GB2610009A

GB2610009A - Compositions for treatment of dental caries

Info

Publication number: GB2610009A
Application number: GB2202761.9A
Authority: GB
Inventors: Bedi Raman; Grootveld Martin
Original assignee: R AND K BEDI Ltd
Current assignee: R AND K BEDI Ltd
Priority date: 2022-02-28
Filing date: 2022-02-28
Publication date: 2023-02-22
Anticipated expiration: 2042-02-28
Also published as: GB202202761D0; WO2023161003A1; GB2610009B

Abstract

A stable pharmaceutical composition is disclosed comprising silver (I) cation species (Ag(I)+) and fluoride anion species (F-), wherein the molar concentration ratio of fluoride (F-):(Ag(I)+) is from 2:1 to 20:1, and wherein the pH pf the solution is from 5.35 to 6.0.

Description

Compositions for Treatment of Dental Caries

FIELD OF THE INVENTION

The present invention relates to compositions and to their use in the treatment or prophylaxis of dental conditions, particularly dental caries. More specifically, the compositions of the invention are aqueous solutions which contain silver(l) fluoride.

BACKGROUND OF THE INVENTION

Compositions comprising silver(I) and fluoride ions, especially in the form of aqueous solutions, are widely used in the treatment and prevention of dental caries, and are known both to have antibacterial activity and to promote the re-mineralisation of demineralised collagen as well as reducing tooth sensitivity. However, silver(I) fluoride solutions are not particularly stable, and metallic silver and/or silver(I) oxide (AgI20) frequently precipitate out of solution during periods of storage, giving rise either to a deposition on the bottom of darkened storage bottles or to a layer on the solution surface.

Loss of the solution phase of both the silver(I) and fluoride active ingredients significantly reduces the clinical potency of these bottled products.

For some years now, it has been accepted that silver(I) fluoride in aqueous solutions may be stabilised somewhat by the complexation of the silver(I) ion by two ammonia ligands as in the near-linear two-coordinate diammine-silver(I) cation ([AgI(NH1)2I), and this complex displays a high level of stability (cumulative stability constant, 137 = 106Im, Bjerrum, 1986). Silver(I) diammine fluoride solution (SDF) is known to be effective in the treatment and prevention of dental caries, especially in patients who are at high risk of dental caries, or in populations to whom other types of dental treatment are not available.

However, aqueous solutions containing SDF frequently have pH values of at least 9 to 10, and as high as pH 13 in some cases. Consequently, not only are the solutions likely to cause irritation of the oral soft tissues, but also, they may be hydrolysed, especially at high temperatures, a process giving rise to the liberation of ammonia. This is a particular problem in formulations in which SDF is present at high solution concentrations (38% (w/v) in some commercial SDF formulations). Moreover, the precipitative deposition of insoluble Ag120 or At is also frequently observed. The longevity and shelf-life of such SDF formulations is therefore in need of improvement.

Aqueous silver(I)-fluoride solutions with a 1:1 molar concentration ratio of fluoride:silver(1) are unstable at alkaline and neutral pH values, and the rate and extent of hydrolysis increases with increasing pH value (i.e. with increasing hydroxide ion concentration). Although newly-prepared aqueous 38% (w/v) silver(I)-fluoride solutions have more favourable, slightly acidic pH values (typically 6.2-6.4), these also degrade at ambient temperature, albeit more slowly than they do at alkaline pH, with hydrated black-coloured AgT70 precipitating out of solution with increasing time of storage. WO-A2019/153033 (SDI Limited) demonstrates that aqueous 1:1 silver(I) fluoride solutions are markedly stabilised when their pH values are adjusted within the range 4.0-5.3. Solutions with pH values greater than 5.3 were said to be unstable for long-term storage with precipitation of silver from the solution. However, pH values lower than 4.0 may cause irritation and inflict chemical damage on oral soft tissues. Moreover, pH values within the 4.0-5.0 pH range may induce the demineralisation of teeth; indeed these values are not dissimilar to those of primary root carious lesions (Silwood eta), 1999).

