Multifunctional compositions

Abstract

The present invention relates to improved phosphopeptide stabilised amorphous calcium phosphate and / or amorphous calcium fluoride phosphate complexes and compositions containing those complexes. Methods of making the complexes of the invention and of treating or preventing oral conditions are also provided. In one aspect, the present invention provides a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

Description

Multifunctional compositionsRelated application

[0001] This application claims the benefit of Australian provisional application no 2024904288 filed on 23 December 2024, the contents of which are incorporated herein by reference in their entirety.Field of the invention

[0002] The present invention relates to phosphopeptide stabilised amorphous calcium phosphate and / or amorphous calcium fluoride phosphate complexes and compositions containing those complexes. Methods of making the complexes of the invention and of treating or preventing various dental conditions are also provided.Background of the invention

[0003] Oral microbes have co-evolved and co-existed with their hosts for millions of years in a mostly harmonious symbiotic relationship. The host and oral microbiome are not distinct entities but together form a 'superorganism' or holobiont, with the oral microbiome playing a significant role in the maintenance and health of the oral cavity. The mouth provides an environment for the second most diverse microbial community in the body, with over 700 resident species of bacteria that colonise the hard surfaces of teeth and the soft tissues of the oral mucosa. Through recent advances in DNA sequencing technology the complexities of the oral microbiome have been revealed which has provided new insights into the role of the different intra-oral polymicrobial biofilms during both health and disease.

[0004] Periodontal diseases are characterised by inflammatory responses to microbes within the plaque accreted to the tooth and surrounding epithelium.Overgrowth of supragingival plaque results in gingivitis (gingival inflammation). If this becomes chronic then an anaerobic periodontal pocket can develop through soft tissue swelling, and this environment can allow the emergence of periodontal pathogens. The resulting dysbiosis leads to destructive periodontal disease (periodontitis) involving degradation of the supporting tissues of the tooth including resorption of the alveolar bone. Porphyromonas gingivalis has been recognised as an important participant in the1006214354development of the pathology of periodontitis and has been described as a keystone pathogen.

[0005] Hypomineralized lesions is another form of dental disease which can be caused by caries and fluorosis.

[0006] Dental caries is initiated by the demineralization of hard tissue of the teeth usually by organic acids produced from fermentation of dietary sugar by dental plaque odontopathogenic bacteria. Dental caries is still a major public health problem.Further, restored tooth surfaces can be susceptible to further dental caries around the margins of the restoration. Even though the prevalence of dental caries has decreased through the use of fluoride in most developed countries, the disease remains a major public health problem. Dental erosion or corrosion is the loss of tooth mineral by dietary or regurgitated acids. Dental hypersensitivity is due to exposed dentinal tubules through loss of the protective mineralized layer, cementum. Dental calculus is the unwanted accretion of calcium phosphate minerals on the tooth surface. All these conditions, dental caries, dental erosion, dental hypersensitivity and dental calculus are therefore imbalances in the level of calcium phosphates.

[0007] Enamel fluorosis (mottling) has been recognized for nearly a century, however, the aetiological role of fluoride was not identified until 1942 The characteristic appearance of fluorosis may be differentiated from other enamel disturbances. The clinical features of fluorotic lesions of enamel (FLE) represent a continuum ranging from fine opaque lines following the perikymata, to chalky, white enamel. The presence of a comparatively highly mineralized enamel outer surface and a hypomineralized subsurface in the fluorotic lesion simulates the incipient enamel “white spot” carious lesion. With increasing severity, both the depth of enamel involved in the lesion and the degree of hypomineralization increases. The development of fluorosis is highly dependent on the dose, duration and timing of fluoride exposure and is believed to be related to elevated serum fluoride concentrations. Chalky “white spot” lesions may also form on developing teeth in children such as after treatment with antibiotics or fever. Such lesions indicate areas of hypomineralization of the tooth enamel.

[0008] Depending on lesion severity, fluorosis has been managed clinically by restorative replacement or micro-abrasion of the outer enamel. These treatments are unsatisfactory because they involve restorations and removal of tooth tissue. What is1006214354desired is a treatment that will mineralize the hypomineralized enamel to produce a natural appearance and structure.

[0009] Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) is a salivary biomimetic which provides bioavailable calcium and phosphate ions to remineralise early stages of dental caries in enamel and dentine. Specific complexes of casein phosphopeptides and amorphous calcium phosphate ("CPP-ACP", available commercially as Recaldent™) have been shown to remineralize enamel subsurface lesions in vitro and in situ.

[0010] WO 98 / 40408 in the name of The University of Melbourne (the contents of which are herein incorporated fully by reference) describes casein phosphopeptide-amorphous calcium phosphate complexes (CPP-ACP) and CPP-stabilised amorphous calcium fluoride phosphate complexes (CPP-ACFP) which have been produced at alkaline pH. Such complexes have been shown to promote remineralization of enamel subsurface lesions in animal and human in situ caries models. Moreover, improvements on these compositions are disclosed in WO 2006 / 066013 and WO 2007 / 090242 and specific uses (the contents of which are herein incorporated fully by reference).

[0011] There is a need for new, improved or alternate treatments for Porphyromonas gingivalis infections, and its related oral diseases, and / or for the treatment of hypomineralized lesions.

[0012] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and / or combined with other pieces of prior art by a skilled person in the art.Summary of the invention

[0013] In one aspect, the present invention provides a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.1006214354

[0014] In any embodiment, the composition comprises equal to, or greater than, about 9% w / v; equal to, or greater than, about 10% w / v; equal to, or greater than, about 11 % w / v; equal to, or greater than, about 12% w / v; equal to, or greater than, about 13% w / v; equal to, or greater than, about 14% w / v; equal to, or greater than, about 15% w / v; equal to, or greater than, about 16% w / v; equal to, or greater than, about 17% w / v; equal to, or greater than, about 18% w / v; equal to, or greater than, about 19% w / v; equal to, or greater than, about 20% w / v; equal to, or greater than, about 21% w / v; equal to, or greater than, about 22% w / v; equal to, or greater than, about 25% w / v; equal to, or greater than, about 30% w / v; equal to, or greater than, about 35% w / v; equal to, or greater than, about 40% w / v; equal to, or greater than, about 45% w / v; equal to, or greater than, about 50% w / v; equal to, or greater than, about 55% w / v; equal to, or greater than, about 60% w / v; equal to, or greater than, about 65% w / v; or equal to, or greater than, about 70% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0015] In any embodiment, the composition comprises equal to, or greater than, 8% w / v; equal to, or greater than, 9% w / v; equal to, or greater than, 10% w / v; equal to, or greater than, 11 % w / v; equal to, or greater than, 12% w / v; equal to, or greater than, 13% w / v; equal to, or greater than, 14% w / v; equal to, or greater than, 15% w / v; equal to, or greater than, 16% w / v; equal to, or greater than, 17% w / v; equal to, or greater than, 18% w / v; equal to, or greater than, 19% w / v; equal to, or greater than, 20% w / v; equal to, or greater than, 21% w / v; or equal to, or greater than, 22% w / v; equal to, or greater than, 25% w / v; equal to, or greater than, 30% w / v; equal to, or greater than, 35% w / v; equal to, or greater than, 40% w / v; equal to, or greater than, 45% w / v; equal to, or greater than, 50% w / v; equal to, or greater than, 55% w / v; equal to, or greater than, 60% w / v; equal to, or greater than, 65% w / v; or equal to, or greater than, 70% w / v (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.1006214354

[0016] In any embodiment, the composition comprises stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, in an amount of from about 8% w / v to about 70% w / v; from about 9% w / v to about 70% w / v; from about 10% w / v to about 70% w / v; from about 11% w / v to about 70% w / v; from about 12% w / v to about 70% w / v; from about 13% w / v to about 70% w / v; from about 14% w / v to about 70% w / v; from about 15% w / v to about 70% w / v; from about 16% to about 70% w / v; from about 17% w / v to about 70% w / v; from about 18% w / v to about 70% w / v; from about 19% w / v to about 70% w / v; from about 20% w / v to about 70% w / v; from about 21 % w / v to about 70% w / v; from about 25% w / v to about 70% w / v; from about 30% w / v to about 70% w / v; from about 35% w / v to about 70% w / v; from about 45% w / v to about 70% w / v; from about 50% w / v to about 70% w / v; from about 55% w / v to about 70% w / v; from about 60% w / v to about 70% w / v; or from about 60% w / v to about 65% w / v.

[0017] In any embodiment, the composition comprises stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, in an amount of from 8% w / v to 70% w / v; from 9% w / v to 70% w / v; from 10% w / v to 70% w / v; from 11 % w / v to 70% w / v; from 12% w / v to 70% w / v; from 13% w / v to 70% w / v; from 14% w / v to 70% w / v; from 15% w / v to 70% w / v; from 16% to 70% w / v; from 17% w / v to 70% w / v; from 18% w / v to 70% w / v; from 19% w / v to 70% w / v; from 70% w / v to about 22% w / v; from 21% w / v to about 70% w / v; from 25% w / v to 70% w / v; from 30% w / v to 70% w / v; from 35% w / v to 70% w / v; from 45% w / v to 70% w / v; from 50% w / v to 70% w / v; from 55% w / v to 70% w / v; from 60% w / v to 70% w / v; or from 60% w / v to 65% w / v.

[0018] In any embodiment, the composition comprises equal to, or greater than, about 8.20% w / v, about 8.36% w / v, about 8.40% w / v, about 8.44% w / v, about 8.60% w / v, or about 8.80% w / v.

[0019] In any embodiment, the composition comprises equal to, or greater than, 8.20% w / v, 8.36% w / v, 8.4% w / v, 8.44% w / v, 8.60% w / v, or 8.80% w / v.1006214354

[0020] In any embodiment, the composition comprises from and to, or between, any 2 values of about 8.20% w / v, about 8.36% w / v, about 8.40% w / v, about 8.44% w / v, about 8.60% w / v, or about 8.80% w / v.

[0021] In any embodiment, the composition comprises from and to, or between, any 2 values of 8.20% w / v, 8.36% w / v, 8.4% w / v, 8.44% w / v, 8.60% w / v, or 8.80% w / v.

[0022] In any embodiment, the composition comprises equal to, or greater than, about 9.23% w / v, about 9.41% w / v, about 9.45% w / v, about 9.50% w / v, about 9.68% w / v or about 9.90% w / v.

[0023] In any embodiment, the composition comprises equal to, or greater than, 9.23% w / v, 9.41% w / v, 9.45% w / v, 9.50% w / v, 9.68% w / v or 9.90% w / v.

[0024] In any embodiment, the composition comprises from and to, or between, any 2 values of about 9.23% w / v, about 9.41% w / v, about 9.45% w / v, about 9.50% w / v, about 9.68% w / v or about 9.90% w / v.

[0025] In any embodiment, the composition comprises from and to, or between, any 2 values of 9.23% w / v, 9.41% w / v, 9.45% w / v, 9.50% w / v, 9.68% w / v or 9.90% w / v.

[0026] In any embodiment, the composition comprises equal to, or greater than, about 10.25% w / v, about 10.45% w / v, about 10.50% w / v, about 10.55% w / v, about 10.75% w / v or about 11.00% w / v.

[0027] In any embodiment, the composition comprises equal to, or greater than, 10.25% w / v, 10.45% w / v, 10.50% w / v, 10.55% w / v, 10.75% w / v or 11.00% w / v.

[0028] In any embodiment, the composition comprises from and to, or between, any 2 values of about 10.25% w / v, about 10.45% w / v, about 10.50% w / v, about 10.55% w / v, about 10.75% w / v or about 11.00% w / v.

[0029] In any embodiment, the composition comprises from and to, or between, any 2 values of 10.25% w / v, 10.45% w / v, 10.50% w / v, 10.55% w / v, 10.75% w / v or 11.00% w / v.

[0030] In any embodiment, the composition comprises equal to, or greater than, about 11.28% w / v, about 11.50% w / v, about 11.55% w / v, about 11.61 % w / v, about 11.83% w / v or about 12.10% w / v.1006214354

[0031] In any embodiment, the composition comprises equal to, or greater than, 11.28% w / v, 11.50% w / v, 11.55% w / v, 11.61 % w / v, 11.83% w / v or 12.10% w / v.

[0032] In any embodiment, the composition comprises from and to, or between, any 2 values of about 11.28% w / v, about 11.50% w / v, about 11.55% w / v, about 11.61 % w / v, about 11.83% w / v or about 12.10% w / v.

[0033] In any embodiment, the composition comprises from and to, or between, any 2 values of 11.28% w / v, 11.50% w / v, 11.55% w / v, 11.61 % w / v, 11.83% w / v or 12.10% w / v.

[0034] In any embodiment, the composition comprises equal to, or greater than, about 12.30% w / v, about 12.54% w / v, about 12.60% w / v, about 12.66% w / v, about 12.90% w / v or about 13.20% w / v.

[0035] In any embodiment, the composition comprises equal to, or greater than, 12.30% w / v, 12.54% w / v, 12.60% w / v, 12.66% w / v, 12.90% w / v or 13.20% w / v.

[0036] In any embodiment, the composition comprises from and to, or between, any 2 values of about 12.30% w / v, about 12.54% w / v, about 12.60% w / v, about 12.66% w / v, about 12.90% w / v or about 13.20% w / v.

[0037] In any embodiment, the composition comprises from and to, or between, any 2 values of 12.30% w / v, 12.54% w / v, 12.60% w / v, 12.66% w / v, 12.90% w / v or 13.20% w / v.

[0038] In any embodiment, the composition comprises equal to, or greater than, about 13.33% w / v, about 13.59% w / v, about 13.65% w / v, about 13.72% w / v, about 13.98% w / v or about 14.30% w / v.

[0039] In any embodiment, the composition comprises equal to, or greater than, 13.33% w / v, 13.59% w / v, 13.65% w / v, 13.72% w / v, 13.98% w / v or 14.30% w / v.

[0040] In any embodiment, the composition comprises from and to, or between, any 2 values of about 13.33% w / v, about 13.59% w / v, about 13.65% w / v, about 13.72% w / v, about 13.98% w / v or about 14.30% w / v.1006214354

[0041] In any embodiment, the composition comprises from and to, or between, any 2 values of 13.33% w / v, 13.59% w / v, 13.65% w / v, 13.72% w / v, 13.98% w / v or 14.30% w / v.

