WO2006100107A1

WO2006100107A1 - Novel use

Info

Publication number: WO2006100107A1
Application number: PCT/EP2006/002834
Authority: WO
Inventors: Manuela Finke; David Myatt Parker
Original assignee: Glaxo Group Limited
Priority date: 2005-03-23
Filing date: 2006-03-21
Publication date: 2006-09-28
Also published as: GB0506015D0

Abstract

Use of calcium in an acidic composition for oral administration as a liquid at elevated temperature in the range 40°C to 80°C, having a pH in the range 3.50 to 4.50 and calcium being present in an amount such that the molar ratio of calcium to acid is in the range 0.30 to 0.80, to inhibit the increase in dental erosion associated with temperature elevation.

Description

NOVEL USE

The present invention relates to the oral administration of acidic compositions at temperatures above 40⁰C, such as beverages, medicament preparations and oral healthcare compositions, and to the use of calcium in such compositions to alleviate or prevent dental erosion associated with the consumption of acidic liquids at elevated temperatures. In particular this invention relates to fruit based or fruit flavoured beverages and medicament preparations for consumption at temperatures above 4O⁰C, such as soft drinks, diverse teas, infusions, extracts, mulled wines, and hot medicaments such as for the alleviation of the symptoms of colds and flu.

Calcium is the most abundant mineral in the body. The vast majority of calcium is deposited in the bones and teeth but the mineral is also essential for other bodily functions such as the regulation of nerve function, the contraction of muscles and clotting of blood.

It is thought that erosion of teeth is caused inter alia by acidic foodstuffs leaching out calcium from the teeth faster than it can be replaced by normal remineralisation processes. Lussi et al (1995, Caries Res 29, 349-354) have associated the titratable acidity of a beverage with its erosive potential; the greater the concentration of acid in the beverage the more damaging to teeth it became.

Calcium is a common constituent of beverages being derived from fruit ingredients and from hard water when this is used in beverage production without prior softening. Values for the concentration of calcium occurring in this way are typically in the range 0.005- 0.02% w/w. Interest in the general nutritional benefits of diet fortification by calcium ion has led to a search for practical ways to incorporate this ion in beverages at higher levels from 0.02% w/w to 2% w/w. The use of calcium as a supplement for beverages has been described in WO88/03762.

WO 97/30601 discloses acidic liquid compositions comprising calcium in a mol ratio of 0.3 to 0.8 per mol of acid and a pH in the range 3.50 to 4.50 for the reduction of dental erosion caused by the consumption of acidic liquids such as acidic beverages.

Whereas the problem of enamel erosion due to consumption of diverse acidified soft drinks, wines and ciders is well documented, little attention has been directed at beverages designed for hot consumption. Hot consumption, or consumption at elevated temperatures, is defined as the deliberate introduction of comestibles into the oral cavity at temperatures greater than ambient temperature. For example teas may be prepared by the extraction of matter with hot or recently boiled water and consumed at temperatures within the range 40 to 80⁰C and beverage syrup concentrates may be diluted with boiled water providing a product temperature within the same range. The present invention relates to hot comestibles and medicaments that are routinely or preferably consumed within the temperature range 40 to 8O⁰C, more usually 45 to 8O⁰C and preferably between 50 and 75⁰C.

It is well known that the rate of many chemical reactions varies with temperature. Most commonly, the rate of a chemical reaction increases at elevated temperature. In a study of synthetic carbonated hydroxyapatite, dissolution in HCI was investigated as a function of various parameters, including temperature (Hankermeyer et a Biomaterials 23, 743- 750, 2002). In this study, a linear dependence of dissolution rate on temperature was observed over the range 8-50⁰C. The pH of a solution of a weak acid also decreases with rising temperature, as dissociation of the acid is more thermodynamically favoured. It is likely, therefore, that the propensity for acidic comestibles to cause dental erosion increases with increasing temperature.

