WO2022006632A1 - Dental compositions - Google Patents

Abstract

The present invention relates to a composition comprising calcium sucrose phosphate – calcium phosphate (CSP-ICP) complexes and between 0.5wt% and 5wt% calcium chloride (CaCl2). The present invention also relates to a method for preparing the composition, a method for using the composition and use of the composition for preparing a medicament.

Description

Dental Compositions

Related Applications

The present invention claims priority from Australian Patent Application No. 2020902362 filed on 8 July 2020, the entire contents of which is incorporated herein by reference.

Technical Field

The present invention relates generally to the field of dentistry. More specifically, the present invention relates to compositions and methods for preventing and/or treating dental diseases including, but not limited to, dental caries, dental erosion, periodontal disease, developmental defects of enamel tooth decay, dentin hypersensitivity and the like.

Background

Dental diseases are a costly burden to health care services. In industrialised countries, dental caries account for between 5% and 10% of total health care expenditure and exceeds the cost of treating cardiovascular diseases, cancer and osteoporosis [1] In most developing countries the prevalence of dental caries is high and more than 90% of caries are untreated because the cost of a conventional restorative treatment is disproportionally expensive and raising it as public health priority would exceed the total resources available for health care [2] Teeth experience periods of mineral loss and repair as a result of pH fluctuations in the oral cavity. When sugars or other fermentable carbohydrates are ingested, the resulting fall in dental pH caused by the organic acids increases the solubility of the hydroxyapatite that makes up the dental hard tissues. Demineralisation takes place as calcium and phosphate are lost from the tooth surface. The pH at which demineralisation occurs is often referred to as the critical pH and is approximately 5.5.

It is well known that dental caries occur as the result of demineralisation of tooth enamel and dentine [3] Net demineralisation makes the hard tooth substances porous and thus makes it easier for bacteria to reach the dentine and tooth pulp and hence net demineralisation can be said to be the primary cause of dental caries. The overall loss or gain of mineral at a given tooth location determines whether the carious process will regress, stabilise or advance to an irreversible state. Numerous inter related patient factors affect the balance between the remineralisation and demineralisation portions of this cycle and include oral hygiene, diet and the quantity and quality of saliva. At the most extreme point in this process, i.e. when a carious lesion has formed, a restoration (filling) will be required to repair the tooth. Dental erosion is the loss of tooth substance by a chemical process (acid exposure) that does not involve bacteria. Erosion softens the tooth surface and the region immediately below the surface (if it is not directly abraded). Erosion may occur whenever the pH in the mouth is less than the critical pH ~ 5.5 as the result of exposure to extrinsic or intrinsic acids. Extrinsic acids include citric acid, phosphoric acid, ascorbic acid, malic acid, tartaric acid and carbonic acids which may be found in fruits, fruit juices, carbonated soft drinks, herbal teas, dry wines and vinegar-containing foods. Intrinsic acids are from vomiting and regurgitation [2]

Erosion is often associated with other forms of tooth wear such as abrasion and attrition caused, for example, by over-zealous brushing of the teeth or by grinding of the teeth. It reduces the size of the teeth and in severe cases leads to total tooth destruction.

With the decrease in caries in developed countries, increasing emphasis is being placed on dental erosion. As with caries, saliva plays a critical role in limiting erosion because of its ability to dilute, clear, neutralise and buffer acids as well as form the pellicle on the tooth surface. Patients with reduced salivary flow are thus particularly exposed to the problems caused by erosion. However erosion is a multi-factorial condition which involves the interplay between chemical, biological and behavioural factors, all of which help to explain why some individuals exhibit more erosion than others [22] According to Moynihan & Petersen [2], epidemiological observations have shown an association between dental erosion and the consumption of a number of acidic foods and drinks including frequent consumption of vinegar and pickles, citrus fruits, berries and the consumption of fruit juice at bed time. It has also been shown that the frequency of intake of acidic foods and beverages is a more important determinant of erosion than the total amount consumed and also that erosion tends to occur in individuals with good oral hygiene.

Also according to Moynihan & Petersen, erosion appears to be an increasing problem in industrialised countries. The age-related incidence of erosion increases with age in low, moderate and high bands of soft drink consumption. For those in the high consumption band, the proportion with erosion increased from 28% for the 7-10 year old group to 52% in the 11-14 year old group. Fruit juices are more erosive than whole fruits and consumption of the former has increased markedly in recent years. In the case of soft drinks, there has been a 800-fold increase in the consumption of soft drinks since the 1950s [23] A number of purported treatments for dental caries and/or dental erosion exist, and several are described below.

Fluoride treatments A well-established anti-caries strategy is the extensively studied use of fluoride.

More than 800 controlled trials of the effect of fluoride on dental caries have been conducted to show that fluoride is an effective agent against caries [4] Fluoride- containing dentifrices and mouth rinses have been demonstrated to significantly reduce caries formation in clinical trials [5]-[9] . The efficacy of these oral care products in reducing caries activity has been attributed to their ability to incorporate fluoride ions into plaque. Several investigators have suggested an inverse relationship between plaque fluoride levels and caries incidence [10]-[13] Fluoride ions in plaque promote the formation of fluoro- hydroxyapatite in the presence of calcium and phosphate ions produced during demineralisation of tooth enamel by plaque bacterial organic acids. This is now believed to be the major mechanism of fluoride ion's action in preventing enamel demineralisation [14]-[16] Just as with its use as an anti-caries agent, fluoride can help reduce erosion by making teeth more resistant to acid attack.

Despite the well-documented advantages associated with conventional fluoride treatments there are also a number of problems associated with their use. One of the more significant problems is the inability of fluoride ions to efficaciously interact with tooth substances during the relatively short residence time of toothpastes and rinses in the oral cavity. Another problem is that fluoride treatments, especially topical treatments, can result in the irregular spotting or blotching of the teeth known as fluorosis. This effect is known to be both concentration related and patient specific. Further, irrespective of the scientifically proven benefits, the well-known toxicology of fluoride continues to be of concern to a significant proportion of the population and pre-disposes them not to favour fluoride in oral care products and to reject it as an additive to food. More generally in the wider population, the toxicity of fluoride at effective concentrations makes it unacceptable as an additive to foods and beverages. Of particular concern would be popular drinks and food items whose consumption is both unknown and uncontrolled.