Some other silver and fluoride-containing compositions which do not contain ammonia are also known, for example those described in WO-A-2020/021494 and WO-A-2020/021495, although these compositions also contain other components, especially iodide and/or thiocyanate ions. However, these compositions have significantly lower concentrations of fluoride ions than either SDF or silver(I) fluoride solutions.

PROBLEM TO BE SOLVED BY THE INVENTION

As noted above, there are various problems with known compositions for treating dental caries. In particular, the compositions have limited storage stability since the silver(1) tends to by hydrolysed to silver oxide, which precipitates out of solution, and SDF solutions also give off malodorous ammonia. Furthermore, the pH of SDF solutions is strongly alkaline because of the presence of ammonia, whereas the pH of silver(I) fluoride solutions is often adjusted so that it is relatively acidic in order to prevent precipitation of silver(I) oxide. Compositions which contain other ions, such as iodide and thiocyanate ions, may have a pH which is less acidic, but have the disadvantage that the concentration of fluoride ions is significantly lower than that of standard commercially available compositions, such that they have a high ratio of silver(I):fluoride. Moreover, both iodide and thiocyanate anions react with silver(1) to predominantly form insoluble complexes.

It is therefore an object of this invention to provide a low-cost composition which does not contain ammonia and which has a longer shelf-life than known compositions

SUMMARY OF THE INVENTION

In accordance with a first aspect of the invention, there is provided a pharmaceutical composition comprising an aqueous solution, wherein the solution comprises silver(I) species (Agar') and fluoride species (F"), wherein the molar concentration ratio of [F]:[Ag(1)111 is from 1.5:1 to 20:1, and wherein the pH of the solution is from 5.35 to 6.0.

ADVANTAGES OF THE INVENTION

The present invention provides the advantage of a composition which can be used for the treatment of dental conditions, particularly dental caries, which does not contain ammonia, which is relatively inexpensive, is simple to prepare, and which has a longer shelf-life than the compositions which are currently in use

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a series of 564 MHz 19F NIV1R spectra of 0.20 mol./L aqueous solutions of 1:1 silver(I)-fluoride treated with increasing concentrations of added fluoride at a constant pH value of 5.40. A, 1:1 silver(I)-fluoride alone; B, C, D and E, as A, but with 0.50, 1.00, 2.00 and 3.00 molar equivalents of added fluoride, respectively. These spectra were recorded un-locked, and chemical shift values were referenced to external CFC13.

Figure 2A is a plot of 19F chemical shift value (6) versus the [F]:[Ag(1)-F] molar concentration ratio, which can be used to estimate the molar ratio of NIVIR-exchangeable 19F to that of Ago) as described in Example 2.

Figure 2B is plot of '9F chemical shift difference between the developing [Ag(I)F11]11"11" complexes and that of free fluoride anion (6[Ag(I)F11]("41") -6F") versus the [F]:[Ag(H-F] molar concentration ratio, which can be used to estimate the molar ratio of 30 NMR-exchangeable '9F to that of Ag(I) as described in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, except where the context requires otherwise due to express language or necessary implication, the word "comprises", or variations such as comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features, but not to preclude the presence or addition of further features in various embodiments of the invention.

All literature and patent documents referred to herein are incorporated by reference to the fullest extent possible.

In the present specification, references to "pharmaceutical use" refer to use for administration to a human or an animal, in particular a human or a mammal, for example a domesticated or livestock mammal, for the treatment or prophylaxis of dental conditions, especially dental caries. The term "pharmaceutical composition" refers to a composition which is suitable for pharmaceutical use, and "pharmaceutically acceptable" refers to an agent which is suitable for use in a pharmaceutical composition. Other similar terms should be construed accordingly.

