ITMI20100196A1 - POLYMERS AND COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF MUCOSAL DETOXATION FROM ELEMENTARY AND BIVALENT MERCURY - Google Patents

Description

DESCRIPTION

POLYMERS AND COMPOSITIONS FOR THE PREVENTION OR TREATMENT OF MUCOSAL DETOXIFICATION BY ELEMENTARY AND BIVALENT MERCURY

FIELD OF INVENTION

The invention refers to the use of non-absorbable polymers in compositions useful for the prevention or simultaneous detoxification of elemental and divalent mercury from the oropharyngeal-gastrointestinal mucosa.

STATE OF THE ART

The problem of dental amalgam has been discussed in depth in the previous patent IT2009MI02147. In addition to dental amalgam, the main sources of mercury are large predatory fish, drinking water contaminated by industrial waste and agriculture in the presence of mercurial antifungicides. The worst consequences of the accumulation of Hg are the neurotoxic effects on children (Environ Health Perspect. 2000; I08; A250-1 and A262) and the correlation with the onset of autism (Med Hypoth. 2001; 56 (4) : 462-71).

With a sub-critical level of intoxication, without clear pathological evidence, it is still advisable to carry out a diagnostic analysis. The confirmation of a state of intoxication is also achievable with the analysis of the hair as the absolute levels of mercury in the hair are about 300 times higher than those of the blood, and are therefore more reliable.

Some 'soft' mercury and heavy metal detoxification systems are based on a diet supplemented with chelating elements such as selenium, zinc and vitamin C.

Pharmacological chelation with meso-2,3-dimercaptosuccinic acid (DMSA; succìmer) and with 2,3 dimercapto l-propane sulfonic acid (DMPS) are used in clinically relevant forms of mercury poisoning. In Clin Toxicol (Phila). 2009; 47 {9): 84l-58 it is highlighted how DMSA and disodium edetate calcium provide good results but with side effects due to non-specific chelation of Zn and Cu, with episodes of nephrotoxicity and mucotoxicity. low molecular weight a risk of the systemic redistribution of mercury. For this reason, non-absorbable materials that are able to capture mercury without redistributing it in the body are preferred.

Patents US5178541 and WO9010433 describe the use of elemental sulfur for the removal of odontological mercury. With the same purpose US 2004180788 describes an activated carbon with gold particles deposited by a non-electrolytic process; while EP 1348417 uses cellulose adsorbed with thiosulfate and alkaline selenites, EDTA and / or DMPS. Other materials such as trojan resins have been tried in the past for the oral detoxification of mercury, eg. by Clarkson TW et al, (J Pharmacol Exp Ther. 1981; 218 (i): 74-83), Aaseth & Frieheim (Acta Pharmacol Toxicol. 1978; 42 (4): 248-52), and by Cikrt & Lenger ( Toxicol Lett, 1980; 5: 51-4) both alone and in combination with classic low molecular weight dolic ketants, obtaining fair but not excellent results.

The usefulness of having an effective composition capable of resolving elemental and bivalent mercury intoxication in the mucous membranes of the oropharyngeal and gastrointestinal tract is therefore confirmed in subjects with evident or latent symptoms of over-exposure to mercury. SUMMARY

It has been verified that an efficient uptake of the whole elemental and divalent mercury released from amalgam fillings can be achieved in the presence of pure polymers or in combinations such as to provide the concomitant presence of functional groups capable of chelating divalent mercury and others capable of capturing elemental mercury.

In one aspect the invention relates to the use of polymers having dual functionality in compositions useful for the simultaneous prevention or detoxification of elemental and divalent mercury from amalgam fillings or from food sources.

In another aspect, the invention refers to the use of suitable associations of polymers in compositions useful for the prevention or combined detoxification of elemental and divalent mercury from amalgam fillings or from food sources,

DETAILED DESCRIPTION

In the inventive context the term â € œdivalent mercuryâ € will define below the various forms of divalent mercury (there) therefore including both the inorganic cation (Hg <++>) and the partially organic species such as methylmercury (MeHg *) and ethylmercury (EtHg <+>), hereinafter collectively referred to as â € œHg (II) â €.

In the present context, the term â € œelemental mercury "defines metallic mercury or â € œHg (0) â € in liquid molecular form or finely dispersed or atomized vapor particles. The materials used in the present invention are capable of capturing both Hg (0) and Hg (IT), in some cases possessing both functions, in others by means of a suitable combination. It has been surprisingly found that thiopolymers with disulfide and thiol groups are able to uptake Hg (G) and Hg ( II). Defects If the thiol-Hg (II) chelation was predictable, the same could not be said of the uptake of (Hg (0) by the sulphide group considering the potentials E <o> (V) Hg <MVHg (0) = 0.85 and E ° (V) SS / 2SH <=> + 0.25 not favorable.

