ORAL MUCOADHESIVE TABLET FOR THE SYMPTOMATIC TREATMENT OF XEROSTOMIA, APHTHES AND INFLAMMATIONS OF THE ORAL CAVITY

Description

Description of the patent for an industrial invention entitled: “ORAL MUCOADHESIVE TABLET FOR THE SYMPTOMATIC TREATMENT OF XEROSTOMIA, APHTHALOS AND INFLAMMATIONS OF THE ORAL CAVITY” on behalf of: RICERFARMA srl 5 with headquarters in: Via Egadi, 7 - 20144 Milan * * * The invention relates to formulations in the form of mucoadhesive tablets useful for the treatment of symptoms caused by xerostomia (dry mouth). STATE OF THE ART 10 Xerostomia (dry mouth) is the dryness of the oral cavity caused by a flow of saliva reduced or absent. This condition can cause discomfort, interfere with speech and swallowing, make it difficult to wear dentures, cause bad breath, and compromise oral hygiene causing a reduction in oral pH and an increase in bacterial growth. Xerostomia 15 long-lasting can lead to destructive tooth decay and oral candidiasis. Xerostomia is a disorder common among the elderly, affecting approximately 20% of them. The typical symptoms of dry mouth, caused by insufficient salivary flow, are dry and sticky mouth sensation, problems chewing, swallowing and tasting, burning sensation, dry and rough tongue, onset of ulcers, 20 predisposition to develop infections in the mouth and lips, bad breath, increased plaque and tooth decay. Conventional symptomatic treatments, which involve the use of saliva substitutes in the form of liquids or gels, they are transitory and short-lived, remaining for a short time time in the oral cavity. 25 DESCRIPTION OF THE INVENTION It has now been found that by inserting high molecular weight hyaluronic acid in the form of sodium salt, in the presence of choline alfoscerate and ascorbyl palmitate, in a tablet mucoadhesive with at least one concave surface based on xylitol improves treatment symptomatic of xerostomia (dry mouth), canker sores and inflammation of the oral mucosa. 30 The invention therefore relates to oral compositions in the form of tablets mucoadhesives comprising xylitol, hyaluronic acid or its salt, choline alfoscerate and ascorbyl palmitate, said tablets being characterized by concave surfaces that adhere to the oral mucous membranes. The tablets of the invention are preferably circular in shape and have two 5136PTIT opposing concave surfaces. The tablets of the invention, applied in the oral vestibules or on the palate in contact with the mucous membranes, produce a suction effect that makes the tablet adhere for a long time, allowing the prolonged release of its active components, in particular high-weight sodium hyaluronate 5 molecular and xylitol able to stimulate salivation (Int J Oral Biol 44:62-70, 2019) and of moisten and lubricate the mucosa and at the same time exert a protective action and anti-inflammatory on tissues irritated by the lack of sufficient salivary flow. Furthermore, the sensation of solid body in the mouth exerts the masticatory stimulus inducing the increase of salivary flow. 10 The salivation-stimulating and humectant action of xylitol and the action anti-inflammatory effect of high molecular weight hyaluronic acid (HA) reduces significantly the discomfort and suffering of the oral mucosa by reducing the painful symptoms and counteracting oral dryness. The presence of choline alfoscerate promotes the trophism of the mucous tissue and increases the 15 bioadhesiveness of hyaluronic acid helping to create a lubricating and protective film, while the anti-hyaluronidase action of ascorbyl palmitate prolongs the protective effect and hyaluronic acid anti-inflammatory. It is known that chewing activity mechanically stimulates the production of saliva from part of the salivary glands. Often, to stimulate saliva, subjects with dry mouth 20 mouth (xerostomia) chew sweets or drinks that contain sugars that are harmful to the healthy teeth and gums. Xylitol works by reducing the levels of bacteria such as Streptococcus mutans in plaque and saliva by counteracting their energy production processes and reducing their adhesion to the tooth surface. The bacteria that cause tooth decay are unable to to metabolize xylitol, which results in an absence of lactic acid production and 25 polysaccharides; therefore, less plaque is formed and the level of acids that attack the surface of the tooth is lower. Xylitol stimulates salivary flow, rich in calcium and phosphate, which helps remineralize Carious lesions in the early stages. Increased saliva can help prevent bad breath. eliminating dry mouth and preventing prolonged exposure to acids and 30 sugars caused by food residues. The topical use of choline alfoscerate on the mucous membranes promotes cellular trophism and This allows for the maintenance and restoration of its integrity. It has also been found that topical use Choline alfoscerate is useful for maintaining the correct pH value of the oral mucosa. Choline alfoscerate is an ampholyte, is very soluble in water and ethanol, has a high 5136PTIT chemical and microbiological stability, has peculiar organoleptic properties as it is practically tasteless, odorless, colorless. These organoleptic properties facilitate its use in orodispersible tablets of the invention. There is scientific evidence of the powerful anti-hyaluronidase action exerted 5 from ascorbic acid and in particular from ascorbyl palmitate. This substance has long been used in the cosmetic sector for its antioxidant and anti-radical properties but concentrations much higher (0.5-0.1% w / w) than those in which it exerts anti- hyaluronidase (0.05 – 0.0004% w / w). Its anti-hyaluronidase action synergises strongly with the action of the acid 10 hyaluronic acid, both endogenous and exogenous. The anti-hyaluronidase action represents an element functional of fundamental importance to increase the anti-inflammatory and restorative efficacy tissue of hyaluronic acid. Furthermore, the anti-hyaluronidase action also has an antibacterial / anti-inflammatory action. In fact, many bacteria exert an inflammatory action through the production of specific 15 hyaluronidases that promote colonization in tissues, thus promoting the establishment and spread of bacterial infections / contamination at a local level. Based on the above, the anti-inflammatory / tissue repair action of HA is protected and strongly enhanced by the anti-hyaluronidase action and by the presence of the film-formulating and bio / mucoadhesive formulation matrix capable of creating a very 20 favorable for tissue protection and repair (wound healing). The diameter of the tablets typically ranges from 7.0 to 18.0 mm (preferably 12 mm), the thickness varies from 2.5 to 7.6 m, and the diameter of the concavities from 5.0 to 10.0 mm (preferably 6.5 mm) with a depth of 0.25 – 0.8 mm (preferably 0.4 mm), a radius of curvature between 10° and 25° (preferably 12.5°). 25 The total xylitol tablet concentration ranges from 80.0% to 95.0% w / w (preferably 85.0%), the concentration of sodium hyaluronate with a molecular weight between 800,000 and 4,000,000 From, varies from 0.0005% to 20.0% w / w (preferably 0.8%), the choline alfoscerate concentration ranges from 0.001% to 15.0% w / w (preferably 0.265%) and The concentration of ascorbyl palmitate ranges from 0.0004% to 0.05% w / w (preferably 0.05%). 30 The tablets may also contain binding, mucoadhesive and film-forming agents. Examples of binding agents include gum arabic (acacia gum), carrageenan, xanthan gum, konjac gum, agar, or locust bean gum. Gum is preferred. Arabica in a concentration of 2.0% to 20.0% (preferably 5.0%). Mucoadhesive agents are preferably selected from polyacrylic acid polymers. 5136PTIT cross-linked with divinyl glycol (polycarbophil) and sodium carboxymethylcellulose, in concentrations of 0.3% to 4.0% w / w (preferably 1.0%) and 0.5% to 10.0% respectively p / p (preferably 3.0%). As a film-forming agent, preferably polyvinyl pyrrolidone of weight 5 molecular weight from 40,000 to 1,200,000 (K30 - K90) in concentrations from 0.5% to 4.0% w / w (preferably 1.5-2.0%). The tablet may include anti-caking ingredients such as magnesium stearate, calcium carbonate and sodium bicarbonate. To improve the workability of the powders the tablet may include anti-caking agents 10 as magnesium stearate, calcium carbonate and sodium bicarbonate in the following concentrations: magnesium stearate 0.5 to 3.0% w / w (preferably 1.0-1.5%) calcium carbonate 0.1 to 1.0% w / w (preferably 0.2-0.4%) sodium bicarbonate 0.05 to 0.5% w / w (preferably 0.1-0.2%). According to a preferred embodiment, the tablets of the invention 15 comprise two layers, one of which for example comprises mucoadhesive agents while the other contains xylitol, hyaluronic acid or its salt, choline alfoscerate and ascorbyl palmitate. 5136PTIT

