biological processes with the intention of chemically modifying them (for example, enzymatic and microbiological processing may give rise to natural ingredients or derived natural ingredients, in which an intentional chemical modification occurs). For example, the at least one water-soluble cellulose derivative is a derived natural ingredient.

[0054] Preferably, the elements of the association are not present as separate components within the formulation. For example, if the formulation is in solid form, for example a tablet, the components of the association are comprised within the matrix of the tablet; if the tablet is layered, they are all in one same layer of the tablet.

[0055] Association means a combination or a mixture of substances. Such substances carry out a synergistic action together. In this sense, the mixture of substances, taken together, shows a significantly better or greater effect with respect to the effect induced by a single substance, in particular the effect related to the association is greater than the sum of the effects induced by the individual components. It should be noted that this effect, for the purposes of the invention, has been demonstrated as a function of the mucoadhesive capacity in the presence of the first element and the second element, the latter being at least one plant food polysaccharide, or at least one glycosaminoglycan, or a combination of the two.

[0056] Mucoadhesive association means an association of substances that has mucoadhesive capacity, i.e., the ability to adhere at the level of the mucosal layer present in one or more body districts.

[0057] Washout-resistant association means an association of substances that has the ability to resist washing mechanisms, whether physiological or induced from the outside, for example, the swallowing of saliva in the oral cavity, the clearance mechanisms of mucous membranes in various body districts, the intake of water.

[0058] Film-forming association means that the association has a barrier effect, in the sense that the association has the ability to form a protective film on the mucous membranes, to protect them from the action of irritating agents, for example gastric juices. Preferably, each of the constituent elements (or components) of the association is water-soluble.

[0059] First element consistins of at least one water-soluble cellulose derivative

[0060] Preferably, at least one water-soluble cellulose derivative means that the association comprises a single water-soluble cellulose derivative, or mixtures of two or more water-soluble cellulose derivatives.

[0061] Preferably, at least one water-soluble cellulose derivative means a synthetically modified cellulose-based compound, preferably chemically modified cellulose. Preferably, the at least one water-soluble cellulose derivative is semi-synthetic (i.e., not completely or exclusively synthetic), in the sense that it is obtained from cellulose, which is a naturally occurring compound, which is modified by chemical synthesis or chemical modifications.

[0062] The at least one water-soluble cellulose derivative is commonly employed in the food industry with a viscosifying, thickening and / or stabilizing function.

[0063] Preferably, the association does not comprise microcrystalline cellulose; preferably, the first element is not microcrystalline cellulose or cellulose as such.

[0064] For the purposes of the invention, the at least one water-soluble cellulose derivative is soluble in cold water, or at room temperature, or in water subjected to heating, preferably heating to a temperature > 50 °C and < 90 °C.

[0065] The expression "cold" means a temperature comprised between 18 °C and 23 °C, preferably between 18 °C and 20 °C, preferably 20 °C.

[0066] The expression "room temperature" means a temperature comprised between 25 °C and 30 °C, preferably between 25 °C and 28 °C, preferably between 25 °C and 27 °C.

[0067] Preferably, the water-solubility of the at least one water-soluble cellulose derivative is > l g / L.

[0068] It should be noted that other cellulose derivatives, such as ethyl cellulose or microcrystalline cellulose, are not soluble in water.

[0069] Preferably, the at least one water-soluble cellulose derivative is a dietary cellulose derivative, in the sense that it is edible. Preferably, the at least one water-soluble cellulose derivative is selected from the group consisting of: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy-propyl-methylcellulose, ethylmethylcellulose, and combinations of the foregoing.

[0070] Preferably, the at least one water-soluble cellulose derivative is carboxymethylcellulose and / or hydroxy ethylcellulose.

[0071] Second element

[0072] The second element is selected from the group consisting of:

[0073] - at least one plant food polysaccharide, preferably extracted from plants, algae or fungi, preferably extracted from fruits, algae or fungi, preferably it is one or two food polysaccharides extracted from fruits or algae,

[0074] - at least one glycosaminoglycan, preferably one glycosaminoglycan,

[0075] - and combinations of the foregoing.

[0076] Preferably, the second element is water-soluble.

[0077] At least one plant food polysaccharide.

[0078] The at least one plant food polysaccharide is also referred to said plant food polysaccharide.

[0079] Preferably, at least one plant food polysaccharide means a plant extract; for the purposes of the invention, plant extract means a substance or a combination of substances obtained from a plant by means of an extraction process, wherein at least one extraction step appears.

[0080] Extraction is a known separation technique that involves the use of solvents, for example water, ethanol or other organic solvents, which takes advantage of the different solubility of the substances in the solvents.

[0081] Preferably, the at least one plant food polysaccharide is not a flour; preferably, the at least one plant food polysaccharide is not obtained by means of a process in which there is at least one fermentation step, preferably it is not a fermented polysaccharide. At least one plant food polysaccharide preferably means a polysaccharide extracted from plants or from fungi or from algae, preferably it is extracted from fruits, and / or seeds, and / or flowers, and / or leaves, and / or roots, and / or tubers of plants, or from fungi or from algae.

[0082] At least one plant food polysaccharide means an edible polysaccharide.

[0083] Preferably, the at least one plant food polysaccharide is soluble in water at room temperature, or water subjected to heating, preferably heating to a temperature > 50 °C and < 90 °C.

[0084] Preferably, the at least one plant food polysaccharide is not starch; starch is poorly soluble in water.

[0085] Preferably, the at least one plant food polysaccharide is selected from the group consisting of: alginic acid and relative salts (alginates), pectin, carrageenan, agar-agar, chitosan, xyloglucan, konjac gum, and combination of the foregoing; preferably, the at least one plant food polysaccharide is selected from the group consisting of: alginic acid and relative salts (alginates), pectin, carrageenan, agar-agar.

[0086] Preferably, the alginic acid is extracted from brown algae belonging to the family Phaeophyceae .

[0087] Preferably, the alginates are the salts of alginic acid, preferably the alginates are selected from the group consisting of: alkaline alginates, magnesium alginate, and combinations of the foregoing.