[0042] In any embodiment, the composition comprises equal to, or greater than, about 14.35% w / v, about 14.63% w / v, about 14.70% w / v, about 14.77% w / v, about 15.05% w / v or about 15.40% w / v.

[0043] In any embodiment, the composition comprises equal to, or greater than, 14.35% w / v, 14.63% w / v, 14.70% w / v, 14.77% w / v, 15.05% w / v or 15.40% w / v.

[0044] In any embodiment, the composition comprises from and to, or between, any 2 values of about 14.35% w / v, about 14.63% w / v, about 14.70% w / v, about 14.77% w / v, about 15.05% w / v or about 15.40% w / v.

[0045] In any embodiment, the composition comprises from and to, or between, any 2 values of 14.35% w / v, 14.63% w / v, 14.70% w / v, 14.77% w / v, 15.05% w / v or 15.40% w / v.

[0046] In any embodiment, the composition comprises equal to, or greater than, about 15.38% w / v, about 15.68% w / v, about 15.75% w / v, about 15.83% w / v, about 16.13% w / v or about 16.50% w / v.

[0047] In any embodiment, the composition comprises equal to, or greater than, 15.38% w / v, 15.68% w / v, 15.75% w / v, 15.83% w / v, 16.13% w / v or 16.50% w / v.

[0048] In any embodiment, the composition comprises from and to, or between, any 2 values of about 15.38% w / v, about 15.68% w / v, about 15.75% w / v, about 15.83% w / v, about 16.13% w / v or about 16.50% w / v.

[0049] In any embodiment, the composition comprises from and to, or between, any 2 values of 15.38% w / v, 15.68% w / v, 15.75% w / v, 15.83% w / v, 16.13% w / v or 16.50% w / v.

[0050] In any embodiment, the composition comprises equal to, or greater than, about 16.40% w / v, about 16.72% w / v, about 16.80% w / v, about 16.88% w / v, about 17.20% w / v or about 17.60% w / v.1006214354

[0051] In any embodiment, the composition comprises equal to, or greater than, 16.40% w / v, 16.72% w / v, 16.80% w / v, 16.88% w / v, 17.20% w / v or 17.60% w / v.

[0052] In any embodiment, the composition comprises from and to, or between, any 2 values of about 16.40% w / v, about 16.72% w / v, about 16.80% w / v, about 16.88% w / v, about 17.20% w / v or about 17.60% w / v.

[0053] In any embodiment, the composition comprises from and to, or between, any 2 values of 16.40% w / v, 16.72% w / v, 16.80% w / v, 16.88% w / v, 17.20% w / v or 17.60% w / v.

[0054] In any embodiment, the composition comprises equal to, or greater than, about 17.43% w / v, about 17.77% w / v, about 17.85% w / v, about 17.94% w / v, about 18.28% w / v or about 18.70% w / v.

[0055] In any embodiment, the composition comprises equal to, or greater than, 17.43% w / v, 17.77% w / v, 17.85% w / v, 17.94% w / v, 18.28% w / v or 18.70% w / v.

[0056] In any embodiment, the composition comprises from and to, or between, any 2 values of about 17.43% w / v, about 17.77% w / v, about 17.85% w / v, about 17.94% w / v, about 18.28% w / v or about 18.70% w / v.

[0057] In any embodiment, the composition comprises from and to, or between, any 2 values of 17.43% w / v, 17.77% w / v, 17.85% w / v, 17.94% w / v, 18.28% w / v or 18.70% w / v.

[0058] In any embodiment, the composition comprises equal to, or greater than, about 18.45% w / v, about 18.81% w / v, about 18.90% w / v, about 18.99% w / v, about 19.35% w / v or about 19.80% w / v.

[0059] In any embodiment, the composition comprises equal to, or greater than, 18.45% w / v, 18.81% w / v, 18.90% w / v, 18.99% w / v, 19.35% w / v or 19.80% w / v.

[0060] In any embodiment, the composition comprises from and to, or between, any 2 values of about 18.45% w / v, about 18.81% w / v, about 18.90% w / v, about 18.99% w / v, about 19.35% w / v or about 19.80% w / v.1006214354

[0061] In any embodiment, the composition comprises from and to, or between, any 2 values of 18.45% w / v, 18.81% w / v, 18.90% w / v, 18.99% w / v, 19.35% w / v or 19.80% w / v.

[0062] In any embodiment, the composition comprises equal to, or greater than, about 19.48% w / v, about 19.86% w / v, about 19.95% w / v, about 20.05% w / v, about 20.43% w / v or about 20.90% w / v.

[0063] In any embodiment, the composition comprises equal to, or greater than, 19.48% w / v, 19.86% w / v, 19.95% w / v, 20.05% w / v, 20.43% w / v or 20.90% w / v.

[0064] In any embodiment, the composition comprises from and to, or between, any 2 values of about 19.48% w / v, about 19.86% w / v, about 19.95% w / v, about 20.05% w / v, about 20.43% w / v or about 20.90% w / v.

[0065] In any embodiment, the composition comprises from and to, or between, any 2 values of 19.48% w / v, 19.86% w / v, 19.95% w / v, 20.05% w / v, 20.43% w / v or 20.90% w / v.

[0066] In any embodiment, the composition comprises equal to, or greater than, about 20.50% w / v, about 20.90% w / v, about 21.00% w / v, about 21.10% w / v, about 21.50% w / v or about 22.00% w / v.

[0067] In any embodiment, the composition comprises equal to, or greater than, 20.50% w / v, 20.90% w / v, 21.00% w / v, 21.10% w / v, 21.50% w / v or 22.00% w / v.

[0068] In any embodiment, the composition comprises from and to, or between, any 2 values of about 20.50% w / v, about 20.90% w / v, about 21.00% w / v, about 21.10% w / v, about 21.50% w / v or about 22.00% w / v.

[0069] In any embodiment, the composition comprises from and to, or between, any 2 values of 20.50% w / v, 20.90% w / v, 21.00% w / v, 21.10% w / v, 21.50% w / v or 22.00% w / v.

[0070] In any embodiment, the composition comprises equal to, or greater than, about 25.63% w / v, about 26.13% w / v, about 26.25% w / v, about 26.38% w / v, about 26.88% w / v, or about 27.50% w / v.1006214354

[0071] In any embodiment, the composition comprises equal to, or greater than, 25.63% w / v, 26.13% w / v, 26.25% w / v, 26.38% w / v, 26.88% w / v, or 27.50% w / v.

[0072] In any embodiment, the composition comprises from and to, or between, any 2 values of about 25.63% w / v, about 26.13% w / v, about 26.25% w / v, about 26.38% w / v, about 26.88% w / v, or about 27.50% w / v.

[0073] In any embodiment, the composition comprises from and to, or between, any 2 values of 25.63% w / v, 26.13% w / v, 26.25% w / v, 26.38% w / v, 26.88% w / v, or 27.50% w / v.

[0074] In any embodiment, the composition comprises equal to, or greater than, about 30.75% w / v, about 31.35% w / v, about 31.50% w / v, about 31.65% w / v, about 32.25% w / v, or about 33.00% w / v.

[0075] In any embodiment, the composition comprises equal to, or greater than, 30.75% w / v, 31.35% w / v, 31.50% w / v, 31.65% w / v, 32.25% w / v, or 33.00% w / v.

[0076] In any embodiment, the composition comprises from and to, or between, any 2 values of about 30.75% w / v, about 31.35% w / v, about 31.50% w / v, about 31.65% w / v, about 32.25% w / v, or about 33.00% w / v.

[0077] In any embodiment, the composition comprises from and to, or between, any 2 values of 30.75% w / v, 31.35% w / v, 31.50% w / v, 31.65% w / v, 32.25% w / v, or 33.00% w / v.

[0078] In any embodiment, the composition comprises equal to, or greater than, about 35.88% w / v, about 36.58% w / v, about 36.75% w / v, about 36.93% w / v, about 37.63% w / v, or about 38.50% w / v.

[0079] In any embodiment, the composition comprises equal to, or greater than, 35.88% w / v, 36.58% w / v, 36.75% w / v, 36.93% w / v, 37.63% w / v, or 38.50% w / v.

[0080] In any embodiment, the composition comprises from and to, or between, any 2 values of about 35.88% w / v, about 36.58% w / v, about 36.75% w / v, about 36.93% w / v, about 37.63% w / v, or about 38.50% w / v.1006214354

[0081] In any embodiment, the composition comprises from and to, or between, any 2 values of 35.88% w / v, 36.58% w / v, 36.75% w / v, 36.93% w / v, 37.63% w / v, or 38.50% w / v.

[0082] In any embodiment, the composition comprises equal to, or greater than, about 41.00% w / v, about 41.80% w / v, about 42.00% w / v, about 42.20% w / v, about 43.00% w / v, or about 44.00% w / v.

[0083] In any embodiment, the composition comprises equal to, or greater than, 41.00% w / v, 41.80% w / v, 42.00% w / v, 42.20% w / v, 43.00% w / v, or 44.00% w / v.

[0084] In any embodiment, the composition comprises from and to, or between, any 2 values of about 41.00% w / v, about 41.80% w / v, about 42.00% w / v, about 42.20% w / v, about 43.00% w / v, or about 44.00% w / v.

[0085] In any embodiment, the composition comprises from and to, or between, any 2 values of 41.00% w / v, 41.80% w / v, 42.00% w / v, 42.20% w / v, 43.00% w / v, or 44.00% w / v.

[0086] In any embodiment, the composition comprises equal to, or greater than, about 46.13% w / v, about 47.03% w / v, about 47.25% w / v, about 47.48% w / v, about 48.38% w / v, or about 49.50% w / v.

[0087] In any embodiment, the composition comprises equal to, or greater than, 46.13% w / v, 47.03% w / v, 47.25% w / v, 47.48% w / v, 48.38% w / v, or 49.50% w / v.

[0088] In any embodiment, the composition comprises from and to, or between, any 2 values of about 46.13% w / v, about 47.03% w / v, about 47.25% w / v, about 47.48% w / v, about 48.38% w / v, or about 49.50% w / v.

[0089] In any embodiment, the composition comprises from and to, or between, any 2 values of 46.13% w / v, 47.03% w / v, 47.25% w / v, 47.48% w / v, 48.38% w / v, or 49.50% w / v.

[0090] In any embodiment, the composition comprises equal to, or greater than, about 51.25% w / v, about 52.25% w / v, about 52.50% w / v, about 52.75% w / v, about 53.75% w / v, or about 55.00% w / v.1006214354

[0091] In any embodiment, the composition comprises equal to, or greater than, 51.25% w / v, 52.25% w / v, 52.50% w / v, 52.75% w / v, 53.75% w / v, or 55.00% w / v.

[0092] In any embodiment, the composition comprises from and to, or between, any 2 values of about 51.25% w / v, about 52.25% w / v, about 52.50% w / v, about 52.75% w / v, about 53.75% w / v, or about 55.00% w / v.

[0093] In any embodiment, the composition comprises from and to, or between, any 2 values of 51.25% w / v, 52.25% w / v, 52.50% w / v, 52.75% w / v, 53.75% w / v, or 55.00% w / v.

[0094] In any embodiment, the composition comprises equal to, or greater than, about 56.38% w / v, about 57.48% w / v, about 57.75% w / v, about 58.03% w / v, about 59.13% w / v, or about 60.50% w / v.

[0095] In any embodiment, the composition comprises equal to, or greater than, 56.38% w / v, 57.48% w / v, 57.75% w / v, 58.03% w / v, 59.13% w / v, or 60.50% w / v.

[0096] In any embodiment, the composition comprises from and to, or between, any 2 values of about 56.38% w / v, about 57.48% w / v, about 57.75% w / v, about 58.03% w / v, about 59.13% w / v, or about 60.50% w / v.

[0097] In any embodiment, the composition comprises from and to, or between, any 2 values of 56.38% w / v, 57.48% w / v, 57.75% w / v, 58.03% w / v, 59.13% w / v, or 60.50% w / v.

[0098] In any embodiment, the composition comprises equal to, or greater than, about 61.50% w / v, about 62.70% w / v, about 63.00% w / v, about 63.30% w / v, about 64.50% w / v, or about 66.00% w / v.

[0099] In any embodiment, the composition comprises equal to, or greater than, 61.50% w / v, 62.70% w / v, 63.00% w / v, 63.30% w / v, 64.50% w / v, or 66.00% w / v.

[0100] In any embodiment, the composition comprises from and to, or between, any 2 values of about 61.50% w / v, about 62.70% w / v, about 63.00% w / v, about 63.30% w / v, about 64.50% w / v, or about 66.00% w / v.1006214354

[0101] In any embodiment, the composition comprises from and to, or between, any 2 values of 61.50% w / v, 62.70% w / v, 63.00% w / v, 63.30% w / v, 64.50% w / v, or 66.00% w / v.