In the present specification, references to silver(I) species (Ag(I)+) and fluoride species (F) refer either to individual ABM+ and F-ions, or to Ag(T)-and F-which are part of a silver(I)-fluoride complex of formula [Ag(I)F,,]°'-I)-with exchangeable F-ions, where n is from 2 to 4, and is suitably an integer. Cluster species with both bridging (Ag(1)--F-Ag(1)) and terminal (Ag(I)--F) F ligands are also possible.

As noted above, the invention relates in a first aspect to a pharmaceutical composition comprising an aqueous solution, wherein the solution comprises silver(I) species (Ag(I)+) and fluoride species (F), wherein the molar concentration ratio of [F]:[Ag(1)+] is from 1.5:1 to 20:1, and wherein the pH of the solution is from 5.35 to 6.0.

Restriction of the availability of hydrolytic OH-ions within this pH range enhances the stabilities and solubilities of Ag(I)-F-complexes.

It has previously been assumed that silver(i) fluoride compositions have a molar concentration ratio of [P]:[Ag(I)+] of about 1:1. However, the present inventors have now discovered that it is possible to form silver(I)-fluoride complexes with exchangeable fluoride anions, specifically [Ag(I)Fu]01-D-complexes, where n is from 2 to 4, and is suitably an integer. The existence of these F" ligand-exchangeable complexes has been established by 19F NIVIR characterisation. The inventors have therefore been able to prepare solutions comprising Ag(I)* ions and F" ions, where there is an excess of F" ions in comparison with the number of Ag(I)+ ions.

Aqueous solutions containing [Ag(I)Filr-complexes may be prepared from Ag(l) fluoride solutions by the addition of further fluoride ions. For aqueous solutions prepared from 0.20 mol./L AgO) fluoride at the stabilising fixed pH value of 5.40, the [Ag(1)F,3](111)-complexes generated by the addition of additional fluoride are characterised by the observation of broadened "F NMR resonances located at 6 = -120.38 to -120.66 ppm regions of spectra acquired, the 6 value observed decreasing with increasing molar ratio of added fluoride to Ag(0-fluoride (with line-width at half-height (Avu3) values >35 Hz for 1:1 silver(I)-fluoride solutions, and those of higher F-Ag(I)-stoichiometry) in "F NMR spectra acquired on the solutions. The Avipvalue of 'free', uncomplexed fluoride (6 = -120.9 ppm) is only 5.5 Hz, so this serves as a clear means of distinguishing exchangeable Ag(I)-complexed F-from its uncomplexed form.

The concentrations of F-species in the composition can also be determined by 19F NMR analysis via electronic integration of their resonances, and expression of their determined intensities relative to that of a known, non-Ag(I) ion-complexing pre-added internal standard of known concentration, for example added BF3 or [BF3(OH)]-. Silver ion, at trace levels if required, can be determined using inductively-coupled plasma-mass spectrometry (ICP-MS) or flameless atomic absorption analysis. Alternatively, the spectrophotometric method of Dagnall and West (1964) may be employed to determine Agar concentrations in diluted solutions of the [Ag(I)F11]("-1)-complexes.

Suitably, at least 60% of the total fluoride species in the composition is present as part of a [Ag(I)Faml)" complex.

In a therapeutic context, in principle the [Ag(I)F11]("1)-complexes present in the compositions of the invention have the ability to deliver more fluoride on a mole-for-mole basis, since each Ag(I) ion carries more than a single F-ligand.

Concentrated aqueous solutions of the invention containing [Ag(T)FrJ(n-I)-complexes also have enhanced stability compared to silver(T) fluoride solutions having a 1:1 ratio of Ag(I)± ions to F-ions. In particular, there is significantly reduced hydrolysis of the complex, even at near neutral pH values, and therefore significantly reduced precipitation of silver(I) oxide and silver metal deposition from the solution on storage.