[0088] It should be noted that calcium alginate, aluminium alginate, iron alginate are not soluble in water.

[0089] Preferably, the pectin is extracted from fruit, preferably from fruit selected from the group consisting of: apples, plums, citrus fruits, quinces, gooseberries and mixtures of the foregoing.

[0090] Preferably, the carrageenan is extracted from red algae, for example from Chondrus crispus and / or from Gigartina mamiliosa. also called carragheen, Irish moss or marine lichen. Preferably, the agar-agar is extracted from red algae belonging to different genera, for example genera selected from the group consisting of: Gelidium, Gracilaria, Gelidiella, Pterocladia, Sphaerococcus, and combinations of the foregoing.

[0091] Preferably, the chitosan is a linear polysaccharide consisting of P(l-4)-bound D- glucosamine and N-acetyl-D-glucosamine.

[0092] Preferably, the xyloglucan (also called "xylogel") is a polysaccharide extracted from tamarind seeds.

[0093] Preferably, the konjac gum is obtained from konjac flour by means of an extraction step.

[0094] Preferably, the at least one plant food polysaccharide consists of one plant food polysaccharide extracted from plants, algae or fungi, or of two food polysaccharides extracted from plants, algae or fungi.

[0095] At least one glycosaminoglycan

[0096] The glycosaminoglycan is preferably of fermentative origin.

[0097] Glycosaminoglycan of fermentative origin means a linear anionic compound consisting of repeating units of disaccharides, obtained by means of microbial fermentation processes.

[0098] Preferably, the glycosaminoglycan of fermentative origin is selected from the group consisting of: hyaluronic acid and / or its salts (for example, sodium hyaluronate), chondroitin sulphate and combinations of the foregoing.

[0099] Preferably, the hyaluronic acid has a molecular weight comprised between 50,000 Da and 2,500,000 Da.

[0100] Weight ratios

[0101] The weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8, preferably between 1 :0.05 and 0.7, preferably between 1 :0.1 and 1 :0.7, preferably between 1 :0.1 and 1 :0.65, preferably between 1 :0.2 and 1 :0.65, preferably between 1 :0.2 and 1 :0.6, preferably 1 :0.22, or 1 :0.3, or 1 :0.47, or 1 :0.53, or still 1 :0.63. It should be noted that, at the aforesaid weight ratios, the synergistic effect in relation to mucoadhesive capacity is obtained. In addition to this, it is also possible to obtain

[0102] - a washout-resistant association, and

[0103] - a barrier / film-forming association.

[0104] Barrier / film-forming association refers to the ability of the association to form a protective layer on at least one mucosal layer of a body district, thus providing a soothing and protective action. This layer also acts as a physical barrier between the irritated mucosa and external agents.

[0105] Preferably, the association can be a ternary association (triad), in the sense that it can consist of three elements. The Applicant has demonstrated that the synergy for the mucoadhesion effect also exists considering the triad of elements (see Examples 2-4 and Figures 1-3).

[0106] Preferably, the association can be an association of five elements. The Applicant has demonstrated that the synergy for the mucoadhesion effect also exists considering five elements (see Example 5 and Figure 4).

[0107] 1st preferred embodiment

[0108] According to a first alternative preferred embodiment, the association consists of

[0109] - a first element consisting of at least one water-soluble cellulose derivative, preferably one or two water-soluble cellulose derivatives,

[0110] - a second element consisting of

[0111] - at least one plant food polysaccharide, preferably extracted from plants, algae or fungi, preferably one or two plant food polysaccharides extracted from plants, algae or fungi, preferably the plant food polysaccharide is selected from the group consisting of: pectin, carrageenan, sodium alginate, xylogel, and combinations of the foregoing,

[0112] - and a third element selected from:

[0113] - at least one plant food polysaccharide, preferably extracted from plants, algae or fungi, preferably one plant food polysaccharide extracted from plants, algae or fungi, preferably the plant food polysaccharide is selected from the group consisting of: pectin, carrageenan, sodium alginate, and combinations of the foregoing, or

[0114] - at least one glycosaminoglycan, preferably one glycosaminoglycan, preferably the glycosaminoglycan is hyaluronic acid or sodium hyaluronate, wherein when the third element is the at least one plant food polysaccharide the latter is a plant food polysaccharide that is (qualitatively) different from the plant food polysaccharide constituting the second element, characterized in that the weight ratio between the amount of the first element and the sum of the amount of the second element and the amount of the third element, as per formula (I) below first element: (second element + third element) (I), is preferably comprised between 1 :0.05 and 1 :5, is preferably comprised between 1 :0.05 and 1 :2, preferably between 1 :0.05 and 1 : 1, preferably between 1 :0.05 and 1 :0.8, preferably between 1 :0.1 and 1 :0.8, preferably between 1 :0.2 and 1 :0.8, preferably between 1 :0.2 and 1 :0.7, preferably between 1 :0.2 and 1 :0.6, preferably comprised between 1 :0.3 and 1 :0.6, preferably equal to 1 :0.6.

[0115] Preferably, the first, second and third elements are water-soluble.

[0116] According to this first embodiment, the association consists of a triad of elements, in the sense that it consists of the first, second and third elements. Alternatively, the association consists of five elements.

[0117] The Applicant would like to point out that, preferably, when the third element is the at least one food polysaccharide, for example it is carrageenan, the latter is a qualitatively different polysaccharide, i.e., it is a different entity, from the one constituting the second element, in the sense that the polysaccharide constituting the second element will not be carrageenan, but a plant food polysaccharide other than carrageenan.

[0118] Preferably, the weight ratio between the first element and the second element is comprised between 1 :0.1 and 1 :0.7, preferably between 1 :0.1 and 1 :0.6, preferably between 1 :0.2 and 1 :0.6, preferably between 1 :0.3 and 1 :0.6, preferably between 1 :0.4 and 1 :0.6, preferably equal to 1 :0.3 or to 1 :0.5.

[0119] Preferably, the weight ratio between the first element and the third element is comprised between 1 :0.05 and 1 :0.2, preferably between 1 :0.07 and 1 :0.2, preferably between 1 :0.08 and 1 :0.2, preferably between 1 :0.1 and 1 :0.2, preferably between 1 :0.1 and 1 :0.15, preferably equal to 1 :0.13.