[0102] In another aspect, the present invention provides a composition comprising equal to or greater than about 8% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes, wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0103] In any embodiment, the composition comprises equal to, or greater than, about 9% w / v; equal to, or greater than, about 10% w / v; equal to, or greater than, about 11 % w / v; equal to, or greater than, about 12% w / v; equal to, or greater than, about 13% w / v; equal to, or greater than, about 14% w / v; equal to, or greater than, about 15% w / v; equal to, or greater than, about 16% w / v; equal to, or greater than, about 17% w / v; equal to, or greater than, about 18% w / v; equal to, or greater than, about 19% w / v; equal to, or greater than, about 20% w / v; equal to, or greater than, about 21% w / v; equal to, or greater than, about 22% w / v; equal to, or greater than, about 25% w / v; equal to, or greater than, about 30% w / v; equal to, or greater than, about 35% w / v; equal to, or greater than, about 40% w / v; equal to, or greater than, about 45% w / v; equal to, or greater than, about 50% w / v; equal to, or greater than, about 55% w / v; equal to, or greater than, about 60% w / v; equal to, or greater than, about 65% w / v; or equal to, or greater than, about 70% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0104] In any embodiment, the composition comprises equal to, or greater than, 8% w / v; equal to, or greater than, 9% w / v; equal to, or greater than, 10% w / v; equal to, or greater than, 11 % w / v; equal to, or greater than, 12% w / v; equal to, or greater than, 13% w / v; equal to, or greater than, 14% w / v; equal to, or greater than, 15% w / v; equal to, or greater than, 16% w / v; equal to, or greater than, 17% w / v; equal to, or greater than, 18% w / v; equal to, or greater than, 19% w / v; equal to, or greater than, 20% w / v; equal to, or greater than, 21% w / v; or equal to, or greater than, 22% w / v; equal to, or greater than, 25% w / v; equal to, or greater than, 30% w / v; equal to, or greater than, 35% w / v; equal to, or greater than, 40% w / v; equal to, or greater than, 45% w / v; equal1006214354to, or greater than, 50% w / v; equal to, or greater than, 55% w / v; equal to, or greater than, 60% w / v; equal to, or greater than, 65% w / v; or equal to, or greater than, 70% w / v (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0105] In any embodiment, the composition comprises phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, in an amount of from about 8% w / v to about 70% w / v; from about 9% w / v to about 70% w / v; from about 10% w / v to about 70% w / v; from about 11% w / v to about 70% w / v; from about 12% w / v to about 70% w / v; from about 13% w / v to about 70% w / v; from about 14% w / v to about 70% w / v; from about 15% w / v to about 70% w / v; from about 16% to about 70% w / v; from about 17% w / v to about 70% w / v; from about 18% w / v to about 70% w / v; from about 19% w / v to about 70% w / v; from about 20% w / v to about 70% w / v; from about 21 % w / v to about 70% w / v; from about 25% w / v to about 70% w / v; from about 30% w / v to about 70% w / v; from about 35% w / v to about 70% w / v; from about 45% w / v to about 70% w / v; from about 50% w / v to about 70% w / v; from about 55% w / v to about 70% w / v; from about 60% w / v to about 70% w / v; or from about 60% w / v to about 65% w / v.

[0106] In any embodiment, the composition comprises phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, in an amount of from 8% w / v to 70% w / v; from 9% w / v to 70% w / v; from 10% w / v to 70% w / v; from 11 % w / v to 70% w / v; from 12% w / v to 70% w / v; from 13% w / v to 70% w / v; from 14% w / v to 70% w / v; from 15% w / v to 70% w / v; from 16% to 70% w / v; from 17% w / v to 70% w / v; from 18% w / v to 70% w / v; from 19% w / v to 70% w / v; from 70% w / v to about 22% w / v; from 21 % w / v to about 70% w / v; from 25% w / v to 70% w / v; from 30% w / v to 70% w / v; from 35% w / v to 70% w / v; from 45% w / v to 70% w / v; from 50% w / v to 70% w / v; from 55% w / v to 70% w / v; from 60% w / v to 70% w / v; or from 60% w / v to 65% w / v.1006214354

[0107] In any aspect or embodiment, complexes or compositions having a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, preferably have a stannous ion content of:• equal to, or greater than about 1.0, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 moles of stannous per mole of PP;• equal to, or greater than 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8 or3.9 moles of stannous per mole of PP;• from and to, or between, any 2 values of about 1.0, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1 , about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 moles of stannous per mole of PP;• from and to, or between, any 2 values of 1.0, 1.1 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 moles of stannous per mole of PP;• equal to, or greater than about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, or about 2.8 moles of stannous per mole of PP;• equal to, or greater than 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, or 2.8 moles of stannous per mole of PP;• from and to, or between, any 2 values of about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, or about 2.8 moles of stannous per mole of PP;from and to, or between, any 2 values of 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, or 2.8 moles of stannous per mole of PP;1006214354• equal to, or greater than about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1 , about 2.2, about 2.3, about 2.4 moles of stannous per mole of PP;• equal to, or greater than 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4 moles of stannous per mole of PP;• from and to, or between, any 2 values of about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, or about 2.4 moles of stannous per mole of PP;• from and to, or between, any 2 values of 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, or 2.4 moles of stannous per mole of PP;• from and to, or between, any 2 values of about 1.8, about 1.9, about 2.0, about 2.1 , or about 2.2 of stannous per mole of PP; or• from and to, or between, any 2 values of 1.8, 1.9, 2.0, 2.1 or 2.2 moles of stannous per mole of PP.

[0108] Preferably, the composition of the invention described herein further includes a pharmaceutically acceptable carrier, diluent or excipient.

[0109] In any aspect or embodiment, the composition further comprising fluoride. Preferably, the fluoride is provided as stannous fluoride and / or sodium fluoride.

[0110] In any embodiment, the composition comprises from about 440 ppm to about 15000 ppm fluoride, preferably about 1100 ppm or 1450 ppm fluoride.

[0111] In any embodiment, the composition comprises equal to, or greater than, about 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 2000, 3000, 4000, 5000 ppm, 6000 ppm, 7000 ppm, 8000 ppm, 9000 ppm, 10000 ppm, 11000 ppm, 12000 ppm, 13000 ppm, 14000 ppm or 15000 ppm fluoride.

[0112] In a preferred embodiment of each aspect of the invention, the stannous ion content above is tightly bound to the PP-ACP or ACFP complex. In assessing the stannous ion content, the tightly bound stannous ion content is measured by the methods described herein, in particular, in Example 2.1006214354

[0113] In any embodiment, the stannous associated phosphopeptide stabilized ACP and / or ACFP complex comprises stannous ions that remain associated with the complex after centrifugation in a 1000 molecular weight cut off filter at about 3000g for 1 hour at room temperature.

[0114] In any embodiment, the stannous associated phosphopeptide stabilized ACP or ACFP complex has at least 50, 60, 65, 70, 75, 80, 85, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the stannous ions associated with the complex as tightly bound as determined by the method in Example 2.

[0115] In any embodiment, the stannous associated stabilized ACP or ACFP complex has at least 50, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the stannous ions used in preparing the complexes incorporated into the complexes. The complex may be prepared as outlined in Example 1.

[0116] In any aspect or embodiment of the invention, the phosphopeptide may be a casein phosphopeptide.

[0117] In one embodiment, the composition comprises from about 8% w / v to about 20% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and from about 800 ppm to about 2500 ppm fluoride.

[0118] In one embodiment, the composition comprises from about 8% w / v to about 15% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and from about 800 ppm to about 1800 ppm fluoride.

[0119] In one embodiment, the composition comprises from about 8% w / v to about 12% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and from about 800 ppm to about 1400 ppm fluoride.

[0120] In one embodiment, the composition comprises about 10% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and 1100 ppm fluoride.1006214354

[0121] In one embodiment, the composition comprises from 8% w / v to 20% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and from 800 ppm to 2500 ppm fluoride.

[0122] In one embodiment, the composition comprises from 8% w / v to 15% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and from 800 ppm to 1800 ppm fluoride.

[0123] In one embodiment, the composition comprises from 8% w / v to 12% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and from 800 ppm to 1400 ppm fluoride.

[0124] In one embodiment, the composition comprises from 10% w / v to 12% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and 1100 ppm or 1450 ppm fluoride.

[0125] In one embodiment, the composition comprises from 60% w / v to 65% w / v stannous associated casein phosphopeptide (CPP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes and 1100 ppm or 1450 ppm fluoride.

[0126] In one embodiment, the stannous-associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) complex consists essentially of, or consists of, phosphopeptides, stannous, calcium, phosphate and hydroxide ions and water.

[0127] In one embodiment, the stannous-associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACFP) complex consists essentially of, or consists of, phosphopeptides, stannous, calcium, phosphate, fluoride and hydroxide ions and water.

[0128] In any aspect or embodiments as described herein, the stannous-associated phosphopeptide (PP) stabilized ACP or ACFP complex may be in a formulation with additional calcium phosphate. Typically, the formulation includes a stannous-associated1006214354phosphopeptide (PP) stabilized ACP or ACFP complex together with at least an equal amount by weight of calcium phosphate.

[0129] In any aspect or embodiment, the composition is a dentifrice for example a toothpaste, a toothpowder or a liquid dentifrice, a mouthwash, a mouthrinse, a mouth spray, a varnish, a dental cement, a troche, a chewing gum, a dental paste, a gingival massage cream, or a gargle tablet. Preferably, the composition is a toothpaste.

[0130] In any aspect or embodiment, the calcium ion content of the stannous associated phosphopeptide stabilised ACP or ACFP complex is greater than about 30 moles per mole of PP. Preferably, the calcium ion content is in the range of about 30 to 100 moles of calcium per mole of PP. More preferably, the calcium ion content is in the range of about 30 to about 50 moles of calcium per mole of PP.

[0131] In any aspect or embodiment, the phase of the ACP is primarily (i.e. >50%) a basic phase, wherein the ACP comprises predominantly the species Ca2+, PC3' and OH-. The basic phase of ACP may have the general formula [Ca3(PO4)2]x[Ca2(PO4)(OH)] where x> 1. Preferably x = 1-5. More preferably, x= 1, i.e. the two components of the formula are present in equal proportions. Accordingly, in one embodiment, the basic phase of ACP has the formula Ca3(PO4)2Ca2(PO4)(OH).

[0132] In any aspect or embodiment, the phase of the ACFP is a primarily (i.e. >50%) basic phase, wherein the ACFP comprises predominantly the species Ca2+, PO43' and F'. The basic phase of ACFP may have the general formula [Ca3(PO4)2]x[Ca2(PO4)F]ywhere x > 1 when y = 1 or where y > 1 when x = 1. Preferably, y = 1 and x = 1-3. More preferably, y = 1 and x = 1 , i.e. the two components of the formula are present in equal proportions. Accordingly, in one embodiment, the basic phase of ACFP has the formula Ca3(PO4)2Ca2(PO4)F.

[0133] In one embodiment, the composition of the invention does not include a polyphosphate and / or a citrate.

[0134] In one embodiment, the composition of the invention does not include a calcium chelator.1006214354

[0135] In another aspect, the present invention provides a method of treating or preventing a P. gingivalis infection in a subject, comprising administering to an individual in need thereof, a composition of the invention as described herein.

[0136] In another aspect, the present invention provides a method for reducing or minimising the severity of a symptom associated with an infection with P. gingivalis, comprising administering to an individual in need thereof, a composition of the invention as described herein, wherein the symptoms are selected from the group consisting of swollen or puffy gums, gums that bleed easily, receding gums, periodontal pockets around the teeth, loss of tooth supporting tissues (periodontal ligament, cementum and / or alveolar bone) pus between gums and teeth, and gingivitis.

[0137] In another aspect, the present invention also provides a method for treating or preventing P. gingivalis-re\ated disease in a subject, the method comprising administering to an individual in need thereof, a composition of the invention as described herein. Preferably the P. gingivalis-re\ated disease comprises a periodontal disease, such as gingivitis.

[0138] In another aspect, the present invention also provides use of a composition of the invention as described herein in the manufacture of a medicament for:• treating or preventing a P. gingivalis infection in a subject;• minimising or reducing the severity of one or more symptoms of P. gingivalis infection; or• treating or preventing a P. gingivalis-re\ated disease in a subject.

[0139] In another aspect, the present invention also provides use of stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes having a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP in the manufacture of a medicament for:• treating or preventing a P. gingivalis infection in a subject;• minimising or reducing the severity of one or more symptoms of P. gingivalis infection; or1006214354• treating or preventing P. gingivalis- related disease in a subject,wherein the medicament comprises equal to, or greater than about 8% w / v stannous associated PP-ACP or ACFP complexes.

[0140] In another aspect, the invention also provides a composition as described herein for use in:• treating or preventing a P. gingivalis infection in a subject;• minimising or reducing the severity of one or more symptoms of P. gingivalis infection; or• treating or preventing a P. gingivalis-re\ated disease in a subject.

[0141] In any aspect of the present invention, the method or use further comprises the step of detecting P. gingivalis in the oral cavity of the subject.

[0142] In any aspect of the present invention, the subject is an adult and has periodontal disease, preferably caused by a P. gingivalis infection.

[0143] In another aspect, the present invention provides a method of mineralizing a dental surface or sub-surface comprising contacting the dental surface or subsurface with a composition of the invention as described herein, thereby mineralizing the dental surface or sub-surface.

[0144] In another aspect, the present invention provides a method of treating fluorosis comprising contacting a fluorotic lesion, preferably in dental enamel, with a composition of the invention as described herein, thereby treating fluorosis.

[0145] In another aspect, the present invention provides a method of treating dental caries comprising contacting a caries lesion with a composition of the invention as described herein, thereby treating dental caries.

[0146] In another aspect, the present invention provides use of a composition of the invention as described herein in the manufacture of a medicament for mineralizing the dental surface or sub-surface.1006214354

[0147] In another aspect, the present invention provides use of a composition of the invention as described herein in the manufacture of a medicament for treating fluorosis.

[0148] In another aspect, the present invention provides use of a composition of the invention as described herein in the manufacture of a medicament for treating dental caries.

[0149] In another aspect, the present invention provides use of stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes having a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP in the manufacture of a medicament for mineralizing the dental surface or sub-surface, wherein the medicament comprises equal to, or greater than about 8% w / v stannous associated PP-ACP or ACFP complexes.

[0150] In another aspect, the present invention provides use of stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes having a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP in the manufacture of a medicament for treating fluorosis, wherein the medicament comprises equal to, or greater than about 8% w / v stannous associated PP-ACP or ACFP complexes.

[0151] In another aspect, the present invention provides use of stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes having a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP in the manufacture of a medicament for treating dental caries, wherein the medicament comprises equal to, or greater than about 8% w / v stannous associated PP-ACP or ACFP complexes.

[0152] In another aspect, the present invention provides a composition of the invention as described herein for use in mineralizing a dental surface or sub-surface.

[0153] In another aspect, the present invention provides a composition of the invention as described herein for use in treating fluorosis.1006214354

[0154] In another aspect, the present invention provides a composition of the invention as described herein for use in treating caries.

[0155] In any aspect of the present invention, a method, use or composition of the invention may be used for treating dental erosion. In this aspect, a lesion in tooth enamel caused by erosion is contacted with a composition or medicament as described herein.

