WO2009074589A2

WO2009074589A2 - Novel use

Info

Publication number: WO2009074589A2
Application number: PCT/EP2008/067158
Authority: WO
Inventors: Christabel Emma Fowler
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2007-12-12
Filing date: 2008-12-10
Publication date: 2009-06-18
Anticipated expiration: 2010-06-12
Also published as: WO2009074589A3; GB0724246D0

Abstract

The use of an oral care composition comprising nanoparticulate calcium fluoride is described for combating dental erosion and tooth wear.

Description

NOVEL USE

FIELD OF THE INVENTION

The present invention relates to the use of an oral care composition comprising nanop articulate calcium fluoride for combating (ie helping to prevent, inhibit and/or treat) dental erosion and/or tooth wear.

BACKGROUND OF THE INVENTION

Tooth mineral is composed predominantly of calcium hydroxyapatite, Ca₁O(PO₄)O(OH)₂, which may be partially substituted with anions such as carbonate or fluoride, and cations such as zinc or magnesium. Tooth mineral may also contain non-apatitic mineral phases such as octacalcium phosphate and calcium carbonate.

Tooth loss may occur as a result of dental caries, which is a multifactorial disease where bacterial acids such as lactic acid produce sub-surface demineralisation that does not fully remineralise, resulting in progressive tissue loss and eventually cavity formation. The presence of a plaque biofϊlm is a prerequisite for dental caries, and acidogenic bacteria such as Streptococcus mutans may become pathogenic when levels of easily fermentable carbohydrate, such as sucrose, are elevated for extended periods of time.

Even in the absence of disease, loss of dental hard tissues can occur as a result of acid erosion and/or physical tooth wear; these processes are believed to act synergistically. Exposure of the dental hard tissues to acid causes demineralisation, resulting in surface softening and a decrease in mineral density. Under normal physiological conditions, demineralised tissues self-repair through the remineralising effects of saliva. Saliva is supersaturated with respect to calcium and phosphate, and in healthy individuals saliva secretion serves to wash out the acid challenge, and raises the pH so as to alter the equilibrium in favour of mineral deposition.

Dental erosion (i.e. acid erosion or acid wear) is a surface phenomenon that involves demineralisation, and ultimately complete dissolution of the tooth surface by acids that are not of bacterial origin. Most commonly the acid will be of dietary origin, such as citric acid from fruit or carbonated drinks, phosphoric acid from cola drinks and acetic acid such as from vinaigrette. Dental erosion may also be caused by repeated contact with hydrochloric acid (HCl) produced by the stomach, which may enter the oral cavity through an involuntary response such as gastroesophageal reflux, or through an induced response as may be encountered in sufferers of bulimia.

Tooth wear (i.e. physical tooth wear) is caused by attrition and/or abrasion. Attrition occurs when tooth surfaces rub against each other, a form of two-body wear. An often dramatic example is that observed in subjects with bruxism, a grinding habit where the applied forces are high, and is characterised by accelerated wear, particularly on the occlusal surfaces. Abrasion typically occurs as a result of three-body wear and the most common example is that associated with brushing with a toothpaste. In the case of fully mineralised enamel, levels of wear caused by commercially available toothpastes are minimal and of little or no clinical consequence. However, if enamel has been demineralised and softened by exposure to an erosive challenge, the enamel becomes more susceptible to tooth wear. Dentine is much softer than enamel and consequently is more susceptible to wear. Subjects with exposed dentine should avoid the use of highly abrasive toothpastes, such as those based on alumina. Again, softening of dentine by an erosive challenge will increase susceptibility of the tissue to wear.

Dentine is a vital tissue that in vivo is normally covered by enamel or cementum depending on the location i.e. crown versus root respectively. Dentine has a much higher organic content than enamel and its structure is characterised by the presence of fluid- filled tubules that run from the surface of the dentine-enamel or dentine-cementum junction to the odontoblast/pulp interface. It is widely accepted that the origins of dentine hypersensitivity relate to changes in fluid flow in exposed tubules, (the hydrodynamic theory), that result in stimulation of mechanoreceptors thought to be located close to the odontoblast/pulp interface. Not all exposed dentine is sensitive since it is generally covered with a smear layer; an occlusive mixture comprised predominantly of mineral and proteins derived from dentine itself, but also containing organic components from saliva. Over time, the lumen of the tubule may become progressively occluded with mineralised tissue. The formation of reparative dentine in response to trauma or chemical irritation of the pulp is also well documented. Nonetheless, an erosive challenge can remove the smear layer and tubule "plugs" causing outward dentinal fluid flow, making the dentine much more susceptible to external stimuli such as hot, cold and pressure. As previously indicated, an erosive challenge can also make the dentine surface much more susceptible to wear. In addition, dentine hypersensitivity worsens as the diameter of the exposed tubules increases, and since the tubule diameter increases as one proceeds in the direction of the odontoblast/pulp interface, progressive dentine wear can result in an increase in hypersensitivity, especially in cases where dentine wear is rapid.