[0120] Preferably, the weight ratio between the second element and the third element is comprised between 1 :0.1 and 1 :0.7, preferably between 1 :0.1 and 1 :0.6, preferably between 1 :0.1 and 1 :0.5, preferably between 1 :0.1 and 1 :0.3, preferably between 1 :0.2 and 1 :0.3, preferably equal to 1 :0.26.

[0121] It should be noted that at the aforesaid weight ratios, the effects of mucoadhesion, washout-resistance and barrier capacity / film formation can be observed.

[0122] 2nd preferred embodiment

[0123] Preferably, the mucoadhesive and washout-resistant association consists of

[0124] - a first element consisting of at least one water-soluble cellulose derivative, preferably one water-soluble cellulose derivative,

[0125] - a second element consisting of two food polysaccharides, preferably extracted from plants, algae or fungi, said primary plant food polysaccharide and secondary plant food polysaccharide, preferably the primary plant food polysaccharide is qualitatively different from the secondary plant food polysaccharide.

[0126] In accordance with this second preferred embodiment, the association consists of a triad of elements.

[0127] The weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8, preferably between 1 :0.1 and 1 :0.8, preferably between 1 :0.2 and 1 :0.8, preferably between 1 :0.2 and 1 :0.7, preferably between 1 :0.2 and 1 :0.6, preferably equal to 1 :0.22, or to 1 :0.47, or still to 1 :0.63.

[0128] It should be noted that this second preferred embodiment is preferably indicated for the preparation of (or is preferably comprised in) formulations in combination with suitable excipients and / or diluents and / or at least one active ingredient, preferably these formulations can be

[0129] - in a liquid form, such as spray solutions, preferably when the weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.2 and 1 :0.8, preferably equal to 1 :0.6; or

[0130] - in a solid form, preferably tablets, preferably when the weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.2 and 1 :0.8, preferably equal to 1 :0.6.

[0131] Preferably, the mucoadhesive and washout-resistant association consists of

[0132] - a first element consisting of at least one water-soluble cellulose derivative, preferably one water-soluble cellulose derivative, preferably it is carboxymethylcellulose,

[0133] - a second element consisting of two food polysaccharides extracted from plants, algae or fungi, said primary plant food polysaccharide being pectin, and secondary plant food polysaccharide being carrageenan.

[0134] 3rd preferred embodiment

[0135] Preferably, the mucoadhesive and washout-resistant association consists of

[0136] - a first element consisting of at least one water-soluble cellulose derivative, preferably one water-soluble cellulose derivative,

[0137] - a second element consisting of

[0138] - at least one plant food polysaccharide extracted from plants, algae or fungi, preferably one plant food polysaccharide extracted from fruits, algae or fungi, and

[0139] - at least one glycosaminoglycan, preferably one glycosaminoglycan.

[0140] According to this third embodiment, the association consists of a triad of elements.

[0141] It should be noted that such third preferred embodiment is preferably indicated for the preparation of (or is comprised in) formulations in combination with suitable excipients and / or diluents and / or at least one active ingredient, in liquid form, preferably liquid formulations, preferably in the form of syrups.

[0142] The weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8, preferably between 1 :0.1 and 1 :0.8, preferably between 1 :0.2 and 1 :0.8, preferably between 1 :0.2 and 1 :0.7, preferably between 1 :0.2 and 1 :0.6, preferably equal to 1 :0.63.

[0143] Preferably, the mucoadhesive, washout-resistant and film-forming association consists of

[0144] - a first element consisting of one water-soluble cellulose derivative, preferably it is carboxymethylcellulose,

[0145] - a second element consisting of

[0146] - a plant food polysaccharide, preferably extracted from fruits or algae, preferably the plant food polysaccharide is selected from: pectin, carrageenan, or sodium alginate, preferably it is pectin or sodium alginate,

[0147] - at least one glycosaminoglycan, preferably one glycosaminoglycan, preferably the glycosaminoglycan is hyaluronic acid.

[0148] 4th preferred embodiment

[0149] Preferably, the mucoadhesive and washout-resistant association consists of

[0150] - a first element consisting of at least one water-soluble cellulose derivative, preferably two water-soluble cellulose derivatives,

[0151] - a second element consisting of

[0152] - at least one plant food polysaccharide extracted from plants, algae or fungi, preferably two plant food polysaccharides extracted from fruits, algae or fungi, and

[0153] - at least one glycosaminoglycan, preferably one glycosaminoglycan.

[0154] According to this third embodiment, the association consists of five elements.

[0155] It should be noted that such third preferred embodiment is preferably indicated for the preparation of (or is comprised in) formulations in combination with suitable excipients and / or diluents and / or at least one active ingredient, in the form of vaginal gels.

[0156] The weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8, preferably between 1 :0.1 and 1 :0.8, preferably between 1 :0.2 and 1 :0.8, preferably between 1 :0.2 and 1 :0.7, preferably between 1 :0.2 and 1 :0.6, preferably between 1 :0.3 and 1 :0.6, preferably equal to 1 :0.3.

[0157] Preferably, the mucoadhesive, washout-resistant and film-forming association consists of

[0158] - a first element consisting of two water-soluble cellulose derivatives, preferably carboxymethylcellulose and hydroxy ethylcellulose,

[0159] - a second element consisting of

[0160] - two plant food polysaccharides, preferably extracted from fruits or algae, preferably pectin and xylogel,

[0161] - at least one glycosaminoglycan, preferably one glycosaminoglycan, preferably sodium hyaluronate or hyaluronic acid.

[0162] Formulation comprising the mucoadhesive, washout-resistant and film-forming association

[0163] The formulation comprises

[0164] - the mucoadhesive, washout-resistant and film-forming association described in the previous paragraphs, regardless of the preferred embodiments, suitable excipients and / or diluents.

[0165] Preferably, the formulation can comprise

[0166] - the mucoadhesive, washout-resistant and film-forming association described in the previous paragraphs, regardless of the preferred embodiments,

[0167] - suitable excipients and / or diluents,

[0168] - at least one active ingredient.