[0156] In any aspect of the present invention, a method, use or composition of the invention may be used for reducing white spot lesions. In this aspect, a white spot lesion, preferably on tooth enamel, is contacted with a composition or medicament as described herein.

[0157] In any aspect of the present invention, a method, use or composition of the invention may be used for remineralizing a lesion in tooth enamel or dentine. In this aspect, the lesion, preferably on tooth enamel, is contacted with a composition or medicament as described herein.

[0158] In any aspect of the invention described herein, the composition is applied to the mouth, tooth or lesion by a dental health care professional.

[0159] In any aspect of the invention described herein, the composition is applied to exposed root surfaces following a periodontal procedure. For example, the composition is injected down a periodontal pocket.

[0160] In any aspect, the dental surface or subsurface, or lesion, is in need of such treatment. Therefore the invention includes in addition to the steps of any method described herein a step of identifying a subject suffering fluorosis, dental caries, dentinal hypersensitivity or dental calculus, a white spot lesion; a fluorotic lesion; a caries lesion; or a lesion caused by tooth erosion.

[0161] In another aspect, the present invention also provides a method for treating or preventing dentinal sensitivity in an individual in need thereof comprising administering composition of the invention as described herein, thereby treating or preventing dentinal sensitivity in the individual.

[0162] In another aspect, the present invention also provides a method for treating or preventing dentinal sensitivity in an individual in need thereof comprising administering1006214354a composition of the invention as described herein, thereby treating or preventing dentinal hypersensitivity in an individual.

[0163] Preferably, the dentinal sensitivity is dentinal hypersensitivity.

[0164] Preferably, the method further comprises the step of identifying an individual in need of treatment. For example, the invention includes, in addition to the steps of any method described herein, a step of identifying a subject suffering dentinal sensitivity, specifically hypersensitivity.

[0165] In another aspect, the present invention provides a method for occluding exposed dentinal tubules in an individual, the method comprising administering a composition of the invention as described herein, thereby occluding exposed dentinal tubules in an individual.

[0166] In another aspect, the present invention provides a method for forming a layer over exposed dentinal tubules in an individual, the method comprising administering a composition of the invention as described herein, thereby forming a layer over exposed dentinal tubules in an individual.

[0167] Preferably, the method of occluding exposed dentinal tubules or forming a layer over exposed dentinal tubules further comprises the step of identifying exposed dentinal tubules in an individual.

[0168] In another aspect, the present invention provides use of a composition of the invention as described herein in the manufacture of a medicament for the treatment or prevention of dentinal sensitivity. Preferably, the dentinal sensitivity is dentinal hypersensitivity.

[0169] In another aspect, the present invention provides use of stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes having a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP in the manufacture of a medicament for the treatment or prevention of dentinal sensitivity, wherein the medicament comprises equal to, or greater than 8 w / v stannous associated PP-ACP or ACFP complexes.1006214354

[0170] In another aspect, the present invention provides a composition of the invention as described herein for use in the treatment or prevention of dentinal sensitivity. Preferably, the dentinal sensitivity is dentinal hypersensitivity.

[0171] In another aspect, the individual or subject in need of treatment may be one who needs treatment for one or more of:• reducing or minimising the severity of a symptom associated with an infection with P.gingivalis',• treating a P. gingivalis infection;• minimising or reducing the severity of one or more symptoms of P. gingivalis infection;• treating P. gingivalis-re\ated disease;• mineralizing a dental surface or sub-surface;• treating fluorosis;• treating caries;• treating dental erosion;• reducing a white spot lesion;• remineralizing a lesion in tooth enamel or dentine;• dentinal sensitivity, for example dentinal hypersensitivity.

[0172] In any aspect of the invention, a composition of the invention as described herein is administered to the oral cavity. Alternatively, administration may be directly to an oral site in need of treatment, for example a site that has exposed dentine. In either case, administration results in contact of the composition to an oral site in need of treatment, such as exposed dentine.

[0173] In any aspect or embodiment, a composition of the invention, may be contacted with the dental surface for a period of about 1 to 60 minutes, for about 1 to 30 minutes, for about 10 to 60 minutes, for about 10 to 30 minutes, for about 20 to 601006214354minutes, or for about 20 to 30 minutes. Preferably, the complex or composition is contacted with the dental surface for about 20 minutes.

[0174] In any aspect or embodiment, a composition of the invention may be contacted with the dental surface at least 1 , at least 2, at least 3, at least 4 or at least 5 times a day.

[0175] In any aspect or embodiment, a composition of the invention may be contacted with the dental surface 1 , 2, 3, 4 or 5 times a day.

[0176] In any aspect or embodiment, a composition of the invention may be contacted with the dental surface for at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or at least 14 consecutive days.

[0177] In any aspect or embodiment, a composition of the invention may be contacted with the dental surface for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more consecutive days.

[0178] The invention also relates to a kit for use in any method or use described herein comprising a composition of the invention as described herein.

[0179] Preferably, the stannous-associated PP-ACP or ACFP complex is in a pharmaceutically acceptable carrier. Desirably, the kit further includes instructions for use in a method or use described herein in an individual in need of such treatment.

[0180] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.

[0181] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.Brief description of the drawings

[0182] Figure 1. Inhibition of P. gingivalis W50 by Sn-CPP-ACFP complex samples on Horse Blood Agar. White highlighted numbers are CPP-ACP percentages1006214354as in the starting materials provided as an 80 pL sample. Centre well contains 29mM SnF2 alone. Sn2+ total starting material: 29 mM.

[0183] Figure 2. Inhibition of P. gingivalis W50 by CPP-ACP only samples on Horse Blood Agar. White highlighted numbers are CPP-ACP percentages as in the starting materials provided as an 80 pL sample. Central well: 10.45% Sn-CPP-ACFP sample positive control.

[0184] Figure 3. Analysis of the level of enamel and dentine remineralisation and enamel surface microhardness recovery (%). Stabilized 10.45% Sn-CPP-ACFP complex (TM Pro) or Colgate TotalSFwas applied 4 times per day for 14 consecutive days to enamel and dentine slabs on palatal appliances worn by participants. Enamel and dentine remineralisation and enamel surface microhardness recovery (%) was measured after 14 days of treatment

[0185] Figure 4. Representative traverse microradiography (TMR) of enamel subsurface lesions before (A) and after (B) treatment with stabilized CPP-ACP / SnF2 complex of the present invention and Colgate TotalSF. Stabilized 10.45% Sn-CPP-ACFP complex (TM Pro) or Colgate TotalSFwas applied 4 times per day for 14 consecutive days to enamel and dentine slabs on palatal appliances worn by participants. Enamel subsurface lesions were imaged by TMR after 14 days.

[0186] Figure 5. Analysis of calcium and stannous ion bioavailability in postrinse saliva following TM pro and Colgate TotalSFtreatment. Stabilized 10.45% Sn-CPP-ACFP complex (TM Pro) or Colgate TotalSFwas applied 4 times per day for 14 consecutive days to enamel and dentine slabs on palatal appliances worn by participants. Calcium and tin levels measured in post-rinse / saliva samples using AAS and ion chromatography.

[0187] Figure 6. Analysis of calcium, phosphate, fluoride and stannous ion bioavailability in post-rinse saliva following TM pro and Colgate TotalSFtreatment.Stabilized 10.45% Sn-CPP-ACFP complex (TM Pro) or Colgate TotalSFwas applied 4 times per day for 14 consecutive days to enamel and dentine slabs on palatal appliances worn by participants. Calcium, tin, inorganic phosphate and fluoride levels measured in post-rinse / saliva samples using AAS and ion chromatography.1006214354

[0188] Figure 7. Inhibition of Porphyromonas gingivalis growth on blood agar.29 mM SnF2 (well A) and 10% CPP-ACP / SnF229 mM (well B) was applied to bloog agar at pH 7.0. Zone of growth inhibition on the blood agar plate (shown with white arrow).Detailed description of the embodiments

[0189] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

[0190] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.

[0191] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.

[0192] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0193] All of the patents and publications referred to herein are incorporated by reference in their entirety.

[0194] For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0195] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or1006214354steps. As used herein, except where the context requires otherwise, “comprise” and “include” can be used interchangeably.

[0196] Embodiments of the present invention are based on the surprising finding that compositions having equal to or greater than about 8% w / v of stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes in the presence of stannous ions results in (a) sufficient soluble and bioavailable stannous ions to reduce the viability of pathogenic oral bacteria, including the keystone periodontal disease causing bacterium P. gingivalis, (b) a phosphopeptide to stannous ion ratio to form self-assembled nanofilaments across dentine tubules, and (c) significant enamel and dentine remineralisation with high microhardness of the recovered enamel.

[0197] Embodiments of the present invention show for the first time that a single composition has the functionality of treating multiple dental conditions or diseases that may affect one or more of the dentine, enamel and gingiva. Without being bound by any theory or mode of action, it is believe that embodiments of the present invention can provide, simultaneously, (a) bioavailable and soluble stannous ions at sufficient amounts for treatment for P. gingivalis related conditions or diseases, (b) a high concentration of bioavailable calcium and phosphate in the correct ratios of normal enamel to promote mineralisation of dentine or enamel, and (c) stannous ions and phosphopeptides to generate a self-assembled network of nanofilaments across a surface, for example across a surface that has exposed dentine tubules thereby occluding or at least partially occluding the tubules.

[0198] The weight percentage of (% w / v) stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes in the compositions described herein refers to the weight of the PP-ACP or ACFP complex with stannous ions associated thereto. The weight percentage of the stannous associated PP-ACP or ACFP complexes can be calculated using the following equation:Weight percentage (% w / v) = x(0.025y + 1) where x is the initial weight percentage of PP-ACP or ACFP prior to stannous ion association,1006214354where y is the number of moles of stannous ion per mole of PP within the final stannous associated PP-ACP or ACFP complex.

[0199] The initial weight percentage of PP-ACP or ACFP prior to stannous ion association may be equal to, or greater than, about 8% w / v, about 9% w / v, about 10% w / v, about 11% w / v, about 12% w / v, about 13% w / v, about 14% w / v, about 15% w / v, about 16% w / v, about 17% w / v, about 18% w / v, about 19% w / v about 20% w / v, about 25% w / v, about 30% w / v, about 35% w / v, about 40% w / v, about 45% w / v, about 50% w / v, about 55% w / v, or about 60% w / v. Alternatively, equal to, or greater than, 8% w / v, 9% w / v, 10% w / v, 11% w / v, 12% w / v, 13% w / v, 14% w / v, 15% w / v, 16% w / v, 17% w / v, 18% w / v, 19% w / v 20% w / v, 25% w / v, 30% w / v, 35% w / v, 40% w / v, 45% w / v, 50% w / v, 55% w / v, or 60% w / v.

[0200] In any aspect or embodiment, w / v may be replaced with w / w.

[0201] The stannous containing compound, or stannous compound, can be any soluble stannous containing compound suitable for oral use. Preferably, stannous containing compound is a stannous salt. The stannous salt may contain fluoride. A stannous salt includes, but not limited to, stannous fluoride, stannous chloride, potassium stannous fluoride, sodium stannous fluorozirconate, stannous chloride fluoride, stannous acetate, sodium stannous fluoride, stannous hexafluorozirconate, stannous sulfate, stannous tartrate, stannous gluconate, disodium monostannous citrate. Preferred stannous salts include stannous fluoride and stannous chloride.

[0202] In any embodiment, two different stannous containing compounds may be used to generate the stannous associated complexes or compositions described herein. For example, stannous fluoride and stannous chloride. Stannous fluoride may be used in an amount to provide a maximum of 1100 ppm fluoride (F) or 1450 ppm F in the composition (i.e. the maximum allowable limit of fluoride ions in an over the counter toothpaste), and stannous chloride may be used to provide additional stannous ions without increasing the fluoride content of the composition, e.g. without increasing beyond 1100 or 1450 ppm F.

[0203] The stannous may be bound to the phosphopeptide stabilized amorphous calcium phosphate (AGP) and / or amorphous calcium fluoride phosphate (ACFP) as determined using the experimental protocol in Example 2. In one embodiment,1006214354stannous-associated PP stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) complex are produced by the method as described herein, including but not limited to the method described in Example 1.

[0204] In any aspect of the invention, the stannous ion content of a complex or composition of the invention may be equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP. For example, the stannous ion content may be equal to, or greater than about 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8 or 4.0 moles of stannous per mole of PP. Also contemplated is a range of stannous ion content between any 2 values of 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8 or 4.0.

[0205] In any aspect of the invention, the stannous ion content of a complex or composition of the invention may be between about 1.2 moles of stannous per mole of PP and about 2.2 moles of stannous per mole of PP. Preferably, the stannous ion content is between about 1.6 moles of stannous per mole of PP and about 2.2 moles of stannous per mole of PP. Most preferably, the stannous ion content of the complex or composition is about 2.0 moles of stannous per mole of PP.

[0206] In any aspect of the invention, the composition comprises equal to, or greater than about 90% soluble stannous. The soluble stannous may be determined by any method known to the skilled person, including atomic absorption spectrometry (AAS), for example as described in Example 3 herein. In other words, 90% of the total Sn present in the composition is soluble stannous (e.g. Sn(ll)). Alternatively, equal to or less than 10% of the Sn present in the composition is not soluble stannous. The non, or in-soluble, component may be stannic (Sn(IV)) or other Sn form.

[0207] In any aspect or embodiment, the composition comprises equal to, or greater than about 90%, equal to, or greater than about 91%, equal to, or greater than about 92%, equal to, or greater than about 93%, equal to, or greater than about 94%, equal to, or greater than about 95%, equal to, or greater than about 96%, equal to, or greater than about 97% or equal to, or greater than about 98% soluble stannous.

[0208] In any aspect or embodiment, the composition comprises equal to, or greater than 90%, equal to, or greater than 91%, equal to, or greater than 92%, equal to, or greater than 93%, equal to, or greater than 94%, equal to, or greater than 95%, equal1006214354to, or greater than 96%, equal to, or greater than 97% or equal to, or greater than 98% soluble stannous.

[0209] In any aspect or embodiment, the soluble stannous is Sn(ll).

[0210] The amount of stannous in a complex or composition may be determined by any method as described herein, or known in the art.