Useful polymers capable of simultaneously capturing Hg (0) and Hg (II) include:

a) polymers in the form of partially oxidized thiol resins, i.e. containing thiol groups (-SH) and disulfide groups (-SS-) at the same time, where the former capture Hg (II) while the latter capture Hg (0 ) with redox mechanism;

b) polymers in the form of partially oxidized thiomers, containing thiol groups (-SH) and disulfide (-SS-), active with a mechanism similar to polymers (a).

c) natural, hydrolyzed and / or derivatized thioi-keratin polymers containing both cysteine (-Cys-SH) and cystine (-Cys-SS-Cys-), active analogously to polymers (a) and (b); d) natural or synthetic methane polymers, simultaneously containing ionic or ionizable carboxylic (COOH), phenolic (Ar-OH), catecholic (Ar- (OH) 2 and / or amino (R-NH) groups and also activity groups redox such as quinones and semquinones, where the former have a sequestering function on Hg (II) while the latter demonstrate the ability to capture Hg (0) with a redox radical mechanism.

The polymers of the type from (d) to (d) can be combined with polymers useful for the uptake of elemental mercury to provide a wide spectrum of prevention or detoxification from mercury. Useful polymers capable of specifically capturing Hg (II) include:

e) amine polymers, or natural or synthetic polyamines, for example natural, modified or cross-linked sheaves, or synthetic high molecular weight synthetic polyamines. 0 polymers with a pair of geminal or vicinal carboxylic groups, ie (polì) immìdoacetic (HOOOC-CHP-COOH) and (poly) maleic (HOOOC-CH-CHP-COOH).

g) flo-activated inorganic polymers such as alumina and silica and alumosilicates on which sulfur molecules useful for the uptake of Hg (ll) such as dimetide (DMSO), or functionalized with sulphide-disulfide groups, are adsorbed.

Hg (ll) uptake type (e) to (g) polymers are usefully combined with Hg (0) uptake polymers to provide a broad spectrum of mercury prevention or detoxification. Polymers capable of specifically capturing Hg (0) include:

h) polymers adsorbed with finely dispersed metals in elemental form such as gold, silver, zinc, aluminum, copper and other non-toxic metals forming Hg-amalgam, ì) polymers adsorbed with finely dispersed natural or synthetic sulphides such as silverite (AgS), sphalerite (ZnS), pyrite (FeS) and chalcopyrite (CuFeS2) capable of reacting by incorporating mercury Hg (0).

The polymers of the type (a) to (f) can also be used in combination with polymer-oxidant adducts useful for promoting the conversion of Hg (0) into Hg (II).

Polymers capable of promoting this conversion to bivalent include, for example:

j) polymer composites with oxidizing agent, such as the association povidone-hydrogen peroxide (PVP-H2O2), where the latter favors the conversion of Hg (0) into Hg <44>. The characteristics of the polymers illustrated above, from (a) to (j), which can be used for the production of the compositions according to the invention, are better specified below in exemplary, although not limiting, form.

The thiolated polymers in the form of partially oxidized resins (a) are obtained by partial oxidation of the thiolated resins generally produced for the separation of heavy metals from wastewater and treatment water, e.g. of mineral waste, previously micronized.

Part of the thiol groups are converted to disulfides by mild oxidants, e.g. by exposure to atmospheric O2 or in iodized solutions in the presence of 02, preferably in a basic environment.

A favorite example is Ambersepâ „¢ GT74 (formerly Duolite GT73) supplied by Rohm and Haas-Dow Corp., thiophenol polystyrol resin with conc. of dolic groups equal to 1, 3 eq / 1. Other examples of thiolated resins are XUS-43604 from Dow Corp .; Lewatitâ „¢ Monoplus TP214 from Lanxess AG (Germ.); Puroliteâ „¢ S924 from Puro lite Int (Cynwyd Bay, PA, USA).

Said resins are marketed in the form of porous macrobeads (from 1000 to 300 microns) therefore the resins must be ground at <100 µm, preferably <60 µm and then subjected to dry or wet partial oxidation treatment, eg. in a stream of hot air, to convert the thiol groups into disulfide groups.

Other thiolated polymers are in the form of partially oxidized hydrocolloids (a) obtained by partial oxidation from thio-functionalized hydrocolloid, called â € œthiolated hydrocolloidâ € or â € œtiomerâ € eg. described by Vauthier & Bouchemal (Pharm Res. 2009; 26: 5: 1025-58).