[0169] Preferably, the at least one active ingredient means a substance having: - a functional effect, in the sense that it is able to perform a function or activity (for example: antioxidant, emollient or similar), which is intrinsic to the substance itself, at the level of one or more body districts: and / or

[0170] - a biological effect, i.e., an effect of restoring physiological functioning when in contact with one or more body districts.

[0171] Preferably, the association can act as a vehicle and promoter of the bioavailability of the at least one active ingredient through at least one mucosal layer.

[0172] Examples of active ingredients are those having a biological activity selected from the group consisting of: antioxidant, protective, emollient, soothing, expectorant, moisturising.

[0173] Examples of active ingredients are preferably selected from the group consisting of: botanical extracts, food / edible substances, and combinations of the foregoing.

[0174] Preferably, examples of active ingredients are selected from the group consisting of: vegetable glycerin, honey, preferably wildflower honey; Icelandic Lichen extract; Verbasco extract; Althea extract, Ivy extract, Thyme extract, Plantain extract, Chamomile extract, Mallow extract, Erisimo extract, Okra extract, Liquorice extract, Melissa extract, Pomegranate extract, Perilla extract, Raspberry extract, Horehound extract, Viola extract, Linden extract, Mugo pine extract; Opuntia powder; fructooligosaccharides; galacto-oligosaccharides; lactoferrin.

[0175] Preferably, the at least one active ingredient is in an amount comprised between 0.01% and 50% by weight, preferably between 0.01% and 48% by weight, preferably between 0.05% and 48% by weight, preferably between 1% and 48% by weight, preferably between 3% and 48% by weight, preferably between 5% and 48% by weight, preferably between 4% and 45% by weight, on the total weight of the formulation.

[0176] Preferably, the at least one water-soluble cellulose derivative is in an amount comprised between 0.1% and 5% by weight, preferably between 0.1% and 3.8% by weight, preferably between 0.1% and 2% by weight, preferably between 0.1% and 1.85% by weight, preferably between 0.1% and 1% by weight, preferably between 0.2% and 0.9% by weight, preferably between 0.3% and 0.9% by weight, preferably equal to 0.36% by weight, or to 0.77% by weight, or still 0.84% by weight, on the total weight of the formulation.

[0177] Preferably, the second element, selected from the group consisting of:

[0178] - at least one plant food polysaccharide, preferably one extract from plants, algae or fungi, preferably extracted from fruits, algae or fungi,

[0179] - at least one glycosaminoglycan, preferably one glycosaminoglycan,

[0180] - and combinations of the foregoing, is comprised in an amount comprised between 0.05% and 3% by weight, preferably between 0.07% and 2% by weight, preferably between 0.1% and 2% by weight, preferably between 0.1% and 1.2% by weight, preferably between 0.1% and 1% by weight, preferably between 0.1% and 0.9% by weight, preferably between 0.1% and 0.7% by weight, preferably between 0.1% and 0.6% by weight, preferably between 0.2% and 0.6% by weight, preferably equal to 0.22% by weight, or to 0.47% by weight, or still 0.53% by weight, on the total weight of the formulation.

[0181] Preferably, when the second element is at least one plant food polysaccharide extracted from fruits or algae, the at least one plant food polysaccharide is equal to two food polysaccharides, preferably the two food polysaccharides are pectin and carrageenan, or are pectin and xylogel.

[0182] Preferably, when the second element consists of two food polysaccharides, the relative amount is comprised between 0.05% and 1.5% by weight, preferably between 0.05% and 1% by weight, preferably between 0.05% and 0.7% by weight, preferably between 0.07% and 0.7% by weight, preferably between 0.1% and 0.7% by weight, preferably between 0.1% and 0.5% by weight, preferably between 0.2% and 0.5% by weight, on the total weight of the formulation.

[0183] Preferably, the second element is a combination of at least one plant food polysaccharide and at least one glycosaminoglycan, preferably it is a combination of a plant food polysaccharide and a glycosaminoglycan, still preferably it is a combination of alginate, preferably sodium alginate, and hyaluronic acid.

[0184] Preferably, when the second element is a combination of at least one plant food polysaccharide and at least one glycosaminoglycan, the relative amount is comprised between 0.05% and 2% by weight, preferably between 0.07% and 2% by weight, preferably between 0.1% and 2% by weight, preferably between 0.1% and 1.2% by weight, preferably between 0.1% and 0.9% by weight, preferably between 0.1% and 0.7% by weight, preferably between 0.1% and 0.6% by weight, preferably between 0.2% and 0.6% by weight, preferably equal to 0.53% by weight, on the total weight of the formulation.

[0185] Preferably, the formulation is in a pharmaceutical form selected from: solid, semi-solid or liquid.

[0186] Examples of solid formulations are: powders; granulates; tablets; capsules; preferably it is a tablet.

[0187] Examples of semi-solid formulations are: gels; ointments; pastes; creams.

[0188] Examples of liquid formulations are: emulsions; suspensions; solutions, for example sprayable solutions; sprays; syrups; drops.

[0189] Preferably, sprayable solutions mean solutions that can be dispensed using compressed air or ultrasound to generate a fine mist of liquid particles, ideal for inhalation.

[0190] Preferably, spray means a solution that is dispensed using a pump or aerosol mechanism to distribute the solution in larger droplets or in a targeted jet.

[0191] Preferably, suitable excipients and / or diluents known in the art for each technology form in which the formulation can be present.

[0192] Examples of suitable excipients and / or diluents for solid formulations are selected from the group consisting of: diluents, binders, disintegrants, lubricants, glidants, colourants, flavourings, buffers, preservatives, antimicrobials, and combinations of the foregoing.

[0193] Examples of suitable excipients and / or diluents for semi-solid formulations are selected from the group consisting of: stabilizers, water, solvents, emulsifiers, rheological modifiers, gelling agents, buffers, preservatives, antimicrobials, thickeners, dispersants, suspending agents, and combinations of the foregoing.