Loss of the protective enamel layer through erosion and/or acid-mediated wear will expose the underlying dentine, and are therefore primary aetiological factors in the development of dentine hypersensitivity.

It has been claimed that an increased intake of dietary acids, and a move away from formalised meal times, has been accompanied by a rise in the incidence of dental erosion and tooth wear. In view of this, oral care compositions which can help prevent dental erosion and tooth wear would be advantageous.

US-A-5049375 (Kao Corporation) describes an oral composition comprising colloidal particles of a poorly soluble fluoride (such asCaF₂) having a particle size of 0.005 to 1 micron and suitably a "peptizer" to colloidize the fluoride. Examples of peptizers include polyol phosphates (such as glucose-phosphate or glycerophosphate), sulphates and caboxylates and salts thereof. Such colloidal particles of CaF₂ having an extremely small particle diameter are described to exhibit an extremely high adsorption on the tooth and can efficiently supply fluoride to the tooth to improve its resistance to decay. Experiment 3 describes a lactic acid challenge and concludes that a stabilised CaF₂ colloid has an excellent effect in improving the acid resistance of the tooth.

WO 00/37033 (Henkel) describes suspensions of poorly water-soluble calcium phosphate, fluoride or fluorophosphates salts in the form of particles having a diameter of 5 to 50 nm and a length of 10 to 150 nm, and stabilised against agglomeration with a surfactant or polymeric protective colloid. Such suspensions are suggested to be suitable as a remineralising component in oral care compositions so to strengthen tooth enamel and close lesions and dentinal tubules. Example 1.7 describes formation of stabilised CaF₂ suspensions with an average particle size of 20nm, used to prepare a toothpaste in Example 2.1.

WO 01/195863 (Henkel) describes a composition for treating tooth and/or bone tissue comprising a poorly water-soluble calcium phosphate, fluoride or fluorophosphates salt having a mean particle diameter of 5 to 300 nm (eg in the form of rod like particles having a thickness of 2 to 50nm & a length of 10 to 150nm) and a polyelectrolyte. It is suggested that such compositions can be used to remineralise teeth and are suitable for smoothing the tooth surface and eliminating lesions and irregularities and thus are useful for the care and repair of tooth defects .

WO 04/060336 (Kao Corporation) describes a multi-component oral care composition comprising (a) a calcium ion supplying compound, (b) a fluoride ion supplying compound other than a monofluorophosphate supplying compound, (c) a polyolphosphate supplying compound and (d) a monofluorophosphate supplying compound, wherein components (a) and (b) are separated until use, such that on mixing of all components fine particles of CaF₂ are formed, eg having a particle size of 0.3 to 15nm. The polyolphosphate component is stated to reduce the size of such primary particles whilst inhibiting their aggregation, thereby apparently providing excellent adsorbability on the tooth surface and excellent effects of inhibiting demineralisation and accelerating remineralisation (of particular benefit in the prevention of caries). Such two phase systems are stated to avoid the problem of poor long term stability apparently exhibited with the colloids described in the above noted Kao Corporation US patent.

WO 06/130167 (ADA) describes a method of preparing pure nanoparticles generally sized less than lOOnm of a partially water soluble compound (eg fluorapatite or CaF₂) by simultaneously spraying and atomising a first solution containing a first component of the compound (eg a source of calcium ions) and a second solution containing a second component of the compound (eg a source of fluoride ions) into a common chamber to evaporate the liquid solvents and to form the said nanoparticles. Data is provided demonstrating that such nanoparticulate CaF₂ is more reactive than macro CaF₂ and can provide higher fluoride levels in the mouth. It is suggested that such nanoparticles can be used to combat sensitivity through more effective occlusion of dentin tubules, can be used to deposit fluoride on or into oral tissues and can provide a source of calcium and fluoride for enhanced remineralisation.