The thiomers useful in the inventive context are detailed in WO / 2007/071375 (Unilever) and include: i) carboxylic thiomers (generally) thiolated with cysteine; ii); thiomers obtained by delation of polyethylenimines, described below, and iiii) thiomers with hydroxy groups thiolated with 2-iminothiolan (Trautâ € ™ s reagent) activated by reaction with activated chloroformate ester (eg 4-nitrophenylformate) and finally reacted with a bi-functional dolo such as 2-aminothioethane, Examples of thiomers include polycarbophil thiolates, poly (meth) acrylic acids (PAA) thiolates, thiolated cellulose, alginates or troiate pectins, chi tosan thiolate, trusted jualuronan, polyisine and polyargin na thiolate, PEG thiolate stearate. Polycarbophil thiolate, PAA thiolate and chitosan thiolate are available manufactured by ThioMatriX GmbH (Innsbruk, Austria) or can be manufactured by known methods, e.g. Cevher (AAPS PharmSciTeeh, 2008; 9 (3): 953-65) or as in example 1B. Further examples of useful thiomers include the chitosan-iminothiolactones described in WO / 2003/020771 by MucoBiomer GmbH (Leobendorf, Austria); Spheron Thiol 1000, thiolated methacrylate gelresin from Lachema (Bmo, Czech Republic); the thiolated polyalkylglycols described in WO / 2008/123389 by Nippon Shokubai (Osaka, J), and others such as for example the series of thiomers produced and offered by CarboMer Ine. (San Diego, CA, USA).

Said thiomers before incorporation into the inventive compositions will be subjected to partial oxidation treatment, preferably wet, eg. in neutral or alkaline solution with air to convert part of the dolic groups into sulphide groups.

The thiolated polymers, thiolated resins or thiomers, will typically contain a quantity of active groups -SH or disulfide -SS- comprised between 10 and 0.1 meq / g of polymer, preferably between 1.5 and 0.15 meql / g, with ratio -SH and -SS- between 10: 1 and 1: 10, preferably between 5: 1 and 1: 5. The keratin polymers (c) useful for our purposes can be of the type keratins of human and animal origin, partially hydrolyzed and / or chemically modified naturally containing different proportions of the cisterna (-Cys-SH) and cystine (~ Cys ~ SS) groups -Cys-), which therefore act with a mechanism similar to polymers (a).

Useful examples of such polymers are cosmetic keratins from 2010 International Cosmetic Ingredient Dictionary and Handbook, 13th Edâ € ž for example provided by Cognis (Monheim am Rhein, D), Croda (East Yorkshire, UK) Fabriquimica (San Martin, Arg.) Gattefosse (Saint Priest, F), Kemira Specialty (Northvale, NJ, USA), Seiwa Kasei (Osaka, J) Seppie (Paris La Defense, F) Variati & Co (Conco rezzo, MI, IT) Vincience (Sophia Antipolis, F )

Said keratinic polymers can be incorporated as such in the compositions, or subjected to partial oxidation treatment, for example with air, if it is desired to increase the content of cystic groups with respect to cysteine and / or if a further decrease of their solubility in aqueous-physiological environment (mucous membranes).

The melanic polymers (c) for our purposes can be of the natural or synthetic type, where the simultaneous presence of ionic or ionizable groups and groups with redox activity such as chi noni and semiquinones allows the simultaneous uptake of divalent and metallic mercury. Melanin structures can be obtained by the classic oxidation in air of thérosine or 1-Dopa in the presence of tyrosinase enzyme (from fungi) or by oxidative polymerization in an alkaline solution of classical melanic precursors such as 1-Dopa and catechol or in combination with plant precursors (polyphenols) to give plant melanins, or â € œphithomelaninsâ €.

The melanieo polymer can be isolated by precipitation at acid pH or dilution in water-soluble solvents (ethanol) from the mother solution and collected by centrifugation / filtration. Useful examples of such polymers are the cosmetic melanins offered by various suppliers of the 2010 International Cosmetic Ingredient Dictionary and Handbook, 13th Ed., Ex. da Vincience (F), Active Concepts (Piscataway, NJ, USA), Creations Couleurs (Dreux, F), Frances Christian Gaskin, Ine. (Albany, NY, USA), Lipo Chemicals Ine. (Paterson, NJ), Lipotec S.A. (Barcelon, S); or hybrids such as Phytomelaninâ „¢ (Dr. Carlo Ghisalberti) and Vegetable Melanin by Active Concepts and Creations Couleurs; and also derivatized melanins such as AC Melanin Quatemium-10 and SilanetrioI Melaninate from Active Concepts.

It has been found that the polymers (a) - (d) can effect the simultaneous removal of elemental and divalent mercury, therefore they are particularly useful in the inventive field.

Other polymers (e) - (g), described in detail, prove particularly effective on Hg (II).