[0194] Examples of suitable excipients and / or diluents for liquid formulations are selected from the group consisting of: stabilizers, water, solvents, emulsifiers, gelling agents, buffers, preservatives, antimicrobials, thickeners, viscosifiers, dispersants, suspending agents, and combinations of the foregoing.

[0195] Preferably, the formulation, preferably the liquid formulation, can contain a solvent, preferably water.

[0196] Preferably, the solvent is in an amount comprised between 50% and 94% by weight, preferably between 50% and 90% by weight, preferably between 60% and 80% by weight, preferably between 65% and 80% by weight, preferably between 65% and 75% by weight, on the total weight of the formulation.

[0197] Preferably, the mucoadhesive, washout-resistant and film-forming association is in an amount comprised between 0.2% and 5.5% by weight, preferably between 0.2% and 5% by weight, preferably between 0.2% and 2.5% by weight, preferably between 0.2% and 2% by weight, preferably between 0.3% and 2% by weight, preferably between 0.5% and 2% by weight, preferably between 0.5% and 1.5% by weight, preferably equal to 0.58% by weight, or to 1.24% by weight, or still equal to 1.37% by weight, or to 4.9% by weight, on the weight of the formulation. According to a preferred form, the mucoadhesive, washout-resistant and film-forming association is in an amount comprised between 0.2% and 5.5% by weight, preferably between 0.3% and 5.5% by weight, preferably between 0.5% and 5.5% by weight, preferably between 0.5% and 5% by weight, on the total weight of the formulation.

[0198] Preferably, regardless of the technological form, the formulation, comprising the association described in the preceding paragraphs, can be oral or topical.

[0199] Topical application preferably involves application to at least one body mucosa, such as, for example, the mucosa of the oral, or nasal, or vaginal, or, again, rectal cavity.

[0200] The composition which is the subject matter of the present invention is preferably in the form of a medical device, food supplement, or cosmetic product or formulation.

[0201] The definition of medical device is contained in Regulation (EU) 2017 / 745 (repealed Directive 93 / 42 / EC). Depending on the purpose and method of use, a product marked as a medical device will have a different risk class and different compliance process. The aforementioned regulation identifies "Devices consisting of substances or combinations of substances intended to be introduced into the human body through a body orifice or to be applied to the skin and which are absorbed by the human body or locally dispersed therein, including: in class III if they, or their products of metabolism, are absorbed systemically by the human body in order to achieve their intended use, in class III if they achieve their intended use in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are absorbed systemically by the human body, in class Ila if they are applied to the skin or if they are applied in the nasal cavity or in the oral cavity up to the pharynx and achieve their intended use on said cavities, and in class lib in all other cases" .

[0202] On the other hand, if a medical device is applied to the body for a medical action and is not absorbed or not locally dispersed, the above rule is not applicable and the product tends to fall into class I.

[0203] "Food supplements" are defined by the sector legislation (Directive 2002 / 46 / EC, implemented by Italian Legislative Decree no. 169 of 21 May 2004) as: "foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients, such as vitamins and minerals, or other substances with a nutritional or physiological effect, in particular, but not exclusively, amino acids, essential fatty acids, fibre and various plants and herbal extracts, both single- and multi-compound, in pre-dosed forms".

[0204] "Cosmetic product" means: any substance or mixture intended to be applied to the external surfaces of the human body (epidermis, hair system and hair, nails, lips, external genital organs) or to the teeth and mucous membranes of the mouth for the sole or main purpose of cleaning, perfuming, changing the appearance thereof, protecting, maintaining them in good condition or correcting body odours (Article 2 of Regulation (EC) n.1223 / 2009; source: Ministry of Health). A substance or mixture intended to be ingested, inhaled, injected or implanted into the human body is not considered a cosmetic product. EXAMPLES

[0205] Illustrative and non-limiting examples of the invention are given below.

[0206] / . Analysis method

[0207] 1.1. Mucoadhesion

[0208] Viscosimetric analysis plays a fundamental role in the evaluation of mucoadhesion, allowing to examine the ability of a mucoadhesive polymer mixture to interact and maintain tight adhesion with mucus. In experimental terms, this method makes it possible to determine whether the addition of mucin, an essential component of mucus, affects the viscosity of the mixture, thus providing indications on its ability to interact with mucus. In practice, a positive reaction between mucin and the substances present in the mixture leads to an increase in the viscosity of the solution. Accordingly, an increase in viscosity indicates an increased ability of the mixture to effectively adhere to the mucosal surface.

[0209] In detail, a 5% solution of mucin is prepared, which represents a simulation of the mucus present on the mucosal surface. The product set out in the examples below is prepared, with all possible intermediate combinations (carrageenan; pectin; carboxymethylcellulose; carrageenan and pectin; carrageenan and carboxymethylcellulose; pectin and carboxymethylcellulose), and finally a solution of the product (or of its constituents alone and in combination) containing 5% mucin is prepared.

[0210] The different formulations, including the product alone, the product combined with mucin and the mucin solution, are analysed using a Brookfield dv2t viscometer (with sc-21 probe; measurements carried out at room temperature; reading time 1 minute). The viscosity of each formulation is measured and compared. The difference between the viscosity of the product added to mucin and that of the mucin-only product provides an indication of the interaction between the polymers and mucin whereby if Ar] > 0, then there is mucoadhesion. A greater difference indicates a greater interaction and a better ability of the product to adhere to and interact with the mucus layer.

[0211] Mucoadhesion can also be expressed as mucoadhesion index, referred to as

[0212] 1.2. Bioadhesion and resistance to washing (or washout)

[0213] Bioadhesion analysis plays a fundamental role in assessing the ability of a product to remain attached to mucin and also assess its resistance to body-washing mechanisms (for example swallowing saliva, mucosal clearance mechanisms, water intake, etc.).

[0214] In experimental terms, this method makes it possible to determine how much product can remain attached to a mucin-functionalized surface before and after washing the product with a saline solution.

