Mucoadhesive oral tablet for symptomatic treatment of xerostomia, mouth ulcers and inflammations of the oral cavity

Abstract

Disclosed are formulations in the form of mucoadhesive tablets useful for treating symptoms caused by xerostomia (dry mouth). The tablets according to the invention comprise hyaluronic acid, choline alfoscerate and ascorbyl palmitate, and are characterised by two concave surfaces that adapt to the oral and gingival mucosa so as to adhere to the oral vestibules or the palate.

Description

[0001] MUCOADHESIVE ORAL TABLET FOR SYMPTOMATIC TREATMENT OF XEROSTOMIA, MOUTH ULCERSAND INFLAMMATIONS OF THE ORAL CAVITY

[0002] The invention relates to formulations in the form of mucoadhesive tablets useful for treating symptoms caused by xerostomia (dry mouth).

[0003] PRIOR ART

[0004] Xerostomia (dry mouth) is dryness of the oral cavity caused by a low or absent flow of saliva.

[0005] Said condition can cause discomfort, interfere with speech and swallowing, make dentures difficult to use, cause halitosis, and adversely affect oral hygiene by reducing the oral pH and increasing bacterial growth. Long-term xerostomia can lead to severe tooth decay and oral candidiasis. Xerostomia is a frequent disorder of the elderly, affecting about 20% of said population.

[0006] The typical symptoms of dry mouth, caused by an insufficient flow of saliva, are the feeling of having a dry, sticky mouth, chewing, swallowing and taste problems, a stinging sensation, a dry, rough tongue, onset of ulcers, a tendency to develop mouth and lip infections, bad breath, increased plaque and tooth decay.

[0007] Conventional symptomatic treatments involving the use of saliva substitutes in liquid or gel form have a temporary, short-lived effect, only remaining in the oral cavity for a short time.

[0008] DESCRIPTION OF THE INVENTION

[0009] It has now been discovered that inserting high-molecular-weight hyaluronic acid in the form of sodium salt, in the presence of choline alfoscerate and ascorbyl palmitate, into a mucoadhesive tablet with at least one concave surface based on xylitol, improves the symptomatic treatment of xerostomia (dry mouth), mouth ulcers and inflammations of the oral mucosa.

[0010] The object of the invention is therefore 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 that adhere to the oral mucosa.

[0011] The tablets according to the invention are preferably circular, and have two opposing concave surfaces.

[0012] The tablets according to the invention, applied in the oral vestibules or on the palate in contact with the mucosa, produce a suction effect that causes the tablet to adhere for a long time, allowing slow release of its active ingredients, especially high-molecular-weight sodium hyaluronate and xylitol, which stimulate salivation (Int J Oral Biol 44:62-70, 2019) and moisten and lubricate the mucosa, and at the same time perform a protective, anti-inflammatory action on tissues irritated by the absence of a sufficient flow of saliva. Moreover, the sensation of a solid body in the mouth triggers chewing, thus inducing an increase in salivary flow.

[0013] The saliva-stimulating and moistening action performed by xylitol, and the antiinflammatory action performed by high-molecular-weight hyaluronic acid (HA), significantly reduce discomfort and damage to the oral mucosa by reducing pain symptoms and counteracting dryness of the mouth.

[0014] The presence of choline alfoscerate aids the trophism of the mucosal tissue and increases the bioadhesion of hyaluronic acid, helping to create a lubricating protective film, while the anti-hyaluronidase action of ascorbyl palmitate prolongs the protective and anti-inflammatory effect of hyaluronic acid.

[0015] Chewing is known to mechanically stimulate the production of saliva by the salivary glands. To stimulate salivation, individuals suffering from dry mouth (xerostomia) often chew candies or beverages containing sugars, which are harmful to the health of the teeth and gums. Xylitol acts by reducing the level of bacteria such as Streptococcus mutans in the plaque and saliva, counteracting their energy production processes and reducing their adherence to the tooth surface. As the bacteria causing tooth decay do not metabolise xylitol, lactic acid and polysaccharides are not produced; less plaque is therefore formed, and the level of the acids that attack the tooth surface is lower.

[0016] Xylitol stimulates the flow of saliva rich in calcium and phosphate, which helps to remineralise tooth decay lesions at the initial stage. Increased saliva can help prevent halitosis by eliminating dryness of the mouth, and prevent lengthy exposure to acids and sugars caused by food residues.

[0017] Topical use of choline alfoscerate on the mucosa promotes cell trophism, thereby enabling cell integrity to be maintained and restored. It has also been found that topical use of choline alfoscerate is useful to maintain the correct pH value of the oral mucosa.

[0018] Choline alfoscerate is an ampholyte, is highly soluble in water and ethanol, possesses a high level of chemical and microbiological stability, and has special organoleptic properties in that it is substantially flavourless, odourless and colourless. Said organoleptic properties facilitate its use in the mouth-dissolving tablets according to the invention.