In more suitable pharmaceutical compositions of the invention, the aqueous solution has a concentration range of [F]:[Ag(1)1 of 2:1 to 10:], more suitably 2:1 to 6:1 or 2:1 to 4:1 (e.g. 2.5:1 to 4:1).

The amount of Ag(I)+ species present in the composition is suitably 10 to 50% w/v (0.93M to 4.63M concentration), more suitably 10 to 40% w/v (0.93M to 3.7M concentration), and especially 20 to 40% w/v (1.85M to 3.7M concentration).

The amount of F-species present in the composition is suitably 2.65 to 42% w/v (1.4M to 22M concentration), more suitably 7 to 42% w/v (3.7M to 22M concentration) and especially 7 to 28% w/v (3.7M to 14.8M concentration) The pH of the composition of the invention is 5.35 to 6.0, more suitably from 5.35 to 5.90, still more suitably from 5.35 to 5.60, and typically about 5.40. It is particularly surprising that the compositions of the invention are stable at this pH since conventional silver(1) fluoride solutions require a pH of 4.0-5.3 in order for them to remain stable. It would not have been expected that acceptable stability could be achieved at a pH of 5.35, and certainly not at a pH of up to 6.0.

As noted above, the composition is in the form of a solution and is suitably adapted for application to the teeth. Application may be achieved using any suitable applicator, for example a toothbrush or small paintbrush, particularly a microbrush. Microbrushes are well known and readily available from dental suppliers and are used for applying dental materials directly onto teeth. These small brushes are ideal for accessing difficult to reach intra-oral areas, as well as small areas where the composition of the invention is to be applied.

The applicator may have antimicrobial properties. For example, the applicator may have been treated with an antimicrobial composition. This is particularly useful when the composition is intended for the prophylaxis of dental caries. The composition of the invention is suitable for arresting dental caries but also makes the cavity more resistant to future decay, and, in addition, the enhanced levels of fluoride present strengthen the enamel. An antimicrobial applicator reduces the bacterial load in the mouth, further preventing dental caries. The combination of the composition of the invention used with an antimicrobial applicator can therefore be considered as a dental immunisation to prevent dental caries.

Suitably, the composition is stored in a darkened bottle as it is sensitive to light. Still more suitably, the bottle is formed from a plastics material as the composition may interact with components of glass.

The compositions of the invention may be prepared by a process comprising adding an aqueous solution comprising fluoride ions to an aqueous solution of silver(1) fluoride having a pH value of 5.35 to 6.0 and a molar concentration ratio of [F-1:[Ag(1)1 of about 1:1. This process forms a further aspect of the invention.

Suitably, the silver fluoride solution has a molar concentration of both silver(1) and fluoride ions of about 1.85M to 4.00M. Suitably, the aqueous solution comprising fluoride ions is a solution of ammonium fluoride, since this is highly soluble in water. In some circumstances, a solution of sodium fluoride may be used, although this has a lower solubility in water than ammonium fluoride. The fluoride ion concentration of the aqueous solution comprising fluoride ions may be chosen so as to adjust the fluoride ion concentration in the final product to the desired level. For example, if an aqueous solution comprising fluoride ions at a concentration of 3.7M (as highly-soluble ammonium fluoride) is added to an equal volume of a 3.7M silver(I) fluoride solution, the final concentration of fluoride ions will be 3.7M, while the final concentration of' silver(I) ions will be 1.85M, and the molar concentration ratio of Ft [Agar] will be 2:1.

In some cases, the process may comprise a step of adjusting the pH of the aqueous solution of silver(I) fluoride to pH 5.35 to 6.0 by the addition of nitric acid before the addition of the aqueous solution comprising fluoride ions. Suitably, the nitric acid is added dropwise and the pH is monitored during the addition.