WO 06/133747 (Henkel) describes an oral care product comprising from 0.005 to 0.1 % by weight of calcium salt(s) in the form of rod like primary particles with a thickness of 2 to 50nm and a length of 10 to 150nm. Examples of salts include hydroxyapatite, fluorapatite and calcium fluoride said to remineralise teeth and make them insensitive to external influences.

WO 07/065856 (Glaxo Group Ltd) describes the use of rod-shaped apatite nanocrystals, optionally with a source of fluoride for combating dental erosion and/or tooth wear.

The present invention is based on the discovery that nanoparticulate calcium fluoride helps prevent demineralisation of dental hard tissues by dietary acids and can therefore combat dental erosion and/or tooth wear.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides the use of nanoparticulate calcium fluoride in the manufacture of an oral care composition for combating dental erosion and/or tooth wear.

In another aspect the present invention provides an oral care composition for combating dental erosion and/or tooth wear which comprises nanoparticulate calcium fluoride.

DETAILED DESCRIPTION OF THE INVENTION

Suitably the nanoparticulate calcium fluoride has a mean particle diameter less then lμm, for example in the ranges from 1 to 750nm, from lnm to 500nm, from lnm to 300nm, from 1 to 150nm and from 1 to 50nm.

The nanoparticulate calcium fluoride may be present in an amount of 0.001 to 20.0% by weight of the total composition, suitably from 0.01 to 10%, for example from 0.1 to 5.0% by weight of the total composition. Suitably the nanoparticulate calcium fluoride is formulated together with a dispersing agent which can adsorb onto the surface of the calcium fluoride particles to provide steric or ionic barriers so to help prevent their agglomeration or aggregation. Suitable dispersing agents are surfactants including solubilising or wetting agents or water-soluble polymers such as polyelectrolytes or polymeric protective colloids, for example as described in the above-noted Henkel patent applications.

The nanoparticulate calcium fluoride is substantive and able to adhere to enamel thereby providing a fluoride reservoir for sustained delivery of fluoride ions thereby providing reduced demineralisation and enhanced remineralisation of dental enamel. The nanoparticulate calcium fluoride is therefore not only able to harden and thereby protect teeth from an acidic erosive challenge but also is able to reharden enamel softened by an acidic erosive challenge.

If desired, the oral care composition may further comprise a source of soluble fluoride ions.

Examples of a source of soluble fluoride ions for use in the present invention include an alkali metal fluoride such as sodium fluoride, an alkali metal monofluorophosphate such a sodium monofluorophosphate, stannous fluoride, or an amine fluoride in an amount to provide from 25 to 3500pm of fluoride ions, preferably from 100 to 1500ppm. A suitable fluoride source is an alkali metal fluoride such as sodium fluoride, for example the composition may contain 0.1 to 0.5% by weight of sodium fluoride, eg 0.205% by weight (equating to 927ppm of fluoride ions), 0.2542% by weight (equating to 1150ppm of fluoride ions) or 0.315% by weight (equating to 1426ppm of fluoride ions).

Additional oral care actives may be included in the compositions for use in the present invention.

In order to treat dentine hypersensitivity the oral compositions for use in the present invention may further comprise a desensitising amount of a desensitising agent. Examples of desensitising agents include tubule blocking agents or nerve desensitising agents and mixtures thereof, for example as described in WO 02/15809. Suitable desensitising agents include a strontium salt such as strontium chloride, strontium acetate or strontium nitrate or a potassium salt such as potassium citrate, potassium chloride, potassium bicarbonate, potassium gluconate and especially potassium nitrate.

A desensitising amount of a potassium salt is generally between 2 to 8% by weight of the total composition, for example 5% by weight of potassium nitrate can be used.

Compositions of use in the present invention will contain appropriate formulating agents such as abrasives, surfactants, thickening agents, humectants, flavouring agents, sweetening agents, opacifying or colouring agents, preservatives and water, selected from those conventionally used in the oral care composition art for such purposes. Examples of such agents are as described in EP 929287.

Compositions of use in the present invention are typically formulated in the form of toothpastes, sprays, mouthwashes, gels, lozenges, chewing gums, tablets, pastilles, instant powders, oral strips and buccal patches.