Calcium phosphate treatments

Calcium phosphate treatments are primarily aimed at increasing the rate of remineralisation in teeth. It is the dynamic balance between demineralisation (the loss of calcium phosphate) and remineralisation (the replacement of calcium phosphate) that determines the quality of tooth enamel, dentine and cementum. Natural remineralisation is always taking place in the oral cavity, with the level of activity varying according to the conditions in the mouth. Incorporation of fluoride during the remineralisation process has been a keystone in preventing caries because by making the enamel more acid resistant it lowers the amount of demineralisation that occurs in subsequent pH cycling events. The rate of remineralisation depends on the available concentrations of calcium and phosphate ions. Natural saliva is generally super-saturated with calcium phosphate and hence more direct strategies for increasing the calcium and ion concentrations at the tooth surface have been developed. The intrinsic low solubility of normal calcium phosphate salts does not increase the bioavailable calcium and phosphate ions concentrations above those existing in normal saliva. Consequently the concentration gradients needed to drive diffusion of these ions into the sub-surface enamel of the tooth cannot be achieved. The solubility challenge is exacerbated by the even lower solubility of calcium fluoride phosphates. As a result of these problems the use of insoluble calcium phosphate salts in clinical delivery platforms has been extremely limited.

Various strategies to reduce or prevent erosive demineralisation by modification of the chemical, biological and behavioural factor involved in the aetiology of erosion have been investigated [24] Preventative measures may involve elimination or reductions of the consumption of acidic drinks. However the success of such a strategy is difficult to achieve because it is highly dependent on patient compliance. For this reason, a more practical approach is to modify the chemical composition of popular acidic drinks.

The greatest technical effectiveness achieved so far has been to add calcium compounds to the drinks but this has not been very successful in practice because the calcium compounds adversely affect the sensory qualities of the drink and some also shorten its shelf life [25]

The use of unstabilised amorphous calcium phosphate has been investigated and products containing amorphous calcium phosphate developed. It is proposed that the formation of the amorphous complex promotes remineralisation but the evidence supporting this hypothesis is considered to be rather weak [17]

Nano-particles of insoluble hydroxyapatite have been used to some effect. It has been proposed that the increased ratio of surface area to volume of such particles increases their solubility and assists in the incorporation of the particles onto the tooth surface [18] Other anti-caries strategies (and products) that aim to overcome the limited bioavailability of calcium and phosphate ions and to facilitate the remineralisation process by increasing the concentration of calcium and phosphate ions at the tooth surface have been developed. One such product is a bioactive glass that contains calcium sodium phosphosilicate (Novamin ® of NovaMin Technology Inc.). It is suggested that the bioactive glass releases calcium and phosphate ions that are available to promote remineralisation [19]

Another approach uses casein phosphopeptide (CPP) which is said to be complexed with amorphous calcium phosphate (ACP) [20] and which has been trademarked as Recaldent ® CCP-ACP by Cadbury Enterprises Pte Ltd). It is hypothesized [20] that the casein phosphopeptide facilitates the stabilisation of high concentrations of ionically available calcium and phosphate even in the presence of fluoride. This complex then binds to the pellicle and plaque, with the casein phosphopeptide preventing the formation of dental calculus and the free ions being available to diffuse down the concentration gradient to the sub-surface enamel lesions and facilitate remineralisation. As evidenced by recent literature reviews [26]-[29], when used in dental products the Recaldent technology is generally accepted as being effective in the prevention of caries and the treatment of hypersensitivity and it has also been successfully applied to a range of other dental problems. Although successful scientifically, from a practical dental perspective, the greatest problem with the Recaldent technology is that its solubility is rather limited. This leads to unacceptably long treatment times in the dental surgery. It also makes patient compliance poor in the case of product for home-use because the product needs to be delivered to the tooth surface in a dental tray and kept in place for extended periods of time. The low solubility also results in Recaldent being a less than ideal candidate for use in toothpastes and mouth rinses which have short residence times in the oral cavity.

Other limitations to the use of Recaldent in dental products include: (i) fact that the calcium to phosphate ratio is not ideal for tooth remineralisation, (ii) the salty, bitter taste of the peptides needs to be carefully masked in product formulation, (iii) the poor microbiological stability requires the use of relatively large amounts of preservatives to achieve economic product shelf-life, (iv) a proportion of the population is allergic to casein-derived products, and (v) the cost of manufacture is quite high.

On the food and beverage front, Recaldent has been successfully added to milk but the added benefits are not easily discerned because milk itself is neither cariogenic or erosive [23] It has also been successfully added to chewing gums and a small dental benefit statistically proven when (a rather impractical) 2 sticks of Recaldent-containing gum were chewed for 20 minutes 4 times a day [30] However all of the limitations described in the previous paragraph apply even more to the use of Recaldent in foods and beverages than they do to the use of Recaldent in dental products. Accordingly Recaldent has limited potential for addition to foods and beverages and is unlikely to be widely effective in stemming the rapidly escalating incidence of dental erosion.

Calcium-sucrose phosphates complexed with inorganic calcium phosphate Another available technology uses a mixture of calcium sucrose phosphates complexed with inorganic calcium orthophosphate [21]

This material is very highly soluble in water, has an affinity for tooth surfaces and rapidly produces high concentrations of calcium and phosphate ions at the tooth surface. These gradients are capable of driving the diffusion of calcium and phosphate into the tooth structure to remineralise the tooth through the formation of a hydroxyapatite complex. Additional factors enhancing the mode of action have also been described in the literature [31] The high phosphate content and the effective buffering this provides is of particular interest because the levels are high enough for it be an effective buffer against acidic drinks which commonly have a titratable acidity or a pH of less than 4.

While the number of studies describing the effectiveness of the calcium sucrose phosphate - calcium phosphate complex (CSP-ICP complex) is rather limited, it is a promising material for use in dental products which remineralise and harden teeth, thereby providing an anti-caries effect and the ability to treat dental hypersensitivity. There are also some studies showing that the dental benefits of the calcium sucrose phosphate-inorganic calcium phosphate are additive with those of fluoride. Since this material was originally developed for use as a food additive, it needed to have all of the desirable properties of such an ingredient. Specifically, in addition to its tooth remineralising abilities, it is highly soluble in water and thermally and chemically robust at temperatures up to 150°C. Importantly, it also has a bland, neutral taste. Accordingly it is easily incorporated in a wide range of foods without requiring any significant change to the manufacturing process of that product. It has been added to flour, bread, cakes, biscuits, confectionery, chewing gums, ice creams, honey, jams, canned fruit, fruit juices and a range of other beverages.

However, as noted in US 3,375,168 [21] the manufacture of calcium sucrose phosphates by esterification reaction of sucrose with phosphorous oxychloride and lime creates a number of reaction by-products. These include calcium chloride and unreacted sucrose together with smaller fractions of fructose & glucose, the last two being by products of the various pathways capable of producing calcium sucrose phosphates.