[0019] Scientific evidence exists of the powerful anti-hyaluronidase action performed by ascorbic acid, and in particular by ascorbyl palmitate. Said substance has long been used in the cosmetic industry for its antioxidant and anti-radical properties, but at much higher concentrations (0.5-0.1% w / w) than those at which anti-hyaluronidase activity takes place (0.05-0.0004% w / w).

[0020] Its anti-hyaluronidase action synergises strongly with the action of hyaluronic acid, whether endogenous or exogenous. The anti-hyaluronidase action represents a functional element of crucial importance to increase the anti-inflammatory and tissue-repair efficacy of hyaluronic acid.

[0021] The anti-hyaluronidase action also performs an antibacterial / anti-inflammatory action, as many bacteria perform an inflammatory action by producing specific hyaluronidases that promote tissue colonisation, thereby promoting the onset and spread of bacterial infections / contamination at local level.

[0022] On the basis of the factors set out above, the anti-inflammatory / tissue repair action of HA is protected and strongly enhanced by the anti -hyaluronidase action and the presence of the film-forming and bio- / mucoadhesive matrix designed to form a highly favourable environment for tissue protection and repair (wound healing).

[0023] The diameter of the tablets typically ranges from 7.0 to 18.0 mm (preferably 12 mm), the thickness ranges from 2.5 to 7.6 m, and the diameter of the concavity from 5.0 to 10.0 mm (preferably 6.5 mm), with a depth of 0.25-0.8 mm (preferably 0.4 mm), and a radius of curvature ranging from 10° to 25° (preferably 12.5°).

[0024] The xylitol concentration ranges from 80.0% to 95.0% w / w (preferably 85.0%) of the total tablet, 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 choline alfoscerate concentration ranges from 0.001% to 15.0% w / w (preferably 0.265%), and the ascorbyl palmitate concentration ranges from 0.0004% to 0.05% w / w (preferably 0.05%).

[0025] The tablets can also contain binding, mucoadhesive and film-forming agents.

[0026] Examples of binding agents comprise gum arabic (gum acacia), carrageenan, xanthan gum, konjac gum, agar and carob-seed gum. Gum arabic at a concentration ranging from 2.0% to 20.0% w / w (preferably 5.0%) is preferred.

[0027] The mucoadhesive agents are preferably selected from polymers of polyacrylic acid crosslinked with divinyl glycol (polycarbophil) and sodium carboxymethylcellulose, at concentrations ranging from 0.3% to 4.0% w / w (preferably 1.0%) and 0.5% to 10.0% w / w (preferably 3.0%) respectively.

[0028] Polyvinylpyrrolidone, with a molecular weight ranging from 40,000 to 1,2000,000 Da (K30-K90), at a concentration ranging from 0.5% to 4.0% w / w (preferably 1.5-2.0%), is preferably used as film-forming agent.

[0029] The tablet can include ingredients with an anti-caking action such as magnesium stearate, calcium carbonate and sodium bicarbonate.

[0030] To improve the workability of the powders, the tablet can include anti-caking agents such as magnesium stearate, calcium carbonate and sodium bicarbonate at the following concentrations: magnesium stearate ranging from 0.5 to 3.0% w / w (preferably 1.0-1.5%) calcium carbonate ranging from 0.1 to 1.0% w / w (preferably 0.2-0.4%) sodium bicarbonate ranging from 0.05 to 0.5% w / w (preferably 0.1-0.2%). According to a preferred embodiment, the tablets according to the invention comprise two layers, one of which comprises mucoadhesive agents, for example, while the other contains xylitol, hyaluronic acid or a salt thereof, choline alfoscerate and ascorbyl palmitate.

Claims

CLAIMS1. 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 adhering to the oral mucous membranes.

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 having a diameter of 5.0 to 10.0 mm and a concavity depth of 0.25 to 0.8 mm.

4. Compositions according to one or more of claims 1 to 3 wherein the xylitol concentration ranges from 80.0% to 95.0% w / w (preferably 85.0%) of the total tablet, the concentration of sodium hyaluronate having a molecular weight between 800.000 and 4,000,000 Da ranges 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 ascorbyl palmitate concentration 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, at a concentration ranging from 2.0% to 20.0% (preferably 5.0%), as binder.

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 carboxymethyl cellulose, at concentrations ranging from 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 polyvinyl pyrrolidone having a molecular weight between 40,000 and 1,2000,000 Da (K30 - K90), at a concentration ranging from 0.5% to 4.0% w / w (preferably 1.5 to 2.0%), as filmforming agent.

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 according to claims 1-9 for use in the symptomatic treatment of dry mouth (xerostomia), mouth ulcers and inflammation of the oral mucosa.