[0215] In detail, an aqueous solution of 12% mucin is prepared and then 2.5 mL of solution is dispersed on a 28 cm2slide and allowed to dry. Once completely dried, 2.5 mL of the composition is evenly dispersed on the mucin layer and allowed to stand for 5 minutes. It is then placed on an inclined plane with an angle comprised between 30° and 90° for 6 minutes and then weighed. It is then immersed in 200 mL of saline solution for 30 seconds and then left inclined for another 6 minutes. The functionalized slide is weighed after the addition of the product, and after both inclinations, in order to determine the amount of product that remains adhered. The data obtained are then compared with the blank, using the same procedure but without the mucin film. Each test is performed in triplicate.

[0216] The percentage of composition that remains attached to the mucin film is calculated as: mg adhered formulation after inclination

[0217] % adhered = - . . . , - 100 mg initial formulation

[0218] The percentage of formulation that remains adhered after washing is calculated as: mg adhered formulation after washing

[0219] % adhered = - — - - 100 mg initial formulation

[0220] Bioadhesion is expressed as: % Bioadhesion = % Adhered with mucin — % Adhered without mucin

[0221] 1.3. Barrier / film- for mins effect

[0222] The film-forming or barrier effect refers to the ability of the product to form a protective layer on the mucous membranes, thus providing a soothing and protective action. This layer acts as a physical barrier between the irritated mucosa and external agents. To evaluate the barrier effect, the reduction of the permeability of caffeine through a membrane coated by the product is studied. To study the permeability of caffeine, the Franz cell is used, in the donor phase of which 200 mg of product are placed, allowed to stand at a temperature of 37 °C and then 1 mL of solution containing 10 mg / mL of caffeine is added. In the receiving phase, a PBS pH 7.4 solution is instead used and samples are taken over time to quantify the permeated caffeine by means of HPLC. The data is then compared with a negative control (0% barrier effect) represented by the permeability of caffeine without treating the membrane with the product and a positive control (100% barrier effect) in which the membrane is first treated with petroleum jelly and then the permeability of caffeine is studied. The result is expressed as a percentage referring to the ability of the product to reduce the permeability of caffeine.

[0223] It should be noted that water was added to examples 2-4 relating to the association comprised in the formulation of the invention to obtain mixtures suitable for performing the simulations of the experimental tests in accordance with 1. Analysis method.

[0224] Example 2: association with carboxymethylcellulose, pectin and carrageenan The association of Example 2 was obtained through the following process: i. carboxymethylcellulose, pectin and carrageenan were weighed; ii. the water is heated to a temperature of 65°C and the powders are added under stirring; iii. the mixture is allowed to stir until fully dissolved and cooled.

[0225] For the evaluation of the synergistic effect of the mixture, solutions of individual components and binary mixtures were also prepared in the same manner.

[0226] Experimental tests were carried out to evaluate the mucoadhesive properties and their synergistic effect of the composition through a test that involves the viscosimetric analysis of the mixture using pig stomach mucin, carried out according to the method reported in section 1. Analysis method. For the evaluation of the synergistic effect, it is expected that, summing all the possible combinations, the final result will be lower than the complete polymer solution.

[0227] Table 1. Mucoadhesion values obtained for the individual components and mixtures of Example 2 Table 1 illustrates the results of the mucoadhesion analyses obtained for the individual components, the combinations and the overall solution of Example 2. As highlighted, it is observed that the mucoadhesion value for the complete solution is excellent, with a considerable increase in terms of viscosity. This suggests a strong interaction between the polymers and mucin, indicating a high capacity for adhesion and interaction with the mucus layer. Furthermore, it is possible to observe a synergistic effect, in which both the sum of the mucoadhesiveness of the individual components, or of the mucoadhesiveness value of the binary mixtures with the value of the single component missing, results in an overall value lower than the experimental mucoadhesiveness of the mixture containing them. This phenomenon confirms that the combination of the polymers produces a greater overall effect than the sum of their individual contributions. By way of example, the sum of carboxymethylcellulose, pectin and carrageenan produces a theoretical mucoadhesion value of 193 cP (actual experimental value 480 cP). A theoretical value of 242 cP is obtained when pectin and carrageenan are added with carboxymethylcellulose. By adding carboxymethylcellulose and pectin with carrageenan, a theoretical value of 301 cP is reached. Finally, a theoretical mucoadhesion value of 334 cP is obtained by adding carboxymethylcellulose and carrageenan with pectin. All these expected “theoretical” mucoadhesion values are considerably lower than the experimental value of the complete mixture, thus confirming a synergistic effect. These results highlight the importance of the combination of polymers in the mucoadhesive formulation, showing how the synergy between them can maximize the adhesion and the overall efficacy of the product on the mucosal surface.

[0228] Example 3: association with carboxymethylcellulose, pectin and hyaluronic acid

[0229] The composition of Example 3 was obtained through the following process: i. carboxymethylcellulose, pectin and hyaluronic acid were weighed; ii. the water is heated to a temperature of 65°C and the powders are added under stirring; iii. the mixture is allowed to stir until fully dissolved and cooled.

[0230] For the evaluation of the synergistic effect of the mixture, solutions of individual components and binary mixtures were also prepared in the same manner.

[0231] Experimental tests were carried out to evaluate the mucoadhesive properties and their synergy through a test that involves the viscosimetric analysis of the mixture using pig stomach mucin, carried out according to the method set out in section 1. Analysis method.

[0232] Table 2. Mucoadhesion values obtained for the individual components and mixtures of Example 3 Table 2 shows the results of the mucoadhesion analyses obtained for both the individual components and the intermediate combinations of ingredients contained in Example 3. The presence of synergistic effects in both the binary mixtures and the tertiary mixture of Example 3 is evident. These results indicate that the combination of the individual components of the mixture of Example 3 creates a system with a strong interaction between the polymers and mucin, which results in a high capacity for adhesion and interaction with the mucus layer.

[0233] Example 4: association with carboxymethylcellulose, sodium alginate and hyaluronic acid

[0234] The composition of Example 4 was obtained through the following process: i. carboxymethylcellulose, sodium alginate and hyaluronic acid were weighed. ii. the water is heated to a temperature of 65 °C and the powders are added under stirring. iii. the mixture is allowed to stir until fully dissolved and cooled.

[0235] For the evaluation of the synergistic effect of the mixture, solutions of individual components and binary mixtures were also prepared in the same manner.