Claims

CLAIMS 1. Oral compositions in the form of mucoadhesive tablets comprising xylitol, hyaluronic acid or a salt thereof, choline alfoscerate and ascorbyl palmitate, said tablets being characterised by concave surfaces which adhere to the oral mucosa.

2. Compositions according to claim 1 wherein the tablets have two opposing concave surfaces.

3. Compositions according to claim 1 or 2 having a diameter of 7.0 to 18.0 mm with concavities of diameter of 5.0 to 10.0 mm and a depth of the concavities of 0.25 - 0.8 mm.

4. Compositions according to one or more of claims 1 to 3 wherein the concentration of xylitol in the total tablet ranges from 80.0% to 95.0% w / w (preferably 85.0%), the concentration of sodium hyaluronate with a molecular weight between 800,000 and 4,000,000 Da) ranges from 0.0005% to 20.0% w / w (preferably 0.8%), the concentration of choline alfoscerate ranges from 0.001% to 15.0% w / w (preferably 0.265%) and the concentration of ascorbyl palmitate ranges from 0.0004% to 0.05% w / w (preferably 0.05%).

5. Compositions according to one or more of claims 1 to 4 comprising gum arabic as a binder in a concentration of 2.0% to 20.0% (preferably 5.0%).

6. Compositions according to one or more of claims 1 to 5 comprising mucoadhesive agents selected from polymers of polyacrylic acid cross-linked with divinyl glycol (polycarbophil) and sodium carboxymethylcellulose, in concentrations of 0.3% to 4.0% w / w (preferably 1.0%) and 0.5% to 10.0% w / w (preferably 3.0%) respectively.

7. Compositions according to one or more of claims 1 to 6 comprising as a film-forming agent polyvinyl pyrrolidone with a molecular weight of 40,000 to 1,200,000 (K30 K90) in a concentration of 0.5% to 4.0% w / w (preferably 1.5-2.0%).

8. Compositions according to one or more of claims 1 to 7 comprising two layers.

9. Compositions according to claim 8 wherein one of the layers comprises mucoadhesive agents and the other contains xylitol, hyaluronic acid or a salt thereof, choline alfoscerate and ascorbyl palmitate.

10. Compositions of claims 1-9 for use in the symptomatic treatment of oral dryness (xerostomia), aphthae and inflammation of the oral mucosa.