West et al (Journal of Oral Rehabilitation 27, 875-880, 2000) pointed out the potential destructive effect of consumption at high temperatures of acidic medicament compositions such as "cold remedies" containing citric acid and found that tooth erosion increased about 2.5-fold between 5 and 60⁰C. Brunton and Hussain (Journal of Dentistry 29, 517- 520, 2001) drew attention to the erosive effect of diverse acidic herbal teas on tooth enamel, which they found to be five times more severe than black tea at 37°C. These observations were confirmed by Phelan and Rees (Journal of Dentistry 31, 241-246, 2003) who found that many herbal teas were more erosive than orange juice. Again their experiments were performed at 37⁰C. Eisenburger and Addy (Journal of Oral Rehabilitation 30, 1076-1080, 2003) studied the erosive effect on tooth enamel of the common beverage acidulant citric acid (0.3%, pH3.2) over the temperature range 4 to 50 ⁰C and found that erosion increased with increasing temperature and was at least three times greater at 50°C than at 4⁰C .

The present invention addresses the problem of the increase in dental erosion associated with the oral administration of acidic liquids at elevated temperatures and provides a surprisingly effective method for inhibiting the increase. It has been found that when a product such as a beverage or other acidic liquid formulation is prepared in accordance with the teaching of WO 97/30601 and introduced into the oral cavity at an elevated temperature, the expected increase in the dissolution or removal of enamel from the teeth by chemical processes with increasing temperature does not occur.

According to the present invention there is provided the use of calcium in the manufacture of an acidic composition for oral administration as a liquid at a temperature in the range 4O⁰C to 80⁰C, having a pH in the range 3.50 to 4.50 and calcium being present in an amount such that the molar ratio of calcium to acid is in the range 0.30 to 0.80, wherein increase in dental erosion associated with temperature elevation is inhibited.

In a further aspect, the present invention provides a method of inhibiting the increase in dental erosion associated with oral consumption of an acidic composition as a liquid at elevated temperatures between 40 and 80°C, which method comprises calcium being , present in the range of 0.3 to 0.8 mol per mol of acid and the liquid having a pH in the range 3.50 to 4.50.

The present invention is applicable to aqueous acidic substances for oral consumption as a liquid at elevated temperature, such as acidic beverages, fruit juices, ciders, mulled wines, fruit and herbal teas, hot medicaments and the like and extends to solid and semisolid compositions intended for dissolution or infusion prior to consumption, for example in hot water. Solid compositions having utility according to the present invention for infusion in hot water, for example as fruit teas, are typically in the form of tea bags.

The absolute concentration of calcium used in the present invention is not critical as this will vary according to the nature and concentration of the acids present. The acidic composition may contain organic and/or inorganic acids and may be supplemented with vitamins such as ascorbic acid. In a concentrated beverage, to be diluted with up to five parts of water prior to consumption, the calcium concentration may vary from 0.001 mol. per litre to more than 0.05 mol. per litre. In a ready to drink beverage the calcium concentration may vary from 0.0002 mol. per litre to more than 0.01 mol. per litre. In a typical tea bag presentation for infusion in a hot liquid, for example hot water, the calcium concentration may vary from 0.00004 mol. per bag to 0.002 mol. or more, for example up to 0.005 mol. per bag. Calcium may be added in the form of any convenient salt such as calcium carbonate, calcium hydroxide, calcium citrate, calcium malate, calcium citrate malate, calcium lactate, calcium chloride, calcium glycerophosphate or calcium formate , suitably selected to minimize any adverse flavour contribution to the composition.

Compositions for use according to the invention may be prepared by mixing an acid constituent (e.g. citric acid) with its corresponding calcium salt (e.g. calcium citrate) or another calcium salt. It may be advantageous to mix an acid with an alkaline calcium salt such as calcium carbonate or calcium hydroxide thereby minimising the concentration of acid applied to the formulation. Acid constituents can also be mixed with inorganic calcium salts such as calcium chloride.

