TITLE

DENTAL COMPOSITION FOR PREVENTING AND TREATING STOMATITIS AND MOUTH ULCERS

DESCRIPTION

Field of the invention The present invention relates to dentistry, more precisely it relates to a composition for preventing and treating stomatitis and mouth ulcers. Short description of the prior art

Oral mucositis, also called stomatitis, is a common and weakening complication of chemotherapy and radiotherapy, with an incidence of 40% among the patients.

This disease is a consequence of chemoterapic agents systemic toxic effects and of radiotherapy local effects on mouth lining. Oral mucositis is a mouth lining inflammation that may be either a simple reddening, or a serious ulcer. The symptoms vary from pain to discomfort or impossibility to take solid food or liquids. Mucositis can be so serious to require a suspension of chemotherapy, which may reduce its effectiveness. Furthermore, patients who suffer from mouth lining diseases and are immunosuppressed due to chemotherapy and radiotherapy, are predisposed to develop opportunistic mouth infections.

Mouth lining ulcers can be also caused by dental prosthesis that are badly made or that badly fit to the gums, by orthodontic devices that traumatize the mouth mucous membrane, by a too energetic toothbrushing and/or by using a too hard toothbrush; moreover, they can be caused by tooth fractures and/or fillings, by bites to the inner mouth tissues, by burning from hot food, by aggressive dental treatments; they can finally be the consequence of bad oral hygiene, or of application of whitening substances, or, more in general, of traumas.

Furthermore, an inflammatory condition of the mouth lining is also known, which is very common, and which is called Recurrent Aphthous Ulcer, RAU; it concerns, even if occasionally, 25% of the population and is characterized by very painful and recurring single or multiple, not infective ulcers.

Many systems are known for treating mucositis, or for reducing mucositis severity and possible complications.

The most commonly used treatments are based on: — allopurinol based mouthwash preparations (that are specific for therapy with 5-fluorideuracile) , or mouth criotherapy during 5-fluoro-uracil bolus (which has a short half-life) , reducing thus, by vasoconstriction, the concentration of antitumoral drugs in the mouth lining: such treatments reduce therefore the toxicity of the chemoterapic drugs in the mouth lining;

— mouthwash preparations which have an anti- inflammatory and/or an antibacterial action, and contain benzydamine, or corticosteroids, or camomile; — local anaesthetic substances such as viscous solutions that contain, for example, xylocaine or lidocaine;

— mouthwash that contain antiseptic substances, such as chlorhexidine, povidone-iodine, hydrogen peroxide;

— mouthwash, or mouth-soluble tablets, that contain antibacterial and/or antmycotic and/or antiviral agents, for example nystatin, clotrimazole, acyclovir, PTA tablets (polymixin and + tobramycin + amphotericine B) ;

— film- forming substances that are adapted to protect the barrier provided by the mouth lining, in particular, solutions which contain sucralphate, sodium alginate, kaolino-pectin;

— cytoprotective substances such as β-carotene (provitamine A) , vitamin E, oxpentifilline, azelastine, prostaglandins El and E2, that are used topically;

— stimulating treatments which operate on mouth mucous membrane cells, such as low energy laser applications, administration of glutamine;

— analgesic substances such as intravenous opioids (morphine) , alfentanil, sweets containing capsaicin;

— psychotherapy, hypnosis, relaxation techniques.

More recently, for treating and avoiding post chemotherapy or radiotherapy stomatitis and mouth lining ulcers in general, mouthwash and/or gel have been used, which are based on:

— vitamin E;

— aloe true + glycyrrhetic acid + benzalkonium chloride + hyaluronic acid and xanthan gum (ALOVEX Recordati, Italy) in the form of mouthwash, gel and spray products;

— glycyrrhetic acid + benzalkonium chloride + hyaluronic acid, polyvinylpyrrolidone, hydroxyethyl cellulose, in powder to be diluted into water to obtain a mouthwash solution (GELCLAIR Sinclair Pharmaceuticals limited, UK) ; — glycyrrhetic acid + true aloe + sodium hyaluronate + polyvinylpyrrolidone in form of mouthwash product (RINCINOL P.R.N. Sunstar Butler) .

Even if the efficacy of the products presently used in the clinical practice is rather satisfactory, the need is felt of a product which has optimal protective, antiinflammatory, analgesic features, as well as a disinfecting efficacy.

Summary of the invention

It is therefore a feature of the present invention to provide a composition that can be used for preventing and treating stomatitis and mouth lining ulcers, which has an enhanced specific therapeutic efficacy, and has also analgesic, anti- inflammatory and antiseptic properties as

- A - well as protective properties, allowing a high efficacy of response .

It is also a feature of the present invention to provide such a composition that is particularly comfortable to use.

These and other objects are achieved by a composition for preventing and treating stomatitis, mouth lining ulcers and mucous membrane lesions, the main characteristic of which being that it comprises: — a Myrrh resin, also called Commiphora molmol or Commiphora Myrrh, as a fluid extract;

— a soluble zinc salt .

