WO2011067653A1 - Oral compositions for use in the mercury intoxication from dental amalgam - Google Patents

Abstract

The invention refers to a composition to treat or prevent in subjects with sub-clinical or acute mercury intoxication from dental amalgam, or a diagnostic tool thereof. The odontostamatologic composition comprising at least a non-resorbable, preoxidised or fully oxidised thiolated polymer are used as efficient detoxifying products in oral care; or as diagnostic aid to asses the mercury exposure on mouth in subjects with dental amalgam. Inventive compositions include dentifrices, pastes, gel, mouthwashes, dental trays, and protective mask for dentistry professionals comprising thiolated polymers such as partially or fully oxidised micronized macroporous or hydrocolloidal thiolated polymers, or urea- functionalized polymer affording the broad sequestration of the intra-oral mercury.

Description

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ORAL COMPOSITIONS FOR USE IN THE MERCURY INTOXICATION FROM DENTAL AMALGAM

FIELD OF THE INVENTION

The invention refers to compositions for the therapeutic/preventive treatment or as diagnostic aid in subjects with dental amalgam.

BACKGROUND OF THE INVENTION

The long dispute about the health hazards by the chronic exposure to the mercury vapour released from the dental amalgam filling is endless. There is sufficient body of evidences that health disturbances from Hg exposure occur in patients bearing amalgam as well as in dental professionals (Lindbohm ML et al. Occup Environ Med. 2007; 64(2): 127-33.; Hilt B et al. Neurotoxicology. 2009; 30(6): 1202-6.).

The use of amalgam filling in dentistry is controversial since beside evident advantages such as low cost, high durability and excellent mechanical strength, several concerns refer to its health risks, i.e. toxic and allergic reactions associated with a chronic Hg exposure.

However, many studies correlate the mercury toxicity with a variety of disorders such as neurodegeneration, birth defects and/or preterm burdens (Palkovicova L et al. J Expo Sci Environ Epidemiol. 2008;18(3):326-31), and a number of oral lesions including lichenoid lesions and burning mouth syndrome. The British Dental Association estimates that around 3% of the population is sensitized to mercury, and this can trigger a host of symptoms, including immune dysfunctions (Hultman P et al. FASEB J, 1994; 8:1183-90).

When a subject has a confirmed acute or chronic Hg intoxication, he/she should undergo an extraction program of amalgam filling and/or a chelation therepy. Chelating agents such as sodium 2,3-dimercaptopropane 1-sulfonate (DMPS) and meso 2,3-dimercaptosuccinic acid (DMSA), along whilst calcium disodium ethylenediamine tetraacetic acid (CaNa₂EDTA) are the best known treatments in mercury poisoning.

However, the systemic chelation bring about several side effects (Risher JF et al., Neurotoxicology. 2005;26:691-9) mostly attributed to due to systemic Hg redistribution. This is the case of lipophilic chelators, that decrease the intracellular stores (Andersen O, et al. Environ Health Perspect. 2002;110 Suppl 5:887-90) but also redistribute mercury to, for example, the brain. Actually, a hydrophilic chelator such as CaNa₂EDTA promotes the renal excretion, but removes the intracellular metal deposits inefficiently.

Noteworthy, the local chelation in oral cavity could represents an efficient therapeutic or preventive treatment in mercury intoxication. The same issue, i.e. systemic redistribution of the sequestered mercury, will however occur if an improper material were used.

The issue is complicated by the coexistence of three redox status: elemental mercury (Hg°), bivalent mercury (Hg^4"1") and methylmercury (MeHg⁺), the latter a by-product of the oral microflora (Heintze U et al., "Methylation of mercury from dental amalgam and mercuric chloride by oral streptococci in vitro". Scand J Dent Res. 1983; 91(2):150-2).

Noteworthy, each of these coexisting form of mercury has a peculiar toxicity profile, with a differentiated reactivity toward ligands and chelators, so that an efficacious mercury sequestration in local compartments is certainly not trivial.

WO 0130707 discloses a device and method to decontaminate the dental waste streams containing mercury. This device is claimed for the removal of both soluble and insoluble forms of Hg in a single step. Indeed, the amalgam separator marketed by SolmeteX Co. (Northborough , Mass, USA) should be a wet-filtering set containing a thiolated resin along with a mechanical filter (activated charcoal), since the former alone seems not to suffice.

US 6013246 discloses a method of inactivating ionic and elemental Hg in oral cavities by the administration of sulfurated amino acid or protein, or small sulfurated molecules such as thiocarbamide, dithioethanol, DMSA, and the like. However, these substances intercept mercury, but then a gastrointestinal re-absorption of the chelated mercury will occur.

US 4141888 discloses the use of reduced keratine for the chelation of toxic cations. According to our findings, however, the reduced thiol groups of keratin do not efficiently sequestrate Hg°. This approach is furthermore endowed of another draw-back, namely the substantial gastrointestinal resorption of the chelated mercury whenever the oral ingestion should happen.

Thus, there is a need to render harmless and/or to detect quantitatively estimated the mercury released within oral cavity, and which were not encumbered with the aforesaid problems. SUMMARY OF THE INVENTION

It has been discovered that certain thiolated polymers provide the broad sequestration of mercury in its different oxidation status on the oral cavity.

The invention therefore provides a composition comprising a non-resorbable thiolated polymer in partially oxidised form to attain the broad sequestration of Hg in the oral cavity in a subject with dental amalgam for therapeutic/preventive or diagnostic use.

In one aspects, the composition of invention are suited for the treatment or the prevention of local and systemic disorders due to the chronic exposure to mercury, as well as for the attenuation of the risk of mercury overloading in the foetus of a pregnant women.

Generally, the inventive composition comprises 'physiologically acceptable eccipients, in an aspect with a macroporous thiolated polymer or a hydrocolloidal thiolated polymer.

In an aspect, said partially oxidised thiolated polymers are characterized in that both thiol (-SH) and disulfide (-SS-) groups are present with a typical SH/SS ratio < 6:1 eq/eq.

In another aspect, the composition for the aforesaid use comprises a fully oxidised thiolic polymer in the form of a thiourea-functionalized thiolated polymer along with physiologically acceptable eccipients.

In yet another aspect, the compositions are characterized by the substantially absence of any low molecular weight thiolic substance to avoid formation of resorbable chelated Hg. In still another aspects, the composition , further comprises complementary substances such as elemental metals having specific affinity for elemental mercury or sulphide thereof; maleate copolymer; thiolated silica or alumina-DMSO complex to enhance efficacy.

These and other aspects will became apparent by the foregoing description.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the particle distribution of Ambersep GT74, hereafter Thiolated polymer A. Fig. 2 is a schematic view of the Hg analyzer used on the in vitro and in vivo assays. Figs. 3-4 show the in vitro data expressed as polymer efficiency (jj,mol[H ]/g of polymer) and probe efficiency (yield, % theoretical value) of Thiolated Polymers as in Examples 1-7. Figs. 5-6 show same data above relevant- to complementary or comparative polymers arid/or combination thereof as in Examples 8-11 and Comparative Examples 1 -4. DETAILED DESCRIPTION OF THE INVENTION

It has been surprisingly found that a synthetic non-resorbable thiolated polymer with a controlled degree of oxidation is able to sequestrate both elemental and bivalent forms of mercury (Hg), hence being suitable for odontostomatologic purposes in subjects bearing dental amalgam with acute, sub-acute or latent mercury intoxication.

Actually, if chelation of a thiol group to Hg(II) by thiolated polymer is expected, this does not apply to the sequestration of Hg° by disulfides, if considering the unfavourable standard potentials: E°(V)Hg(n)/Hg° = +0,85 and E°(V)SS/2SH = +0,25.

The expression "bivalent mercury" as used herein means the forms of bivalent mercury, including the inorganic form (Hg⁴ ) as well as the organic species such as methylmercury (MeHg ) and ethylmercury (EtHg⁴), also herein collectively referred to as "Hg(II)".

The expression "elemental mercury" as used herein means the metallic mercury (Hg°) in liquid or vaporized state present in the oral cavity of a subject with dental amalgam.

The term "non-resorbable polymer" as used herein means a polymer which cannot be broken down and assimilated from the oral cavity, or even upon the fortuitous swallowing.

The term "partially oxidised thiolated polymer" or "partially oxidised thiolated polymer" means a thiolic polymer subjected to a controlled oxidation to convert part of the thiol (SH) groups into disulfide (SS) groups. The SH/SS molar ratio is comprised from about 5:1 to about 1 :100 eq/eq. Preferably the SH/SS ratio is at least lower than 6:1 eq/eq.

The expression "partially oxidised thiolated polymer" and "controlled oxidation of thiolated polymer" herein may be used interchangeably.

The controlled oxidation can be obtained with a flux of air or oxygen, or by treating with oxidant such as hydrogen peroxide, either in dry or wet condition. After pre-treatment, the thiolated polymer shall have from 1/5 to at least 3/4 of oxidised S, preferably at least 1/3 of the S-groups present in the form of disulfides groups.

In one embodiment, the composition of invention comprises a partially oxidised macroporous thiolated polymer, i.e. cross-linked thiolated resin in partially oxidised form.

The expression "macroporous thiolated polymer" as used herein means a high crosslinked polymer (>5%) with 50 nm to 1 μηι porous within its structure, originally produced in beads before the micronization step, herein also named "thiolated resins". Example of commercial thiolated resins useful as starting material include: Ambersep GT74 and XUS-43604 (Dow Corp.); Lewatit Monoplus TP214 (Lanxess AG); Purolite S924 (Purolite Int.); Indion MSR (Ion Exchange Ltd); SIR-200 (ResinTech Corp.); QuadraPure DET and MPA (Johnson Matthey); and Ionac SR-4 (Lanxess Chemicals Inc.). The afore said thiolated resin are offered as 400-1200 μηι beads stored in wet conditions. Before use the beads are preferably dried, and then micronized. The micronization may be carried out by several means including jet milling, ball milling and the like, until a particle size of, generally, < 50 μηι is attained. More preferably, the micronized resin shall have a particle size < 20 μηι for at least 90% of the particles.

Noteworthy, thiolated resin are stored under water to prevent oxidation. When both drying and micronization steps are carried out in ambient air, this may suffice to attain the desired oxidation level. Otherwise, the polymer is further oxidised in wet or dry conditions.

A peculiar form of thiolated resin is on fibers, e.g. Smopex™ fibers by Johnson-Metthey such as Smopex 111, p-thiobenzyl functional fiber; Smopex 112, a vinyl thioglycerolate functional fiber; and Smopex 234, a carboxy 2-ethylthiolated fiber.

In one embodiment, the composition of invention comprises a partially oxidised hydrocolloidal thiolated polymer.

The expression "hydrocolloidal thiolated polymer" means a water-soluble or water- swellable polymer functionalized with thiol groups, characterized by no or low cross- linldng (< 5%), e.g. as described by Bernkop-Schniirch A, in Adv Drug Deliv Rev. 2005,3;57(l l):1569-82.

Examples of hydrocolloidal thiolated polymer include thiolated polycarbophil and thiolated polyacrylates (PAA), and other conjugated hydrocolloid polymers manufactured by Thiomatrix GmbH (Innsbruck, Austria) of Bernkop-Schnurch.

Other hydrocolloidal thiolated polymers include Spheron Thiol 1000 (Lachema, Brno, Czech Republic); QuadraPure™ MPA (Johnson-Metthey); thiolated polyalkylglicols as disclosed in WO2008123389 (Nippon Shokubai, Osaka, J); and the hydrocolloidal thiolated polymers described in WO/2007/071375 (Unilever), including the ammino-thiols and hydroxy-thiols obtained with bifunctional reagents such as 2-iminothiolane (the Traut's reagent). Noteworthy, the resorbable hydrocolloidal thiolated polymers such as thiolated cellulose, thiolated alginate, thiolate chitosan, thiolated hyaluronan, thiolated polylysine or polyarginine, and thiolated PEG stearate may used exclusively in rinse off oral care products to avoid the systemic Hg resorption.

The hydrocolloidal thiolated polymers may came partially oxidized directly as supplied by the manufacturers, such as those from Thiomatrix, which general SH/SS ratio < 3 eq/eq. Otherwise a further oxidation step, e.g. in solution with ambient air, shall be carried out. The oxidation step may be performed during the manufacturing of the composition by suspending the hydrocolloidal thiolated polymer in water, neutralizing with a base (e.g. NaOH) in case of PAA and the like, and vigorous stirring to incorporate air and until at least 1/3 of the thiol groups are converted into the corresponding disulfides.

A particular hydrocolloidal thiolated polymer is Crodasone™ cystine, a ~ 20 kd copolymer of cystine and silicone from Croda Chemicals (East Yorkshire, UK), which is a fully oxidized hydrocolloidal thiolated polymer. This material is supplied as 2% w/v aqueous solution, and shall be preferably used in rinse-off, liquid or gel formulations.

In one embodiment, the composition comprises a thiourea-functionalized polymer.

A thiourea group is at a higher oxidation level than a thiolic group, see the comparison between a >C=S moiety with the >CH-SH moiety, which parallels the alcohol-aldehyde redox pair. Note that the expression "thiourea-functionalized polymer" or "thiourea resins" as interchangeable and herein includes thiourea and isothiorea-functionalised polymers.

Preferred thiourea-functionalized polymer are those originally produced in 1.2-0.5 mm beads, that shall be therefore micronized before use in the inventive formulations.

Example of such thiourea resins include: Lewatit MP 500 (Lanxess AG); Purolite S920 (Purolite Int.); QuadraPure TU (Johnson Matthey; Indion TCR (Ion Exchange Ltd; Mumbai, India); Relite MAC4 (Mitsubishi-Resindion); SIR-400 (ResinTech Inc.); Ionac SR-4 (Lanxess Sybron Chemicals Inc.).

The afore said thiourea resins are generally supplied in form of macroporous beads of 1400-400 μιη in size. Therefore they may be micronized by jet milling, ball milling and the like until a particle size generally < 50 μιη is attained. More preferably, the micronized thiourea resins shall have a particle size < 20 μηα of 90% of the particles. 6

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The above thiolated polymer may be formulated with know techniques in odontostomatologic, oral care dosage product to afford the inventive compositions.

The amount of thiolated polymers within the composition of invention may be from 50% to 0.005% w/w, preferably between 5% and 0.01% w/w, even more preferably between 2% and 0.2% w/w of the composition.

In another embodiment, a thiolated polymer is combined with compounds having high affinity for elemental mercury.

The expression "compounds high specific affinity for elemental mercury" as used herein means certain elemental metals forming amalgam with Hg and their sulfides. Elemental metals suitable the inventive purposes include elemental gold, silver, zinc, aluminium, copper and other metals amalgamating with mercury, in finely dispersed form. The sulfides suitable for our purposes include: argentite (AgS), sphalerite (ZnS), pyrite (FeS) and calcopyrite (CuFeS₂) in finely dispersed form. The compounds with specific affinity for Hg° may be added to the composition of invention from 1% to 0.001% w/w, preferably from 0.1% to 0.01% w/w.

In another embodiment, the composition further comprises a polymaleate.

Polymaleates are copolymer of maleic anhydride (MA) with other ethylenic monomers. Exemplary polymaleates include the MVE/MA copolymer, Gantrez™ AN-139 and S97BF (ISP, Winston-Salem, NC, USA); Ethylene/MA/Propylene copolymers, ZeMac™ (Vertellus; Indianapolis, ΓΝ, USA); Octadecene/MA copolymers (Chevron, Boston, MA, USA); PVM/MA copolymer, Luviform™ FA 139 (BASF, Ludwigshafen, Germany); and C4-12 Olefin/MA copolymers (Kao Corp., Wakayama-shi, Japan). The composition of the invention may include a polymaleate from 0.05% to 5% w/w, preferably from 1% to 0.1% w/w of the composition.

In another embodiment, the composition further comprises a thiolated silica gel.

Examples of thiolated silica gel are QuadraSil™ MP (marcaptopropyl) from Johnson- Metthey; SiliaBond™ Cysteine, SiliaBond™ DMT, and SiliaBond™ Thiol from SiliCycle Inc. (Quebec City, Canada); and MSA-FC Si-3 (BASF, Germany).

Said thiolated silica gel may be used as such when supplied as 40 to 70 μηι poweders, otherwise are micronized by jet milling and the like until a particle size lower than 20 μπι. In another embodiment, the composition of invention further comprises a alumina reacted with dimethylsulfoxide (DMSO), hereafter named "alumina-DMSO complex".

Said complex are obtainable by dry-mixing alumina and DMSO at ambient temperature or under moderate heating as described by Soliman et al. (Talanta 2006; 69(l):55-60) with formation of a (CH₃)₂-S-0-Al-0 moieties. Other alumosilicates or silicates may be used.

The composition of invention are further characterized by the substantially absence of low molecular weight thiolic substances (hereafter also named "LWM thiolates") so to avoid the presence of chelated mercury undergoing the systemic resorption.

The expression "substantially absence" as used herein means that the residual content of unbonded LMW thiolates is < 1 % w/w, more preferably < 0.1 % w/wf the composition.

The composition according to the invention comprises physiologically acceptable eccipients, being formulated according to known techniques with a variety of ingredients suitable for oral-care, e.g. those described in ADA/PDR: Guide to Dental Therapeutics, 4th Edition by Physicians' Desk Reference and American Dental Association (ADA).

In one embodiment, the composition of invention is a liquid or semi-liquid rinse-off, substantially non-ingestible, oral formulation such as mouthwash, oral solution, spray, gel on film, and other mouth-rinse products.

In one embodiment, the composition of invention is a "dentifrice", including any product for the dental hygiene such as mono- and multiphase tooth paste, liquid dentifrice, tooth powder, dental tablets, cream and dental gels.

In one embodiment, the composition of invention is a chewing gum, chewable tablets, lozenges, and a variety of chewable presentations classifiable as "chewing gum".

In other embodiment, the composition of inventions are gel, film, gel on film, granules, paste, spreadable powders, etc. to be applied on denture directly or by an external device. Such external devices may be in the form of a dental tray, which has the function to contain a gel, paste or other semi-solid formulations comprising a thiolated polymer and keep in contact with the subject's denture for an extended period of time.

In one embodiment, the composition of invention is a dental tray surface-coated with, or produced from (a blend of polymer comprising), a thiolated polymer. These dental trays give the advantage of a long contact time, for example if applied overnight during sleep time, or during several hours in day time to afford an extended Hg detoxification.

Other ingredient useful in the inventive composition may include anti-caries, desensitizers, rheologic agents, diluents, emulsifiers, foam modulators, pH modifiers, abrasives, humectants, taste modifier, sweeteners, flavour and aroma, dyes, biocides, etc. In an applicative embodiment, the compositions according to the invention in form of dentifrice, chewing gum, gel, and mouthwash are applied from 1 to 3 times a day in subjects, or at least 1 to 2 times a week for the treatment of acute and sub-acute patients, or for the prophylactic/preventive use in asympthomatic subjects.

The treatment may be carried out under dentist supervision or upon patient responsibility for few day to 6 months or more, until the relieve of symptom of local intoxication from mercury.

Preferred subjects for the use of the compositions according to the present invention have a certain number of amalgam fillings, for example from 5 to 20 or more, preferably more than 8, although subjects with a lower number of amalgam fillings (1 to 5) may beneficially use the inventive composition.

In a further applicative embodiment, the composition according to the present invention is a working mask imbedded with the thiolated polymers. Said device are intended as disposable working mask for the dentistry personnel.

In other embodiment, the composition of invention is administered to a pregnant woman with dental amalgam to attenuate foetus Hg overloading and the risk of autistic outcome.

The composition of invention are useful in the treatment or prevention of local lesions such as oral lichenoid lesion, cheilitis, stomatitis, burning mouth syndrome, aphtous stomatitis, amalgam tattoo, and disorders on adjacent skin such as dermatitis and acrodynia The composition of invention are also useful in the treatment or prevention of systemic disorders due to mercury such as neuro-diseases, ulcerative damages on gastrointestinal tract, autoimmune disorders, or damages to the endocrine-reproductive system.

In other embodiment, the composition of invention is a diagnostic aid for the evaluation of mercury exposure in a subject with dental amalgam. The diagnostic aid will comprise a composition capable to sequestrate mercury in the oral cavity by applying therein, and analyzed for the mercury content for the assessment of Hg exposure. For example a chewing gum comprising 01% w/w of thiolated polymer is chewed by the subject for at least 5 minutes. The chewed gum is withdrawn and analyzed with an specific instrument, e.g. DMA-80 or AMA-254 (see example section).

The examples are intended to illustrate, but not to limit, the present invention.

EXAMPLES

EXAMPLE 1

In vitro efficacy assessment on a preoxidised macroporous thiolated polymer

This in vitro model aims to screen the efficiency of a thiolated polymer in the Hg sequestration.

Amalgam preparation A number of Dispersalloy™ Self-activating capsules (Dentsplay, York, PA, USA) with the following composition: Silver 277.2 mg; Tin 71.6 mg; Copper 47.2 mg; Zinc 4.0 mg; Mercury (Hg°) 396 mg; were treated for 7-8 sec. in amalgamator. The capsules were conditioned by flushing with water at 14-18°C for 48 hours before use. The assay method Each mercury amalgam was charged in a PE cap-screw of 100 mm length and 25 mm of diameter, loaded with 50 ml of sample suspension (the probe). Upside-down (180°) rotations a 30 rpm were applied during 2 min. (t₂), than a 25 ml of sample was recovered. Next 25 ml sample was obtained after further 20 min. at 30 rpm (t₂₂). Samples of the probes (stirred suspensions) were analyzed by DMA-80 or AMA-254 to quantify mercury. NB The aliquots taken at time 0, i.e. analysed before contacting the test solution with an amalgam capsule, provided non-significant levels of mercury (data not shown).

Mercury analysis Measurement of mercury was carried out either with DMA-80 (Direct Mercury Analyzer) of Milestone Sri (Sorisole (BG), Italy) or by AMA-254 of Leco Corp. (St. Joseph, Mich, USA). Both apparatuses work without wet chemistry pre-treatment but by thermal decomposition, gold amalgamation and thermal desorption, with final UV reading of the released Hg°, in accordance to ASTM Method D-6722.

The apparatus is detailed in FIG. 2. In brief, weighted samples (10-200 μg) loaded into the sampler (1) are inserted on a platinum boat (2) into the dry and decomposition furnace (3) where are first dried and then thermally decomposed into the catalytic furnace (4). Mercury and other combustion products move from the catalytic section where C, N and S oxides and other interfering compounds are eliminated. Released Hg° is selectively trapped in the release furnace (5) by an amalgamator (6), a gold trap which is then heated to flows through an oxygen carrier into the cell heating block (9) section composed of a dual-cell (10, 11) or tri-cell, wherein the Hg lamp (7), the shutter (8), the filter (12) and the detector

(13) provide the relevant absorption value at 253.65 nm, which go into the read-out system

(14) to be further processed via pc.

Determination of thiol and disulfide groups Quantification of SH and SS content may be performed by IR spectophotometry, or by chemical titration with Ellman's reagent (DTNB, 5,5'-Dithiobis(2-nitrobenzoic acid)). In brief, 9 mg of the thiolated polymer are swelled for in 1 ml of a solution of 100 mM phosphate buffer at pH 8, 2.50 mN HC1 and 4% NaCl. After adding 50 μΐ of IN NaOH, aliquots of 200 are transferred in wells of a microtitration plate incubated for 45 min. with 100 μΐ, of 0.4% w/v DTNB in 0.5 M phosphate buffer pH 7, and then read at 405 nm. The thiol groups are calculated using a standard curve of cysteine solutions. The disulfide content is also determined by Ellman's reagent prior reduction with NaBH₄ as per Habeeb et al. Anal. Biochem. 1973, 56: 60-5.

Sample preparation and Results The resin Ambersep GT74 is a macroporous resin with thiolphenolic functionality; a SH content of 0.7 meq/g and residual sulfonic groups < 20% of total sulfur. The beads of 450-700 μηι were dried and then jet milled in a MCIOOBD apparatus at 6.5 bar, PE 6.6 up to a particle size < 20 μηι (see FIG. 1 for details) and with a SH/SS ratio ~3:1 eq/eq, hereafter named Thiolated polymer A. 100 mg of micronized resin were suspended in water at 0.2% w/v, and tested as described. Results are noted in Table I.

EXAMPLE 2

In vitro efficacy assessment on another preoxidised macroporous thiolated polymer

The test described in Example 1 was carried out with Purolite S924 instead of Ambersep. Purolite™ S924 is a PS/DVD resin with -CH₂-SH groups and a thiol content of 2 meq/g of dry polymer before oxidation. The resin supplied as beads of 400-800 μηι was dried and jet milled to < 20 μηι, with SH/SS ratio -3:1 eq/eq after fluxing in warm air for 30 min., hereafter Thiolated polymer B. Results are noted in Table I. EXAMPLES 3-5

In vitro efficacy assessment on preoxidised hydrocoUoidal thiolated polymers

The same test described in Example 1 was carried out with hydrocoUoidal thiolated polymers supplied by Thiomatrix after dissolution in water and neutralization with NaOH. Tested materials were: polyacrylate low cystein-conjugated, SH+SS of 600 meq/g and SH/SS ratio of 5:3 eq/eq (PAA-Cys LC); polyacrylate high cystein-conjugated, SH+SS content of 870 meq/g and SH/SS ratio > 10:1 eq/eq (PAA-Cys HC); and a polycarbopol 974 F cystein-conjugated, SH+SS content of 430 meq/g and SH/SS ratio of 5:3 eq/eq, (PCP-Cys). B The PAA-Cys HC in neutralized solution was vigorously stirred until at least 1/3 of the thiol groups were oxidised. The hydrocoUoidal thiolated polymers, hereafter Thiolated polymer C, D and E, respectively, were tested accordingly. Results of the assays are noted in Table I.

EXAMPLE 6

In vitro efficacy assessment on a thiolated polymer of thiourea type

The test described in Example 1 was carried out with Purolite S920 instead of Ambersep. Purolite™ S920 is a thiourea-funcional resin having 2 meq/g on dry basis. The 1200 μηι beads were dried and milled in a mortar to 100-20 μιχι, hereafter Thiolated polymer F. Results are noted in Table I.

EXAMPLE 7

In vitro efficacy assessment on a silicon-cystine thiolated polymer

The test as in Example 1 was carried out with Crodasone™ cystine instead of Ambersep. Crodasone Cystine is a copolymer cystine-silicone ~ 20 kd supplied by Croda Chemicals, hereafter named Thiolated polymer G. It was diluted to 0.2 % w/v and tested accordingly. Results are noted in Table I.

As shown in Table I, the selected polymers have excellent efficiency with regard to Hg sequestration in the model test. Resins and hydrocoUoidal thiolated polymers with comparable contents of SH and SS groups own an equivalent potency. The performance at t₂ of the Thiolated polymers C and E followed by a lower results at t₂₂ shall mean that the saturation capacity of the available sequestering groups is achieved.

The other Thiolated polymer F having thiourea-functional groups also shows an excellent performance, thus confirming that the C=S group within the thiourea moiety has the same ability to sequestrate the Hg°, which actually is the prevalent form of released mercury from the dental amalgam.

TABLE I

Tested polymer Probe Sample Hg Hg in Polymer Recovery Probe

(contact time, min.) cone. weight found Probe capacity [ g(Hg)/ efficiency

(w/v) (mg) [ng] [ppb] [mmol_Hg/g] probe] (yield)

(i) (ii) (iii) (iv) (v) (vi) (vii) (viii)

Thiolated polymer A 2' 0.2% 102 11.3 110 0.3 5.5 23%

" 22' 0.2% 58 52.4 906 2.3 22.7 94%

Thiolated polymer B 2' 0.2% 97 3.5 36 0.1 1.8 8%

22' 0.2% 100 90.6 906 2.3 22.6 94%

Thiolated polymer C 2' 0.2% 75 26.3 351 0.9 17.6 73%

22' 0.2% 75 50.9 679 1.7 17.0 71%

Thiolated polymer D 2' 0.2% 96 18.4 191 0.5 9.6 40%

22' 0.2% 100 88.7 887 2.2 22.2 92%

Thiolated polymer E 2' 0.2% 85 12.8 150 0.4 7.5 31%

22' 0.2% 85 59.7 703 1.8 17.6 73%

Thiolated polymer F 2' 0.2% 97 7.5 77 0.2 3.9 16%

22' 0.2% 100 95.7 957 2.4 23.9 100%

Thiolated polymer G 2' 0.2% 50 14.0 281 0.7 7.0 29%

22' 0.2% 50 21.3 425 1.1 10.6 44%

Note that Table I has the following meaning: column (i) lists the polymer tested at time t₂ and t₂₂; column (ii) is the polymer concentration within the probe suspension; (iii) is the sample weight in mg; column (iv) is the actual value found; column (iv) is the calculated sequestered Hg in μg/kg of probe (ppb); column (v) is the sequestered Hg (mmol) per g of thiolated polymer; column (vi) is the Hg actually sequestered by each probe calculated on the total volume; and column (vi) represents the efficiency of a given probe compared with the theoretical (maximal) value of 24 μg, herein used as reference. EXAMPLE 8

In vitro efficacy assessment on thiolated silica

The test aims to evaluate the efficacy of complementary material such as thiolated silica gel. The test as in Example 1 was carried out with QuadraSil MP instead of Ambersep. QuadraSil MP is thiolated silica of 70-40 μηι with an original SH content of 1.2 meq/g. It was suspended in water at 0.2% w/v under stirring until, hereafter "thiolated silica gel" and tested. Results are noted in Table II.

EXAMPLE 9

In vitro efficacy assessment on Alumina-DMSO

The test aims to evaluate the efficacy of a particular complex with sufurated molecule. The test as per Example 8 was carried out with a alumina-DMSO instead of QuadraSil. In brief, 6 g of aluminium oxide (Sigma- Aldrich cat. N. 11028) was grinded in a mortar with 1.2 g of dimethyl sulfoxide, DMSO (Sigma- Aldrich) and dried at room temperature for three days, hereafter "Alumina-DMSO". It was suspended in water at 1% w/v and tested.

EXAMPLE 10

In vitro efficacy assessment on an elemental metal in cooperation with a thiolated polymer The test aims to evaluate the complementary activity of elemental metals amalgamating with mercury for the inventive purposes. In this frame, < 3 um elemental dendritic copper from Sigma-Aldrich (Aldrich Cat. N. 357456) was suspended at 0.05% w/v, hereafter noted as "Elemental Cu°" in Table II. In parallel, a mix of 25 mg of Cu° and 50 mg of Thiolated polymer A (0.05% + 0.1% w/v) was tested. Results are noted in Table Π. EXAMPLE 11

In vitro efficacy assessment on a polymaleate in cooperation with a thiolated polymer

The test aims to evaluate the complementary activity of a polymaleate. In this frame, a polymaleate, namely Gantrez™ S97BF (hereafter Polymer A) was assayed in combination with the Thiolated polymer A as per Example 1 in suspension at 0.2% and 0.05% w/v, respectively, and tested accordingly. Results are noted in Table II. COMPARATIVE EXAMPLE 1

In vitro efficacy assessment on a low oxidised thiolated polymer

The assay aims to evaluate the efficiency of a low oxidised thiolated polymer. A low oxidized polymer was obtained by micronizing Purolite™ S924 in wet condition. The powder was exposed to cold ambient air to ensure a final SH/SS ratio of around 10:1 eq/eq, hereafter Polymer B, tested at 0.2% w/v as Example 1. Results are noted in Table Π.

COMPARATIVE EXAMPLE 2

In vitro efficacy assessment on keratin

The assay aims to evaluate the efficiency of a proteinacous thiolic polymer. A keratine solution was obtained by diluting Keratec™ IFP (Croda, East Yorkshire, UK) to 2% w/v aqueous solution, hereafter Polymer C. The assay was performed as usual. Results are noted in Table II. COMPARATIVE EXAMPLE 3

In vitro efficacy assessment on a non-thiolic polymer

The assay aims to evaluate the efficiency of a non-thiolated polymer. Amberlite IRC748 (Rohm&Haas-Dow) is an iminodiacetic chelating resin in beads form with 4.2 eq/g on dry basis. It underwent a micronization step before suspending it at 0.2% w/v, hereafter Polymer D. The assay was performed as usual. Results are noted in Table Π.

COMPARATIVE EXAMPLE 4

In vitro efficacy assessment of thiolated polymer in the presence of a low thiolic substance The test aims to ascertain the competition among thiolated polymers and cysteine. In this frame, Thiolated polymer A as per Example 1 (the partially oxidised and micronized Ambersep GT74) was dispersed in water at 0.1% w/v along with 0.1 % w/v 1-cysteine, i.e. 50 + 50 mg of each in 50 ml of water, hereafter named "Thiolated polymer A + Cys". The assay were carried out as in Example 1 except that aliquots of the suspension after the test were filtrated to afford the cysteine solution, hereafter "Cysteine filtrate". All samples were analyzed for Hg and results are noted in Table V As shown in Table Π, the is a large diversity in behaviour among the material tested.

Thiolates silica gel provided a modest result, at least in the model test, whilst the alumina-DMSO complex shows a high efficiency. Elemental copper and polymaleate (polymer A) enhance the efficiency of thiolated polymers, which can be therefore used at lower concentration with comparative efficiency. Instead, low-oxidised thiolated polymer, keratin and the non-thiolic chelating polymers show limited capacity of Hg sequestration, being prevalent the presence of Hg° released by the dental amalgam both in vitro and in vivo conditions. Moreover, a low molecular weight thiolic substance such as cysteine actually competes with thiolated polymers in Hg sequestration. This poses a risk of having chelated mercury suitable of re-absorption and systemic uptake, unwanted effects.

TABLE Π

Tested polymer, Probe Sample Hg Hg in Polymer Recovery Probe substance or mixes cone. weight found Probe capacity I Hg)/ efficiency

(contact time, min.) (w/v) (mg) [ng] [ppb] [mmol_Hg/g] probe] (yield)

(i) (ii) (iii) (iv) (v) (vi) (vii) (viii)

Thiolated silica 2' 0.2% 75 3.3 44 0.1 2.2 9%

" 22' 0.2% 74 20.5 276 0.7 6.9 29%

AlOx-DMSO 2' 1.0% 204 20.9 102 0.1 5.1 21%

22' 1.0% 201 201.9 1003 0.5 25.1 105%

Thiolat. pol A+Cys 2' 0.2% 98 12.6 129 0.3 6.4 27%

22' 0.2% 100 48.6 486 1.2 12.2 51%

Cysteine 2' 0.1% 96 0.8 9 0.0 0.4 2%

" 22' 0.1% 100 34.3 343 1.7 8.6 36%

Elemental Cu° 2' 0.1% 50 2.8 56 0.6 2.8 12%

22' 0.1% 100 66.6 666 6.7 16.6 69%

Thiolated pol A+Cu° 2' 0.2% 50 6.1 123 0.4 6.1 26%

22' 0.2% 100 70.0 700 2.3 17.5 73%

Thiolat. pol A+Pol A 2' 0.5% 106 10.8 102 0.1 5.1 21%

22' 0.5% 84 82.3 978 1.0 24.5 102%

Polymer B 2' 0.2% 98 1.6 17 0.0 0.8 3%

" 22' 0.2% 99 31.0 314 0.8 7.8 33%

Polymer C 2' 2.0% 101 5.9 59 0.0 7.9 33%

" 22' 2.0% 99 11.2 114 0.1 10.5 44%

Polymer D 2' 0.2% 101 0.0 0 0.0 0.0 0%

" 22' 0.2% 102 26.6 260 0.7 6.5 27% EXAMPLE 12

Dentifrice #1

The commercial dentifrice Mentadent™ White Now (Unilever) was modified by the adding to the extracted gel the Thiolated polymer A as obtained in Example 1 at a level of 0.2 % w/w, gently stirred until a homogenous mixture was produced.

EXAMPLES 13

In vivo efficacy assessment with dentifrice #1

The experiment aims to test a dentifrice in a subject with dental amalgam.A subject with 8 dental amalgams (hereafter "Subject 8 A") used 5 g of dentifrice as obtained in Example 17 for four consecutive days, every evening 30 min. before dinner. The rinsing waters (10 ml) were collected, diluted to 50 ml and analyzed for mercury. Data provide a total sequestration of 73.3 g of Hg, mean value of 18.3 μg Hg (std dev. 22.5). EXAMPLE 14

Dentifrice #2

A dentifrice was prepared having ingredients as set forth in Table VI below.

TABLE VI

Ingredients Quantity (per 100 g)

Purolite S924 oxidized and micronized

(Thiolated polymer B of Example 2) 1.00 g

Glycerin 5.00 g

Propylen glycol 2.50 g

Sodium lauryl sulfate 1.70 g

Macrogol 1600 1.00 g

Xylitol 1.00 g

Fragrancies 0.90 g

Sodium carboxyimethyl cellulose 0.80 g

Sodium saccharinate 0.20 g

Sodium phosphate 0.20 g

Brilliant blue (E133), sol. 0.07% o.io g

Parabens 0.20 g

Water 20.0 g

Sorbitol syrup (70%) q.b. to 100 g EXAMPLE 15

Chewing gum #1

Tablet were obtained with Pharmagum™ S (SPI Pharma, Aix en Provence, France) that allows directly compressible chewing gum with a minimum increase in tooling temperature and showed limited sticking/adhering to the press. A chewing gum was prepared having the ingredients as set forth in Table III by direct compression.

TABLE ΙΠ

Ingredients Quantity (per 100 g)

Ambersep GT74 oxidised and micronized

(Thiolated polymer A of Example 1) 0.20 g

Xylitol 14.6 g

Sucralose 0.20 g

Sodium stearyl fumavate (Pruv™) 2.00 g

Grape aroma 2.00 g

Colloidal silica (Elisphere B33) 1 -00 g

Pharmagum™ M q.b. to 100 g

The operation ended up with tablet-shaped chewing gums of around 1.5 g in weight

EXAMPLE 16

In vivo efficacy assessment with chewing gum #1 in regular, once-a-day administration

The experiment aims to test the chewing gum obtained according to the present invention in Subject 8A used the chewing gum #1 of Example 15 once-a-day for 5 consecutive days, 30 minutes before dinner. Chewed samples were withdrawn and analyzed with DMA-80. Recalculated data provide a total 49.6 μg Hg sequestered, with a mean value of 9.9 μg Hg (std dev. 2.85).

EXAMPLE 17

In vivo efficacy assessment with chewing gum #1 in fractionated administration

Subject 8A chewed the same chewing gum used in Example 16 in 3 fractionated doses during 4 min. followed by 5 min. resting. The Hg analysis provided a total sequestration of 8.45 pg Hg. EXAMPLES 18-20 and COMPARATIVE EXAMPLES 5-7

Chewing gum #2-4

Tablets of Daygum™ Protex, Mentos™ Pure Fresh, and Vivident™ Cube (Perfetti van Melle, Lainate, Italy) were incorporated with 2 mg/tablet of Thiolated polymer A (Ambersep GT74 micronized and oxidised) obtained as in Example 1. The original, unmodified chewing gums represent the Comparative Examples used in the next test.

EXAMPLES 21-23

In vivo efficacy assessment with chewing gums #2-4 in comparison with the originals

The experiment aims to compare the efficacy of chewing gums according to the invention with the unmodified (original) chewing gums. Subject 8A chewed every day a chewing gum obtained as described in Examples 18-20 during 4 minutes. In each other day he chewed the unmodified chewing gums of Comparative Ex. 5-7. Samples (130 - 10 μg) of the chewed gums were analyzed with DMA-80.

Results are noted in Table IV, wherein: column (ix) is the mean weight of wet gum base; columns (xii) and (xiii) are, respectively, the increments of sequestered Hg expressed as difference g Hg) and % increase in chewing gum according to the invention over control (comparative). Noteworthy, the gum bases have a meaningful influence on the overall performance.

TABLE TV

EXAMPLE 24

Chewmg gum #5

Tablets of Mentos™ Pure Fresh were admixed with 8 mg of Thiolated polymer A obtained as described in Example 1. EXAMPLES 25

In vivo dose finding by chewing gum #3 and #5

The experiment aims to ascertain the optimal usage level of thiolated polymer in a chewing gum. The chewing test was carried out with two loading levels, i.e. at 2 and 8 mg of resin per tablet as per Example 22 and 24, respectively. Mercury analysis by DMA-80 of samples after 4 minutes of chewing revealed an increase in uptake of 0.56 μg Hg.

EXAMPLE 26

Mouthwash #1

A mouthwash was prepared having ingredients as set forth in Table V below.

TABLE V

Ingredients Quantity (per 100 g)

PAA-Cys HC (Thiolated polymer D of Example 4) 0.20 g

Glycerol 5.00 g

Sucralose o.io g

Flavours 0.15 g

Ethyl alcohol 5.00 g

Benzyl alcohol 0.50 g

Thymol 0.30 g

Purified water q.b. to 100 g

EXAMPLE 27

In vivo efficacy assessment with mouthwash #1

The aim of this experiment is to check the use of a mouthwash according to the invention in a subject with dental amalgam. The mouthwash was used by Subject 8A. The analysis of spats afforded a mean value of 1.81 μg Hg per minute.

EXAMPLE 28

hi vivo diagnostic assessment - Detection of mercury levels in different subjects

Three volunteers, including Subject 8A and further two subjects bearing 4 and 1 dental amalgams, respectively - herein "Subject 4A" and "Subject 1 A" - were tested for the level of intraoral mercury. Each subject chewed for 10 min the chewing gum as described in Example 22 and the chewed gum were analyzed by DMA-80. The results are noted in Table VI, wherein column (xiv) is the Hg found in each gum; column (xv) expresses the same value in ppb (^ig/kg); column (xvi) is the calculated total sequestered Hg by a chewing gum on each subject.

TABLE VI

The mercury sequestrated approaches the threshold limits established by the WHO based on a maximum allowable environmental level of 50 μg/day, and higher than the daily mercury exposure that the same authority estimates in a range from 3 μg day to 9 μg day.

Moreover, the results well-correlate with the Hg level in the oral cavity of subjects with dental amalgam. Hence the procedure is predictive in patients presenting local or systemic disorders associable with the reactivity to Hg and/or to the chronic Hg intoxication.

A diagnostic kit may consists in a formulation for the quantitative sequestration of oral Hg, e.g. a chewing gum comprising a thiolated polymer. After chewing a sample is collected and returned to a laboratory equipped with a Hg analyzer such as DMA-80 or AMA-254. A dentist specialist staff will assess level of mercury burden and the consequent regimen/treatment to be adopted, e.g. Studio Ronchi Associato (Milan, Italy).

EXAMPLE 30

Customized dental tray

An accurate dental tray is produced to provide the contact with the detoxifying gel as described in Examples 31-33. In brief, a dental impression (the negative imprint of denture) of a subject with dental amalgam is produced with standard techniques and used as master cast. A Pro-form™ Soft E.V.A. (Dental Resources, Delano, MI, USA) is applied to the master cast and moulded by vacuum former Pro-line Air Vac 2000 from the same supplier to cast a customized tray suitable for loading a gel as obtained herein after. EXAMPLE 31

Gel #l

A gel for application on dental tray have the ingredients as set forth in Table XI.

TABLE XI

Ingredients Quantity (per 100 g)

Purolite S920 (Thiolated polymer F of Exampl e 6) 0.20 g

Gantrez S97BF (Polymer A of Example 11) 0.80 g

Glycerol 5.00 g

Sucralose 0.10 g

Flavours 0.15 g

Methyl paraben 0.30 g

Propyl paraben 0.30 g

Benzyl alcohol 0.20 g

NaOH IN q.b. to pH 6.5

Purified water q.b. to 100 g

Approximately 2 g of the gel are applied over-night on a subject with dental amalgam by a commercially available dental tray Dr.Brux™ soft type, from QuattroTi Dentech S.r.l. (Cislago, Italy) pre-formed on the patients' denture. EXAMPLE 32

Gel #2

A gel as described in Example 30 contains 0.8% w/v of PAA-cys HC (Thiolated polymer D) and 0.05 % w/v of dendritic Cu° (Aldrich Cat. N. 357456) instead of the combination of 0.2 % w/v of Polymer A and 0.8 % w/v of Thiolated polymer B. The gel is similarly applied with the dental tray Dr.Brux™.