[0236] Experimental tests were carried out to evaluate the mucoadhesive properties and the synergy of the composition through a test that involves the viscosimetric analysis of the mixture using pig stomach mucin, carried out according to the method reported in section 1. Analysis method.

[0237] Table 3. Mucoadhesion values obtained for the individual components and mixtures of Example 4

[0238] Table 3 shows the results from the mucoadhesion analyses obtained for both the individual components and the combinations present in Example 4. The presence of synergistic effects in both the binary mixtures and the tertiary mixture of Example 4 is evident. These results indicate that the combination of the individual components of the mixture of Example 4 creates a system with a strong interaction between the polymers and mucin, which results in a high capacity for adhesion and interaction with the mucus layer. Example 5: association with carboxymethylcellulose, hydroxy ethylcellulose, pectin, hyaluronic acid and xylogel

[0239] The composition of Example 5 was obtained through the following process: i. Weigh the water and heat up to 75 °C. ii. Add the polymers, carboxymethylcellulose, and hydroxy ethylcellulose to the water, and cloud at 1500rpm for 20 minutes. iii. Add hyaluronic acid, Pectin and Xylogel and cloud at 1000 rpm for 20 minutes. iv. Cool the system.

[0240] For the evaluation of the synergistic effect of the mixture, solutions of individual components and mixtures of the first element (carboxymethylcellulose and hydroxy ethylcellulose) and the second element (pectin, hyaluronic acid and xylogel) were also prepared in the same manner.

[0241] Experimental tests were carried out to evaluate the mucoadhesive properties and the synergy of the composition through a test that involves the viscosimetric analysis of the mixture using pig stomach mucin, carried out according to the method reported in section 1. Analysis method.

[0242] Table 4. Mucoadhesion values obtained for the individual components and mixtures of Example 5 Table 4 shows the results from the mucoadhesion analyses obtained for both the individual components and the combinations present in Example 5. These results indicate that the combination of the individual components of the mixture of Example 5 creates a system with a strong interaction between the polymers and mucin, which results in a high capacity for adhesion and interaction with the mucus layer.

[0243] Example 6: formulation in the form of a syrup comprising the mucoadhesive, washout-resistant and film-forming association

[0244] The composition of Example 6 is a syrup and was obtained through the following process: i. the water was heated to a temperature of 65 °C with the honey and left to stir for at least 30 min. ii. carboxymethylcellulose, sodium alginate, sodium hyaluronate and fructose were added and left to stir until completely hydrated and dissolved. iii. the glycerin is added and mixed until the temperature drops below 30 °C. iv. the potassium sorbate is added and mixed until it completely dissolves. v. the citric acid is added and mixed until completely dissolved.

[0245] For the evaluation of the improved effect of the mixture with technology ("tech"), the same composition without technology ("no-tech") was also prepared, replacing carboxymethylcellulose, sodium alginate and sodium hyaluronate with water.

[0246] Below is the formulation in syrup form without technology.

[0247] Experimental tests were carried out to evaluate the mucoadhesive properties with the relative synergy, bioadhesion and resistance to washing, and the barrier effect of the composition of Example 6, through three different tests: a mucoadhesion test that involves the viscosimetric analysis of the mixture using pig stomach mucin, a bioadhesion test carried out with the inclined plane method, and the barrier effect test using the Franz cell, according to the methods reported in section 1. Analysis method. The table shows the mucoadhesion, bioadhesion, washing resistance and barrier effect data for the products containing the components which are the subject of the present invention (tech) and those without (no-tech) of Example 6.

[0248] Table 5. Data comparing mucoadhesion, bioadhesion, washing resistance and barrier effect between the tech v.s non-tech product

[0249] Table 5 highlights the difference between the formulation of Example 6 with and without technology. From the data obtained, it can be seen how the product with tech is more performing both in terms of mucoadhesion and bioadhesion and barrier effect compared to the same without the technology. It is therefore possible to define that the composition which is the subject of the present invention significantly improves the formulation.

[0250] Example 7: formulation in the form of a throat spray comprising the mucoadhesive, washout-resistant and film-forming association

[0251] The composition of Example 7 is a throat spray and was obtained through the following process: i. the water was heated to a temperature of 65 °C with the honey and left to stir for at least 30 min. ii. carboxymethylcellulose, pectin, carrageenan and verbasque were added and allowed to stir until completely hydrated and dissolved. iii. the glycerin is added and mixed until the temperature drops below 30 °C. iv. the potassium sorbate is added and mixed until it completely dissolves. v. the citric acid is added and mixed until completely dissolved. For the evaluation of the improved effect of the mixture with technology (tech), the same composition without technology (no-tech) was also prepared, replacing carboxymethylcellulose, pectin and carrageenan with water.

[0252] Below is the formulation in the form of throat spray without technology.

[0253] Experimental tests were carried out to evaluate the mucoadhesive properties with the relative synergy, bioadhesion and resistance to washing, and the barrier effect of the composition of Example 7, through three different tests: a mucoadhesion test that involves the viscosimetric analysis of the mixture using pig stomach mucin, a bioadhesion test carried out with the inclined plane method, and the barrier effect test using the Franz cell, according to the methods reported in section 1. Analysis method.

[0254] The table shows the mucoadhesion, bioadhesion, washing resistance and barrier effect data for the products containing the ingredients which are the subject of the present invention (tech) and those without (no-tech) of Example 7.

[0255] Table 6. Data comparing mucoadhesion, bioadhesion, washing resistance and barrier effect between the tech vs non-tech product

[0256] Table 6 highlights the difference between the formulation of Example 7 with and without technology. From the data obtained, it can be seen how the product with tech is more performing both in terms of mucoadhesion and bioadhesion and barrier effect compared to the same without the technology. It is therefore possible to define that the composition which is the subject of the present invention significantly improves the formulation.