Preferably, the composition comprises also a disinfecting substance. Advantageously, the composition comprises also a glycyrrhetic acid.

Preferably, the disinfecting substance is a cationic disinfecting substance.

The pharmaceutical composition, according to the invention, allows to overcome the drawbacks due to the limited analgesic / anti- inflammatory / disinfecting efficacy of the products that are currently used in clinical practice for preventing and treating stomatitis, mouth lining ulcers and mucous membrane lesions. In particular, the association of a cationic disinfecting substance with a zinc salt, with the Myrrh extract, and with glycyrrhetic acid, allows eliminating the symptoms in a considerably shorter time, and obtaining a higher chance of recovery with respect to commonly used products. This surprising activity is due to:

— a synergistic action of the disinfecting properties of the zinc ion, in particular in combination with a cationic disinfecting substance, and the disinfecting and analgesic activity of the Myrrh;

— an anti- inflammatory action of glycyrrhetic acid.

In particular, the cationic disinfecting substance is selected from the group comprised of : benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetrimide, cetylpyridinium chloride, or a mixture thereof. Preferably, the cationic disinfecting substance used is the chlorhexidine gluconate.

Preferably, the glycyrrhetic acid is 18-β-glycyrrhetic acid. Advantageously, the soluble zinc salt is selected from the group comprised of: zinc chloride, zinc citrate, zinc sulphate, zinc gluconate, zinc acetate, or a mixture of such zinc salts.

Preferably, the soluble zinc salt is zinc chloride. Advantageously, the composition comprises a mucoadhesive substance. The task of the mucoadhesive substances is to enhance the composition viscosity, in order to assist its adhesion on the lesions to be treated, and to increase the duration of the active principles that are present in the composition.

Preferably, the mucoadhesive substance is selected from the group comprised of: polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate, chitosane, hyaluronic acid, sodium alginate, ethylcellulose, sucralphate, xanthan gum, hydrossipropylmethylcellulose, carboxymethyl- cellulose.

The composition can be formulated in a form selected from the group comprised of: a mouthwash product, a topic gel, a toothpaste. The composition comprises therefore a solution that can be topically applied by means of a spraying device on the above-mentioned zone or that can be taken as a mouthwash solution, or as a topic gel by applying it directly on the lesions by means of a small tube with an applicator needle, or by a finger or by a

cotton swab. If this composition is in the form of a gel, it can be used also as a toothpaste, by tooth-brushing.

In the case of compositions in the form of a mouthwash product, or of a toothpaste, the mucoadhesive substance is preferably polyvinylpyrrolidone vinylacetate, while in case of compositions in form of a mouthwash product, or of toothpaste, the preferred mucoadhesive substance is ethylcellulose .

Preferably, the weight proportions for 100 g of composition in form of mouthwash or toothpaste are set in the ranges indicated hereafter, for each ingredient:

— Myrrh fluid extract 0,01 g í 3 g

— Glycyrrhetic acid, in particular, 18-β-glycyrrhetic acid, 0, 01 g í 3 g — Chlorhexidine digluconate 0,01 g í 0,5 g

— Zinc chloride 0,01 g í 0,5 g

— polyvinylpyrrolidone-vinylacetate 0,1 g í 5 g

— Excipients and depurated water up to 100 g. Preferably, in the case of a mouthwash product, at least one excipient can be used selected from the group comprised of :

— Mint flavour 0,05 g í 0,5 g;

— Orange flavour 0,05 g í 1 g;

— Sodium saccharine 0,1 g í 0,5 g; — Green colouring matter 0,01 g í 0,05 g;

— Methyl -para-hydroxybenzoate 0,01 g í 0,03 g; Preferably, in the case of a toothpaste, at least one excipient can be used selected from the group comprised of: — Sodium saccharine 0,05 g í 0,5 g;

— Green colouring matter 0,01 g í 0,05 g;

— Glycerine 30 g í 60 g;

— micronized Silica 5 g í 30 g;

— Mint flavour 0,05 g í 0,5 g;

— Orange flavour 0,05 g í 1 g;

— Sodium lauryl sulphate 1 g í 4 g;

— polyvinylpyrrolidone vinylacetate 0,5 g í 3 g. Preferably, the weight proportions for 100 g of composition in form of gel topic are set in the range hereafter indicated for each ingredient :

— Myrrh fluid extract 0,01 g í 3 g

— Glycyrrhetic acid, in particular, 18-β-Glycyrrhetic acid, 0, 01 g í 3 g — Zinc chloride 0,01 g í 0,5 g

— Chlorhexidine digluconate 0,01 g í 0,5 g

— Hydroxyethylcellulose 1 g í 5 g

— Excipients and depurated water up to 100 g. Preferably, in the case of a topic gel, at least one excipient can be used selected from the group comprised of:

— Green colouring matter 0,01 g í 0,05 g

— Methyl -para-hydroxybenzoate 0,01 g í 0,3 g

— Mint flavour 0,05 g í 0,5 g — Orange flavour 0,05 g í 1 g

— Sodium saccharine 0,1 g í 0,5 g

The use of such combinations of Myrrh resin, also called Commiphora molmol , which has analgesic and disinfecting properties, and of a soluble zinc salt, which has a disinfecting and antiviral efficacy, possibly together with a cationic disinfecting substance and/or with a glycyrrhetic acid, which has an anti-inflammatory action, is not known in the dentistry practice, where, instead, a combination of these substances can be profitably used according to the present invention.