[0211] In one aspect, the present invention provides a method of mineralizing a dental surface or sub-surface comprising contacting the dental surface or subsurface with an about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complex as described herein, thereby mineralizing the dental surface or subsurface.

[0212] In any aspect, the present invention is applied to a dental surface of an oral site which may be dental enamel or dentine. Typically, the surface is exposed dentine which may be exposed as a result of loss of enamel or cementum. The exposed dentine is preferably causing dentinal hypersensitivity. The exposed dentine as a result of a breach of cementum may be identified by gingival recession and exposure of the root surface to the oral environment. Typically, the oral site is on a molar.

[0213] Typically, the exposed dentine contains dentinal tubules with openings greater than 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, or 2.5pm in diameter.

[0214] An individual suffering from dentinal sensitivity, preferably hypersensitivity, may be one that experiences pain when an area of a tooth is exposed to thermal or tactile stimuli. Specifically, the individual may experience pain when an area of a tooth comes into contact with cold air, hot and cold liquids, foods that are sweet or acidic, or is touched with a metal object. In any aspect, an individual may be identified for treatment by exposure to any one of these stimuli prior to treatment to determine whether they experience a pain sensation. An individual with tooth hypersensitivity may be identified as having a larger number of open dentinal tubules and / or tubules with a larger in diameter than normal, for example the individual may have, or have a greater number of, dentinal tubules with openings greater than 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, or 2.5pm in diameter.1006214354

[0215] In any aspect, the composition as described herein is applied to a periodontal pocket, preferably by injection. In preferred embodiments, the subject has received a periodontal procedure prior to application of the composition.

[0216] The words ‘treat’ or ‘treatment’ refer to therapeutic treatment wherein the object is to slow down (lessen) an undesired physiological change or disorder. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of the condition, stabilized (i.e. , not worsening) state of the condition, delay or slowing of condition progression, amelioration or palliation of the disease / condition state, and remission (whether partial or total), whether detectable or undetectable. Treatment may not necessarily result in the complete absence of detectable symptoms of the condition but may reduce or minimise complications and side effects of the condition. The success or otherwise of treatment may be monitored by physical examination of the individual or response to any thermal, tactile or chemical treatment as described herein. Preferably, the individual experiences a reduction in the severity of the pain or a reduction in the incidence of pain over time. Methods for identifying individuals having different degrees of dentinal sensitivity, and for measuring success of treatment or prevention, are described herein and also include those outlined in Med Oral Patol Oral Cir Bucal. 2008 Mar 1;13(3):E201-6. Treatment of an individual may be determined by comparing the level of pain experienced when exposed to any stimuli described herein before and after treatment, whereby a reduction in pain after treatment indicates a reduction in sensitivity.

[0217] The words ‘prevent’ and ‘prevention’ generally refer to prophylactic or preventative measures for protecting or precluding an individual not having sensitivity from progressing to sensitivity. Individuals in whom prevention may be required are those undergoing a dental procedure, particularly a dental procedure that exposes dentine. In some embodiments, the procedure is a periodontal procedure.Phosphopeptide stabilised ACP or ACFP complexes

[0218] In any aspect of the present invention, the stannous ion is provided as stannous fluoride, preferably with from about 440 ppm to about 15,000 ppm fluoride, more preferably about 1100ppm F (29mM stannous ion) or 1450 ppm F (38mM stannous ion).1006214354

[0219] In any embodiment, the stannous ion is provided as stannous fluoride with equal to, or greater than, about 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 2000, 3000, 4000, 5000 ppm, 6000 ppm, 7000 ppm, 8000 ppm, 9000 ppm, 10000 ppm, 11000 ppm, 12000 ppm, 13000 ppm, 14000 ppm or 15000 ppm.

[0220] In any embodiment, the stannous ion is provided as a stannous compound comprising equal to, or greater than, about 12, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130 mM, about 135 mM, about 140 mM, about 145 mM, about 150 mM, about 155 mM, about 160 mM, about 165 mM, about 170 mM, about 175 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM, about 260 mM, about 270 mM, about 280 mM, about 290 mM, about 300 mM, about 310 mM, about 320 mM, about 330 mM, about 340 mM, about 350 mM, about 360 mM, about 370 mM, about 380 mM or about 390mM stannous ions.

[0221] In any embodiment, the stannous ion is provided as a stannous compound comprising 12, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 190 mM, 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM, 300 mM, 310 mM, 320 mM, 330 mM, 340 mM, 350 mM, 360 mM, 370 mM, 380 mM or 390mM stannous ions.

[0222] In any embodiment, the stannous ion is provided as a stannous compound comprising from about 12 mM to about 130 mM, from about 15 mM to about 120 mM, from about 15 mM to about 110 mM, from about 15 mM to about 100 mM, from about 15 mM to about 90 mM, from about 15 mM to about 80 mM, from about 15 mM to about 70 mM, from about 15 mM to about 65 mM, from about 15 mM to about 60 mM, from about 15 mM to about 50 mM, from about 15 mM to about 40 mM, from about 15 mM to about 35 mM, from about 15 mM to about 30 mM, from about 20 mM to about 30 mM or from about 25 mM to about 30 mM stannous ions.

[0223] In any embodiment, the stannous ion is provided as a stannous compound comprising from 12 mM to 130 mM, from 15 mM to 120 mM, from 15 mM to 110 mM, from 15 mM to 100 mM, from 15 mM to 90 mM, from 15 mM to 80 mM, from 15 mM to100621435470 mM, from 15 mM to 65 mM, from 15 mM to 60 mM, from 15 mM to 50 mM, from 15 mM to 40 mM, from 15 mM to 35 mM, from 15 mM to 30 mM, from 20 mM to 30 mM or from 25 mM to 30 mM stannous ions.

[0224] In any embodiment, the stannous ion is provided as a stannous compound comprising from about 130 mM to about 390 mM, from about 150 mM to about 380 mM, from about 150 mM to about 350 mM, from about 150 mM to about 300 mM, from about 150 mM to about 280 mM, from about 150 mM to about 260 mM, from about 150 mM to about 240 mM, from about 150 mM to about 220 mM, from about 150 mM to about 200 mM, from about 155 mM to about 200 mM, from about 160 mM to about 200 mM, from about 165 mM to about 200 mM, from about 170 mM to about 200 mM, from about 170 mM to about 190 mM or from about 170 mM to about 180 mM stannous ions.

[0225] In any embodiment, the stannous ion is provided as a stannous compound comprising from 130 mM to 390 mM, from 150 mM to 380 mM, from 150 mM to 350 mM, from 150 mM to 300 mM, from 150 mM to 280 mM, from 150 mM to 260 mM, from 150 mM to 240 mM, from 150 mM to 220 mM, from 150 mM to 200 mM, from 155 mM to 200 mM, from 160 mM to 200 mM, from 165 mM to 200 mM, from 170 mM to 200 mM, from 170 mM to 190 mM or from 170 mM to 180 mM stannous ions.

[0226] In a preferred embodiment, the stannous associated phosphopeptide stabilised amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complex has tightly bound and loosely bound calcium, wherein the bound calcium in the complex is less than the tightly bound calcium in an ACP or ACFP complex formed at a pH of 7.0. Optionally, the ACP or ACFP is predominantly in a basic form.

[0227] In another aspect the invention also provides a composition including stannous associated phosphopeptide stabilized ACP or ACFP as described herein, further comprising fluoride, wherein fluoride is provided as stannous fluoride and / or sodium fluoride. Preferably, there are 2 moles of fluoride for every mole of stannous. Preferably, the composition is toothpaste or any other oral care composition as described herein.

[0228] In a preferred embodiment, the calcium ion content of the stannous associated phosphopeptide stabilised ACP or ACFP complex is in the range of about 30 to 1001006214354moles of calcium per mole of PP. More preferably, the calcium ion content is in the range of about 30 to about 50 moles of calcium per mole of PP.

[0229] In a preferred embodiment the stannous-associated phosphopeptide ACP and / or ACFP complex is in the form of a stannous-associated casein phosphopeptide stabilized ACP and / or ACFP complex.

[0230] In a preferred embodiment the phosphopeptide ACP and / or ACFP complex is in the form of a casein phosphopeptide stabilized ACP and / or ACFP complex.

[0231] In any aspect of the invention, the phosphopeptide or phosphoprotein is a casein phosphopeptide or phosphoprotein or a tryptic digest thereof.

[0232] In any aspect of the present invention, the stannous ion content above may be the stannous ion content tightly-bound to the complex (as described herein). In assessing the stannous ion content, the tightly-bound stannous ion content is measured by the methods described herein, in particular, in Example 2.

[0233] A stannous-associated PP stabilized ACP or ACFP complex as referred to herein includes a stannous-associated PP stabilized-ACP or ACFP complex formed at a pH of at, or below, 7.3. Preferably the complex is formed at a pH in the range of about 5.0 up to but below 7.3. More preferably the complex is formed at a pH range of about 4.0 to 7.3, or 5.0 to about 6.0. In one embodiment, the pH during formation is maintained at pH 7.3 or below. In a preferred embodiment, the complex is formed at a pH of about 5.5. Preferably, the ACP or ACFP in the complex is predominantly in a basic form. The stannous associated stabilized ACP or ACFP complex when produced on an industrial scale may be produced in a bulk solution that may have a pH greater than about 7.3, preferably about 9.0, however the local pH at formation of the complexes is below about 7.3, preferably about 4.0 to 6.5, preferably about 5.5.

[0234] When stannous-associated PP stabilized ACP or ACFP, or stabilized ACP or ACFP, is produced in the laboratory, in smaller quantities than commercial production the pH of the entire solution may be maintained at a given pH, i.e. if the CPP-ACP was prepared at pH 5.5, then the entire solution during CPP-ACP formation was maintained at pH 5.5. However, it may be neither necessary nor desirable to reduce the pH of the entire bulk solution in commercial manufacture to 5.5 as the only part of the bulk solution required to have the acidic pH is where the complexes are forming and the bulk1006214354solution can have, and does have, localised fluctuations in pH. The pH fluctuations arise particularly from protons provided by the phosphate compound, for example dihydrogen phosphate, as it is added and the protons liberated from acidic phosphate ions when they convert into the basic form, PO43-. Therefore, while the overall pH of the bulk solution may be at above 7.3, for example about pH 9, the localised pH at which the CPP-ACP is formed is lower, typically below 7.3 or 6.5, preferably about 4.0 to 7.3, more preferably about 5.5. These fluctuations are localised due to the size of the bulk solution.

[0235] In another aspect, the present invention provides a method or process for forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, the method or process comprising or consisting of:(i) obtaining a solution comprising at least one phosphopeptide and;(ii) admixing solutions comprising phosphopeptides, calcium ions, phosphate ions, hydroxide ions and optionally fluoride ions, while maintaining the pH at about 7.3 or below, to form a composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP; and(iii) admixing a solution comprising from about 12 mM to about 390 mM stannous ions, more preferably from about 22 mM to about 38mM, with the composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP with slow addition, mixing and maintaining the solution pH,thereby forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0236] In another aspect, the present invention provides a method or process for forming a composition comprising equal to or greater than about 8% w / v1006214354phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, the method or process comprising or consisting of:(i) obtaining a solution comprising at least one phosphopeptide and;(ii) admixing solutions comprising phosphopeptides, calcium ions, phosphate ions, hydroxide ions and optionally fluoride ions, while maintaining the pH at about 7.3 or below, to form a composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP; and(iii) admixing a solution comprising from about 12 mM to about 390 mM stannous ions, more preferably from about 22 mM to about 38mM, with the composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP with slow addition, mixing and maintaining the solution pH,thereby forming a composition comprising equal to or greater than about 8% w / v ] phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0237] In one embodiment, the solutions are added slowly at a rate of less than about 1% volume addition per minute with adequate mixing.

[0238] The hydroxide ions may be titrated into the solution to maintain the phosphopeptide solution at an essentially constant pH. The calcium and phosphate ions may be titrated into the phosphopeptide solution with constant mixing and at a rate that avoids the formation of a calcium phosphate precipitate in the phosphopeptide solution.

[0239] Preferably, the method or process does not involve any additional base or acid. For example, no hydroxide ions are added separately to the solution comprising calcium ions, phosphate ions or stannous compound.

[0240] In another aspect, the present invention provides a method or process for forming a composition comprising equal to or greater than about 8% w / v stannous1006214354associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, the method or process comprising or consisting of:(i) providing a comprising comprising equal to or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP; and(ii) admixing a solution comprising from about 12 mM to about 390 mM stannous ions, more preferably from about 22 mM to about 38mM, with the composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP with slow addition, mixing and maintaining the solution pH,thereby forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0241] In another aspect, the present invention provides a method or process for forming a composition comprising equal to or greater than about 8% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the composition has a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, the method or process comprising or consisting of:(i) providing a comprising comprising equal to or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP; and(ii) admixing a solution comprising from about 12 mM to about 390 mM stannous ions, more preferably from about 22 mM to about 38mM, with the composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP with slow addition, mixing and maintaining the solution pH,thereby forming a composition comprising equal to or greater than about 8% w / v phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous1006214354calcium fluoride phosphate (ACFP) complexes wherein the composition have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

[0242] In another aspect, the present invention provides a composition obtained or obtainable by a method or process described herein.

[0243] A stannous-associated PP stabilized ACP of the invention may be produced by a method comprising the step of admixing CPP-ACP and a stannous compound in an aqueous solution, while maintaining the pH at about 7.3 or below.

[0244] A stannous-associated PP stabilized ACFP of the invention may be produced by a method comprising the step of admixing CPP-ACFP and a stannous compound in an aqueous solution, while maintaining the pH at about 7.3 or below.

[0245] A stannous-associated PP stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) complex of the invention may be formed by mixing stabilized PP amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) complex with stannous fluoride.

[0246] In any method described herein for producing a stannous-associated PP stabilized amorphous calcium phosphate (ACP) and / or amorphous calcium fluoride phosphate (ACFP) complex or composition, the amount of stannous compound, preferably stannous fluoride, may be greater than or equal to about 12 mM to about 390 mM stannous ions. When stannous fluoride is used, preferably the stannous fluoride comprises 440 ppm to 15000 ppm F, more preferably 1100 ppm or 1450 ppm F.