The amino and amino-thiol polymers (e) have non-oxidized amino and even thiol groups. Examples of amine polymers are natural or cross-linked chitosan, such as Chitopharmâ „¢ L, M and S from Cognis (Monheim, D). Other chitosans with degree of de vinegar 1 action between 60 and 100% eg. from suppliers mentioned in 2010 International Cosmetìc Ingredient Dictionary and Handbook, 13th Ed., under the entry â € œchitosanâ € (INC1). Examples of cross-linked chitosan are e.g. described in AAPS PharmSciTech 2006; 7 (2): E2-E6 or in US patent 5015293.

Example of amine polymers are synthetic polyamines which include branched polyethylenimines [9002-98-6] Sigma-Ai drich cat. No. 408727 and polyethylenimines in solution [9002-98-6] Sigma-AIdrieh cat. Nos. P3143, 03880, 482595, 408700 and 181978.

Example of amino-thiol polymers are polymers of the thio-functionalized type with cysteines or thioglycolic acid or of the thiolated type with functional heterobes such as N-suecinimdyI-3- (pyridyldìthio) propinate or with 2-iminotìolano (reagent of Trautâ € ™ s).

Polymers with geminal or vicinal carboxyl pairs (f) include (poly) imidoacetates (HOOOC-CHP-COOH) n and (poly) maleates (HOOOC-CH-CHP-COOH) n, where P indicates the polymeric component to which said functional groups are connected.

Polyiminoacetates are generally obtained by post-modification of preformed polyers and resins, with glycidyl group linkers as described by Qaykara T et al. Mater Scien Engin. C, 2009; 29: 20-4.

Examples of polyiminodiacetates include: Amberliteâ „¢ IRC748I from Rohm & Haas-Dow, Diaionâ„ ¢ CRI 1 from Mitsubishi, Lewatìtâ „¢ TP 207 from Lanxess GmbH; Chelex 100 from Sigma-Aìdrich cat. N-C790I; IDA-agarose from Sigma- Aldrich cat. N, 14758; IDA-coupled Sepharoseâ „¢ Fast Flow from GE Healthcare; and Dionex ProPac IMAC-10â „¢ from Dionex Corp.

The polymaleates can be obtained by comopolymerization of the maleic anhydride with other ethylene monomers. Examples of polymaleates include methyl vinyl ether / MA Gantrezâ „¢ AN-139 and AN-I69 copolymers from ISP (Winston-Salem, NC, USA), Ethylene / MA / Propylene ZeMacâ„ ¢ copolymer from Vertellus (Indianapolis, IN, USA) , Octadecene / MA copolymer from Chevron (Boston, MA, USA), PVM / MA Luvifonnâ „¢ FA 139 copolymer from BASF (Ludwigshafen, D) and C4-12 Olefin / MA copolymer from Kao Corp. (Wakayama-shi, J) , where MA = maleic acid or anhydride.

The thio-activated inorganic polymers (g) include alumina and silica and alumosilicates on which sulfur molecules useful for the uptake of Hg (II) such as dimethylsophoxide (DMSO) are adsorbed, or functionalized with sulphide-disulfide groups. obtain activation by simple dry or solvent mixing of alumina, silica gel, neosilicates, sorosilicates, cyclosilicates, inosilicates, phyllosilicates and tectosiiicates, kaolin, clays (e.g. bentonite), andalusite, sillimanite and zeolites can be thio-activated by adsorption with a suitable sulphide such as fossid dimethylsol, for example, as illustrated by Soliman et al. (Talanta 2006; 69 (l): 55-60).

Yes, it has been found that polymers (e) - (g) can perform the selective removal of Hg (ll), while they are not very active on elemental mercury.

In an inventive field they are associated with materials capable of acting as elemental mercury collectors such as amalgam forming metals and sulphides.

Polymers with adsorbed finely dispersed metals in elemental form (h) such as gold, silver, zinc, aluminum, copper and other non-toxic metals capable of forming amalgam with IIg (0), are eg. obtained as per J Biomater Sci Polym Ed 2009, 20 (3): 311-24 or Carb Polymers 2006, 65: 430-34 or sold as susp. 3% on bio-polymer, denominated â € œNano Biosi 1 verâ €. Polymers with adsorbed finely dispemi (i) sulphides such as silver (AgS), sphalerite (ZnS), pyrite (FeS) and chalcopyrite (CuFeS2) are able to react and incorporate Hg (Q).

Composite polymers with polymer-oxidizing agent association (j) are e.g. povidone peroxide of hydrogen (PVP-H2O2) to favor the conversion Hg (0) -> Hg <4>, in the presence of acceptor materials of the latter selected in the group from (a) to (g).

This material is available as Gantrezâ „¢ from ISP (Wayne, NJ, USA) or can be produced in situ when preparing the composition, e.g. by spray-drying polyvinylpyrrolidone (e.g. PVP K-30) with 70% H2O2 solution at 15-25 g of solution / minute / kg PVP for about 20 minutes, to give a PVP containing 18% H2O2 and 6% humidity.

The amount of polymers in the composition of the present invention varies between 50% and 0.005% by weight of the composition, preferably between 1% and 0.01% by weight of the composition, even more preferably around 0.1% by weight of the composition.

The use of said polymers in simple or associated form in compositions intended for administration in the oropharyngeal and gastrointestinal tract allows the uptake and detoxification of mercury and other heavy metals from fillings or from food sources.

In an inventive embodiment a polymer with simultaneous uptake of Hg (0) and Hg (II) selected between (a) and (d) and their mixtures are used for the prevention or detoxification from mercury. In another inventive embodiment a Hg (II) (e) - (g) uptake polymer is associated with a Hg (Q) uptake polymer selected between (h) and (i). In another inventive embodiment a polymer with simultaneous Hg (0) and Hg (ll) (a) - (d) uptake is associated with a Hg (0) uptake polymer chosen between (h) and (i ) and / or to a Hg (II) uptake polymer chosen between (e) and (g). In a further inventive embodiment a Hg (II) uptake polymer selected between (e) and (g) Ã A polymer converting Hg (0) into Hg (II) type (j) is associated.

Preferably the composition of the present invention will take the form of mouthwash, toothpaste, liquid toothpaste, gel, film, gel on film, granules, toothpaste, dental powder, prophy paste, and chewing gum in various dental confectionery presentations.

li The term "mouthwash" includes liquid non-ingestible oral compositions such as hydroalcoholic mouthwash solutions, sprays and other rinsing products. The term â € œtoothpasteâ € includes compositions designed for dental hygiene such as single- and multi-stage toothpaste, liquid or powder toothpaste, tablets, creams and dental gels. The term â € œchewing gumâ € includes chewable tablets, lozenges and other modalities under the heading â € œchewing gumâ €.

Other forms of compositions such as gels, films, gels on films, granules, pastes and dental powder, are spreadable and / or applicable on the teeth and / or oral mucosa directly or with external support. The compositions according to the invention may contain various ingredients used in the dental-dental preparations, e.g. anti-caries agents, desensitizers, viscosifiers and rheological agents, diluents, surfactants and emulsifiers, foam modulators, pH modifiers, abrasives, humectants, taste modifiers, sweeteners, flavors, dyes, preservatives, etc. In one application mode, the compositions for odontostomatological use according to the invention, for example in the form of toothpaste, chewing gum, gel or mouthwash, will be used 1 to 3 times a day in subjects with amalgam fillings or by operators (dentists and dental staff), or at least once a day, or once or twice a week or a month in the case of prophylactic-preventive use in asymptomatic subjects. The treatment to be carried out in an outpatient or home setting may vary from a few days to 6 months or 1 year or more, or for a period of time sufficient for the disappearance of the symptoms of local or systemic intoxication such as those described below.

Preferred subjects for the use of the odontostomatological compositions according to the invention are carriers of a large number of dental amalgam fillings, for example from 5 to 20 and more, preferably from 9 upwards, although also subjects with a limited number of such fillings (from 1 to 5) can benefit from occasional use for preventive-detoxifying purposes.

Other particularly preferred subjects for the use of these compositions are those from whom one or more fillings and / or teeth with amalgam fillings have been removed, with the following or accompanying method of administration, eg. with rinses, such intervention. In a further inventive embodiment, the compositions according to the invention consist of masks soaked, impregnated or soaked with the materials from (a) to (j). Such devices can be conceived as disposable masks eg. dentists or dental technicians, replacing the heavy anti-mercury masks eg. produced by Mercury Safety Products Ltd. Preferred subjects for the use of dental templates according to the invention are dental operators such as dentists and support staff (dental technicians).

The compositions can also be designed for oral administration in the form of sachets, soft or hard gelatin capsules, fast or delayed release tablets, or in liquid form for gastrointestinal detoxification, e.g. Remington: The Science and Practice of Pharmacy (20th ed.), Ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000. Preferred subjects for the use of the gastroenterological compositions according to the invention are carriers of dental amalgam fillings, dental operators and other subjects with mercury poisoning such as chemical implant workers, etc.

The compositions are used to treat / prevent local mercury damage such as burning mouth syndrome, oral leukoplakia, lichenoid stomatitis, contact dermatitis, urticaria, cheilitis, stomatitis, baboon syndrome, acrodynia, orofacetal granulomatosis, ponfolytic eczema, sarcoid reactions, itching, rashes, osteonecrosis, delayed / deficient scarring. Further advantages of the inventive compositions relate to the prevention or treatment of systemic mercury poisoning with disorders such as: neuro-otological disorders, hypo-enthusiasm, dizziness, tinnitus, headache, insomnia, fatigue, emotional disorders, depression, memory loss, adrenal gland dysfunction , alopecia, anorexia, fetal malformations, autism, thyroid and immune system dysfunction, insomnia, kidney damage, tingling or pain in the limbs, tremors, muscle weakness, excessive salivation, colitis. In fact, the following examples illustrate some executive methods of the invention, not being intended to limit the purposes thereof.

EXAMPLES

Example 1 - Preparation of gel and evaluation of the detoxifying potential

(A) Rohm and Haas-Dow Ambersep GT74 resin is dried and ground to a fine powder with particles ranging from 5 to 20 Î1⁄4Ï € ι. The powders are then treated in a stream of hot air at 40 ° C for about 4 hours, then a gel is obtained by suspending 0.2 g in 100 ml of water with 0.5 g of Carbopolâ „¢ Ultrez 10NF , finally neutralizing at pH 6.5 with 5N NaOH. (B) A hydrocolloid-cìsteine thiomer is prepared by reaction of the Gantrezâ „¢ AN-119 copolymer with ì-cìsteine to give the corresponding thiomer as described in WO / 1991/003521 with suitable modifications. Briefly, a mixture of THF and DMSO (750 ml) placed in a reactor equipped with stirrer, reflux condenser and thermometer is added with 78.1 g (0.5 mol) of Gantrezâ „¢ AN-119 heating to 60 ° C for 1 hour under nitrogen. Then 1-cysteine (48.4 g, 0.4 moles) is added in portions with progressive precipitate formation. The stirring is continued for another 2 hours at 60 ° C, then it is cooled to 30 ° C and the resulting product is filtered and dried under vacuum to give about 120 g of product (yield 97%). Analysis of the product after hydrolysis with 0.1N HC1 and FT-IR spectrophotometry confirm a conversion of approximately 75% of the diacidomal functions into amidothiol groups. A partially oxidized polimaleate-cysteine gel is obtained by suspending a share of 02 g in 100 ml of water and keeping the suspension under strong aerated agitation for 30â € ™. (C) A keratin gel is obtained by suspending 0.2 g of cosmetic keratin in 100 ml of water with 0.5 g of Carbopolâ „¢ Ultrez 10NF, neutralizing to pH 6.5 with 5N NaOH.

(D) A hybrid melanin type Phytomelanìnâ „¢ is obtained by dissolving in a liter of NaOH IN 46 g of 1-Dopa, 15 g of rutin trihydrate, 17 g of gallic acid monohydrate, 22 g of OPC from grapeseed under bubbling of air at 37 ° for 24 hours. On a portion of 10 ml diluted with 90 ml of water and citric acid to pH 8, then 0.5 g of Carbopolâ „¢ to give a dark gel.

(E) A chitosan gel is obtained by dissolving 2 g of Chitopharmâ „¢ L (Cognis) in 100 ml of an aqueous solution of 1 g of acetic acid and 3 g of glycerol under continuous stirring for 2 hours. The yellowish solution is then neutralized to pH 7 with 5N NaOH to give a transparent gel. (F) A gel of (poly) maleate type MVE / MA is obtained by suspending 4 g of Gantrexâ „¢ AN-119 tn 100 ml of water adjusted to pH 7.5 with soda, leaving under stirring for 30â € ™ .

(G) A thio-activated inorganic composite is prepared by adsorbing dimethyl sulfoxide on neutral alumina in the manner described by Soliman et al. (Talanta 2006; 69 (l}: 55-60), therefore a gel is obtained by suspending 0.4 g in 100 ml of Carbopolâ „¢ gel brought to pH 6.5. (H) A gel of particles of silver is obtained by diluting 3 ml of Nano Biosìlver (www.nanobiosilver.com) sold online as a 3% suspension on unspecified biopolymer in 97 ml of water, freezing with 0.4 g of Carbopolâ " ¢ neutralized to pH 6.5 with 5N NaOH. (I) A ZnS gel can be obtained by precipitation of 0.2 g of synthetic sphalerite obtained by Sigma-Aldrich (cat, N. 244627) adsorbed and gelified in 100 ml of Carbopolâ „¢ gel.

(J) A fluid gel of povidone-hydrogen peroxide is obtained by adding to a suspension of 8 g of PVP K-30 an amount of 2 g of H2 <3⁄4 70% and stirring for about 20â € ™. ability to capture elemental and ionic mercury

The total fraction of Hg (0) and Hg (II) captured by the gels containing the polymers according to the invention can be evaluated quickly and reliably with the DMA-80 Direct Mercury Analyzer (Milestone Srl, Sorisoie (BG), Italy).

The method is cited as a reference in U.S. EPA Method 7473, U.S. EPA Draft Method 30 B and ASTM Method D6722-01 as it does not require sample preparation and provides reliable results on the total mercury content with a dynamic range of 0.0015 ng - 1000 ng. In practice, the verification can be carried out in vitro on teeth with amalgam fillings extracted by dentists in the dental practice, or directly in vivo in the mouth cavity of patients with a certain number of amalgam fillings.

An efficacy evaluation performed on gels prepared as above, calculated net of the initial content of Hg de! pre-treatment sample, can provide results as per Table I. TABLE 1

Polymer in gelled suspension Conc, (w / w) Range of Hg tot captured (A) Ambersepâ „¢ GT74 part. oss, 0.2% 30-350 ng

(B) Polimaleate-cysteine thiomer gel part. obs. 0.2% 20 - 230 ng

(E) Chitopharmâ „¢ Chitosan gel 2.0% 0.5 - 30 ng

(F) Gantrezâ „¢ 4.0% 1.0 -45 ng polymaleate gel

(G) Alumina-DMSO gel 0.4% 1.0-25 ng

(H) Colloidal Ag ° gel 0.1% 10 - ISO ng

(J) PVP-H2O2 gel. _ _ 10% 2 -75 ng

The maximum efficiency will be provided by thiol dual-function polymers (A) - (C), followed by the specific metal-polymer for the uptake of Hg (0) type (H), while the polymers with chelating capacity towards Hg (II ) type (E) - (G) are less effective due to the low presence of the ionic mercurial species (Hg <++>) and methylmercury in the oral cavity. The experimentation, duly validated, will lead to the evidence that effective detoxification can be achieved with polymers with simultaneous uptake of ionic and metallic mercury and / or with combinations of polymers with specific uptake of one of the two species.

Example 2 - Mouthwash

Ingredients Quantity

Polymers according to the invention <(1)> q.s.

Glycerol 5.0 g

Sucralose 0.1 g

Flavors 0.15 g

Ethyl alcohol 5.0 g

Benzyl alcohol 0.5 g

Demineralized water_ q.s. to 100 g

- Thiomer polymaleate-cysteine part. obs. 0.2 g

- Natural cosmetic keratin 0.2 g

- Chitosan Chitopharmâ „¢ L 2,0 g Maleico Gantrez copolymer 2 g

- Polimaleate Gantrezâ „¢ 2.0 g Colloidal Ag ° 0.1 g

- Polimaleate Gantrezâ „¢ 2.0 g PVP-H2O24.0 g

Example 3 - Chewing gum

Ingredients_ Quantity

Polymers according to the invention q.s.

Lemon flavor 0.5 g

Sucralose 0.3 g

Annatto yellow color (E160b) 0.05 g

Blue dye (E 133) sol. 0.1% 0.1 g

Citric acid 1.0 g

Talc 1.0 g

Magnesium stearate 5.0 g

Colloidal silica 1.0 g

Pharmagumâ „¢ M _ q.b. to 100 g

- Ambersepâ „¢ GT74 resin resin parz. obs. micronized 0.1 g

- Ambersepâ „¢ GT74 resin resin parz. obs. 0.05 g alumina-DMSO 0.2 g

- Chitosan Chitopharmâ „¢ L 1 g alumina-DMSQ 0.4 g Cosmetic keratin 0.1 g - Phytomelaninâ„ ¢ 0.15 g (replaces the dyes in the formula)

Example 4 - Toothpaste

Ingredients_ Quantity

Polymers according to the invention q.s.

Glycerin 5.0 g

Propylene glycol 2.5 g

Sodium lauryl sulfate 1, 7 g

Macrogol 1600 1.0 g

Xylitol 1.0 g

Flavors 0.9 g

Sodium carboxymethyl cellulose 0.8 g

Sodium saccharin 0.2 g

Sodium phosphate 0.2 g

Blue dye (E 133) sol. 0.1% 0.1 g

Parabenì 0.2 g

Water 20 g

Sorbitol syrup (70%) _ q.b, 100 g

- Ambersepâ „¢ GT74 resin resin parz. oss, micronized 0.1 g

- Thiomer polymaleate-cysteine part. obs. 0.1 g,

- Thiomer polymaleate-cysteine part. obs. 0.05 g alumina-DMSO 0.4 g

- Chitosan Chitopharmâ „¢ L 1, 5 g PVP-H2O 24,0 g

Example 5 - Protective masks for dental operators

Masks with elastics of the Ecomask Ondaâ „¢ type (Kumapan, Online) are impregnated with 10 ml of a solution containing 0.05% of a partially oxidized polymaleate-cysteine-type thiomer sprayed manually with a common pump spray, alternatively use suspensions of pure materials or combinations as per previous examples.