The crude liquor from the reaction phase typically contains -25-30% calcium chloride and -15-20% residual sugars. For various reasons each of these by-products were previously considered to be highly undesirable in the finished product at the concentrations in which they occurred in the crude reaction product.

Calcium chloride was considered undesirable because it was thought to adversely affect the taste and because it was thought likely to have an adverse effect on the stability and utility of the dried product. Calcium chloride has undesirable organoleptic properties with its taste and mouth feel being variously described as bitter, astringent, chalky, metallic and salty. The taste threshold for calcium chloride in water is in the range 200- 300 mg per litre [32] and the taste of coffee is adversely affected if it is made with water containing more than 530 mg per litre [33] Calcium chloride is also deliquescent and this deliquescent quality has two adverse consequences on the dried product. Firstly the various calcium sucrose phosphates are fermentable carbohydrates and the presence of moisture gathered by the calcium chloride increases the risk of contamination by microorganisms. Fungi and bacteria are able to cleave the glycoside bond of the sucrose moiety as well as the ester bond of the phosphate group on the sucrose phosphate anion and such actions completely destroy the compound and render it useless for its intended purpose. Secondly, absorption of moisture by the calcium chloride causes aggregation of the dried powder into a lumpy, sticky solid which affects the ability of the end user to measure and mix the CSP-ICP complexes into finished goods.

As for the residual sugars, while the sucrose moiety of calcium sucrose phosphate is fermentable, the beneficial effects of the calcium and phosphate far out weight the negative effects of fermentation of the sucrose phosphate anion. On the other hand, fermentation of the residual sucrose, glucose and fructose generally has a net detrimental effect on oral health because oral microbes present in plaque produce acids during the metabolism of these sugars and these acids result in demineralisation of the teeth.

According to the known art, the calcium sucrose phosphates-inorganic calcium phosphate complexes were always provided in the form of a dry, white, free-flowing powder with a typical analysis as follows [34]:

Note that a chloride specification of 0.3% implies a calcium chloride content of <0.5%.

Historically, removal of the undesired calcium chloride and residual sugars has been achieved by successive cycles of precipitation and washing with mixtures of ethanol and water. The calcium chloride is dissolved and carried away in the waste solvent while precipitated CSP-ICP complexes remain as solids. Experience shows that each successive extraction reduces the calcium chloride level by between 20-30%. Accordingly 5-8 ethanol extraction phases are required to achieve a final calcium chloride level of <0.5%. The same washing cycles result in the desired reduction in the concentration of the residual sugars. The established practice has been to complete the purification process with a final wash of pure ethanol. The final product is then dried to achieve a final ethanol concentration of <1%.

However, the CSP-ICP complexes made according to the prior art have at least two limitations, one economic and one technical.

From an economic viewpoint, purification using 5-8 cycles of washing with ethanol- water lowers the yield of the ultimate product. At the same time it also requires the use of capital intensive equipment and air extraction facilities, consumes large quantities of flammable ethanol, requires a large amount of thermal energy to dry the wet solids and needs labour and machinery to deal with the handling requirements. With ethanol now priced at levels linked to its use as a fuel for motor vehicles, the cost of ethanol dominates the cost of production of a finished good that satisfies the historical specifications. This cost then imposes limits on the potential market for large quantities of the material to be used as an anti-erosive agent in foods and beverages. From a technical viewpoint, the calcium to phosphate ratio of the CSP-ICP complex made according to the prior art is not well matched to the ratio of these chemical entities in teeth and bones. Teeth and bones are composed primarily of hydroxyl or carbonate apatite in which the molar ratio is 1.62: 1. The ratio in the known in the product made according to the prior art is in the range 1.20 - 1.25 depending on the proportions of the various calcium sucrose phosphate compounds that make up the historical product and accordingly it falls short on calcium relative to the ideal ratio of 1.62: 1. This is important not only in an absolute sense but also in the sense that, since a rapid remineralisation rate is desired during short exposure times in the oral cavity, we do not want the rate to be limited by a shortage of calcium. The rate of remineralisation depends on the ion product of [Ca] and [PO4] within and at the surface of the tooth. A deficit of [Ca] thus lowers the rate of remineralisation. The [Ca] deficit also limits the total remineralisation that can take place. If, for example, the remineralising solution only contains a 1:1 ratio of calcium to phosphate, the remineralisation process will stop once the calcium runs out because it is the limiting reactant.

The present invention aims to solve at least one of the problems associated with prior art dental compositions and/or dental disease prevention/treatment methods highlighted above.

Summary of the Invention

The present inventors have surprisingly identified that the economic and/or technical limitations of CSP-ICP complexes made according to the prior art can be overcome by reducing the number of purification cycles to thereby improve the calcium to phosphate ratio of the CSP-ICP complex while maintaining palatability.

Accordingly, the present invention relates to at least the following (non-limiting) embodiments. Embodiment 1. A composition comprising calcium sucrose phosphate - calcium phosphate (CSP-ICP) complexes and between 0.5wt% and 5wt% calcium chloride (CaCh).

Embodiment 2. A composition comprising calcium sucrose phosphate - calcium phosphate (CSP-ICP) complexes and calcium chloride (CaCh), wherein the composition is prepared by: performing an esterification reaction of sugar with phosphorous oxychloride and a base comprising calcium to thereby form a product comprising CSP-ICP complexes and CaCh; and removing a portion of the CaCh from the product to reduce the CaCh content to between 0.5wt% and 5wt%.

Embodiment s. The composition of embodiment 1 or embodiment 2 comprising between 3wt% and 5wt% CaCh.

Embodiment 4. The composition of any one of embodiments 1 to 3, further comprising more than 2wt% of free sugar molecules and/or more than lwt% of ethanol. Embodiment 5. The composition of any one of embodiments 1 to 4, wherein the composition has a calciuimphosphate ratio of between 1.3-1.6:1.

Embodiment 6. A method for preparing a composition comprising calcium sucrose phosphate - calcium phosphate (CSP-ICP) complexes and calcium chloride (CaCh), the method comprising: performing an esterification reaction of sugar with phosphorous oxychloride and a base comprising calcium to thereby form a product comprising CSP-ICP complexes and CaCh; and removing a portion of the CaCh from the product to reduce the CaCh content to between 0.5wt% and 5wt%, thereby providing the composition.

Embodiment 7. The method of embodiment 6, wherein the sugar is selected from any one or more of glucose, sucrose, fructose, galactose, and mannose.

Embodiment 8. The method of embodiment 6 or embodiment 7, wherein the base comprising calcium is selected from a base comprising any one or more of a calcium hydroxide (CaOH), calcium oxide (CaO), and calcium carbonate (CaCCb).

Embodiment 9. The method of any one of embodiments 6 to 8, wherein the CaCh content is reduced to between 3wt% and 5wt% CaCh.

Embodiment 10. The method of any one of embodiments 6 to 9, wherein the composition has a calciuimphosphate ratio of between 1.3-1.6:1.

Embodiment 11. The method of any one of embodiments 6 to 10, wherein the composition comprises more than 2wt% of free sugar molecules.

Embodiment 12. The method of any one of embodiments 6 to 11, wherein removing a portion of the CaCh from the product comprises solvent extraction. Embodiment 13. The method of embodiment 12, wherein the solvent is aqueous ethanol and the composition comprises more than lwt% ethanol.

Embodiment 14. The method of embodiment 12 or embodiment 13, wherein the removing a portion of the CaCh from the product comprises less than 5, less than 4, or less than 3 rounds of solvent extraction. Embodiment 15. A composition comprising calcium sucrose phosphate - calcium phosphate (CSP-ICP) complexes and calcium chloride (CaCh) obtained or obtainable by the method of any one of embodiments 6 to 14.

Embodiment 16. A method for remineralising a tooth or teeth, or for preventing or treating a dental disease, the method comprising contacting the tooth or teeth with the composition of any one of embodiments 1 to 5 or 15. Embodiment 17. Use of a composition of any one of embodiments 1 to 5 or 15 in the preparation of a medicament for remineralising a tooth or teeth, or for preventing or treating a dental disease.

Embodiment 18. A composition of any one of embodiments 1 to 5 or 15 for use in remineralising a tooth or teeth, or for preventing or treating a dental disease.

Embodiment 19. A composition of any one of embodiments 1 to 5 or 15 when used for remineralising a tooth or teeth, or for preventing or treating a dental disease.

Embodiment 20. The method of embodiment 16, the use of embodiment 17, or the composition of embodiment 18 or embodiment 19, wherein the tooth or teeth are remineralised for the purpose of preventing or treating any one or more of dental caries, dental erosion, periodontal disease, developmental defects of enamel tooth decay, and/or dentin hypersensitivity. Definitions

As used in this application, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

As used herein, the term “comprising” means “including.” Variations of the word “comprising”, such as “comprise” and “comprises,” have correspondingly varied meanings. Thus, for example, a composition “comprising” CSP-ICP complexes may consist exclusively of CSP-ICP complexes or may include one or more additional components.

As used herein, the term “subject” includes any animal of economic, social or research importance including bovine, equine, ovine, primate, avian and rodent species. Hence, a “subject” may be a mammal such as, for example, a human or a non -human mammal.

It will be understood that use of the term “between” herein when referring to a range of numerical values encompasses the numerical values at each endpoint of the range. For example, a polypeptide of between 10 residues and 20 residues in length is inclusive of a polypeptide of 10 residues in length and a polypeptide of 20 residues in length.

Any description of prior art documents herein, or statements herein derived from or based on those documents, is not an admission that the documents or derived statements are part of the common general knowledge of the relevant art. For the purposes of description all documents referred to herein are hereby incorporated by reference in their entirety unless otherwise stated. Detailed Description

The present invention provides improved calcium sucrose phosphate - calcium phosphate complex (CSP-ICP complexes) and methods for their production. The CSP- ICP complexes of the present invention comprise a favourable calcium to phosphate ratio which is closer to that of teeth and bones compared to those of prior art complexes, while unexpectedly maintaining palatability.

CSP-ICP complexes of the prior art are typically produced by esterification reaction of sucrose with phosphorous oxychloride in the presence of an appropriate base. It was thought necessary to remove reaction by-products including calcium chloride (CaCh), unreacted sucrose and smaller fractions of fructose and glucose. Despite reducing the effectiveness of CSP-ICP complexes in dental applications by altering the calcium to phosphate ratio, it has been deemed necessary to remove CaCh from the complexes to make them palatable for oral application. The adverse effects on palatability arising from calcium in such compositions are well-documented in the prior art.

Removal of the undesired calcium chloride and residual sugars has been achieved by successive cycles of precipitation and washing with mixtures of ethanol and water. The calcium chloride is dissolved and carried away in the waste solvent while precipitated CSP-ICP complexes remain as solids. However, this process has the effect of lowering the calcium to phosphate ratio of the CSP-ICP complex to below the ratio of these chemical entities in teeth and bones, and has a number of economic drawbacks including increased time and reagent use, as well as reduced yield. The present invention provides CSP-ICP complexes with increased calcium ion concentration and favourable palatability characteristics.

Preparation of CSP-ICP complexes CSP-ICP complexes according to the present invention can be prepared by suitable means known in the art.

In some embodiments, CSP-ICP complexes can be formed by esterification reaction of an appropriate sugar (e.g. glucose, sucrose, fructose, galactose, mannose) with phosphorous oxychloride in the presence of an appropriate base comprising calcium (e.g. a base comprising calcium hydroxide, calcium oxide, calcium carbonate, and/or any other suitable calcium salt or mixtures thereof). US patent number 3,375,168, the entire contents of which are incorporated herein by cross-reference, provides a non-limiting example of how to perform an esterification reaction of sucrose with phosphorous oxychloride in the presence of an appropriate base. The CSP-ICP complexes formed by esterification reactions typically produce mixtures of different CSP-ICP complexes that have varying relative amounts of calcium and phosphate (i.e., some complexes in a mixture may have more calcium relative to the phosphate, and some complexes may have less calcium compared to phosphate). For instance, different complexes with calcium : phosphate molar ratios of 3:2, 3:1, 2:2, 2:1, 1:1, 0:1 and 0:0 have been observed by the inventors. The precise structures of many of these complexes are unknown, however they are known to differ in both their absolute and relative calcium and phosphate ratios. Under standard laboratory conditions, such as those taught in the prior art (discussed above), the mixture of CSP-ICP complexes usually results in a net calcium : phosphate molar ratio of about 1.2:1. However, both reaction conditions (such as reaction pH, shear, temperature, rate of reactant addition) and purification conditions (such as ethanol to water ratios at the precipitation stage, membrane filtration, HPLC and crystallization) may be used in conjunction with the residual calcium chloride species to favour the production and/or purification of those complexes with higher relative calcium content, resulting in a product closer to the preferred calcium : phosphate ratios of 1.3-1.7:1; 1.4-1.7:1; 1.4-1.65:1; 1.5-1.65:1; 1.55- 1.65:1, 1.58-1.62:1, or 1.62:1, preferably 1.62:1. If complexes with higher calcium : phosphate ratios, and/or complexes with a higher total calcium and phosphate content can be favoured, higher absolute quantities of calcium and/or phosphate can be delivered with smaller quantities of the finished product needed to be used in order to achieve the desired effect, without substantially increasing manufacturing costs. This may lead to improved products that are more efficacious, with a lower production cost and may provide greater flexibility in formulating the finished product.

Production of CSP-ICP complexes by esterification reaction of the sugar with phosphorous oxychloride in the presence of an appropriate base comprising calcium typically provides residual calcium chloride (e.g. 25-30% by weight), and residual sugars such as, for example, sucrose and glucose and fructose (e.g. 15%-20% by weight).

The amount/proportion of residual calcium chloride and/or residual sugars remaining in the composition following production of CSP-ICP complexes by the esterification reaction may be reduced using standard techniques known in the art. For example, solvent extraction may be used for this purpose. Any suitable solvent extraction method may be used including, for example, alcohol solvent extraction. The alcohol solvent may be ethanol.

In some embodiments, the composition may comprise residual calcium chloride. The proportion of residual calcium chloride present in the composition may be reduced such that the weight percentage remaining in the composition is less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%, but in each case greater than 0.5%.

In some embodiments, the proportion of residual calcium chloride present in the composition may be reduced such that the total calcium: phosphate ratio of the composition may be 1.3-1 7:1; 1.4-1 7:1; 1.4-1.65:1; 1.5-1.65:1; 1.55-1.65:1, 1.58-1.62:1, or 1.62:1.

In some embodiments, the composition may comprise residual solvent (e.g. alcohol, ethanol). The proportion of residual solvent present in the composition may be reduced such that the weight percentage remaining in the composition is less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1.5%, but in each case greater than 1%.

The prior art (e.g. US patent number 3,375,168) teaches the production of CSP-ICP complexes by esterification reaction of an appropriate sugar (e.g. sucrose) with phosphorous oxychloride in the presence of an appropriate metal cation base (e.g. calcium hydroxide). Following the reaction, residual calcium chloride is removed by 5-8 ethanol extraction phases to bring the final calcium chloride level to less than 0.5% by weight.

In accordance with the methods of the present invention, the residual calcium chloride may be removed (e.g. by solvent extraction such as ethanol extraction) such that the final calcium chloride level of the composition is more than 0.5%, more than 0.6%, more than 0.75%, more than 1%, more than 1.5%, more than 2%, more than 3%, more than 4% or more than 5% calcium chloride by weight. The residual calcium chloride may be removed by: less than 5 phases, 4 phases, less than 4 phases, 3 phases, less than 3 phases, or 2 phases, of solvent extraction (e.g. ethanol extraction).

The acceptable amount of residual calcium chloride may be dictated by the specific use or form of the finished product. For instance, a pure powder product applied directly to the teeth via a pneumatic wand, without any other excipients to mask the calcium chloride, may need to have a content of calcium chloride between 0.5 % and 1 %. Contrarily, products with less of the CSP-ICP complexes added, such as a toothpaste comprising 5% w/w of the CSP-ICP complexes, or foodstuffs with 1% w/w CSP-ICP added, may have a higher (i.e., greater than 1 %) calcium chloride content and still be acceptable for that use.

In some embodiments, alternative purification methods may also be used in place of the ethanol-water washing cycles described above to produce CSP-ICP complexes. Whilst such alternative purification methods may be more expensive initially to set up, they may prove to be more cost-effective in use over time, as the costs saved relating to the amount of solvents used (e.g., ethanol) offsets the initial capital expenditure of the alternative purification methods. Examples of purification systems used in industry to remove solutes that could be used in the purification of CSP-ICP complexes include, but are not limited to, membrane filtration systems (i.e., nanofiltration, microfiltration, or ultrafiltration), ion exchange resins, high performance liquid chromatography (HPLC), crystalisation and precipitation techniques and the like.

Compositions The present invention provides compositions for oral administration (e.g. to a tooth or teeth of a mammal such as a human) comprising CSP-ICP complexes with increased calcium chloride content compared to prior art compositions. The CSP-ICP complexes may be prepared according to the methods of the present invention such as those described in the section above entitled “Preparation of CSP-ICP complexes” . CSP-ICP complexes according to the present invention can be prepared by esterification reaction of an appropriate sugar (e.g. glucose, sucrose, fructose, galactose, mannose) with phosphorous oxychloride in the presence of an appropriate base comprising calcium (e.g. a base comprising: calcium hydroxide, calcium oxide, calcium carbonate, and/or any other suitable calcium salt). In some embodiments, compositions of the present invention comprise CSP-ICP complexes in combination with calcium salts (e.g. calcium chloride). The compositions may comprise, for example, more than 0.5%, more than 0.6%, more than 0.75%, more than 1%, more than 1.5%, more than 2%, more than 3%, more than 4% or more than 5% calcium salt (e.g. calcium hydroxide, calcium oxide, calcium carbonate, and/or any other suitable calcium salt) by weight. For example, the compositions may comprise between: 0.5% and 25%, 0.5% and 20%, 0.5% and 15%, 0.5% and 10%, 0.5% and 5%, 0.5% and 4%, 0.5% and 3%, 0.5% and 2%, 0.5% and 1%, 1% and 25%, 1% and 20%, 1% and 15%, 1% and 10%, 1% and 5%, 1% and 4%, 1% and 3%, 1% and 2%, 1% and 1.5%, 2% and 25%, 2% and 20%, 2% and 15%, 2% and 10%, 2% and 5%, 2% and 4%, 2% and 3%, 2% and 2.5%, 3% and 25%, 3% and 20%, 3% and 15%, 3% and 10%, 3% and 5%, 3% and 4%, 3% and 3.5%, 4% and 25%, 4% and 20%, 4% and 15%, 4% and 10%, 4% and 7.5%, 4% and 5%, 5% and 25%, 5% and 20%, 5% and 15%, 5% and 10%, 5% and 7.5%, 5% and 6%, 6% and 25%, 6% and 20%, 6% and 15%, 6% and 10%, 6% and 7.5%, 7% and 25%, 7% and 20%, 7% and 15%, 7% and 10%, 7% and 8%, 8% and 25%, 8% and 20%, 8% and 15%, 8% and 10%, 9% and 25%, 9% and 20%, 9% and 15%, 9% and 10%, 10% and 25%, 10% and 20%, or 10% and 15%, calcium salt (e.g. calcium hydroxide, calcium oxide, calcium carbonate, and/or any other suitable calcium salt) by weight. The calcium salt (e.g. calcium hydroxide, calcium oxide, calcium carbonate, and/or any other suitable calcium salt) may be residual from a process used to prepare CSP-ICP complexes of the composition (e.g. those described in the section above entitled “Preparation of CSP-ICP complexes ”).

In some embodiments, the compositions may comprise a calcium:phosphate ratio of 1-1.7: 1, 1-1.65:1, 1-1.62:1, 1-1 6:1, 1-1.55:1, 1-1.5:1, 1-1 4:1, 1-1.3:1, 1-1.2:1, 1-1.15:1, 1.1-1.7:1, 1.1-1.65:1, 1.1-1.62:1, 1.1-1 6:1, 1.1-1.55:1, 1.1-1.5:1, 1.1-1 4:1, 1.1-1.3:1, 1.1- 1.2:1, 1.1-1.15:1, 1.2-1.7:1, 1.2-1.65:1, 1.2-1.62:1, 1.2-1.6:1, 1.2-1.55:1, 1.2-1.5:1, 1.2-

1.4:1, 1.2-1.3:1, 1.2-1.25:1, 1.3-1 7:1, 1.3-1.65:1, 1.3-1.62:1, 1.3-1.6:1, 1.3-1.55:1, 1.3-

1.5:1, 1.3-1.4:1, 1.3-1.35:1, 1.4-1 7:1, 1.4-1.65:1, 1.4-1.62:1, 1.4-1 6:1, 1.4-1.55:1, 1.4-

1.5:1, 1.4-1.45:1, 1.5-1.7 1, 1.5-1.65:1, 1.5-1.62:1, 1.5-1 6:1, 1.5-1.55: 1, 1.6-1.7:1, or 1.6-

1.65:1, 1.61:1, or 1.62:1, by weight. In some embodiments, the compositions comprise free sugars. The compositions may comprise, for example, more than 2%, more than 3%, more than 4% or more than 5% free sugars by weight. The compositions may comprise, for example, less than 2%, less than 3%, less than 4% or less than 5% free sugars by weight. The free sugars may be residual from a process used to prepare CSP-ICP complexes of the composition (e.g. those described in the section above entitled “ Preparation of CSP-ICP complexes”).

In some embodiments, the compositions comprise alcohol (e.g. ethanol and/or methanol). The compositions may comprise, for example, more than 1%, more than 1.5%, more than 2%, more than 3%, more than 4% or more than 5% alcohol (e.g. ethanol and/or methanol) by weight. The compositions may comprise, for example, less than 1%, less than 1.5%, less than 2%, less than 3%, less than 4% or less than 5% alcohol (e.g. ethanol and/or methanol) by weight. The alcohol may be residual from a process used to prepare CSP-ICP complexes of the composition (e.g. those described in the section above entitled “Preparation of CSP-ICP complexes”).

In some embodiments, the compositions comprise a flavour-masking agent. The flavour-masking agent may mask bitter flavours (e.g. sugars or other sweeteners). The compositions may comprise a pharmaceutically acceptable carrier and/or diluent. The carriers and/or diluents must be “acceptable” in terms of being compatible with the other ingredients of the composition, and are generally not deleterious to the recipient thereof. Non-limiting examples of pharmaceutically acceptable carriers or diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil; sesame oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxy methyl cellulose or hydroxypropylmethylcellulose; lower alkanols, for example ethanol or isopropanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1,3- butylene glycol or glycerin; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate; polyvinylpyrolidone; agar; gum tragacanth or gum acacia, and petroleum jelly. Typically, the carrier or carriers will form from about 10% to about 99.9% by weight of the compositions.

The compositions may comprise liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof. In compositions that are liquid, such compositions may be concentrated by any suitable standard industrial method. For example, the liquid compositions may be concentrated by vacuum evaporators (such as rotary evaporators or pan vacuum evaporators) or membrane concentrators (such as reverse osmosis membrane filtration). Any other suitable methods known to the skilled person may be used to concentrate liquid compositions.

The compositions may be in the form of suspensions for oral administration and comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly- vinyl-pyrrolidone, sodium alginate or acetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono-or di-oleate, -stearate or- laurate, polyoxyethylene sorbitan mono-or di- oleate, -stearate or-laurate and the like. Prevention and Treatment of Dental Diseases

The CSP-ICP complexes and compositions according to the present invention may be used to prevent and/or treat dental diseases. Accordingly, the present invention provides methods for preventing and or treating dental diseases by contacting a tooth or teeth in a subject (e.g. a mammal such as a human) with the CSP-ICP complexes or compositions described herein.

Without particular limitation, the subject may be suffering from, or may be susceptible to suffering from, a dental disease selected from any one or more dental caries, dental erosion, periodontal disease, developmental defects of enamel tooth decay, dentin hypersensitivity and the like.

Other Uses

The CSP-ICS complexes described herein have been developed with the treatment of dental diseases in mind. However, the skilled person would be aware that complexes with a preferred ratio of calcium to phosphate of about 1.62: 1 may beneficially be used to promote general bone remineralisation. It is envisioned that the CSP-ICP complexes described herein may be used to promote systemic bone remineralisation prophylactically, such as in formulations of human and/or veterinary supplements or in foodstuffs, or they may be used in human and/or veterinary medicaments to treat conditions that result in low bone mineral content, such as osteoporosis, or they may be used to improve recovery from surgical interventions, such as following orthopedic surgery (e.g., bone implants, bone reconstruction, bone grafts and the like).

Embodiments of the Present Invention The CSP-ICP complexes, methods for producing CSP-ICP complexes, and compositions according to the present invention may provide one or more benefits over prior art teachings. Without limitation, some of these benefits are described below. It will be understood that the present invention may meet a plurality of the benefits described below, one of the benefits described below, or none of the benefits described below.

Faster remineralisation

Calcium chloride is highly water-soluble (approximately 75 grams per 100 ml of water at 20°C) and hence the residual calcium chloride in the CSP-ICP complex rapidly dissociates and increases the concentration of calcium ions in the mouth and at the surfaces of the teeth. The rate of remineralisation depends on the [Ca] and [PCU] ion concentrations at the tooth surface. Accordingly, boosting the calcium ion concentration by leaving greater residual level of calcium chloride in the CSP-ICP complexes may increase the rate of remineralisation. This can be particularly advantageous for products formulated to include the CSP-

ICP complexes but which have relatively short residence times in the mouth. Non limiting examples include toothpastes, mouth rinses and beverages.

Enhanced remineralisation CSP-ICP complexes containing higher amounts of residual calcium chloride boosts the ratio of calcium:phosphate from the previous 1.2-1.25:1 to something closer to the theoretically ideal value of 1.62:1.

Doing so may ensure that a deficiency in the calcium content does not prematurely limit the amount of remineralisation that can take place and may also ensure that material deposited into the tooth structure is as close as possible in chemical structure to the natural tooth materials.

Allowing the residual calcium chloride to be approximately 10% of the weight of the CSP-ICP complex may be sufficient to bring the ratio to the ideal value. - Residual sugars

A consequence of reducing the number of purification cycles to allow higher residual levels of calcium chlorides is may be that it is accompanied by a slight increase in the residual sucrose, fructose and glucose in the CSP-ICP complexes.

Equilibrium exists between tooth minerals and the oral fluids in which they are bathed.

The critical pH of tooth minerals is the pH at which teeth begin to dissolve. The critical pH can be determined by the interplay between two factors, pH and the concentrations of tooth mineral constituent ions in oral fluids bathing the teeth. Generally, low pH and low concentrations of [Ca] [PCri] ion concentrations in oral fluids favour demineralization and conversely high pH and high concentrations of [Ca] [PCri] ion concentrations favour remineralisation. The ideal pH for remineralisation under conditions of [Ca] [PO4] ion saturation is generally between 5.5-6.0.

The average resting pH in the oral cavity is generally around 6.5 compared with CSP-ICP solutions that have a native pH of around 7.5. While highly soluble carbohydrates such as sucrose, fructose and glucose are essentially benign at the levels and short exposure times of the teeth to the CSP-ICP complexes, the effect of any fermentation that does take place tends to drive the oral pH closer towards the 6.0-5.5 value at which optimum remineralisation takes place.

In this way, the presence of sucrose, fructose and glucose impurities that were otherwise thought to be non-functional waste can in fact assist in optimizing the final remineralising potential of calcium sucrose phosphates.

An additional but unexpected benefit of increasing the residual sugar levels above the prior art specification of less than 0.7% is that they have been identified to assist in masking the unpleasant sensory properties generated by the higher levels of calcium chloride.

Flavour masking

Although flavour masking is by no means a requirement has been found that flavour masking in the CSP-ICP complexes and compositions of the present invention is unexpectedly easy.

Stability of powders and concentrated solutions

In an attempt to provide adequate shelf stability, the prior art teaches the drying of the purified CSP-ICP complex to a powder as well as the reduction in the calcium chloride content to less than 0.5%.

The present inventors have determined that the shelf stability of dried powder containing calcium chloride (e.g. 1.8% w/w) is unaffected by the higher deliquescent effects associated with the higher calcium chloride concentration provided the powder is adequately dried and packed in air-tight plastic bags (e.g. within 15 kg boxes). The present inventors have also unexpectedly discovered that dental caries inhibitor solutions (e.g. Anticay) above 50% w/w are relatively stable against microbial challenge.

The stability may increase with increasing CSP-ICP complex concentration but higher concentrations may become increasingly viscous and difficult to handle. The present inventors have demonstrated that if concentrates of >60% are prepared the stability can be enhanced by the use of established preservative systems such as parabens and benzoates. For example, the mixture may be filled into sterile nitrogen bladders and irradiated prior to shipping. Lower concentrations can also be shipped using this method with slightly higher additions of the preservatives.

Shipping liquid concentrates A further advantage of shipping stable concentrates rather than the powder previously regarded as necessary for adequate stability is that any adverse consequences of the deliquescent properties of the calcium chloride become irrelevant.

Additionally, from the customer’s perspective, production costs for finished goods are generally lower because it is no longer necessary to solubilise the CSP-ICP complexes before they are used by the customer in the manufacture of their final products.

Ethanol content

Although the shipping as a concentrate has its advantages, some applications still require the shipping of the CSP-ICP complexes as a powder.

As previously mentioned, the prior art taught the need for a final wash of the CSP- ICP complexes with 100% ethanol. This left wet, granular calcium sucrose phosphate solids similar in consistency to sand and containing approximately 24% ethanol by weight. According to the prior art the product had to be dried before shipping. Drying can be achieved by various evaporative methods but always sought to achieve a finished powder containing less than 1% ethanol by weight. Any suitable refining method may be used to produce a powder of the CSP-ICP complexes described herein by removing the residual ethanol and/or water from the product. Examples of suitable industry refining methods include vacuum drum drying, centrifugation, vacuum belt drying, spray drying. The skilled person may be aware of alternative refining methods which may be suitable for this use. Some refining methods may be further adapted so that the ethanol and/or water can be collected (e.g., by distillation) and recycled, further reducing the operating costs related to purchasing fresh solvent. A fault in drying Anticay powder led the present inventors to the unexpected discovery that higher residual levels of ethanol in the CSP-ICP complex powder actually confer a protective benefit for the stability of the powder against microbial degradation. Crucially it has been found that this microbial stability of the powder remained in spite of higher levels of residual calcium chloride that draws in more moisture from the air. The previous physical clumping of the powder due to water being drawn in from the air is also avoided to some extent by the higher ethanol content because the CSP-ICP complex is insoluble in solutions containing more than 15% ethanol. Allowing higher levels of residual ethanol may thus allow for greater volumes of absorbed moisture to be absorbed from the air before the complex becomes soluble and therefore aggregates into large, solid, toffee-like lumps. Considering that the inclusion rate of dental caries inhibitors (e g. Anticay) into certain products is as low as 1% even relatively large quantities of residual ethanol are quite acceptable in terms of the influence on composition of finished goods. - Production cost

The energy requirement for the evaporation of ethanol from dental caries inhibitor solutions (e.g. Anticay) is a significant cost of production. The ability to allow residual ethanol far in excess of the previously documented 1% is therefore represents a significant improvement to the efficiency of producing a finished dental caries inhibitor (e.g. Anticay) powder product.

The cost of manufacturing a product according to the prior art was dominated by costs associated with the use of large quantities of ethanol in the post-reaction phases of production.

The unexpected discovery made by the present inventors that the CSP-ICP complex suppresses the adverse organoleptic properties of the residual calcium chloride makes it possible to eliminate a number of the purification stages previously designed to reduce the calcium chloride content to less than 0.5%.

Eliminating these now unnecessary stages reduces the costs of production at least by reducing the amount of ethanol required for purification, lowering the capital cost of the manufacturing equipment required, and/or lowering the equipment and labour costs of multiple handling at the purification stages

The additional discoveries of the present inventors that concentrated solutions are stable and can be safely shipped, and residual ethanol content can be higher than 1% further reduce the costs of production by eliminating the energy costs associated with evaporative reduction of the ethanol content and/or eliminating the energy costs associated with drying the CSP-ICP complex to a powder.

It will be appreciated by persons of ordinary skill in the art that numerous variations and/or modifications can be made to the present invention as disclosed in the specific embodiments without departing from the spirit or scope of the present invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Examples

The present invention will now be described with reference to specific Example(s), which should not be construed as in any way limiting. Example 1

Since a shortage of calcium is the limiting factor in CSP-ICP products known in the art, the present inventors investigated the possibility of overcoming this deficiency by blending into aqueous solutions of the CSP-ICP complexes solutions of calcium salts with concentrations sufficient to bring the total calcium to phosphate ratio up closer to the desired 1.62:1. As calcium chloride has often been proposed and examined as a possible additive to dental and oral hygiene products, it was considered a suitable choice for these tests. The CSP-ICP complexes contain approximately 11% calcium by weight whereas calcium chloride is 40% calcium by weight. Therefore, relatively small amounts of calcium chloride are potentially able to make a significant contribution towards moving the existing calcium: phosphate ratio from 1.2-1.25 closer to the ideal of 1.62.

The present inventors estimated that approximately 10 grams of calcium chloride for every 100 grams of the known product CSP-ICP complex solutions would be required to bring the total calcium: phosphate ratio up to the desired 1.62:1. Note that if these quantities are dissolved in 1 litre of water, the calcium chloride content is about 80 times more than the 250 mg/litre taste threshold for calcium chloride in water. In anticipation of a negative result because of the adverse organoleptic properties of calcium chloride, the present inventors limited initial tests to the addition of a more modest 3-5% calcium chloride. Despite this limitation, all 16 members of a subjective taste panel found these mixtures totally unpalatable.

However, a surprising and very different result was obtained when the present inventors attempted to improve the calcium: phosphate ratio not by adding external calcium chloride but by adjusting and reducing the number of purification cycles (washing the precipitated crude product with ethanol: water mixtures) so that 3-5% calcium chloride remained in the partially purified product. Unexpectedly, the 16 person taste panel which had previously completely rejected the simple mixture of CSP-ICP and 3-5% added CaCk found that a liquid containing the same proportions by weight of these materials was either directly palatable or could be rendered palatable by the addition of small quantities of sweetener and/or flavour. To confirm this finding, the present inventors prepared a 40% w/w aqueous gel of the CSP-ICP complexes purified only to the point at which they contained 1.8% w/w calcium chloride, this being more than almost 4X higher the previously established upper limit for CaCk inclusion. This gel contained 7200 pm of calcium chloride which is more than 28 times higher than the 250 mg/litre taste threshold. The gel was rendered palatable to all members of our test panel by the simple inclusion of 0.25% w/w saccharin. This modified material defies conventional expectations and that it is easily adapted to formulations of all kinds including toothpastes, rinses, gels, polishing agents and the like. At the same time, it essentially preserves the bland taste of the original CS-ICP complexes and thus the new material continues to lend itself to inclusion in acidic foods and beverages.

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Claims

1. A composition comprising calcium sucrose phosphate - calcium phosphate (CSP- ICP) complexes and between 0.5wt% and 5wt% calcium chloride (CaCh).

2. A composition comprising calcium sucrose phosphate - calcium phosphate (CSP-

ICP) complexes and calcium chloride (CaCh), wherein the composition is prepared by: performing an esterification reaction of sugar with phosphorous oxychloride and a base comprising calcium to thereby form a product comprising CSP-ICP complexes and CaCh; and removing a portion of the CaCh from the product to reduce the CaCh content to between 0.5wt% and 5wt%.

3. The composition of claim 1 or claim 2 comprising between 3wt% and 5wt% CaCh.

4. The composition of any one of claims 1 to 3, further comprising more than 2wt% of free sugar molecules and/or more than lwt% of ethanol.

5. The composition of any one of claims 1 to 4, wherein the composition has a calcium: phosphate ratio of between 1.3-1.6:1.

6. A method for preparing a composition comprising calcium sucrose phosphate - calcium phosphate (CSP-ICP) complexes and calcium chloride (CaCh), the method comprising: performing an esterification reaction of sugar with phosphorous oxychloride and a base comprising calcium to thereby form a product comprising CSP-ICP complexes and CaCh; and removing a portion of the CaCh from the product to reduce the CaCh content to between 0.5wt% and 5wt%, thereby providing the composition.

7. The method of claim 6, wherein the sugar is selected from any one or more of glucose, sucrose, fructose, galactose, and mannose.

8. The method of claim 6 or claim 7, wherein the base comprising calcium is selected from a base comprising any one or more of a calcium hydroxide (CaOH), calcium oxide (CaO), and calcium carbonate (CaCCb).

9. The method of any one of claims 6 to 8, wherein the CaCk content is reduced to between 3wt% and 5wt% CaCk.

10. The method of any one of claims 6 to 9, wherein the composition has a calcium: phosphate ratio of between 1.3-1.6:1.

11. The method of any one of claims 6 to 10, wherein the composition comprises more than 2wt% of free sugar molecules.

12. The method of any one of claims 6 to 11, wherein removing a portion of the CaCk from the product comprises solvent extraction.

13. The method of claim 12, wherein the solvent is aqueous ethanol and the composition comprises more than lwt% ethanol.

14. The method of claim 12 or claim 13, wherein the removing a portion of the CaCk from the product comprises less than 5, less than 4, or less than 3 rounds of solvent extraction.

15. A composition comprising calcium sucrose phosphate - calcium phosphate (CSP- ICP) complexes and calcium chloride (CaCk) obtained or obtainable by the method of any one of claims 6 to 14.

16. A method for remineralising a tooth or teeth, the method comprising contacting the tooth or teeth with the composition of any one of claims 1 to 5 or 15.

17. Use of a composition of any one of claims 1 to 5 or 15 in the preparation of a medicament for remineralising a tooth or teeth.

18. A composition of any one of claims 1 to 5 or 15 for use in remineralising a tooth or teeth.

19. A composition of any one of claims 1 to 5 or 15 when used for remineralising a tooth or teeth.

20. The method of claim 16, the use of claim 17, or the composition of claim 18 or claim 19, wherein the tooth or teeth are remineralised for the purpose of preventing or treating any one or more of dental caries, dental erosion, periodontal disease, developmental defects of enamel tooth decay, and/or dentin hypersensitivity.