The process may further comprise an initial step of preparing an aqueous solution of silver(I) fluoride (AgF) having a molar concentration ratio of [F]:[Ag(1)-] of about 1:1, comprising mixing an aqueous solution comprising silver(I) ions with an aqueous solution comprising fluoride ions wherein the silver(I) ions and fluoride ions are in a molar ratio of about I: I. Suitably, in this step the aqueous solution comprising silver(I) ions is a silver(I) nitrate solution and the aqueous solution comprising fluoride ions is ammonium or sodium fluoride, especially ammonium fluoride.

In a further aspect of the invention there is provided a composition of the first aspect for use in medicine, especially in the treatment or prophylaxis of dental conditions, particularly dental caries.

There is also provided the use of a composition of the first aspect in the manufacture of a medicament for the treatment or prophylaxis of dental conditions, particularly dental caries There is further provided a method for the treatment or prophylaxis of dental conditions, particularly dental caries, the method comprising administering to a patient in need of such treatment an effective amount of a composition according to the first aspect In some cases, the composition of the invention may be applied using an applicator, for example a toothbrush or small paintbrush, for example a microbrush. In some cases, the brush may itself have antimicrobial properties, for example, it may have been treated with an antimicrobial composition. As noted above, suitable microbntshes are readily available from a number of sources. Applicators having antimicrobial properties are particularly suitable when the composition of the invention is used for the prophylaxis of dental caries, i.e. for delivery of a dental immunisation.

Therefore, in a further aspect of the invention, there is provided a kit comprising a composition according to the first aspect together with an applicator. Suitably, the applicator is a toothbrush or small paintbrush, for example a microbrush. More suitably, the applicator has antimicrobial properties. Suitably in the kit, the composition according to the first aspect is provided in a darkened bottle, especially a darkened bottle made from a plastics material.

EXAMPLES

Example 1 -Preparation of composition Primarily, the pH values of aqueous concentrated stock solutions of silver(I)-fluoride, ammonium (or sodium) fluoride and, where required, an HPLC-or pharmaceutical-grade water solution diluent were carefully adjusted to a final value of 5.40 with the dropwi se addition of nitric acid with continuous stirring. During this process, much care was taken in order to ensure that theses solutions' pH values do not exceed 6.0.

A hand-held portable pH meter was employed to control and monitor pH values.

An aqueous solution of [Ag(1)Fe1>" containing 20% (w/v) Ag(I)-(1.85 mol./L) and 7.04% (w/v) fluoride (3.70 mol./L), so that the molar ratio of F" to Ag(I)-was exactly 2:1, was prepared. The preparation was conducted by the careful addition of a 10.0 mL volume of a 3.70 mol./L ammonium fluoride solution to an equivalent volume of one containing 3.70 mol./L Ag(I)-fluoride at ambient temperature (c.a. 20-25°C) in light-protected plastic (polypropylene) vessels with thorough stirring of the medium during addition. Subsequently, the mixture was allowed to equilibrate under these conditions with constant stirring for a minimum period of 1.00 hr. post-mixing.

It should be noted that it is recommended that the use of glassware should be strictly avoided during the above preparation process, since both "F and I NMR analyses have demonstrated that firstly, in silver(I)-fluoride solutions, boron trifluoride (BF3)-type adducts such as [BF3(OH)f arise from the reactions of F-with borosilicate glass materials; since these products were only observed in silver(I)-fluoride, and those containing [Ag(I)Fu]-n-, but not free fluoride solutions, it certainly appears that Ag(I) ions catalyse this process. Secondly, in aqueous solutions containing the above silver(I)fluoride, and free sodium or ammonium fluoride alone, 19F NMR spectra also contain a signal which is largely assignable to silicon tetrafluoride (SiF4)-type species, and this appears to arise from the attack of solution-phase F-on borosilicate glassware. Since these BF3 and SiF4 adducts may both be considered potentially toxic, some further investigations are required. Moreover, we also found both sets of these signals present in the 19F NIVIR spectra of one out of three commercially available solutions of silver(I)-diammine fluoride for therapeutic dental use, so it appears that borosilicate glassware was utilised during their preparation.

Example 2 -Characterisation of composition and measurement of molar concentrations of Agar and F-species Solutions containing [Ag(I)Fa]"lp" species prepared according to Example 1 were diluted so that the concentration of Ago) is 0.20 mol./L for 19F NMR analysis at this pH value, A precise cut-off threshold HF NMR chemical shift value of? -120.45 ppm (with a line-width at half-height value of? 30 Hz) at pH 5.40 was determined, and these analyte concentrations are parameters which are considered sufficient to fully distinguish [Ag(I)F,,]1-ft species from conventional 1:1 Ag(I)-F-adducts (Figure 1).

Under these experimental conditions, the molar ratio of NMR-exchangeable 19F to that of Ag(I) may be reliably estimated from plots of 19F chemical shift (5) value versus the ratio of excess or total F-concentration to that of 1:1 silver(I)-fluoride (or total F.-level to that of the fixed Ag(I) concentration, the latter being 0.20 mol./L), or alternatively the difference in 5 value between the [Ag(I)F.]°11)" species and that of free fluoride ion versus the above ratios (Figures 2A and 2B respectively).

Total fluoride concentrations of these solutions are determined by either quantitative '9F NMR analysis as described above, or by a fluoride-specific ion-selective electrode (ISE), the latter applied to very highly diluted solutions of the product generated.

Total silver(1) concentrations are determined by inductively-coupled plasma-mass spectrometry (ICP-MS) or flameless atomic absorption analysis of very highly diluted sample solutions. Alternatively, the spectrophotometric method of Dagnall and West (1964) may be utilised for this purpose.

Example 3 -Measurement of storage stability (preliminary data) The pH values of individual solutions of conventional 1:1 silver(I)-fluoride (0.40M), along with those also containing one molar equivalent of excess fluoride (0.40M) prepared using a similar method to that described in Example 1, were adjusted to 5.40 or 12.50, and these were then equilibrated at 23°C for a period of 20 days with continuous exposure to sunlight during the day, and also artificial laboratory light overnight. Each solution was then evaluated for the performance attributes provided in Table I. Table 1 -Comparison of preliminary stability data for compositions of Example A and Comparative Examples A. B and C Example A Comparative Example A Comparative Example B Comparative Example C pH value 5.40 5.40 12.50 12.50 Agent 0.40M 0.40M 1:1 Silver(I)-Fluoride 0.40M 1:1 Silver(I)-Fluoride 0.40M Silver(I)-Silver(I)-Fluoride/0.401\4 Excess Fluoride Fluoride/0.40M Excess Fluoride Appearance (20 days exposed to sunlight and laboratory light for 20 days) Clear colourless solution Minor level of discolouration (very low level of silver metal sediment deposition) Significant level of discoloration (silver metal sediment deposition) Significant level of discoloration (silver metal sediment deposition) The results are a preliminary indication that the stability of a composition according to the invention, having a 2:1 molar concentration ratio of [F]:[Ag(1)11] and a pH of 5.40, is more stable to light than a conventional composition having a 1:1 molar concentration ratio of [F]:[Ag(I)11] and a pH of 5.40. Both of these compositions are much more stable than similar compositions having a pH of 12.5.

The invention has been described with reference to a preferred embodiment.

However, it will be appreciated that variations and modifications can be effected by a person of ordinary skill in the art without departing from the scope of the invention.

REFERENCES

Bjerrum, J. Metal amine formation in solution 30CVI. Stability constant and UV absorption spectrum of the triammine silver(I) complex. Ada Chimica Scandinavica 1986, A40, 392396.

Dagnall, R. NI.; West, T. S. A selective and sensitive colour reaction for silver. Talanta 1964, 11(11), 1533-1541, ISSN 0039-9140, httu::.:(,:d,v0.)u,z,,' I '' Silwood, C.J.L., Lynch, E.J., Seddon, S., Sheerin, A., Claxson, A.W.D., Grootveld, M.C.

