WO2014124950A1

WO2014124950A1 - Novel composition

Info

Publication number: WO2014124950A1
Application number: PCT/EP2014/052689
Authority: WO
Inventors: Christabel Fowler; Robert KARLINSEY
Original assignee: Glaxo Group Limited; Indiana Nanotech Llc
Priority date: 2013-02-14
Filing date: 2014-02-12
Publication date: 2014-08-21

Abstract

Aqueous single phase oral care compositions are described comprising a fluoride salt and an unfunctionalised calcium phosphate compound, which is not β-tricalcium phosphate, characterised in that the calcium phosphate compound is present in a catalytic and fluoride-stable amount relative to the fluoride salt. Such compositions are of use in combating dental caries, dental erosion and/or tooth wear.

Description

Novel Composition

FIELD OF THE INVENTION

The present invention relates to an aqueous single phase oral care composition comprising a fluoride salt and a catalytic and fluoride-stable amount of a calcium phosphate compound, which is not β-tricalcium phosphate. The calcium phosphate compound is present in an amount sufficient to increase the efficacy of fluoride ions in strengthening dental enamel of teeth against acidic challenges, whilst not significantly compromising the long term storage stability of the fluoride ions in the oral care composition. Such compositions are of use in combating (i.e. helping to prevent, inhibit and/or treat) dental erosion and/or tooth wear. Such compositions are of use in combating dental and/or root caries. Such compositions are of use in combating dentine hypersensitivity.

BACKGROUND OF THE INVENTION

Tooth mineral is composed predominantly of calcium hydroxyapatite, Cai₀(PO₄)6(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 biofilm 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 in 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 (ie 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, in addition to dental caries, would be advantageous.

Oral care compositions comprising a source of fluoride ions have been known for many years for combating dental caries. Fluoride ions are known to inhibit plaque bacteria that can cause plaque acid. Fluoride ions are also known to enhance remineralisation and to decrease demineralisation of dental enamel, thereby strengthening dental enamel from acidic challenges. In more recent years, oral care compositions comprising a source of fluoride ions have also been marketed for combating dental erosion; for example using the technologies described in WO 2006/100071 and WO 2010/066655 (both in the name of Glaxo Group Limited). WO 2006/100071 describes a dentifrice composition especially formulated to maximise both the availability of fluoride ions in the composition and their uptake by dental enamel, so to strengthen teeth from both dietary and plaque acidic challenges. It is suggested that such dentifrices suitably do not contain a calcium salt. Attempts have been made over many years to maximise the efficacy of fluoride ions, in strengthening dental enamel, by including a source of calcium and phosphate ions to supplement the natural remineralisation provided by such ions already present in saliva.

However, as described in US-A-6159448 (in the name of Enamelon) and the many references cited therein, formulating a source of fluoride ions together with a calcium (phosphate) compound is technically challenging given that the presence of calcium ions together with a source of fluoride ions, can cause the precipitation of insoluble calcium fluoride, thereby significantly reducing the availability of fluoride in an oral care composition. Various solutions to this problem have been suggested including the incorporation of an antinucleating agent or an alkali metal phytate together with the calcium and fluoride ions or the separation of a calcium compound from a source of fluoride ions either by means of a physical barrier in a two phase aqueous composition or by formulating the ingredients in a single phase anhydrous system (see for example US patents 4,098,435, 4,177,258, 4,183,915, 4,348,381 and 4,528,181 in the name of Colgate- Palmolive or US patents 5,603,922, 5,605,675 or 5,571,502 in the name of Enamelon).

US-A-5993786 (in the name of ADAHF) describes, amongst other formulations, anti- carious remineralising gels, toothpastes and dentifrices comprising from about 0.5 to 10% by weight of a-tricalcium phosphate, tetracalcium phosphate or monocalcium phosphate monohydrate, suitably present in a dry mixture to be reconstituted into a gel by the addition of water which may contain other components including a source of fluoride ions, so to prevent premature reaction of the calcium and fluoride ions. US-A-6159448 (Enamelon) describes oral care compositions comprising various partially water soluble calcium salts, such as calcium sulphate, together with a source of phosphate and fluoride ions. Such calcium salts are separated until use from the source of phosphate and fluoride ions either by being formulated in a single phase anhydrous system or by means of a physical barrier in a two phase aqueous composition. It is suggested that the oral care compositions preferably contain from about 0.05% to about 15.0% by weight, more preferably from about 0.10% to about 10.0% by weight of the calcium salt(s), from about 0.05%) to about 15.0% by weight, more preferably from about 0.10 to about 10.0% by weight of the phosphate salt(s) and from about 0.01% to about 5.0%, more preferably from about 0.02%> to about 2.0%> by weight of the fluoride salt(s).