[0247] A stannous-associated PP stabilized-ACP or ACFP complex as described in the current specification may have the form of a “closed” complex are shown in Figure 2 of Cross et al., 2007. Current Pharmaceutical Design, 13, 793-800.

[0248] A composition comprising a stannous-associated PP stabilized ACP and / or ACFP complex may further include at least an equal amount by weight of calcium phosphate. Preferably the calcium phosphate is CaHPCU. Preferably, the calcium phosphate (e.g. CaHPO4) is dry blended with the PP stabilized ACP and / or ACFP complex. In a preferred embodiment, the PP-ACP and / or PP-ACFP complex: calcium phosphate ratio is about 1:1-50. more preferably about 1: 1-25, more preferably about10062143541:5-15. In one embodiment, the PP-ACP and / or PP-ACFP complex: calcium phosphate ratio is about 1:10.

[0249] Preferably, the form of calcium phosphate for dry blending is any soluble calcium phosphate including, but not limited to, CaHPC , Ca2HPC>4 and calcium lactate.

[0250] A composition as described herein may further include free fluoride ions. The fluoride ions may be from any suitable source. A source of fluoride ions may include free fluoride ions or fluoride salts. Examples of sources of fluoride ions include, but are not limited to the following: sodium fluoride, sodium monofluorophosphate, stannous fluoride, sodium silicofluoride and amine fluoride. These may be provided in solution (typically an aqueous solution), or a suspension.

[0251] The fluoride ions are preferably present in the composition in an amount greater than 1 ppm. More preferably, the amount is more than 3 ppm. In another embodiment, it is preferably more than 10 ppm. In typical embodiments described below, the amount may be 100 ppm to 5,000 ppm, preferably 400ppm to 3000ppm, preferably from 1100 ppm to 1450 ppm. The fluoride content is typically measured as a ppm in oral compositions in the manner commonly used in the art. Where the fluoride is provided from a source with the stabilized ACP, the ppm refers to the concentration of the fluoride in that source, typically a solution or suspension of bioavailable fluoride.

[0252] In other embodiments, the composition does not include free fluoride.

[0253] A composition as described herein may not include polyphosphates, citrates and citric acids. Preferably, the composition does not includealpha-hydroxycarboxylates and polycarboxylates that chelate calcium, including any one or more of citrate, citric acid, tartrate, tartaric acid, lactate, lactic acid, gluconate, and pyrophosphate or polyphosphate salts. In one embodiment, the composition does not include any one or more of a citrate, citric acid, pyrophosphate, polyphosphate, tartrate, gluconate and calcium chelator.

[0254] “Phosphopeptide” in the context of the description of this invention means an amino acid sequence in which at least one amino acid is phosphorylated. Preferably, the phosphopeptide includes one or more of the amino acid sequence -A-B-C-, where A is a phosphoamino residue, B is any amino acyl residue including a phosphoamino residue and C is selected from a glutamyl, aspartyl or phosphoamino residue. Any of1006214354the phosphoamino residues may independently be a phosphoseryl residue. B is desirably a residue the side-chain of which is neither relatively large nor hydrophobic. It may be Gly, Ala, Vai, Met, Leu, lie, Ser, Thr, Cys, Asp, Glu, Asn, Gin or Lys.

[0255] In another embodiment, at least two of the phosphoamino acids in the sequence are preferably contiguous. Preferably the phosphopeptide includes the sequence A-B-C-D-E, where A, B, C, D and E are independently phosphoserine, phosphothreonine, phosphotyrosine, phosphohistidine, glutamic acid or aspartic acid, and at least two, preferably three, of the A, B, C, D and E are a phosphoamino acid. In a preferred embodiment, the phosphoamino acid residues are phosphoserine, most preferably three contiguous phosphoserine residues. It is also preferred that D and E are independently glutamic or aspartic acid.

[0256] In one embodiment, the AGP or ACFP is stabilized by a casein phosphopeptide (GPP), which is in the form of intact casein or fragment of the casein, and the complex formed preferably has the formula [CPP(ACP)8]n or [(CPP)(ACFP)8]n where n is equal to or greater than 1 , for example 6. The complex formed may be a colloidal complex, where the core particles aggregate to form large (eg 100 nm) colloidal particles suspended in water. Thus, the PP can be a casein protein or a phosphopeptide.

[0257] The PP may be from any source; it may be present in the context of a larger polypeptide, including a full length casein polypeptide, or it may be isolated by tryptic or other enzymatic or chemical digestion of casein, or other phosphoamino acid rich proteins such as phosvitin, osteopontin or by chemical or recombinant synthesis, provided that it comprises the sequence -A-B-C- or A-B-C-D-E as described above. The sequence flanking this core sequence may be any sequence. However, those flanking sequences in asi(5979), P(1 -25), aS2(46-70) and aS2(1-21) are preferred. The flanking sequences may optionally be modified by deletion, addition or conservative substitution of one or more residues. The amino acid composition and sequence of the flanking region are not critical. Preferably, the PP is obtained from a food source, e.g phosvitin from eggs, osteopontin from milk, or any chemical or recombinantly synthesised PP comprising the sequence -A-B-C-.

[0258] In one embodiment, the ACP or ACFP is stabilized by a casein phosphopeptide (GPP), osteopontin phosphopeptide (OPN-PP), phosvitin1006214354phosphopeptide (PPP) or a chemical or recombinantly synthesised PP comprising the sequence -A-B-C- as described above. Preferably the ACP or ACFP is stabilized by casein phosphopeptide (CPP).

[0259] Examples of conservative substitutions are shown in Table A below.

[0260] Table A

[0261] The flanking sequences may also include non-naturally occurring amino acid residues. Commonly encountered amino acids which are not encoded by the genetic code, include:2-amino-4-phosphonobutyric acid for Phosphoserine [Ser(P)];2-amino adipic acid (Aad) for Glu and Asp;2-aminopimelic acid (Apm) for Glu and Asp;2-aminobutyric (Abu) acid for Met, Leu, and other aliphatic amino acids;2-aminoheptanoic acid (Ahe) for Met, Leu and other aliphatic amino acids;2-aminoisobutyric acid (Aib) for Gly;cyclohexylalanine (Cha) for Vai, and Leu and lie;1006214354homoarginine (Har) for Arg and Lys;2, 3-diaminopropionic acid (Dpr) for Lys, Arg and His;N-ethylglycine (EtGly) for Gly, Pro, and Ala;N-ethylasparigine (EtAsn) for Asn, and Gin;Hydroxyllysine (Hyl) for Lys;allohydroxyllysine (AHyl) for Lys;3-(and 4) hydroxyproline (3Hyp, 4Hyp) for Pro, Ser, and Thr;alloisoleucine (Alle) for lie, Leu, and Vai;p-amidinophenylalanine for Ala;N-methylglycine (MeGly, sarcosine) for Gly, Pro, Ala.N-methylisoleucine (Melle) for lie;Norvaline (Nva) for Met and other aliphatic amino acids;Norleucine (Nle) for Met and other aliphatic amino acids;Ornithine (Orn) for Lys, Arg and His;Citrulline (Cit) and methionine sulfoxide (MSO) for Thr, Asn and Gin;N-methylphenylalanine (MePhe), trimethylphenylalanine, halo (F, Cl, Brand I) phenylalanine, triflourylphenylalanine, for Phe.

[0262] In one embodiment, the PP is one or more phosphopeptides selected from the group consisting of asi(59-79) [1], P(1-25) [2], aS2(46-70) [3] and aS2(1-21) [4]:[1] Gln59-Met-Glu-Ala-Glu-Ser(P)-lle-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-lle-Val-Pro-Asn-Ser(P)-Val-Glu-Gln-Lys79asi(59-79) (SEQ ID NO: 1)[2] Arg1-Glu-Leu-Glu-Glu-Leu-Asn-Val-Pro-Gly-Glu-lle-Val-Glu-Ser(P)-Leu- Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-lle-Thr-Arg25p(1-25) (SEQ ID NO: 2)1006214354[3] Asn46-Ala-Asn-Glu-Glu-Glu-Tyr-Ser-lle-Gly-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser(P)-Ala-Glu-Val-Ala-Thr-Glu-Glu-Val-Lys70as2(46-70) (SEQ ID NO: 3)[4] Lys1-Asn-Thr-Met-Glu-His-Val-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-lle-lle-Ser(P)-Gln-Glu-Thr-Tyr-Lys21as2(1-21) (SEQ ID NO: 4).Porphyromonas gingivalis

[0263] In another aspect of the invention, the present invention provides methods for reducing or minimising the severity of a symptom associated with an infection with P. gingivalis; treating or preventing a P. gingivalis infection; and treating or preventing a P. gingivalis related disease.

[0264] P. gingivalis has been described as a keystone pathogen as it dysregulates the host immune response to favour the polymicrobial biofilm disrupting homeostasis to cause dysbiosis and disease. The level of P. gingivalis in subgingival plaque above threshold levels (-10% of total bacterial cell load) has been demonstrated to predict imminent clinical attachment loss (disease progression) in humans. P. gingivalis is found as microcolonies in the superficial layers of subgingival plaque adjacent to the periodontal pocket epithelium which helps explain the strong association with underlying tissue inflammation and disease at relatively low proportions (10%) of the total bacterial cell load of the plaque. The mouse periodontitis model has been used to show that inflammation is essential to allow establishment of P. gingivalis at the levels in plaque (10% or greater of total bacterial cell load) necessary to produce dysbiosis and disease.

[0265] A P. gingivalis infection is an infection that is characterised by invasion or contamination of tissues or cells by P. gingivalis. A P. gingivalis infection may have clinical or subclinical manifestations including acute or chronic inflammation of the gingiva. The hallmarks of acute inflammation may be present including an increased movement of plasma and leukocytes from the blood into the injured tissues. Clinical signs of acute infection of the gingiva may also be present including rubor (redness), calor (increased heat), tumor (swelling), dolor (pain), and functio laesa (loss of function). Chronic inflammation may be characterised by leukocyte cell (monocytes, macrophages, lymphocytes, plasma cells) infiltration. Tissue and bone loss may be observed. A P. gingivalis infection may also be characterised by an increased level of P.1006214354gingivalis bacteria above a normal range observed in individuals without a P. gingivalis infection. In these circumstances the P. gingivalis are part of a subgingival biofilm which provides a source of P. gingivalis bacteria that invades or contaminates surrounding tissues and cells. The P. gingivalis infection may be an abscess.

[0266] A “P. gingivalis infection” in an individual or an individual “infected with a P. gingivalis" generally refers to:(1) an elevated level of P. gingivalis in a sample taken from the individual compared to an uninfected control sample;(2) an increased proportion of P. gingivalis bacteria in a sample taken from the individual compared to the total level of bacteria in an uninfected control sample, for example above about 10% of the total levels of bacteria in subgingival plaque;(3) an increased proportion of P. gingivalis bacteria relative to one or more other bacteria species in a sample taken from the individual when compared to an uninfected control sample; or(4) the presence of P. gingivalis bacteria in a sample compared to an uninfected control sample when P. gingivalis is undetectable in the uninfected control.

[0267] An individual with high levels of P. ginigivalis present in their saliva or in subgingival plaques may also present with severe forms of periodontal disease characterised by spontaneously bleeding gums, deep (> 6 mm) periodontal pockets around the teeth and substantial periodontal tissue attachment loss around the teeth (> 6 mm).Oral compositions

[0268] In another embodiment of the invention, the stannous-associated PP stabilized AGP and / or stannous-associated PP stabilized ACFP complex or compositions of the invention are incorporated into oral compositions such as toothpaste, mouth washes or formulations for the mouth to aid in the prevention and / or treatment of P. gingivalis related infections, conditions or disease; the promotion of mineralisation of dentine or enamel; and the treatment or prevention of dentinal hypersensitivity.1006214354

[0269] The oral composition of this invention which contains a complex or composition of the invention may be prepared and used in various forms applicable to the mouth such as dentifrice including toothpastes, toothpowders and liquid dentifrices, mouthwashes, mouthrinses, mouth sprays, varnish, dental cement, troches, chewing gums, dental pastes, gingival massage creams, gargle tablets, dairy products and other foodstuffs including yoghurt. The oral composition according to this invention may further include additional well known ingredients depending on the type and form of a particular oral composition. Certain compositions of the invention such as toothpastes, toothpowders and liquid dentifrices, mouthwashes, mouthrinses and mouth sprays have relatively low viscosity.

[0270] A dentifrice or paste for localized application to a sensitive tooth site such as breached cementum of an orally exposed root surface may be one that is applied with a soft applicator. Such a dentifrice or paste may or may not contain conventional abrasive, foaming agent, and flavoring agents.

[0271] In certain preferred forms of the invention an oral composition may be substantially liquid in character, such as a mouthwash, rinse or spray. In such a preparation the vehicle is typically a water-alcohol mixture desirably including a humectant as described below. Generally, the weight ratio of water to alcohol is in the range of from about 1 : 1 to about 20: 1. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70 to about 99.9% by weight of the preparation. The alcohol is typically ethanol or isopropanol. Ethanol is preferred.

[0272] In other desirable forms of this invention, the composition may be substantially solid or pasty in character, such as toothpowder, a dental tablet or a toothpaste (dental cream) or gel dentifrice. The vehicle of such solid or pasty oral preparations generally contains dentally acceptable polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, hydrated alumina, calcined alumina, aluminium silicate, zirconium silicate, silica, bentonite, and mixtures thereof. Other suitable polishing material include the particulate thermosetting resins such as melamine-, phenolic, and urea-formaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include crystalline silica having particle sizes of up to about 5 microns, a mean particle size of1006214354up to about 1.1 microns, and a surface area of up to about 50,000 cm2 / g., silica gel or colloidal silica, and complex amorphous alkali metal aluminosilicate.

[0273] When visually clear gels are employed, a polishing agent of colloidal silica, such as those sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100, alkali metal aluminosilicate complexes are particularly useful since they have refractive indices close to the refractive indices of gelling agent-liquid (including water and / or humectant) systems commonly used in dentifrices.

[0274] Many of the so-called "water insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner, for example as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit only a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates (IMP). There is present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 4% by weight. The amount of soluble phosphate material, which is believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate, may be reduced or eliminated by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than 1% of the material is larger than 37 microns.