Example 6 - Capsules

Ingredients Quantity (per capsule)

Polymers according to the invention << 4)> q.s.

Cellulose {microcrystalline) 50 mg

Colloidal silica 10 mg

PVP K 30 0.5 mg

Ethanol 95 ° Q.S. for granulation

(4) - Ambersepâ „¢ GT74 resin resin parz. obs. micronized 15 mg / capsule

- Thiomer polymaleate-cysteine part. obs. 10 mg / capsule

The compositions administered for $ 0 in mercury intoxicated subjects can be monitored with the analysis of the hair sample, eg. Doctorsâ € ™ Data Ine. (Chicago, IL, USA.

Claims (1)

CLAIMS 1. Use of a polymer in simple or associated form characterized by the concomitant or associated presence of functional groups capable of capturing elemental mercury and other functional groups capable of chelating divalent mercury for the production of a composition useful for preventing o detoxify mercury from amalgam fillings or food sources, must said polymer is different from activated carbon, 2, Use according to claim 1 wherein said composition comprises at least one elemental and divalent mercury concomitant capture polymer selected from: (a) thiolated polymer in the form of partially oxidized thiolated resin; (b) thiolated polymer in the form of a partially oxidized thiomer; (c) natural, hydrolyzed or derivatized thiol-keratin polymer; or (d) melanine polymer; where the thiol polymers (a) - (c) are characterized by the concomitant presence of thiol groups (â € œ-SHâ €) and disulfide (â € œ-SS-â €). 3, Use according to claim 2 wherein said thiolate polymer (a) or (b) comprises both -SH and -SS- groups in a total quantity comprised between 10 and 0.1 meq / g of polymer, with a ratio between -SH groups and -SS- between 5: 1 and 1: 5. 4. Use according to claim 1 wherein said composition comprises a divalent mercury capture polymer selected from: (e) amino and amino-thiol polymer selected from natural or cross-linked chitosan, polyethylene imine and thiolated polyethylene imine; (f) polymer with geminal or vicinal carboxyl pairs selected from (poly) imidoacetate and (poly) maleate; and (g) thio-activated polymeric inorganic polymer such as alumina and silica and alumosilicates with adsorbed sulfur molecules such as dimethyl sulfoxide; where said polymer (e) - (g) is used in association with a divalent mercury capture polymer chosen from: (h) polymer adsorbed with a metal in a finely dispersed elemental form such as gold, silver, zinc, aluminum, copper; and (i) polymer adsorbed with an inorganic sulfide such as argentite, sphalerite, pyrite and chalcopyrite and other non-toxic metal sulfides. Use according to claims 2 and 3 wherein a polymer with simultaneous curing of elemental and divalent mercury selected between (a) and (c) is associated with a divalent mercury curing polymer selected between (e) and (g). 6. Use according to claims 2 and 3 where a polymer with simultaneous capture of elemental and divalent mercury selected between (a) and (c) is associated with an elemental mercury capture polymer selected between (h) and (i). 7. Use according to one or more of the preceding claims where a simultaneous capture polymer selected between (a) and (g) is associated with an active polymer by conversion of elemental mercury into divalent as (i) polymer-oxidizing agent such as povidone- H2O2. 8. Odontostomatological composition comprising a polymer (a) - (d), alone, in mixture or in combination with a polymer (e) - {g) or a polymer (h) - (ÃŒ), or a combination of a polymer (e) - (g) and a polymer (h) - (i) according to one or more of the preceding claims, said composition in liquid or semi-solid form such as mouthwash, toothpaste, chewing gum or other presentation for hygiene oral useful for the detoxification of mercury from the oral cavity; or in the form of a disposable mask impregnated or coated with said polymers to prevent mercury fumes. 9. Gastroenterological composition comprising a polymer (a) - (d), alone, in mixture or in combination with a polymer (e) - (g) or a polymer (h) - (i), or a combination of a polymer (e) - (g) and a polymer (h) - (i) according to one or more of the preceding claims, said composition in the form of a tablet, hard or soft capsule, microcapsules, pellets, pills, powder, syrup, gel, granules , suspensions, dispersions, emulsions, liquids, solutions and other oral presentation useful for detoxifying gastrointestinal mercury. 10. Composition according to claim 9 or 10 to prevent or treat a subject subjected to or liable to mercury poisoning and the consequent local damage and / or systemic disturbances.