WO 2006/133747 (in the name of Henkel) describes oral care compositions comprising low quantities (ie from 0.01 to 0.09 % by weight of the composition) of various sparingly soluble rod-shaped nanoparticulate calcium compounds such as hydroxyapatite, fluorapatite or calcium fluoride. It is suggested that such compositions can also contain other calcium compounds, which need not be nanoparticulate, such as calcium glycerophosphate, or calcium containing abrasives such as chalk, calcium pyrophosphate or dicalcium phosphate dihydrate. Such compositions can also comprise a source of fluoride ions, preferably in an amount of 0.01 to 0.2% by weight.

WO 2009/074589 (in the name of Glaxo Group Limited) describes oral care compositions comprising nanoparticulate calcium fluoride for combating dental erosion and/or tooth wear. 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. It is stated that the oral care composition may further comprise a source of soluble fluoride ions, which can be present in an amount to provide from 25 to 3500 ppm, preferably from 100 to 1500 ppm of fluoride ions.

US patent 4, 193,988 (in the name of Beecham Group Ltd) describes anti-cariogenic oral hygiene compositions comprising calcium glycerophosphate and from 0.08 to 7.6% by weight of sodium monofluorophosphate, the sodium monofluorophosphate and the calcium glycerophosphate being present in the composition in a weight ratio of 10: 1 to 3 : 1. WO 2007/089894 (in the name of Indiana University Research & Technology Corporation) describes dentifrices comprising an alloy comprising amorphous tricalcium phosphate and at least one metal oxide, such as titanium dioxide or silicon dioxide. Such dentifrices may further comprise a fluoride ion source.

WO 2008/137190, US 2010/0068159, US 2010/0291164 and US2011/0020245 (in the name of Indiana Nanotech) describe dental or confectionary products comprising a functionalised calcium compound such as calcium phosphate, especially tricalcium phosphate (TCP), functionalised by mechanochemically combining the calcium compound with an organic compound such as an surfactant, eg sodium lauryl sulphate (SLS) or an acid such as fumaric acid. It is suggested that the surfactant treated minerals such as TCP/SLS are compatible with fluoride and can improve reminineralisation efficiency.

WO 20010/017104 (in the name of Indiana Nanotech) describes dental formulations with fluoride comprising a functionalised calcium phosphate material comprising substantially crystalline β-tricalcium phosphate, at least one metal oxide (such as silica) and at least one organic compound (such as urea).

WO 2010/068359 (in the name of 3M) describes oral care compositions comprising a fluoride providing agent and calcium phosphate (especially tricalcium phosphate) particles surface-treated with a sugar alcohol, (such as xylitol) or glycerophosphoric acid or a mixture thereof.

It has now been discovered that an uniunctionalised calcium phosphate compound is compatible with a source of fluoride ions in an aqueous single phase oral care composition, providing the uniunctionalised calcium phosphate compound is used in a low enough amount relative to the amount of fluoride ions present.

However, using an uniunctionalised calcium phosphate compound in such a low amount relative to the source of fluoride ions would not necessarily be expected to augment the natural remineralisation provided by calcium and phosphate ions already present in saliva. It has further been discovered that such low amounts of a calcium phosphate compound can enhance the efficacy of fluoride in strengthening dental enamel from acidic challenges.

The present invention is therefore based upon the two-fold discovery that a fluoride salt can be combined together with an unfunctionalised calcium phosphate compound in a single phase aqueous oral care composition providing that the calcium compound is present in a catalytic and fluoride-stable amount relative to the fluoride salt, so to enhance fluoride efficacy but not to compromise long term storage stability of the fluoride in the composition.

SUMMARY OF THE INVENTION

Accordingly, in a first aspect, the present invention provides an aqueous single phase oral care composition comprising a fluoride salt and an unfunctionalised calcium phosphate compound, which is not β-tricalcium phosphate, characterised in that the calcium phosphate compound is present in a catalytic and fluoride-stable amount relative to the fluoride salt.

The compound, β-tricalcium phosphate, is expressly excluded from the definition of an unfunctionalised calcium phosphate compound and does not fall within the scope of the present invention. This is because an aqueous single phase oral care composition comprising a fluoride salt and unfunctionalised β-tricalcium phosphate is the subject of, and is being claimed in, a separate patent application, filed on the same day as the present patent application. Without wishing to be bound by theory, it is believed that a catalytic amount of an unfunctionalised calcium phosphate compound can act as a nucleating template or seed, thereby enhancing the efficacy of fluoride, together with calcium and phosphate ions naturally present in saliva, in remineralising dental enamel. DETAILED DESCRIPTION OF THE INVENTION

By "aqueous single phase" is meant that the oral care composition comprises water as an excipient and that all ingredients of the oral care composition are combined in one phase; ie they are not kept apart in separate compartments or by means of an anhydrous carrier. By "catalytic and fluoride-stable amount" is meant an amount sufficient to enhance the efficacy of fluoride in strengthening dental enamel from acidic challenges but not sufficient to compromise the long term storage stability of fluoride ions in the oral care composition.

The minimum amount of a calcium phosphate compound that can be present relative to the amount of fluoride salt in an oral care composition, to enhance fluoride efficacy, can be determined by adding decreasing amounts of a calcium phosphate compound to a fixed amount of a fluoride salt and determining the relative efficacy of the oral care compositions (with and without the calcium phosphate compound) in strengthening dental enamel using a variety of methods, such as surface microhardness measurements as shown in Examples 1 and 2. The maximum amount of a calcium phosphate compound that can be present relative to the amount of fluoride salt in an oral care composition, without compromising fluoride stability, can be determined by adding increasing amounts of a calcium phosphate compound to a fixed amount of a fluoride salt and measuring the levels of available fluoride over time using accelerated aging conditions, as shown in Examples 3 and 4. A composition is deemed to have acceptable fluoride stability if the levels of available fluoride are no less than 10% of the theoretical amount that should be present.

Suitable fluoride salts are those that directly provide free fluoride ions in the oral care composition, such as alkali metal fluorides (eg sodium or potassium fluoride) or stannous fluoride.

Excluded from this definition are salts that indirectly provide free fluoride ions, such as sodium monofluorophosphate, which is hydro lyzed by salivary enzymes in the mouth, releasing free fluoride in situ. Sodium monofluorophosphate has previously been used in aqueous oral care compositions comprising ingredients, such as calcium compounds, which are incompatible with free fluoride ions, especially on long term storage. The present invention, however, avoids the need to use such a salt, and instead has found an elegantly simple way of formulating a calcium phosphate compound with a salt directly providing free fluoride ions.

A preferred fluoride salt is sodium fluoride.

The fluoride salt is generally present in an amount to provide from 10 to 5000ppm, eg from 25 to 3500pm of fluoride ions, preferably from 100 to 1500ppm, 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).

By "an unfunctionalised calcium phosphate compound" is meant a calcium phosphate compound that is not functionalised in the manner described in the above noted Indiana Nanotech or 3M patent applications, and which is not β-tricalcium phosphate.

An unfunctionalised calcium phosphate compound may be selected from the group consisting of calcium glycerophosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, a-tricalcium phosphate, octacalcium phosphate, hydroxyapatite or fluroapatite, or a mixture thereof.

Suitably the unfunctionalised calcium phosphate compound is selected from the group consisting of tetracalcium phosphate, a-tricalcium phosphate, octacalcium phosphate, hydroxyapatite or fluroapatite, or a mixture thereof. Such compounds are sparingly soluble in water.

Suitably the unfunctionalised calcium phosphate compound is selected from the group consisting of calcium glycerophosphate or dicalcium phosphate dihydrate, or a mixture thereof. Such compounds are generally more water soluble than the other calcium phosphate compounds described hereinbefore.

The weight ratio of fluoride ions to total calcium ions will vary depending upon the relative solubilities of the calcium compounds and the presence of other excipients used in the oral care compositions. However, as noted above, suitable amounts of the calcium phosphate compounds can readily determined by assessing the fluoride stability and relative fluoride efficacy of the oral care compositions according to the methods described in the Examples. For the relatively insoluble calcium phosphate compounds such as tetracalcium phosphate, a-tricalcium phosphate, octacalcium phosphate, hydroxyapatite or fluroapatite, or a mixture thereof, suitably the weight ratio of fluoride ions to total calcium ions present in the oral care composition of the present invention ranges from about 2: 1 to 100: 1, suitably from 2.5: 1 to 50: 1, more suitably from 3: 1 to 40: 1, preferably from 3.5: 1 to 30: 1.

For the relatively more soluble calcium phosphate compounds such as calcium glycerophosphate or dicalcium phosphate dihydrate, or a mixture thereof, suitably the weight ratio of fluoride ions to total calcium ions present in the oral care composition of the present invention ranges from about 5: 1 to 100: 1, suitably from 7.5: 1 to 50: 1, more suitably from 10: 1 to 40: 1, preferably from 12.5: 1 to 30: 1.

By total calcium ions is meant all the calcium ions provided by the calcium compound, both dissolved and undissolved in the oral care composition. Unlike the aqueous compositions described in the above-noted Colgate patents, which comprise solubilised calcium, phosphate and fluoride ions, the compositions of the present invention do not require, and suitably do not contain, an alkali metal phytate or an anti- nucleating agent, for example as defined in US patents 4,177,258, 4,183,915, 4,348,381 or 4,528,181, the contents of which are incorporated herein by reference.

Compositions of the present invention may further comprise one or more active agents conventionally used in oral healthcare compositions, for example, a desensitising agent, an anti-erosion agent, an anti-plaque agent; an anti-calculus agent, a whitening agent, an oral malodour agent, anti-inflammatory agent, an anti-oxidant, anti-fungal or wound healing agent or a mixture of at least two thereof. Such agents may be included at levels to provide the desired therapeutic effect. Compositions of the present invention may comprise a desensitising agent, for combating dentine hypersensitivity. Examples of desensitising agents include a tubule blocking agent or a nerve desensitising agent 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 the present invention may comprise an anti-erosion agent, for example a polymeric mineral surface active agent or a stannous, zinc or copper compound, as described in WO 04/054529 (Procter & Gamble) or a nanoparticulate zinc oxide, as described in WO 08/054045 (Glaxo Group Limited), or a mixture thereof.

Compositions of 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.

Suitable oral care actives and orally acceptable carriers or excipients (ie the above-noted formulating agents) are described for example in US 2007/0053849 (Procter & Gamble) or EP 929287 (Beecham Group Ltd).

Compositions of the present invention are typically formulated in the form of toothpastes, sprays, mouthwashes, or gels.

Compositions of 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 9.0 The pH is measured when the composition is slurried with water in a 1 :3 weight ratio of the composition to water.

In a further aspect the calcium phosphate compound may be incorporated into an oral care composition of the type described in WO2006/100071 or WO 2010/066655, the contents of which are incorporated herein by reference.

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

The present invention also provides a method of combating dentine hypersensitivity 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

20-day pH cycling protocol, surface and cross-sectional microhardness and enamel fluoride uptake results - In vitro anti-caries study White-spot lesions were produced in bovine enamel cores using conventional methods and then organized into the following groups (N=12):

1. Distilled water

2. l lOO ppm F

3. 1100 ppm F + 98 ppm β-TCP (ie 37.93 ppm Ca, providng a F ion to Ca ion ratio of 29: 1)

These groups were then subjected to a remineralization/demineralization pH cycling model for 20 days. The model includes two one-minute treatment periods performed an hour apart in the morning, followed by one four-hour lactic acid-polyacrylic acid challenge, and finally two more one-minute treatment periods in the afternoon, administered daily for 10 days. In between the daily treatments and acid challenge, specimens were immersed in artificial saliva (AS). The treatments were diluted three-fold with distilled (DI) water (5 mL treatment solution: 10 mL DI water). The treatments and saliva events were magnetically agitated at 300 rpm, while the acid challenge was static. After each treatment and acid challenge, the specimens were rinsed with DI water prior to placement into AS. Four fresh treatment slurries and fresh acid solution were used daily, with the artificial saliva solution changed once daily after the third treatment. Solution used for the acid challenge was the same as used to prepare the initial white-spot lesions.

After 20 days of cycling, the enamel specimens were examined for Vickers surface hardness (200 gf, 15 second dwell time). The change in Vickers hardness number (AVHN) was determined as the difference between the post and baseline values (AVFIN = VFfN_post - VFINbase). These data are presented in Table 1.

Then, six enamel specimens were examined for cross-sectional surface microhardnes (CSMH). A series of three indentation lanes per specimen are made under a load of 10 gf at 12.5 μιη, 25 gf at 25 and 37.5 μιη, and 50 gf at 50, 75, 100, 125 and 150 μιη below the specimen surface. The Knoop indentation lengths were then converted to Knoop Hardness Numbers (KHN). Relative to KHN of sound enamel, relative lesions sizes in units of square root of KHN (VKHN) times enamel depth (μηι) were then calculated using Simpson's Composite Rule. These data are presented in Table 2.

Enamel fluoride uptake (EFU) was determined for the remaining six specimens in units of micrograms of fluoride per unit enamel area ^g F/cm²). The enamel specimens were immersed and continuously agitated in 0.5 ml of 1 N HC10₄ for 15 seconds. To determine fluoride concentration, 0.25 ml of this etchant was combined with 0.25 ml of 1 N NaOH and 0.5 ml of TISAB II. This solution was magnetically stirred, and a fluoride ion specific electrode was used to measure the free fluoride ion potential. These measurements were then converted to fluoride concentrations by using a fluoride electrode calibration curve constructed from known standards prepared with NaF. These data are presented in Table 3.

The microhardness and enamel fluoride uptake data were analyzed for normality using the Kolmogorov-Smirnov test with p=0.05. One-way analysis of variance (ANOVA) was performed to test for significant differences, followed by comparison tests at a 95% confidence level (p<0.05).

In summary, the addition of a low level of β-TCP to NaF solutions produced improved surface and subsurface benefits in white-spot enamel lesions. Additionally, remineralization benefits from this invention may be associated with or without increases in fluoride uptake.

Surface Microhardness Results:

Group VH VHN " AVH

Distilled Water 35.8 (2.1) 35.8 (2.4) 0.0 (1.6)

1100 ppm F 35.6 (2.0) 115.7 (3.2) 84.2 (3.8)

1100 ppm F + 98 ppm β-TCP 35.6 (2.0) 165.0 (3.2) 128.9 (3.2)

Table 1. Summary of surface microhardness results after cycling through the 20-day cycling model.

VHN⁰ = mean baseline Vickers Hardness Number (VHN) and (SEM) (N= 12);

VHN²⁰ = mean VHN (SEM) (N=12) after 20 days of cycling;

AVHN²⁰ = difference between mean VHN²⁰ (SEM) (N=12) and VHN⁰ after 20 days of cycling; CSMH Results:

Group ΔΖ ( ΚΗΝ·μηι)

Distilled Water 539.0 (27.4)

1100 ppm F 171.8 (24.6)

1100 ppm F + 98 ppm P-TCP 58.6 (23.5)

Table 2. Summary of cross-sectional microhardness (CSMH) after cycling through the 20-day remin/demin model.

ΔΖ

= mean (SEM) lesion size (N=6) after 20 days of cycling.

EFU Results:

Group EFU ^g F/cm²)

Distilled Water 0.4 (0.0)

1100 ppm F 2.9 (0.3)

1100 ppm F + 98 ppm β-TCP 2.2 (0.3)

Table 3. Summary of mean (SEM) enamel fluoride uptake (EFU) results from white spot lesions (N=6) after cycling. Example 2

20-day pH cycling protocol, surface microhardness and enamel fluoride uptake results - In vitro anti-erosion study Erosive lesions were produced in bovine enamel cores using 1% citric acid (pH = 3.8) for 30 minutes and then organized into the following groups (N=12):

1. Distilled water)

2. l lOO ppm F

3. 1100 ppm F + 186 ppm β-TCP (ie 71.98 ppm Ca, providng a F ion to Ca ion ratio of 15.3: 1)

These groups were then subjected to a remineralization/demineralization pH cycling model for 20 days. This model includes three two-minute treatment periods and five two-minute acid challenge periods. In between these events, the specimens are immersed in an artificial saliva (AS). The treatments were diluted three-fold with distilled (DI) water (5 mL treatment solution: 10 mL DI water). The treatment and AS systems were magnetically agitated at 300 rpm, while the acid challenge (0.3% citric acid, pH = 3.3) was static. After each treatment and acid challenge, the specimens were rinsed with DI water prior to placement into the saliva mixture, which was changed once daily after the third acid challenge.