The composition according to the invention can be used for avoiding and treating stomatitis and mouth lining ulcers, which may be a consequence of chemotherapy and radiotherapy, or of dental prosthesis that are badly made

or that badly fit to the gums, or of orthodontic devices that are traumatizing for the mouth mucous membrane, or of a too energetic tooth brushing and/or of using too hard toothbrushes, or of tooth fractures and/or fillings, or of biting mouth inner tissues, or of food burnings, or of aggressive dental treatment, or of bad oral hygiene , or of professional whitening, or, more in general, of traumas, or of Recurrent Aphthous Ulcer (RAU) and also of lesions after mouth surgery treatment. Some examples of dental compositions, according to the present invention, are presented below, for preventing and treating stomatitis and mouth ulcers.

EXAMPLE 1

A composition for preventing and treating stomatitis and mouth lining ulcers in the form of a mouthwash product comprising Myrrh resin extract, chlorhexidine gluconate and zinc chloride, together with glycyrrhetic acid, in the following weight proportions:

— myrrh fluid extract 0,2 ml; — glycyrrhetic acid, in particular, 18-β-glycyrrhetic acid, 0,2 g;

— chlorhexidine digluconate 0,2 g;

— zinc chloride 0,1 g;

— polyvinylpyrrolidone-vinylacetate 1 g; — strong mint flavour 0,3 g;

— orange flavour 0,4 g;

— sodium saccharine 0,2 g;

— green colouring matter 0,02 g;

— methyl-para-hydroxybenzoate 0,02 g; — depurated water up to 100 g

It is applied by mouth washing for about 2-3 minutes with 10 ml of solution, and repeating the mouthwash three times a day, or according to dentist's suggestions; after such mouthwashing it is preferable not to wash the mouth any

longer and not to have food or drinks, for at least one hour.

EXAMPLE 2

A composition for preventing and treating stomatitis and mouth lining ulcers in the form of a topic gel based on Myrrh resin extract, chlorhexidine gluconate and zinc chloride, together with Glycyrrhetic acid, in the following weight proportions:

— myrrh fluid extract 0,2 ml; — glycyrrhetic acid, in particular, 18-β-glycyrrhetic acid, 0,2 g;

— zinc chloride 0,2 g;

— chlorhexidine digluconate 0,2 g;

— green colouring matter 0,02 g; — hydroxyethylcellulose 3,25 g;

— methyl-para-hydroxybenzoate 0,1 g;

— mint flavour 0,3 g;

— orange flavour 0,5 g;

— sodium saccharine 0,3 g; — depurated water up to 100 g. it is applied by laying the gel on the desired zone directly with the needle of an applicator, or with a finger, or with a cotton swab, repeating the application each 4-6 hours, or according to the dentist's suggestions; after each application, it is preferable not to have food or drinks, for at least one hour.

EXAMPLE 3

A composition for preventing and treating stomatitis and mouth lining ulcers in the form of a gel toothpaste based on Myrrh resin fluid extract, chlorhexidine gluconate and zinc chloride together with Glycyrrhetic acid, in the following weight proportions:

— myrrh fluid extract 3 ml;

— glycyrrhetic acid, in particular, 18-β-glycyrrhetic acid, 0,3 g;

— zinc chloride 0,2 g;

— chlorhexidine digluconate 0,2 g; — sodium saccharine 0,25 g;

— green colouring matter 0,03 g;

— glycerine 60 g;

— micronized silica 15 g;

— mint flavour 0,3 g; — orange flavour 0,5 g;

— sodium lauryl sulphate 2 g;

— polyvinylpyrrolidone vinylacetate 1 g;

— depurated water up to 100 g

The composition is used by laying a desired amount of gel toothpaste on a soft toothbrush, by softly brushing both dental arches moving downwards the toothbrush for about two minutes, and stressing on the teeth regions that are close to the zone of the mucous membrane that is affected by the inflammatory/ulcerative processes. Then the mouth is washed with plenty of water. The procedure should be repeated three times a day, after the meals; food and drinking should be avoided for at least one hour after applying the gel toothpaste.

The foregoing description of specific embodiments will so fully reveal the invention according to the conceptual point of view, so that others, by applying current knowledge, will be able to modify and/or adapt for various applications such embodiments without further research and without parting from the invention, and it is therefore to be understood that such adaptations and modifications will have to be considered as equivalent to the specific embodiments. The means and the materials to realise the different functions described herein could have a different nature without, for this reason,

departing from the field of the invention. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation.