WO2023161003A1 - Compositions pour le traitement de caries dentaires - Google Patents

Compositions pour le traitement de caries dentaires Download PDF

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Publication number
WO2023161003A1
WO2023161003A1 PCT/EP2023/052874 EP2023052874W WO2023161003A1 WO 2023161003 A1 WO2023161003 A1 WO 2023161003A1 EP 2023052874 W EP2023052874 W EP 2023052874W WO 2023161003 A1 WO2023161003 A1 WO 2023161003A1
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WO
WIPO (PCT)
Prior art keywords
fluoride
silver
composition
aqueous solution
ions
Prior art date
Application number
PCT/EP2023/052874
Other languages
English (en)
Inventor
Raman Bedi
Martin Grootveld
Original Assignee
R And K Bedi Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by R And K Bedi Ltd filed Critical R And K Bedi Ltd
Publication of WO2023161003A1 publication Critical patent/WO2023161003A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/16—Fluorine compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/20—Halogens; Compounds thereof
    • A61K8/21—Fluorides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Definitions

  • compositions of the invention relate 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(I) fluoride.
  • 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.
  • silver(I) fluoride solutions are not particularly stable, and metallic silver and/or silver(I) oxide (Ag ⁇ O) 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.
  • 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.
  • 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 AgkO or Ag° 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(I) 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).
  • 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 blackcoloured AgkO precipitating out of solution with increasing time of storage.
  • WO-A- 2019/153033 (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 et al, 1999).
  • 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.
  • these compositions have significantly lower concentrations of fluoride ions than either SDF or silver(I) fluoride solutions.
  • compositions for treating dental caries have limited storage stability since the silver(I) tends to by hydrolysed to silver oxide, which precipitates out of solution, and SDF solutions also give off malodorous ammonia.
  • SDF solutions also give off malodorous ammonia.
  • 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 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.
  • iodide and thiocyanate anions react with silver(I) to predominantly form insoluble complexes.
  • 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(I) + ] is from 1.5: 1 to 20: 1, and wherein the pH of the solution is from 5.35 to 6.0.
  • the solution comprises silver(I) species (Ag(I) + ) and fluoride species (F‘), wherein the molar concentration ratio of [F']:[Ag(I) + ] is from 1.5: 1 to 20: 1, and wherein the pH of the solution is from 5.35 to 6.0.
  • 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.
  • Figure 1 is a series of 564 MHz 19 F NMR 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.
  • These spectra were recorded un-locked, and chemical shift values were referenced to external CFCh.
  • Figure 2A is a plot of 19 F chemical shift value (6) versus the [F']:[Ag(I)-F] molar concentration ratio, which can be used to estimate the molar ratio of NMR- exchangeable 19 F to that of Ag(I) as described in Example 2.
  • Figure 2B is plot of 19 F chemical shift difference between the developing [Ag(I)F n ] (n ) ' complexes and that of free fluoride anion (5[Ag(I)F n ] (n ’ 1) ’) - 5F") versus the [F']:[Ag(I)-F] molar concentration ratio, which can be used to estimate the molar ratio of NMR-exchangeable 19 F to that of Ag(I) as described in Example 2.
  • 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.
  • pharmaceutical composition refers to a composition which is suitable for pharmaceutical use
  • pharmaceutically acceptable refers to an agent which is suitable for use in a pharmaceutical composition.
  • Other similar terms should be construed accordingly.
  • references to silver(I) species (Ag(I) + ) and fluoride species (F‘) refer either to individual Ag(I) + and F’ ions, or to Ag(I) + and F’ which are part of a silver(I)-fluoride complex of formula [Ag(I)F n ] (n ) ' with exchangeable F’ ions, where n is from 2 to 4, and is suitably an integer.
  • Cluster species with both bridging (Ag(I)— F— Ag(I)) and terminal (Ag(I)— F’) F’ ligands are also possible.
  • the invention relates in a first aspect to a pharmaceutical composition
  • 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(I) + ] 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.
  • silver(I) fluoride compositions have a molar concentration ratio of [F‘] : [Ag(I) + ] of about 1 : 1.
  • the present inventors have now discovered that it is possible to form silver(I)-fluoride complexes with exchangeable fluoride anions, specifically [Ag ⁇ FJ ⁇ ’ 1 ⁇ 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 19 F NMR 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 ⁇ FJ ⁇ ’ 1 ⁇ complexes may be prepared from Ag(I) fluoride solutions by the addition of further fluoride ions.
  • the concentrations of F’ species in the composition can also be determined by 19 F 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.
  • ICP-MS inductively-coupled plasma-mass spectrometry
  • the spectrophotometric method of Dagnail and West (1964) may be employed to determine Ag(I) + concentrations in diluted solutions of the [Ag ⁇ FJ ⁇ ’ 1 ⁇ complexes.
  • At least 60% of the total fluoride species in the composition is present as part of a [Ag(I)F n ] (n ) ' complex.
  • the [Ag ⁇ Fn] ⁇ ’ 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(I)F n ] (n ' 1) ' complexes also have enhanced stability compared to silver(I) fluoride solutions having a 1 : 1 ratio of Ag(I) + ions to F’ ions.
  • the aqueous solution has a concentration range of [F']:[Ag(I) + ] of 2: 1 to 10: 1, 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(I) 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.
  • 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.
  • 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.
  • 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.
  • compositions of the invention may be prepared by a process comprising adding an aqueous solution comprising fluoride ions to an aqueous solution of silver(I) fluoride having a pH value of 5.35 to 6.0 and a molar concentration ratio of [F']:[Ag(I) + ] of about 1 : 1. This process forms a further aspect of the invention.
  • the silver fluoride solution has a molar concentration of both silver(I) and fluoride ions of about 1.85M to 4. OOM.
  • 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.
  • 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.
  • 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(I) + ] 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 1 : 1.
  • AgF silver(I) fluoride
  • 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.
  • composition of the first aspect for use in medicine, especially in the treatment or prophylaxis of dental conditions, particularly dental caries.
  • a composition of the first aspect in the manufacture of a medicament for the treatment or prophylaxis of dental conditions, particularly dental caries.
  • a method for the treatment or prophylaxis of dental conditions comprising administering to a patient in need of such treatment an effective amount of a composition according to the first aspect.
  • the composition of the invention may be applied using an applicator, for example a toothbrush or small paintbrush, for example a microbrush.
  • the brush may itself have antimicrobial properties, for example, it may have been treated with an antimicrobial composition.
  • suitable microbrushes 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.
  • kits comprising a composition according to the first aspect together with an applicator.
  • the applicator is a toothbrush or small paintbrush, for example a microbrush. More suitably, the applicator has antimicrobial properties.
  • the composition according to the first aspect is provided in a darkened bottle, especially a darkened bottle made from a plastics material.
  • 19 F 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 19 F NMR 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.
  • SiF4 silicon tetrafluoride
  • the molar ratio of NMR-exchangeable 19 F to that of Ag(I) may be reliably estimated from plots of 19 F chemical shift (6) 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 6 value between the [Ag(I)F n ] (n ) ' 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 19 F 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(I) 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 Dagnail and West (1964) may be utilised for this purpose.
  • 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(I) + ] 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) + ] and a pH of 5.40. Both of these compositions are much more stable than similar compositions having a pH of 12.5.

Abstract

L'invention concerne une composition pharmaceutique comprenant des espèces argent (I) et des espèces fluorure, le rapport de concentration molaire de [F-]:[Ag(I)+] étant de 2: 1 à 20: 1, et le pH de la solution étant de 5,35 à 6,0.
PCT/EP2023/052874 2022-02-28 2023-02-06 Compositions pour le traitement de caries dentaires WO2023161003A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2202761.9 2022-02-28
GB2202761.9A GB2610009B (en) 2022-02-28 2022-02-28 Stable compositions for the treatment of dental caries

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WO2023161003A1 true WO2023161003A1 (fr) 2023-08-31

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WO (1) WO2023161003A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU554112B2 (en) * 1982-08-06 1986-08-07 Agson Chemical Export Pty. Ltd. Silver fluoride compositions for treatment of dental caries
WO2018058199A1 (fr) * 2016-09-30 2018-04-05 R.M Creighton Dental Pty Ltd Solutions de divulgation de l'état de caries dentaires
WO2019153033A1 (fr) 2018-02-12 2019-08-15 Sdi Limited Solutions de fluorure d'argent pour compositions dentaires
WO2020021495A1 (fr) 2018-07-27 2020-01-30 3M Innovative Properties Company Compositions aqueuses contenant du thiocyanate pour soins buccodentaires, procédés et kits
WO2020044230A1 (fr) * 2018-08-28 2020-03-05 3M Innovative Properties Company Solutions aqueuses de soin buccal, procédés, kits et surfaces dentaires comportant un revêtement dérivé de la solution de soin buccal

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU554112B2 (en) * 1982-08-06 1986-08-07 Agson Chemical Export Pty. Ltd. Silver fluoride compositions for treatment of dental caries
WO2018058199A1 (fr) * 2016-09-30 2018-04-05 R.M Creighton Dental Pty Ltd Solutions de divulgation de l'état de caries dentaires
WO2019153033A1 (fr) 2018-02-12 2019-08-15 Sdi Limited Solutions de fluorure d'argent pour compositions dentaires
WO2020021495A1 (fr) 2018-07-27 2020-01-30 3M Innovative Properties Company Compositions aqueuses contenant du thiocyanate pour soins buccodentaires, procédés et kits
WO2020021494A1 (fr) 2018-07-27 2020-01-30 3M Innovative Properties Company Compositions aqueuses contenant de l'iodure pour des soins buccaux, procédés et trousses
WO2020044230A1 (fr) * 2018-08-28 2020-03-05 3M Innovative Properties Company Solutions aqueuses de soin buccal, procédés, kits et surfaces dentaires comportant un revêtement dérivé de la solution de soin buccal

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BJERRUM, J: "Metal amine formation in solution XXVI. Stability constant and UV absorption spectrum of the triammine silver(I) complex", ACTA CHIMICA SCANDINAVICA, vol. A40, 1986, pages 392 - 396
DAGNALL, R. M.WEST, T. S.: "A selective and sensitive colour reaction for silver", TALANTA, vol. 11, no. 11, 1964, pages 1533 - 1541, XP026566546, DOI: 10.1016/0039-9140(64)80225-3
SILWOOD, C.J.L.LYNCH, E.J.SEDDON, S.SHEERIN, A.CLAXSON, A.W.D.GROOTVELD, M.C.: "1H NMR analysis of microbial-derived organic acids in primary root carious lesions and saliva", NMR IN BIOMEDICINE, vol. 12, 1999, pages 345 - 356, XP055328651, DOI: 10.1002/(SICI)1099-1492(199910)12:6<345::AID-NBM580>3.0.CO;2-C

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GB2610009B (en) 2023-11-08
GB202202761D0 (en) 2022-04-13

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