After 20 days of cycling, the enamel specimens were examined for Vickers surface hardness (200 gf, 15 second dwell time). The change in Vickers hardness number (AVHN) was determined as the difference between the post and baseline values (AVFIN = VFfN_p0St - VFINbase). These data are presented in Table 4.

Enamel fluoride uptake was determined in units of micrograms of fluoride per unit enamel area (μ F/cm²). Six enamel specimens were immersed and continuously agitated in 0.5 ml of 1 N HCIO₄ for 15 seconds. To determine fluoride concentration, 0.25 ml of this etchant was combined with 0.25 ml of 1 N NaOH and 0.5 ml of TISAB II. This solution was magnetically stirred, and a fluoride ion specific electrode (Thermo Fisher, Pittsburgh, PA, USA) was used to measure the free fluoride ion potential. These measurements were converted to fiuoride concentrations by using a fluoride electrode calibration curve constructed from known standards prepared with NaF. These data are presented in Table 5. The microhardness and enamel fluoride uptake data were analyzed for normality using the Kolmogorov-Smirnov test with p=0.05. One-way analysis of variance (ANOVA) was performed to test for significant differences, followed by comparison tests at a 95% confidence level (p<0.05). Surface Microhardness Results:

Group VHN⁰ VHN²⁰ AVHN²⁰

Distilled Water 214.6 (2.6) 264.2 (3.3) 49.2 (4.4) l lOO ppm F 214.5 (2.6) 281.5 (3.7) 67.7 (2.8)

1100 ppm F + 186 ppm P-TCP 214.7 (2.5) 303.9 (3.4) 89.3 (4.2)

Table 4. Summary of surface microhardness results after cycling through an anti- erosion remin/demin model lasting 20 days.

VHN⁰ = mean baseline Vickers Hardness Number (VHN) and (SEM) (N=12);

VHN²⁰ = mean VHN (SEM) (N=12) after 20 days of cycling;

AVHN²⁰ = difference between mean VHN²⁰ (SEM) (N=12) and VHN⁰ after 20 days of cycling;

Enamel Fluoride Uptake Results:

Group EFU ^g F/cm²)

Distilled Water 2.7 (0.2)^a

l lOO ppm F 3.2 (0.1)^b

1100 ppm F + 186 ppm P-TCP 3.7 (0.0)^c

Table 5. Summary of mean (SEM) enamel fluoride uptake (EFU) results from eroded enamel (N=6) after cycling through an anti-erosion remin/demin model lasting 20 days.

In summary, the addition of a low level of β-TCP to NaF solutions produced improved surface benefits, including microhardness and fluoride uptake in eroded enamel. Example 3

Fluoride Stability

Fluoride availability was measured in triplicate for fluoride plus β-TCP. Solutions/suspensions of 0.24% NaF (1100 ppm F^") plus β-TCP were prepared and stored at elevated conditions for 32 days at 40°C. Measurements were made using a fluoride- sensitive electrode and Accument AR Dual Channel pH meter. TISAB II ionic strength adjuster was added in a 1 : 1 ratio with a sample volume (e.g. 5 ml), and standards were and measured in order to generate the calibration curve. Conversions from mV to ppm were determined based on the calibration curve and the data are presented in Table 6.

Table 6. Fluoride compatibility after accelerated aging conditions for 32 days at 40°C in aqueous solutions of sodium fluoride. Example 4

30-, 60- and 90-day Fluoride Stability with Low Levels of CaP Systems Protocol:

Fluoride availability was measured in triplicate for the fluoride plus CaP system combinations described in Table 7. Solutions/suspensions of 0.05%> NaF (225 ppm F ion) plus CaP systems were prepared and stored at elevated conditions for 30, 60 and 90 days at 40°C. Measurements were made using a fluoride-sensitive electrode and Accument AR Dual Channel pH meter. TISAB II ionic strength adjuster was added in a 1 : 1 ratio with a sample volume (e.g. 5 ml), and standards were made and measured in order to generate the calibration curve. Conversions from mV to ppm were determined based on the calibration curve and the data are presented in Tables 8, 9 and 10.