[0275] The polishing material is generally present in the solid or pasty compositions in weight concentrations of about 10% to about 99%. Preferably, it is present in amounts from about 10% to about 75% in toothpaste, and from about 70% to about 99% in toothpowder. In toothpastes, when the polishing material is silicious in nature, it is generally present in an amount of about 10-30% by weight. Other polishing materials are typically present in amount of about 30-75% by weight.

[0276] In a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from about 10% to about 80% by weight of the preparation.Glycerine, propylene glycol, sorbitol and polypropylene glycol exemplify suitable humectants / carriers. Also advantageous are liquid mixtures of water, glycerine and1006214354sorbitol. In clear gels where the refractive index is an important consideration, about 2.5 - 30% w / w of water, 0 to about 70% w / w of glycerine and about 20-80% w / w of sorbitol are preferably employed.

[0277] Toothpaste, creams and gels typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10, preferably about 0.5 to about 5% w / w. A suitable thickener is synthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex clay available for example as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D is, approximately by weight 58.00% SiO2, 25.40% MgO, 3.05% Na2O, 0.98% Li2O, and some water and trace metals. Its true specific gravity is 2.53 and it has an apparent bulk density of 1.0 g / ml at 8% moisture.

[0278] Other suitable thickeners include Irish moss, iota carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as Natrosol), sodium carboxymethyl cellulose, and colloidal silica such as finely ground Syloid (e.g. 244). Solubilizing agents may also be included such as humectant polyols such propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters such as amyl acetate, ethyl acetate and benzyl benzoate.

[0279] It will be understood that, as is conventional, the oral preparations will usually be sold or otherwise distributed in suitable labelled packages. Thus, ajar of mouth rinse will have a label describing it, in substance, as a mouth rinse or mouthwash and having directions for its use; and a toothpaste, cream or gel will usually be in a collapsible tube, typically aluminium, lined lead or plastic, or other squeeze, pump or pressurized dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste, gel or dental cream.

[0280] Organic surface-active agents may be used in the compositions of the present invention to achieve increased prophylactic action, assist in achieving thorough and complete dispersion of the active agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organic surface-active material is preferably anionic, non-ionic or ampholytic in nature and preferably does not interact1006214354with the active agent. It is preferred to employ as the surface-active agent a detersive material which imparts to the composition detersive and foaming properties. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkylsulfo-acetates, higher fatty acid esters of 1,2-dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material. The use of these sarconite compounds in the oral compositions of the present invention is particularly advantageous since these materials exhibit a prolonged marked effect in the inhibition of acid formation in the oral cavity due to carbohydrates breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions. Examples of water-soluble non-ionic surfactants suitable for use are condensation products of ethylene oxide with various reactive hydrogencontaining compounds reactive therewith having long hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbon atoms), which condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monostearate) and polypropyleneoxide (e.g. Pluronic materials).

[0281] The surface active agent is typically present in amount of about 0.1-5% by weight. It is noteworthy, that the surface active agent may assist in the dissolving of the active agent of the invention and thereby diminish the amount of solubilizing humectant needed.

[0282] Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds and / or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired.1006214354

[0283] Any suitable flavouring or sweetening material may also be employed.Examples of suitable flavouring constituents are flavouring oils, e.g. oil of spearmint, peppermint, Wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), saccharine, and the like. Suitably, flavour and sweetening agents may each or together comprise from about 0.1% to 5% more of the preparation.

[0284] The compositions of this invention can also be incorporated in lozenges, or in chewing gum or other products, e.g. by stirring into a warm gum base or coating the outer surface of a gum base, illustrative of which are jelutong, rubber latex, vinylite resins, etc., desirably with conventional plasticizers or softeners, sugar or other sweeteners or such as glucose, sorbitol and the like. The composition of the invention may be a dual phase composition wherein each phase permits release of components over different time periods. For example, in use a dual phase composition may release stannous-associated stabilized ACP and / or stannous-associated stabilized ACFP, preferably CPP-ACP / SnF2 and / or CPP-ACFP / SnF2, from a first phase at a faster rate than a compound that is capable of increasing or maintaining the pH of a solution from a second phase. Preferably, the dual phase composition is a dual phase chewing gum.

[0285] An alternative composition may be one that provides phosphopeptide stabilized ACP or ACFP and a stannous compound that then in situ, such as the oral cavity, forms stannous-associated phosphopeptide stabilized ACP or ACFP complexes of the invention. An exemplary composition may be a chewing gum that contains stabilized ACP or ACFP in the pellet and a stannous compound in the centre chew.

[0286] Compositions of the invention may be in the form of a gel, liquid, solid, powder, cream or lozenge. Therapeutic compositions may also be in the form of tablets or capsules. In one embodiment, the stannous-associated PP stabilized ACP or ACFP complexes of the invention are substantially the only active components of such a composition. For example, a creme formulation may be employed containing: water; glycerol; complex of the invention; D-sorbitol; silicon dioxide; sodium carboxymethylcellulose (CMC-Na); propylene glycol; titanium dioxide; xylitol; phosphoric acid; guar gum; zinc oxide; sodium saccharin; ethyl p-hydroxybenzoate; magnesium oxide; butyl p hydroxybenzoate and propyl p-hydroxybenzoate.1006214354

[0287] The invention further includes a formulation described above provided together with instructions for its use for the prevention and / or treatment of P. gingivalis related conditions or disease, the promotion of mineralisation of dentine or enamel, and the treatment or prevention of dentinal hypersensitivity.

[0288] In another embodiment, the compositions of the invention as described herein do not include a phosphate buffer and / or a calcium chelator. For example, any dentifrice described herein may not include a phosphate buffer and / or a calcium chelator.

[0289] In an embodiment of the present invention there is provided a composition for treating or preventing dentinal hypersensitivity comprising administering a stannous-associated PP stabilized ACP and / or ACFP complex or composition of the invention, wherein the composition does not include a phosphate buffer and / or calcium chelator.

[0290] In another embodiment, the compositions of the invention as described herein do not include a viscosity regulator, or a viscosity regulator at 0.5 to 50%.

[0291] In another embodiment, the compositions of the invention as described herein do not include sodium carboxymethylcellulose, or 0.01 to 10% sodium carboxymethylcellulose having the esterification degree of 0.7 to 1.0.

[0292] In one embodiment, the active components of the composition consist essentially of the stannous-associated PP stabilized ACP or ACFP complexes of the invention.

[0293] It will be clearly understood that, although this specification refers specifically to applications in humans, the invention is also useful for veterinary purposes. Thus in all aspects the invention is useful for domestic animals such as cattle, sheep, horses and poultry; for companion animals such as cats and dogs; and for zoo animals.

[0294] The invention also provides a kit comprising a composition as described herein said kit being adapted for use in the above described methods.

[0295] The kit may include:- a container holding a composition as described herein; and- a label or package insert with instructions for use.1006214354

[0296] In certain embodiments the kit may contain one or more further active principles or ingredients for treatment of a disease or condition.

[0297] The kit may comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a therapeutic composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the therapeutic composition is used for treating the condition of choice. In one embodiment, the label or package insert includes instructions for use and indicates that the therapeutic composition can be used for treatment of the given disease or condition.

[0298] The kit may comprise (a) a therapeutic composition; and (b) a second container with a second active principle or ingredient contained therein. The kit in this embodiment of the invention may further comprise a package insert indicating that the composition and other active principle can be used to treat a disorder or condition as described herein or prevent a complication stemming from dysbiosis. Alternatively, or additionally, the kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0299] The invention will now be further described with reference to the following nonlimiting examples.

[0300] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.ExamplesExample 1 - Preparation of stannous associated casein phosphopeptide stabilised ACP complexes (Sn2+-CPP-ACP)1006214354

[0301] Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) was acquired from Cadbury Enterprises Pte Ltd under the trademark name Recaldent™. Solutions were prepared using CPP-ACP and SnF2 to produce each of the following stannous associated PP stabilized ACP complexes:- 4% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 4.5:1), forming 4.45% w / v Sn-CPP-ACP complexes;- 8% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 2.2:1), forming 8.44% w / v Sn-CPP-ACP complexes;- 10% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 1.8:1), forming 10.45% w / v Sn-CPP-ACP complexes; and- 20% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 0.9:1), forming 20.45% w / v Sn-CPP-ACP complexes.

[0302] Specifically, the CPP-ACP / SnF2 complexes were prepared by first adding CPP-ACP to distilled / deionised water and then SnF2 (solid or cone solution) added slowly at a rate of <10% SnF2 volume addition per minute. If the pH needed adjustment it would be adjusted by the addition of 1 M HCI or 1M NaOH to maintain the pH between 4.0 - 7.3. The pH was not allowed to go above 7.3.

[0303] The total volume of acid / base added was less than 1 % of the CPP-ACP / SnF2 solution volume. The final solution contained stannous associated CPP stabilized ACP complexes.

[0304] These steps are required to permit substantive dissociation of the SnF2, prevent oxidation of stannous ions to stannic ions which leads to undesirable precipitation, and ultimately making the stannous ions available for association with the CPP-ACP / ACFP complexes.Example 2 - Ion analysis

[0305] The following is a protocol for CPP stabilized ACP / SnF2 solution ion analysis. Total (tightly & loosely-bound) and loosely-bound samples were prepared as follows:

[0306] Total (tightly and loosely-bound): One ml of any treatment solution 2) to 4) as shown in Example 3 solution can be taken and placed into 19 ml of 1M HNO3 and1006214354incubated at room temperature with constant slow end over end mixing for 24 hrs (20 rpm). The mixture is centrifuged at 1000g for 15 minutes at room temperature. The supernatant is analyzed for calcium, stannous, phosphate and fluoride.

[0307] Loosely-bound: A sample of the same solution as for the ‘total’ analysis immediately above is taken and placed in a centricon with a 1000 MWCO filter and centrifuged at 3000g for 1hour at room temperature to produce enough filtrate ( <10% of total sample to not affect equilibrium) for analysis by atomic absorption spectrophotometry (AAS) and ion chromatography (IC). The filtrates are then measured to give loosely-bound ions.

[0308] The total and loosely bound calcium, stannous, phosphate and fluoride in the solution are determined by ion chromatography (for fluoride and phosphate) and Atomic Absorption Spectrometry (for calcium and stannous).

[0309] CPP tightly-bound (colloidal retentate) ions are calculated from the difference between Total and loosely-bound (as explained above).Example 3 - Inhibition of P. gingivalis by CPP-ACP / SnF2 by different Sn / CPP molar ratios

[0310] P. gingivalis (W50 and ATCC33277) bacterial culture (OD650 ~ 1.0) spread on the horse blood agar (HBA) plates for inhibition tests was prepared by anaerobically growing P. gingivalis W50 in heart infusion broth supplemented with 0.5 mg / mL cysteine and 5.0 ug / mL hemin which had been inoculated with 5% (v / v) starter culture (OD650 ~ 0.9). After a 150 pL volume of P. gingivalis W50 culture was spread on a Horse Blood Agar plate, wells were made in the agar and the followings samples (80 pL) were added to the wells, one sample per well.1) 0% CPP-ACP + 1100 ppm F as SnF2 (negative control)2) 4% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 4.5:1), forming 4.45% w / v Sn-CPP-ACP complexes;3) 8% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 2.2:1), forming 8.44% w / v Sn-CPP-ACP complexes;10062143544) 10% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 1.8:1), forming 10.45% w / v Sn-CPP-ACP complexes; and5) 20% CPP-ACP + 1100 ppm F as SnF2 (Sn:CPP molar ratio 0.9:1). forming 20.45% w / v Sn-CPP-ACP complexes.

[0311] pH of each sample was 7.0, adjusted with HCI or NaOH where necessary. The amount of soluble ions present in the sample is provided in the table below.

[0312] Table 1. Soluble ion in the sample at pH 7.0CPP-ACP Soluble Sn Soluble Sn J., ,o / . . ... / o / . Moot.aalrSrant / CioPP(w / v%) (mM) (%)0 0.2 0.94 23.6 81.54 58 27.4 94.82 210 27.5 95.11 820 27.7 95.80 9

[0313] Soluble Sn2+ in the samples at pH 7.0 was determined with atomic absorption spectrometry (AAS. flame source: N2O / acetylene). The total added stannous ions (29 mM) was confirmed by AAS and used for calculations of the ratios of soluble form to total Sn2+.

[0314] Bacteria on the agar was then allowed to grow in anaerobic chamber at 37°C, inspected visually every day. Day 6 images are presented (Figure 1).

[0315] As is shown in Figure 1 the zone of inhibition (white arrow) is greatest for 8-10% CPP-ACP and 29mM SnF2 with a molar ratio of 1.8 - 2.2 (8.44-10.45% w / v Sn-CPP-ACP complexes). Interestingly, the effect observed is not simply related to solubility as the 20% CPP-ACP / SnF2 showed maximum Sn(ll) solubility but inhibition was less than 10% CPP-ACP / SnF2. The molar ratio has been shown to be important as well for example with the 10% CPP-ACP / SnF2 where the ratio is closer to 2.0.1006214354

[0316] Figure 7 also shows the zone of inhibition with 29 mM SnF2 alone and 10% CPP-ACP / SnF229 mM (1100 ppm F). 10% CPP-ACP significantly (P<0.001) increased the solubility of Sn ions at pH 7.0 from 0.1 ± 0.1 mM Sn (0.1% soluble Sn / total; 29mM SnF2 alone) to 26.3 ± 1.5 mM Sn (91% soluble Sn / total) and produced a defined clear zone of growth inhibition on the blood agar plate (Figure 7; zone of growth inhibition shown with white arrow).Example 4 - Inhibition of P. gingivalis by CPP-ACP only

[0317] Horse blood agar plates with P. gingivalis cultures were prepared as described in Example 3. In brief, after a 150 pL volume of P. gingivalis W50 culture was spread on a Horse Blood Agar plate, wells were made in the agar and the followings samples (80 pL) were added to the wells, one sample per well.1) 10% CPP-ACP + 1100 ppm F as SnF2 (positive control)2) 4% CPP-ACP3) 8% CPP-ACP4) 10% CPP-ACP; and5) 20% CPP-ACP.

[0318] As shown in Figure 2, CPP-ACP alone at any concentration did not produce a visible zone of inhibition. The results of Example 3 and 4 indicates that a CPP-ACP / SnF2 complex at the molar ratio of about 1.8 - 2.2 Sn / CPP provides for synergistic inhibition of P gingivalis.Example 5 - Enamel and dentine remineralisation by two SnF2-containing formulations in a blinded, randomized, crossover in situ caries model

[0319] This experiment compares Colgate’s TotalSFformulation comprising 1100 ppm as SnF2 with a 10% stannous-associated CPP-ACP complex of the present invention (prepared as 10% CPP-ACP + 1100 ppm F as SnF2; referred to in this Example as TM Pro).

[0320] Participants wore palatal appliances containing 4 x enamel and 2 x dentine slabs with demineralised subsurface lesions for 14 consecutive days in each of the1006214354treatment periods. Each treatment consisted of a 1 min rinse with 5 ml of suspension (1g of dentifrice suspended in 4 ml Milli Q water) four times per day (after each meal and before retiring at night), for 14 consecutive days. Participants crossed over to each randomly assigned treatment after one week washout period.

[0321] At the completion of each treatment:- Post-rinse saliva samples collected- Enamel and dentine slabso Paired with their respective demineralised controlo Embedded, sectioned, microhardness testedo Transverse microradiography (TMR)o Electron probe microanalysis.

[0322] Analyses:- Level of remineralisation (R%: TMR)- Surface microhardness recovery (%SMHR)- Calcium, tin, inorganic phosphate and fluoride levels measured in post- rinse / saliva samples using AAS and ion chromatography- Linear Mixed Model with sequence, period and treatment included as fixed factors and participant as a random factor within sequence.

[0323] TM Pro significantly increased enamel remineralisation, dentine remineraliation and enamel surface microhardness recovery (5) compared to Colgate TotalSF(Figures 3 and 4).

[0324] TM Pro treatment also resulted in significantly high bioavailability of Calcium, tin, inorganic phosphate and fluoride levels in the oral cavity of participants post-rinse, compared to Colgate TotalSF(Figures 5 and 6).

[0325] Together these results indicate that 10% stannous associated phosphopeptide stabilised PP ACP complexes are capable of promoting significantly higher levels of1006214354enamel and dentine remineralisation and enamel surface microhardness recovery compared to the gold standard stannous containing dentrifice on the market.Example 6 - Self-assembly of a nanofilament network on dentine by SnF2 / CPP-ACP

[0326] SnF2 / CPP-ACP complexes are capable of self-assembly of a nanofilament network on dentine that occludes exposed dentine tubules thereby reducing dentinal hypersensitivity.

[0327] The hydrodynamic theory of dental hypersensitivity indicates restriction of fluid movement through dentine tubules can result in a clinical reduction of hypersensitivity. Here the inventor describes a method for combining CPP-ACP and SnF2 to test for the occlusion of tubules of surface dentine using scanning electron microscopy (SEM).

[0328] Extracted human third molars will be sectioned to create coronal discs approximately 1 mm thick. The discs will be covered with acid resistant nail varnish to expose a window of central dentine and will then be submerged in 15% EDTA for 2 minutes to remove the smear layer. Discs will be randomly allocated to treatment groups and will be exposed to the treatment for 20 min.

[0329] The discs will then be dehydrated and sputtered with gold for examination under SEM.Example 7 - High concentration Sn-CPP-ACP complexes

[0330] A composition comprising 62.7% Sn-CPP-ACP complexes (Sn:CPP molar ratio 1.8:1) was prepared by mixing 60% CPP-ACP and 176mM SnF2 (approximately 6700 ppm fluoride) following the method described in Example 1.

[0331] The composition comprising 62.7% Sn-CPP-ACFP complexes will be applied to tooth enamel or dentine (e.g. painted on) to promote remineralisation and / or treat dentinal hypersensitivity. The composition will be also be injected into a periodontal pocket to treat a tooth root surface in a subject following periodontal treatment.1006214354

Claims

CLAIMS1. A composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

2. The composition of claim 1, wherein the composition comprises equal to, or greater than, about 9% w / v; equal to, or greater than, about 10% w / v; equal to, or greater than, about 11% w / v; equal to, or greater than, about 12% w / v; equal to, or greater than, about 13% w / v; equal to, or greater than, about 14% w / v; equal to, or greater than, about 15% w / v; equal to, or greater than, about 16% w / v; equal to, or greater than, about 17% w / v; equal to, or greater than, about 18% w / v; equal to, or greater than, about 19% w / v; equal to, or greater than, about 20% w / v; equal to, or greater than, about 21% w / v; equal to, or greater than, about 22% w / v; equal to, or greater than, about 25% w / v; equal to, or greater than, about 30% w / v; equal to, or greater than, about 35% w / v; equal to, or greater than, about 40% w / v; equal to, or greater than, about 45% w / v; equal to, or greater than, about 50% w / v; equal to, or greater than, about 55% w / v; equal to, or greater than, about 60% w / v; equal to, or greater than, about 65% w / v; or equal to, or greater than, about 70% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

3. The composition of claim 1 or 2, wherein composition comprises the stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes, wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, in an amount of from about 8% w / v to about 70% w / v; from about 9% w / v to about 70% w / v; from about 10% w / v to about 70% w / v; from about 11% w / v to about 70% w / v; from about 12% w / v to about 70% w / v; from about 13% w / v to about 70% w / v; from about 14% w / v to about 70% w / v; from about 15% w / v to about 70% w / v; from about 16% to about 70% w / v; from about 17% w / v to about 70% w / v; from about 18% w / v to about 70% w / v; from about 19% w / v1006214354to about 70% w / v; from about 20% w / v to about 70% w / v; from about 21 % w / v to about 70% w / v; from about 25% w / v to about 70% w / v; from about 30% w / v to about 70% w / v; from about 35% w / v to about 70% w / v; from about 45% w / v to about 70% w / v; from about 50% w / v to about 70% w / v; from about 55% w / v to about 70% w / v; from about 60% w / v to about 70% w / v; or from about 60% w / v to about 65% w / v.

4. The composition of any one of claims 1 to 3, wherein the complexes have a stannous ion content of equal to, or greater than about 1.0, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 moles of stannous per mole of PP.

5. The composition of any one of claims 1 to 4, wherein the composition further includes a pharmaceutically acceptable carrier, diluent or excipient.

6. The composition of any one of claims 1 to 5, wherein the composition further comprises fluoride, preferably the fluoride is provided as stannous fluoride and / or sodium fluoride.

7. The composition of claim 6, wherein the composition comprises from about 480 ppm to about 15000 ppm fluoride, preferably about 1100 ppm or about 1450 ppm fluoride.

8. The composition of any one of claims 1 to 7, wherein the stannous associated phosphopeptide stabilized ACP and / or ACFP complex comprises stannous ions that remain associated with the complex after centrifugation in a 1000 molecular weight cut off filter at about 3000g for 1 hour at room temperature.

9. The composition of any one of claims 1 to 8, wherein the phosphopeptide is selected from casein phosphopeptide, phosvitin phosphopeptide, osteoponin phosphopeptide and a chemical or recombinantly synthesised phosphopeptide comprising the sequence -A-B-C-, where A is a phosphoamino residue, B is any amino acyl residue including a phosphoamino residue and C is selected from a glutamyl, aspartyl or phosphoamino residue.100621435410. The composition of any one of claims 1 to 9, wherein the phosphopeptide is a casein phosphopeptide.

11. The composition of any one of claims 1 to 10, wherein the composition is a dentifrice, including a toothpaste, a toothpowder or a liquid dentifrice, a mouthwash, a mouthrinse, a mouth spray, a varnish, a dental cement, a troche, a chewing gum, a dental paste, a gingival massage cream, or a gargle tablet.

12. The composition of any one of claims 1 to 11 , wherein the composition is a toothpaste.

13. The composition of any one of claims 1 to 12, wherein the composition does not include any one of more of a polyphosphate, a citrate or a calcium chelator.

14. A method of treating or preventing a P. gingivalis infection, comprising administering to an individual in need thereof, a composition of any one of claims 1 to 13.

15. A method for reducing or minimising the severity of a symptom associated with an infection with P. gingivalis, comprising administering to an individual in need thereof, a composition of any one of claims 1 to 13, wherein the symptoms are selected from the group consisting of swollen or puffy gums, gums that bleed easily, receding gums, periodontal pockets around the teeth, loss of tooth supporting tissues (periodontal ligament, cementum and / or alveolar bone) pus between gums and teeth, and gingivitis.

16. A method for treating or preventing P. gingivalis- related disease in a subject, the method comprising administering to an individual in need thereof, a composition of any one of claims 1 to 13.

17. The method of claims 16, wherein the P. gingivalis-re\ated disease comprises periodontal disease.

18. A composition of any one of claims 1 to 13, in the manufacture of a medicament for:• treating or preventing a P. gingivalis infection in a subject;1006214354• minimising or reducing the severity of one or more symptoms of P. gingivalis infection; or• treating or preventing a P. g / ng / va / / s-related disease in a subject.

19. A composition of any one of claims 1 to 13, for use in:• treating or preventing a P. gingivalis infection in a subject;• minimising or reducing the severity of one or more symptoms of P.gingivalis infection; or• treating or preventing a P. gingivalis-related disease in a subject.

20. The method, use of composition for use of any one of claims 15 to 19, further comprising the step of detecting P. gingivalis in the oral cavity of the subject.

21. A method of mineralizing a dental surface or sub-surface comprising contacting the dental surface or subsurface with a composition of any one of claims 1 to 13, thereby mineralizing the dental surface or sub-surface.

22. A method of treating fluorosis comprising contacting a fluorotic lesion, preferably in dental enamel, with a composition of any one of claims 1 to 13, thereby treating fluorosis.

23. A method of treating dental caries comprising contacting a caries lesion with a composition of any one of claims 1 to 13, thereby treating dental caries.

24. Use of a composition of the invention of any one of claims 1 to 13, in the manufacture of a medicament for:• mineralizing the dental surface or sub-surface;• treating fluorosis; or• treating dental caries.

25. A composition of any one of claims 1 to 13, for use in:• mineralizing the dental surface or sub-surface;1006214354• treating fluorosis; or• treating dental caries.

26. A method for treating or preventing dentinal sensitivity in an individual in need thereof comprising administering composition of any one of claims 1 to 13, thereby treating or preventing dentinal sensitivity in the individual.

27. A method for treating or preventing dentinal sensitivity in an individual in need thereof comprising administering a composition of any one of claims 1 to 13, thereby treating or preventing dentinal hypersensitivity in an individual, preferably wherein the dentinal sensitivity is dentinal hypersensitivity.

28. A method for occluding exposed dentinal tubules in an individual, the method comprising administering a composition of any one of claims 1 to 13, thereby occluding exposed dentinal tubules in an individual.

29. A method for forming a layer over exposed dentinal tubules in an individual, the method comprising administering a composition of any one of claims 1 to 13, thereby forming a layer over exposed dentinal tubules in an individual, preferably, the method of occluding exposed dentinal tubules or forming a layer over exposed dentinal tubules further comprises the step of identifying exposed dentinal tubules in an individual.

30. Use of a composition of any one of claims 1 to 13, in the manufacture of a medicament for the treatment or prevention of dentinal sensitivity, preferably, the dentinal sensitivity is dentinal hypersensitivity.

31. A composition of any one of claims 1 to 13, for use in the treatment or prevention of dentinal sensitivity, preferably, the dentinal sensitivity is dentinal hypersensitivity.

32. The method, use or composition for use of any one of claims 15 to 31 , wherein the composition is administered to the oral cavity.

33. The method, use of composition for use of any one of claims 15 to 32, wherein the composition is applied to the mouth, tooth or lesion by a dental health care professional.100621435434. The method, use of composition for use of any one of claims 15 to 33, wherein the composition is contacted with the dental surface for a period of about 1 to 60 minutes, for about 1 to 30 minutes, for about 10 to 60 minutes, for about 10 to 30 minutes, for about 20 to 60 minutes, or for about 20 to 30 minutes, preferably, the complex or composition is contacted with the dental surface for about 20 minutes.

35. A kit for use in any method or use of any one of claims 15 to 34 comprising a composition of any one of claims 1 to 13, preferably the stannous-associated PP-ACP or ACFP complex is in a pharmaceutically acceptable carrier.

36. A method or process for forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, the method or process comprising or consisting of:(i) obtaining a solution comprising at least one phosphopeptide and;(ii) admixing solutions comprising phosphopeptides, calcium ions, phosphate ions, hydroxide ions and optionally fluoride ions, while maintaining the pH at about 7.3 or below, to form a composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP; and(iii) admixing a solution comprising from about 12 mM to about 390 mM stannous ions, more preferably from about 22 mM to about 38mM, with the composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP with slow addition, mixing and maintaining the solution pH,thereby forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

37. The method or process of claim 36, wherein the solutions are added slowly at a rate of less than about 1% volume addition per minute with adequate mixing.100621435438. The method or process of claim 37, wherein the method or process does not involve any additional base or acid.

39. A method or process for forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP, the method or process comprising or consisting of:(i) providing a composition comprising equal to or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP; and(ii) admixing a solution comprising from about 12 mM to about 390 mM stannous ions, more preferably from about 22 mM to about 38 mM, with the composition comprising equal to, or greater than about 8% w / v phosphopeptide stabilized ACP or ACFP with slow addition, mixing and maintaining the solution pH,thereby forming a composition comprising equal to or greater than about 8% w / v stannous associated phosphopeptide (PP) stabilized amorphous calcium phosphate (ACP) or amorphous calcium fluoride phosphate (ACFP) complexes wherein the complexes have a stannous ion content of equal to, or greater than, 1 mole of stannous per mole of PP but less than 4 moles of stannous per mole of PP.

40. The method or process of any one of claims 36 to 39, wherein the stannous ions are provided in the form of stannous fluoride.

41. The method or process of claim 40, wherein the stannous fluoride comprises greater than or equal to about 440ppm and less than 15000 ppm fluoride, preferably about 1100 ppm or 1450 ppm fluoride.1006214354

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