The molar ratio of calcium to acid may be 0.30 - 0.75, more typically 0.30 - 0.65, preferably 0.30 - 0.60 or 0.30 - 0.55. Most preferably the molar ratio is at least 0.40, and a value of about 0.50 has been found to be especially effective.

The pH of compositions may be adjusted to the desired range by the addition of a calcium compound in the appropriate proportion relative to the molar quantity of acid. If necessary, depending on the acid present, the pH may be further adjusted by the application of an alkali e.g. sodium hydroxide or a suitable salt for example sodium citrate, sodium malate or sodium lactate.

The pH of the composition is preferably from 3.70 to 4.50. Compositions with a pH of about 3.80 to 4.00 have been found to be especially effective.

Typical citric or malic acid concentration in a concentrated fruit beverage would be in the range 0.1% w/w to 4.0% w/w. In a ready to drink beverage, acid concentrations are typically in the range 0.01% w/w to 1.00% w/w. Other potable acids conventional for beverages may also be used, such as lactic acid. Mixtures of potable acids may be used.

The invention may be applied to a variety of beverage compositions such as still fruit drinks, teas or infusions and in particular to health drinks such as blackcurrant juice drinks. The invention is advantageously applied to drinks containing natural or added citric acid and to compositions where the source of the acid is dried fruit. Beverages may be unsweetened or sweetened with sugar or intense sweeteners such as saccharin, aspartyl phenylalanyl methyl ester, or other sweeteners known in the art. Beverages may also contain other conventional additives such as sodium benzoate, sorbic acid, sodium metabisulfite, ascorbic acid, flavourings and colourings.

In a preferred aspect, an acidic composition for use according to the invention is a beverage prepared from a natural fruit juice such as blackcurrant juice, for example from a flavoured syrup concentrate of the fruit juice. Calcium may be added in a suitable form to a concentrate, especially when the beverage is sold to the consumer as a concentrate for dilution with hot water before drinking. Beverage compositions may be sold to the consumer by means of vending machine applications where the beverage is dispensed at an elevated temperature. Where sweeteners are included, compositions for use according to the invention preferably contain reduced levels of sugar or carbohydrate or are of low calorie type containing intense sweeteners although this is not a limitation of the invention.

Beverage compositions may also contain an effective amount of malic acid or potable salts thereof to maintain the solubility of the calcium so as to prevent or minimise the precipitation of insoluble calcium salts. Added malic acid may provide as little as 10% of the total acidity of a beverage, the remainder of the acidity being provided by other acids, for fruit beverages preferably by acids naturally present in fruit, such as citric acid, or by ascorbic acid.

Beverage compositions may be prepared by mixing the ingredients according to conventional methods. Solid ingredients may be dissolved in water or in hot water if required prior to addition to the other components. Typically beverages are pasteurised prior to filling in bottles or cans or other packs or are "in-pack pasteurised" after filling. Typically compositions for infusions are blended and packed in tea bags. Dry preparations may be compounded from dry ingredients and packed in bulk packs or sachets to be dissolved or infused in hot water by the consumer, for example instant tea preparations and analgesic preparations where "hot lemon" preparations are popular treatments.

The invention is illustrated by the following Examples:

Example 1

The erosive effect of a conventional soft drink purchased in the United Kingdom (formulation A) was evaluated to illustrate the problem addressed by this invention. The formulation comprised approximately 2.5g. I^"1 citric acid in total including acid from included 2% mixed fruit juice, 60ppm calcium, 20 g. I^"1 sugar, high intensity sweeteners, colourings, flavourings and preservatives. The composition was found to have a pH of 3.40 at 4°C, 3.10 at 25°C, 3.04 at 5O⁰C and 2.97 at 75°C and to have a calcium to acid molar ratio of about 0.12.