The following compounds were investigated

Alpha-tricalcium phosphate (a-TCP)

Beta-tricalcium phosphate (β-TCP)

HA (hydroxyapatite)

DCPD (dicalcium phosphate dihydrate)

CaGLYP (Calcium glycerophosphate)

Calcium sulfate

Calcium chloride dehydrate

Test Groups (0.05% NaF, 0.02%/225 ppm F :

Table 7 - Amounts of each calcium compound tested

Results obtained are described in the following Tables 8 to 10 Concentration (in ppm ± standard deviation) of available fluoride

[F ] after 30 days of accelerated aging (measured in triplicate):

MW % 5 ppm 15 ppm 25 ppm 40 ppm 50 ppm 60 ppm

Compound

(g/mol) Ca [Ca] [Ca] [Ca] [Ca] [Ca] [Ca]

Na F control 42.0 0.0 221.2 (0.5)

219.4 219.1 211.0 208.9 204.9 205.1 a-TCP 310.2 38.7

(0.5) (0.9) (0.0) (0.5) (0.0) (0.5)

209.8 212.4 210.7 209.2 213.3 214.5 β-TCP 310.2 38.7

(0.5) (0.5) (0.5) (0.9) (1.0) (0.0)

211.3 211.3 205.5 203.4 194.8 194.0

DCPD 172.0 23.3

(1.0) (1.0) (0.5) (0.5) (0.8) (0.8)

221.2 220.9 220.0 217.3 214.2 215.7

HA 502.3 39.8

(0.5) (0.9) (0.9) (0.9) (0.5) (0.5)

206.9 198.6 191.5 173.4 167.5 161.7

Calcium sulfate, 136.1 29.4

(0.5) (0.5) (0.8) (0.4) (0.7) (0.4)

Calcium chloride 214.5 208.3 198.1 182.9 174.4 157.7

147.0 27.2

dihydrate (0.9) (0.9) (0.8) (0.0) (0.8) (0.4)

216.0 208.9 200.0 184.4 181.6 172.4

CaGLYP 210.1 19.0

(0.5) (0.5) (1.0) (0.8) (1.2) (0.7)

Table 8. 30-d ay fluoride stability data at 40°C.

Concentration (in ppm ± standard deviation) of available fluoride [F ] after 60 days of accelerated aging (measured in triplicate):

MW % 5 ppm 15 ppm 25 ppm 40 ppm 50 ppm 60 ppm

Compound

(g/mol) Ca [Ca] [Ca] [Ca] [Ca] [Ca] [Ca]

Na F control 42.0 0.0 225.4 (0.9)

216.6 215.2 208.5 206.5 202.9 201.0 a-TCP 310.2 38.7

(1.4) (0.5) (0.9) (1.0) (1.3) (0.8)

207.7 208.2 207.1 209.1 210.2 209.1 β-TCP 310.2 38.7

(0.0) (1.3) (1.3) (1.3) (0.9) (0.5)

206.2 203.4 198.8 196.9 193.1 190.5

DCPD 172.0 23.3

(1.3) (0.8) (0.5) (0.0) (0.5) (0.8)

221.1 221.1 218.7 216.6 216.6 214.6

HA 502.3 39.8

(0.5) (1.9) (0.5) (0.5) (1.8) (0.9)

195.0 192.9 189.7 167.3 160.6 154.2

Calcium sulfate, 136.1 29.4

(1.7) (0.0) (0.8) (1.7) (1.7) (1.6)

Calcium chloride 204.8 200.4 188.2 174.6 167.8 148.8

147.0 27.2

dihydrate (1.3) (1.3) (0.8) (0.4) (0.7) (0.9)

210.5 207.4 193.7 175.5 170.1 166.4

CaGLYP 210.1 19.0

(1.3) (0.5) (0.8) (0.0) (0.4) (0.7)

Table 9. 60-day fluoride stability data at 40°C. Concentration (in ppm ± standard deviation) of available fluoride

[F ] after 90 days of accelerated aging (measured in triplicate):