[0257] Example 8: formulation in the form of a throat tablet comprising the mucoadhesive, washout-resistant and film-forming association The composition of Example 8 is a throat tablet and was obtained by the following process: i. after sieving, mixing sorbitol, Verbasco flowers dry extract, Icelandic Lichen, carboxymethyl cellulose, pectin, carrageenan, magnesium stearate, tribasic calcium phosphate, aroma and isomalt; ii. compressing the mixture obtained from i. For the evaluation of the improving effect of the mixture with technology (tech), the same composition was also prepared without technology (no-tech), removing carboxymethylcellulose, pectin and carrageenan.

[0258] Below is the formulation in tablet form without technology.

[0259] Experimental tests were carried out to evaluate the mucoadhesive properties with the relative synergy, bioadhesion and resistance to washing, and the barrier effect of the composition of Example 8, through three different tests: a mucoadhesion test that involves the viscosimetric analysis of the mixture using pig stomach mucin, a bioadhesion test carried out with the inclined plane method, and the barrier effect test using the Franz cell, according to the methods of section 1. Analysis method.

[0260] The table shows the mucoadhesion, bioadhesion, washing resistance and barrier effect data for the products containing the components which are the subject of the present invention (tech) and those without (no-tech) of Example 8.

[0261] Table 7. Data comparing mucoadhesion, bioadhesion, washing resistance and barrier effect between the tech vs non-tech product

[0262] Table 7 highlights the difference between the formulation of Example 8 with and without technology. From the data obtained, it can be seen how the product with tech is more performing both in terms of mucoadhesion and bioadhesion and barrier effect compared to the same without the technology. It is therefore possible to define that the composition which is the subject of the present invention significantly improves the formulation.

[0263] Example 9: formulation in the form of a vaginal gel comprising the mucoadhesive, washout-resistant and film-forming association

[0264] The composition of Example 9 is a vaginal gel and was obtained by the following process: i. Weigh the water and heat up to 75 °C. ii. Add the polymers, carboxymethylcellulose, and hydroxy ethylcellulose to the water, and cloud at 1500rpm for 20 minutes. iii. Add Hyaluronic Acid, Pectin and Xylogel and cloud at 1000 rpm for 20 minutes. iv. Cool the system. v. T<30 °C Add lactic acid and mix for 10 minutes. vi. Add the preservatives and perilla and mix for 20 minutes.

[0265] For the evaluation of the improved effect of the mixture with technology (tech), the same composition without technology (no-tech) was also prepared, removing pectin, sodium hyaluronate and xylogel. Below is the formulation in gel form without technology. Experimental tests were carried out to evaluate the mucoadhesive properties with the relative synergy, bioadhesion and resistance to washing, and the barrier effect of the composition of Example 9, through three different tests: a mucoadhesion test that involves the viscosimetric analysis of the mixture using pig stomach mucin, a bioadhesion test carried out with the inclined plane method, and the barrier effect test using the Franz cell, according to the methods of section 1. Analysis method.

[0266] The table shows the mucoadhesion, bioadhesion, washing resistance and barrier effect data for the products containing the components which are the subject of the present invention (tech) and those without (no-tech) of Example 9. Mucoadhesion, bioadhesion and washing resistance tests were performed by diluting the samples 1 :5 for technical feasibility. It should be noted that the no-tech formulation contains CMC and HEC because the elimination of all the components of the tech formulation would not have led to the formation of the gel, i.e., a technological form that is important for the purposes of this specific vaginal application.

[0267] Table 8. Data comparing mucoadhesion, bioadhesion, washing resistance and barrier effect between the tech vs non-tech product

[0268] Table 8 highlights the difference between the formulation of Example 9 with and without technology. From the data obtained, it can be seen how the product with tech is more performing both in terms of mucoadhesion and bioadhesion and barrier effect compared to the same without the technology. It is therefore possible to define that the composition which is the subject of the present invention significantly improves the formulation.

Claims

CLAIMS1. Formulation comprising an association consisting of- a first element consisting of at least one water-soluble cellulose derivative,- a second element selected from the group consisting of:- at least one plant food polysaccharide,- at least one glycosaminoglycan,- and combinations of the foregoing, suitable excipients and / or diluents, wherein the weight ratio between the amount of the first element and the amount of the second element is comprised between 1 :0.05 and 1 :0.8.

2. Formulation according to claim 1, wherein the at least one water-soluble cellulose derivative is selected from the group consisting of: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxy-propyl- methylcellulose, ethylmethylcellulose, and combinations of the foregoing.

3. Formulation according to claim 1 or 2, wherein the at least one plant food polysaccharide is extracted from plants, algae or fungi, preferably it is selected from the group consisting of: alginic acid and relative salts, pectin, carrageenan, agar-agar, chitosan, xyloglucan, konjac gum, and combinations of the foregoing.

4. Formulation according to any one of claims from 1 to 3, wherein the at least one glycosaminoglycan is selected from the group consisting of: hyaluronic acid and / or its salts, chondroitin sulphate, and combinations of the foregoing.

5. Formulation according to any one of claims from 1 to 4, wherein the weight ratio between the first element and the second element is comprised between 1 :0.1 and 1 :0.7.

6. Formulation according to any one of claims from 1 to 5, wherein the association is in powder form.

7. Formulation according to any one of claims from 1 to 6, wherein the first element consists of the at least one water-soluble cellulose derivative, and wherein- the second element consists of two food polysaccharides extracted from plants, algae or fungi, said primary plant food polysaccharide and secondary plant food polysaccharide, preferably the primary plant food polysaccharide is qualitatively different from the secondary plant food polysaccharide, or, alternatively, wherein- the second element consists of- at least one plant food polysaccharide extracted from plants, algae or fungi, preferably one or two plant food polysaccharide, preferably the at least or one food polysaccharide is extracted from fruits, algae or fungi, and- at least one glycosaminoglycan, preferably one glycosaminoglycan.

8. Formulation according to any one of claims from 1 to 7, wherein the first element consisting of the at least one water-soluble cellulose derivative is carboxymethylcellulose.

9. Formulation according to any one of claims from 1 to 8, the formulation being in a form selected from: solid, semi-solid or liquid.

10. Formulation according to any one of claims from 1 to 9, wherein the association is present in the formulation in an amount comprised between 0.2% and 5.5% by weight on the weight of the formulation.

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