Ill NMR analysis of microbial-derived organic acids in primary root carious lesions and saliva. NAIR in Biomedicine 1999; 12: 345-356.

Claims

CLAIMS1. A pharmaceutical composition comprising an aqueous solution, wherein the solution comprises silver(I) species (Ag(I)+) and fluoride species (F), wherein the molar concentration ratio of [F]:[Ag(1)1 is from 2:1 to 20:1, and wherein the pH of the solution is from 5.35 to 6.0.
2. A pharmaceutical composition as claimed in claim 1, wherein the molar concentration ratio of [P]:[Ag(1)±1 is from 2:] to 10:1.
3. A pharmaceutical composition as claimed in claim 2, wherein the molar concentration ratio of [F]:[Ag(I)] is from 2:1 to 4:1.
4. A pharmaceutical composition as claimed in any one of claims 1 to 3, wherein the amount of Ag0)-species present in the composition is from 10 to 50% w/v.
5. A pharmaceutical composition as claimed in claim 4, wherein the amount of Ag(I) species present in the composition is from 10 to 40% w/v.
6. A pharmaceutical composition as claimed in any one of claims 1 to 5, wherein the amount of F-species present in the composition is from 2.65 to 42% w/v.
7. A pharmaceutical composition as claimed in claim 6, wherein the amount of F species present in the composition is from 7 to 42% w/v.
8. A pharmaceutical composition as claimed in any one of the preceding claims wherein the pH is from 5.35 to 5.90.
9. A pharmaceutical composition as claimed in claim 8, wherein the pH is from 5.35 to 5.60.
10. A pharmaceutical composition as claimed in any one of the preceding claims which is adapted for topical administration to the teeth and gums.
11. A process for the preparation of a pharmaceutical composition as defined in any one of the preceding claims, the process comprising adding an aqueous solution comprising fluoride ions to an aqueous solution of silver(I) fluoride having a pH of 5.35 to 6.0 and a molar concentration ratio of [F]:[Ag(ITI of about 1:1.
12. A process as claimed in claim 11, wherein the silver fluoride solution has a molar concentration of both silver and fluoride ions of about 1.85M to 4.00M.
13. A process as claimed in claim 11 or claim 12, comprising adjusting the p1-1 of the aqueous solution of silver(I) fluoride to pH 5.35 to 6.0 by the addition of nitric acid before the addition of the aqueous solution comprising fluoride ions
14. A process as claimed in any one of claims 11 to 13, further comprising the initial step of preparing an aqueous solution of silver(I) fluoride (AgF) having a molar concentration ratio of [F]:[Ag(I)+] of about 1:1, by mixing an aqueous solution comprising silver(I) ions with an aqueous solution comprising fluoride ions wherein the silver(I) ions and fluoride ions are in a molar ratio of about 1:1.
15. A process as claimed in claim 14, wherein the aqueous solution comprising silver(1) ions is a silver(1) nitrate solution and the aqueous solution comprising fluoride ions is ammonium or sodium fluoride, especially ammonium fluoride.
16. A composition as claimed in any one of claims 1 to 10 for use in medicine, especially in the treatment or prophylaxis of dental conditions.
17. The use of a composition as defined in any one of claims 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of dental conditions.
18. A method for the treatment or prophylaxis of dental conditions, the method comprising administering to a patient in need of such treatment an effective amount of a composition as defined in any one of claims 1 to 10.
19. A composition for use, a use or a method as claimed in any one of claims 16 to 18, wherein the dental condition is dental caries
20. A kit comprising a composition as defined in any one of claims Ito 10 together with an applicator.
21. A kit as claimed in claim 20, wherein the applicator has antimicrobial properties 22 A kit as claimed in claim 20 or claim 21, wherein the composition is provided in a darkened bottle made from a plastics material