MW % 5 ppm 15 ppm 25 ppm 40 ppm 50 ppm 60 ppm

Compound

(g/mol) Ca [Ca] [Ca] [Ca] [Ca] [Ca] [Ca]

Na F control 42.0 0.0 226.5 (0.9)

215.1 215.9 208.3 205.5 202.5 201.5 a-TCP 310.2 38.7

(0.9) (0.0) (0.8) (0.5) (0.8) (0.9)

207.7 207.2 206.3 206.6 207.4 205.2 β-TCP 310.2 38.7

(0.5) (0.5) (1.0) (0.8) (0.0) (0.5)

204.7 205.0 202.0 199.3 195.4 191.8

DCPD 172.0 23.3

(0.5) (0.0) (0.5) (0.8) (0.8) (1.1)

219.7 219.1 220.3 216.8 212.5 213.6

HA 502.3 39.8

(0.5) (1.0) (0.9) (0.9) (0.8) (0.5)

193.6 194.1 191.2 168.9 165.6 158.5

Calcium sulfate, 136.1 29.4

(0.9) (1.2) (0.4) (1.4) (1.0) (1.3)

Calcium chloride 199.3 194.1 186.0 177.0 165.4 153.3

147.0 27.2

dihydrate (1.6) (1.2) (1.5) (1.1) (1.0) (1.3)

203.1 204.2 186.7 170.5 168.9 168.7

CaGLYP 210.1 19.0

(1.2) (0.0) (0.4) (0.7) (0.4) (1.0)

Table 10. 90-day fluoride stability data at 40°C.

Acceptable fluoride levels should be within 10% of the theoretical at 30, 60 and 90 days . The relatively high solublility formats of calcium include DCPD, calcium sulfate, calcium chloride and calcium glycerophosphate. The relatively low solubility formats of calcium include a-TCP, β-TCP, and HA. Over the duration and in consideration of the calcium concentration range of this stability study, the more soluble formats appeared to impair fluoride availability relative to the less soluble systems.

Calcium sulfate and calcium chloride dihydrate did not provide good stability of fluoride at any of the concentrations investigated.

DCPD and calcium glycerophospate at a level of 15 ppm calcium ion provided good stability of fluoride present at 225 ppm, representing a fluoride ion to calcium ion ratio 15 : 1. a-TCP, β-TCP, and HA at a level of 60 ppm calcium ion provided good stability of fluoride present at 225 ppm, representing a fluoride ion to calcium ion ratio of 3.75 : 1.

Claims

1. An aqueous single phase oral care composition comprising a fluoride salt and an unfunctionalised calcium phosphate compound, which is not β-tricalcium phosphate, characterised in that the calcium phosphate compound is present in a catalytic and fluoride-stable amount relative to the fluoride salt.

2. An composition according to claim 1 wherein the fluoride salt is an alkali metal fluoride or stannous fluoride.

3. A composition according to claim 1 or 2 wherein the fluoride salt is sodium fluoride.

4. A composition according to any one of claims 1 to 3 wherein the unfunctionalised calcium phosphate compound is selected from the group consisting of tetracalcium phosphate, a-tricalcium phosphate, octacalcium phosphate, hydroxyapatite or fiuroapatite, or a mixture thereof.

5. A composition according to any one of claims 1 to 3 wherein the unfunctionalised calcium phosphate compound is selected from the group consisting of calcium glycerophosphate or dicalcium phosphate dihydrate, or a mixture thereof.

6. A composition according to claim 4 wherein the weight ratio of fluoride ions to total calcium ions ranges from about 2: 1 to 100: 1, suitably from 2.5: 1 to 50: 1, more suitably from 3: 1 to 40 : 1 , preferably from 3.5 : 1 to 30 : 1.

7. A composition according to claim 5 wherein the weight ratio of fluoride ions to total calcium ions ranges from about 5: 1 to 100: 1, suitably from 7.5: 1 to 50: 1 , more suitably from 10: 1 to 40: 1, preferably from 12.5: 1 to 30: 1.

8. A composition according to any one of claims 1 to 7 comprising a desensitising agent.

9. A composition according to claim 8 wherein the desensitising agent is a strontium salt or a potassium salt.

10. A composition according to any one of claims 1 to 9 comprising an anti-erosion agent.