Compositions of use in the present invention may be prepared by admixing the ingredients in the appropriate relative amounts in any order that is convenient and if necessary adjusting the pH to give a desired value for example from 5.5 to 9.

The present invention also provides a method for combating dental erosion and/or tooth wear which comprises applying an effective amount of a composition as hereinbefore defined to an individual in need thereof.

The invention is further illustrated by the following Examples.

Example 1 - Energy dispersive X-ray (EDX) analysis

Energy dispersive X-ray analysis was used to assess the retention of fluoride on polished human enamel after treatment with 2.5 wt% suspensions of nanoparticulate CaF₂ versus bulk (ie microparticulate) CaF₂. Human enamel was immersed for 2 minutes in the test suspension and then washed with distilled water. Scanning electron microscopy with EDX was then performed to look for retention of fluoride on the enamel surface. The data obtained showed that when the enamel was treated with the nanoparticulate CaF₂, more fluoride was retained on the surface after washing than in the case of treatment with the bulk material, i.e. the nanoparticles were found to be more substantive and can adhere effectively to the enamel thereby providing a fluoride reservoir for sustained delivery of fluoride ions to the enamel.

Example 2 - Hydroxyapatite Microplate Method

The wells of 96-well 200μl microplates were filled with a concentrated suspension of high resolution hydroxyapatite (HA) powder (2Og HA in 200ml acetone). The plates were allowed to dry under agitation (50 rpm on an orbital shaker) and then washed thoroughly with deionised water to remove any loose HA. For erosion experiments, the wells of the HA coated microplates were filled with deionised water and left to hydrate for 60 minutes. The water was then removed and each of the 8 wells of one lane of the microplate filled with 200μl of one of the agents to be tested. Each plate contained 12 lanes, so 6 agents or concentrations could be tested in duplicate (at n=8) in each microplate. The actives were left in the wells for 30 minutes under agitation, after which time the plates were again washed thoroughly with deionised water. The erosive challenge used for the study was an orange juice mimic, 1% citric acid, pH 3.8. The wells of the plate were exposed to 200μl of the citric acid solution under agitation for 30 minutes. After the challenge, 50 μl of the citric acid was removed from each well and placed into the corresponding well of a new 96-well microplate. 50 μl of vanadomolybdate reagent was then added to each well and after 5 minutes, the absorbance of the solution in each well at 450nm was read using a microplate plate reader. The test agents assessed using this technique were nanoparticulate and bulk calcium fluoride, with nanoparticulate calcium fluoride being tested in suspension at three different concentrations (0.5, 1.0 and 1.5 wt% nano CaF₂) . The positive control used was 300ppm fluoride, and the negative control was deionised water. Graph 1 contains the data for the microplate erosion study. The chart contains data from one microplate, where treatments have been carried out in duplicate at n=8 each time, as described above.

It is evident that nanoparticulate CaF₂ prevents demineralisation of hydroxyapatite to a greater extent than 300ppm fluoride or bulk CaF2. In this in vitro experiment, although a directional dose response to nano CaF₂ is suggested by the data, 0.5 wt% CaF₂ is statistically equivalent to 1.5 wt% nano CaF₂ in preventing hydroxyapatite demineralisation.

Graph 1. Hydroxyapatite microplate erosion data to assess the antierosion efficacy of suspensions of nanoparticulate and bulk calcium fluoride.

300 ppm F nano CaF nano CaF nano CaF Bulk CaF Water

0 5% 1 0% 1 5% 0 5%

Claims

1. The use of nanoparticulate calcium fluoride in the manufacture of an oral care composition for combating dental erosion and/or tooth wear.

2. The use according to claim 1 wherein the oral composition further comprises a source of soluble fluoride ions.

3. The use according to claim 1 or 2 wherein the oral composition further comprises a desensitising agent.

4. An oral care composition for combating dental erosion and/or tooth wear which comprises nanoparticulate calcium fluoride.

5. A composition according to claim 4 which further comprises a source of soluble fluoride ions.

6. A composition according to claim 4 or 5 which further comprises a desensitising agent.

7. A method for combating dental erosion and/or toothwear which comprises applying an effective amount of an oral care composition as defined in any one of claims 1 to 6 to an individual in need thereof.