EXAMPLE 33

On-site cast dental tray impregnated with a thiolated polymer

A specimen of DentaWorks Soft Mouth Tray (Soft DentaWorks, London, UK) is dip in Crodasone™ cystine (Thiolated polymer G) warmed at around 50°C until the tray softens and becomes mouldable. It is placed in the mouth and hand-moulded to copy the denture. The dental tray is trimmed to eliminate the handling pad and the trays on gum line. EXAMPLE 34

Customized dental tray coated with a thiolated polymer

A customized dental tray coated with a thiolated polymer is obtained with Pro-form™ Soft E.V.A. spread with Thiolated polymer B (as in Example 2), inserted in oven for 15 min., and conditioned for 1 hour at 37°C in water. Sheets are moulded by Pro-line Air Vac 2000 on a denture master cast, ready for the application on the subject's denture.

EXAMPLE 35

Customized dental tray imbedded with a thiolated polymer

A customized dental tray is produced with a blend including a thiolated polymer. In brief, 20 g of Elvax™ 150 from DuPont is melted at 80°C and added under slow stirring with 1 g of Resindion MAC4 (Resindion-Mitsubishi), a thiourea-functional resin having 4.4 eq/g on dry basis previously milled at 100-20 μπι. The molten blend is formed into a plastic tray to afford specimens of 12.7 cm x 12.7 cm x 4 mm in size. The sheet are cast into the Pro-line Air Vac 2000 on denture master cast, being ready for prolonged contact.

EXAMPLE 36

Protective masks for dental operators

A Hg-absorbing mask for the use in protection of dental personnel is produced as follows. A "Mascherina Chirurgica Superfiltrante" by Henry Schein Krugg SpA. (Buccinasco, Italy) is embedded with hydrocolloidal thiolated polymer PAA-Cys medium conjugation (SH+SS content of 830 meq/g and a SH/SS ratio of 5:3 eq/eq) by spreading 5 ml of a thick 0.5% w/v polymer gel neutralized with NaOH. The mask is dried at ambient conditions and used during interventions involving operations on amalgam fillings. Mercury analysis by AMA- 254 revealed a local concentration of around 2-3 ng(Hg)/cm².

EXAMPLE 37

Multilayer striped dentifrice #1

A anhydrous 2-component dentifrice, designated "Component 1" and "Component 2", is prepared according to Example 1 in USP5599525 with ingredients as set forth in Table ΧΠ. TABLE ΧΠ

Ingredient Quantity (per 100 g)

Component 1 Component 2

Sodium saccharinate 0.50 0.50

FD&C - Blue #l (l% soln) ~ 0.25

FD&C - Yellow #10 (1% soln) ~ 0.25

Trisodium phosphate 2.00 2.00

Sodium tripolyphosphate 3.00 3.00

Ti0₂ 2.00 ~

Zeodent 115 18.5 16.2

Alumina-DMSO complex as in Ex. 9 3.00 3.00

Purolite S920

(Thiolated polymer F of Example 2) 1.00 ~

NaHC0₃ 12.0 12.0

Na₂C0₃ 2.00 2.00

Flavor 1.00 1.00

Sodium lauryl sulfate 1.70 1.70

Glycerin 19.75 20.25

PEG 2000 3.00 3.00

PEG 400 q.b. to 100 g

It should be understood that while the present invention has been described in considerable detail with respect to certain specific embodiments thereof, it should not be considered limited to such embodiments but may be used in other ways without departure from the spirit of the invention and the scope of the appended claims.

Claims

I . An odontostomatologic composition for therapeutic/preventive use or diagnostic use in subjects exposed to the mercury intoxication from dental amalgam, said composition comprising a partially or fully oxidised thiolated polymer.

2. Composition according to claim 1, wherein said polymer is a non-resorbable thiolated polymer whose thiol groups (SH) are partially oxidized to disulfide (SS) groups, and with a SH/SS ratio from 6:1 eq/eq to 0:1 eq/eq.

3. Composition according to claims 1 and 2, wherein said polymer is a partially oxidised macroporous thiolated polymer in the form of micronized powder.

4. Composition according to claim 3, wherem said micronized powder is < 50 μηι.

5. Composition according to claims 1 and 2, wherein said polymer is a partially oxidised hydrocolloidal thiolated polymer.

6. Composition according to claim 1, wherein said polymer is a thiourea-functionalized polymer.

7. Composition according to any of claims 1 to 6 characterized in that cysteine or any low other molecular weight thiolated substance are substantially absent.

8. Composition according to any of claims 1 to 7, wherein said polymer is comprised from 10% to 0.1% w/w in the presence of customary eccipients.

9. Composition according to claim 8 in the form of dentifrice.

10. Composition according to claim 8 in the form of chewing gum.

I I . Composition according to claim 8 in the form of mouthwash, oral solution, spray, gel, or another mouth-rinse products.

12. Composition according to claim 8 in the form of dental tray carrying a gel or a past comprising a polymer as described before.

13. Composition according to claim 8 in the form of dental tray blended or coated with a polymer as described before.

14. Composition according to claim 8 in the form of a mask for dentistry imbedded with a polymer as described before.

15. Composition according to claim 8, further comprising an thiolated silica gel.

16. Composition according to claim 8, further comprising DMSO-alumina complex.

17. Composition according to claim 9, further comprising a compound with specific affinity for elemental mercury selected from the group consisting of elemental Au, Ag, Zn, Al, Cu, or a sulfide thereof, in finely dispersed form.

18. Composition according to claim 9, further comprising a polymaleate.

19. Composition according to any proceeding claim for the treatment or prevention of a mercury-related disorder in a subject in need thereof.

20. Composition according to claim 19, wherein said disorder is selected from the group consisting of lichenoid lesion, cheilitis, stomatitis, burning mouth syndrome, amalgam tattoo, acrodynia, and mercury-related allergic contact dermatitis.

21. Composition according to claim 19, wherein said disorder is correlated to a sub-chronic or latent mercury intoxication.

22. Composition according to claim 21, wherein said disorder is a neurodegeneration.

23. Composition according to claim 19, wherein the subject is a pregnant women bearing dental amalgam to attenuate mercury overloading on foetus and the risk of autism.

24. Composition according to any of claims 8 to 11 for the diagnostic use in the determination of the mercury exposure in a subject bearing dental amalgam.