The erosive effect of a composition for use in accordance with the invention (formulation B), was also evaluated to illustrate the utility of the invention. This formulation contained approximately 2.5g. I^"1 citric acid in total including acid from included 7% blackcurrant fruit juice, 265ppm calcium, high intensity sweeteners, colourings, flavourings and preservatives. The composition was found to have a pH of 4.10 at 4°C, 3.95 at 25°C, 3.80 at 50⁰C and 3.75 at 75°C and to have a calcium to acid molar ratio of about 0.50.

The erosive effects of the two formulations on human dental enamel were evaluated by both a nanoindentation method and by a non-contact profilometric method. Nanoindentation has been shown to be extremely sensitive to very early stages of enamel erosion and statistically significant enamel softening has been demonstrated after only 30 seconds exposure to citric acid solutions at pH 3.30 ( Barbour et al., Journal of Oral Rehabilitation, 32, 16-21, 2005). Profilometry has been used extensively to investigate dental erosion. In the most commonly used method, an enamel sample is polished to obtain a flat surface and adhesive tape is used to protect the two sides of the sample while the middle section is exposed to the erosive solution. A more detailed description of the method can be found in West et al. (Journal of Dentistry 26, 329-335, 1998 ). The conventional stylus profilometer is most frequently used in which a sharp stylus is drawn across the sample to obtain a trace of the surface topography and a measurement of the depth of mineral lost in the exposed area. More recently, the non-contact optical profilometer has been employed (Zhang et al., Caries Research 34, 164-174, 2000). This technique makes use of a light beam to track the surface rather than physical contact by a stylus. This technique has the advantage that the whole enamel area can be imaged rapidly and simply. Since profilometry measures material loss rather than softening, it is used to investigate more advanced stages of erosion than nanoindentation.

For nanoindentation experiments, enamel sections were cut from healthy enamel taken from erupted molars using a water-cooled diamond saw. The sections were embedded in epoxy resin and polished parallel to the natural surface using 1200 grit silicon carbide paper and 0.25 μm aluminium oxide powder.

For profilometric experiments, enamel sections were cut from erupted molars as described above, embedded in epoxy resin and polished using 1200 grit silicon carbide paper only. Adhesive tape was used to cover the two edges of the enamel sample, leaving the central region uncovered for exposure to the drink. This allowed for direct comparison between the eroded and uneroded areas.

Enamel samples for nanoindentation were placed individually in 50 mL of the formulation under test and maintained at a constant temperature (4°C, 25⁰C, 5O⁰C or 75°C) using a water bath for 5 minutes and then rinsed in distilled water for 10 seconds and allowed to dry in air.

Enamel samples for profilometry were placed in 750 mL of the formulation under test and maintained at a constant temperature (4°C, 25°C, 50⁰C or 75°C) using a water bath for 30 minutes with gentle stirring by means of an overhead stirrer. The samples were then rinsed in distilled water for 10 seconds and allowed to dry in air.

When evaluated in a nanoindentation experiment, formulation A was found to cause a significant amount of enamel softening at all temperatures. Untreated tooth enamel has a hardness value of about 4.5 GPa (gigapascals) whereas enamel after treatment with formulation A was considerably softened: 4°C - 2.5GPa, 25⁰C - 1.7GPa, 50⁰C - 0.8GPa, 75°C - 0.35GPa. Formulation B had little effect on enamel at all temperatures: 4°C - 3.85GPa, 25⁰C - 3.4GPa, 50⁰C - 3.4GPa, 75°C - 3.4Gpa.

A similar pattern of effect emerged following profilometric assessment. Formulation A was found to cause a significant amount of enamel loss at all temperatures. 4⁰C - 3.3 microns, 25°C - 5.5 microns, 5O⁰C - 10 microns, 75°C - 15.3 microns. Formulation B had little effect on enamel loss at all temperatures: 4°C - 0.1 micron, 25⁰C - 0.3 micron, 50⁰C - 0.7 micron, 75°C - 0.4 micron.

The conventional beverage, formulation A, was discovered to be erosive at all temperatures but exceptionally highly erosive at hot drinking temperatures; the risk of tooth damage would appear to be three- and five-fold increased when consumed between 50 and 75⁰C respectively compared to consumption at 4⁰C. In contrast, formulation B, applying control of pH and calcium:acid molar ratio, had very little effect on enamel at all and the utility of the invention is clearly demonstrated. Example 2

A concentrated beverage product, for dilution with four parts of water prior to consumption was prepared by mixing the ingredients as follows. The calcium carbonate was added to the other ingredients as a final addition. Raw material %w/w

Blackcurrant juice concentrate 35.4

Aspartyl phenylalanyl methyl ester^* 0.173

Acesulfame K 0.058

Ascorbic acid 0.264 Potassium sorbate 0.08

Sodium metabisulfite 0.027

Blackcurrant flavouring 0.116

Water 63.66

Calcium carbonate 0.242 *sold as Aspartame (RTM)

MoI ratio of calcium to acid : 0.42

The concentrate was adjusted to pH 3.70 with sodium hydroxide solution. On dilution of the concentrate with four parts water (to drinking strength), the pH of the composition (formulation C) was found to be 3.85.

In a further test conducted as described in Example 1 , nanoindentation revealed almost no effect of formulation C on enamel with hardness values of about 4 GPa at all four temperatures (4°C to 75°C). Similarly, profilometry after 30 minutes exposure of enamel to formulation C showed virtually no loss of enamel: 4°C - 0.2 micron, 25°C - 0.35 micron, 50⁰C - 0.35 micron, 75°C - 0.8 micron. The utility of the method is clearly demonstrated.

Example 3 A variety of commercially available fruit teas was obtained in the form of tea bags for infusion. Teas were prepared by pouring 20OmL of freshly boiled water over a tea bag and leaving it to infuse for 3-5 minutes. From the original set of samples, three different teas showing a pH of around 3 were chosen. Two of the teas were tested for erosive effect without modification. The third tea and a sample of one of the already prepared teas were made up as before and then modified using the low erosive calcium technology.

The erosive potential of the four samples was evaluated by exposing enamel samples to the drinks at 6O⁰C for up to four hours. The observed material loss is an indication for the erosive potential of the tested solution. Measurements were made using profilometry as described in Example 1 above. Results:

Tea A was tested for its erosive potential directly and after modification Tea B was tested for its erosive potential directly.

Tea C was tested for its erosive potential after modification

Adjustments made to modify teas:

• Tea A (blackcurrant) : o Addition of 0.57 g/L calcium carbonate to the prepared infusion o Final pH: 3.91 o Calcium : acid mole ratio 0.78

• Tea C (cranberry, raspberry and elderflower) : o Addition of 0.35 g/L calcium carbonate to the prepared infusion o Final pH: 3.88 o Calcium : acid mole ratio 0.70

SD: standar deviation Conclusion:

The results indicate that:

• Fruit teas are highly erosive at a 6O⁰C consumption temperature.

• The calcium based low erosion technology is capable of significantly reducing their erosive potential at 6O⁰C.

Claims

1. The use of calcium in the manufacture of an acidic composition for oral administration as a liquid at a temperature in the range 40⁰C to 8O⁰C, having a pH in the range 3.50 to 4.50 and calcium being present in an amount such that the molar ratio of calcium to acid is in the range 0.30 to 0.80, wherein increase in dental erosion associated with temperature elevation is inhibited.

2. Use as claimed in claim 1 wherein the calcium to acid molar ratio is 0.30 to 0.55.

3. Use as claimed in claim 1 or 2 wherein the calcium to acid molar ratio is at least 0.4.

4. Use as claimed in any one of claims 1 to 3 wherein the pH of the acidic liquid composition is in the range 3.70 to 4.50.

5. Use as claimed in any of claims 1 to 4 wherein the acidic composition is a beverage.

6. Use as claimed in claim 5 wherein the beverage is a still fruit drink.

7. Use as claimed in any one of claims 1 to 5 wherein the acidic composition is a fruit or herbal tea infusion.