MXPA02001269A - Composition for restoring defects in calcified tissues - Google Patents

Abstract

A composition for restoring defects in calcified tissues comprises an amorphous bioactive particulate consisting essentially of calcium, silicon and oxygen. Said agent may be selected from the group consisting of:a) a reaction product of an organic silicate source and a source of calcium;b) a calcium containing hydrolysis product of tetraethylorthosilicate;c) a calcium containing silica sol-gel;d) a binary calcium oxide and silicate precipitated material;e) a synthetic analog of a naturally occurring wollastonite-likecalcium silicate;and f) a precipitated reaction product of soluble calcium source and a silicate solution. A process for producing the amorphous bioactive particulate consists essentially of adding a sufficient amount of a solution of a soluble calcium source to a solution of a silicate or silicate precursor to cause a precipitation of calcium-containing silicate particulate.

Description

COMPOSITION FOR RATING DEFECTS IN TEXTILE C OR TISSUES FIELD OF THE INVENTION The present invention relates generally to compositions of bioactive master particulates consisting essentially of calcium, silicon and oxygen and methods for their use to restore defects in calcified tissues.

BACKGROUND OF THE INVENTION It is known that products, such as bioactive particulates can be used to repair or repair defects in calcified tissues, such as periodontal cavities, extraction sites, dentin hypersensitivity treatments, bone tissue formation. and similar. The biocompatibility of particulates to restore or repair defects in calcified tissues, such as bone tissue formation, as evidenced by the strong apposition of hard tissue to implanted glassy particles, was first demonstrated in 1971. Specifically, the use of vviiddrriioo bbiiooaaccttiivvoo ffuuee rreeppoorrttated originally by Hench et al. in J. Biomed. Mater. Res. Symp., 2: 117-141 (1971). The bone grows by apposition on bioactivated glass placed adjacent to fleshless surfaces and new bone can be subsequently driven over short distances.

Pactive glass beads have been described in subsequent bone tissue formation applications. U.S. Patent No.

No. 4,239,113 describes a composition for the preparation of bone cement. U.S. Patent No. 5,658,332 discloses a method for forming bone tissue in defects in sities in the appendicular skeleton or sites exhibiting metabolic network red blood using bioactive glass granules containing 40 to 58% SiO2, 10 to 30% NaO, 10 to 30% CaO and 0 a % of P2O5, and in the size range from 200 to 300 micrometers. In the area of repair or restoration of defects in dental tissues, the bioactive particulate has been used for repairing periodontal bone defect (U.S. Patent No. 4,851,046), using a size range of 90-710 μm and a composition range of 40-55% by weight of SiO210-30% by weight of CaO, 10-35% by weight of Na2O, 2-8% by weight of CaF2, and 0-10% by weight of B2O3. U.S. Patent No. No. 4,851,046 discloses compositions containing bioactive glass particles of various size ranges for use in periodontal applications. U.S. Patent No. 5,204,106 discloses that bioactive glass particles within the narrow size range of 280 to 425 microns, elicit a biological response altered in a manner distinct from that previously described. Bioactive particulates have also been used in the treatment of dentine hypersensitivity. Dentin is a hard but resilient limestone tissue that mechanically supports the dental varnish.

The dentine encloses and protects the dental pulp. Dentin also has a large number of continuous endothelial tubules, which connect the In a melt-derived process, there are three reactions, which lead to the development of a porous hydrated silica gel layer: ion exchange, silica solution and silanol condensation to form rings or chains of hydrated silica bound to siloxane. As the SiO2 content in fusion-derived glasses increases, the rates of these reactions decrease, reducing the availability of C + 2 ions and the ability to develop the silica gel layer on the surface. The result is the reduction and eventual elimination of the bioactivity of the glass derived by fusion as the SiO2 content approaches 60%. The process imposes narrow effective composition zones, which obstruct the formulator's ability to modify and design the material for a specific application. The bioactive glasses prepared by the melt-derived process and as shown in the prior art (patent '942) are processed in pyro crucible at high temperatures., normally around 1350 ° C little more or less. As a result, melting-derived glasare cost DS and difficult to transfer to a production facility. The high temperature processing plus the multiple handling steps make the bioactive glass prepared by the process of melting quite expensive, effectively limiting the practicality of using bioactive glass for oral care products. In addition to the high production cost, there are other inherent disadvantages with the prior art. First, it is difficult to maintain the very high purity required for optical bioactivity due to the process derived from fusion by itself and the low Dontenido of silica and high of alkali of the compositions of traditional bioactive glass. In certain place, the prior art requires processing steps which involve grinding, polishing, sintering, sieving, etc., all of which expose the bioactive powder to potential contaminants that may negatively affect the bioactivity. Third, there is a limitation of composition imposed on glass bioactives and glass ceramics made by conventional high temperature processes due to the extremely high equilibrium liquid temperature of SiO2 of 1713 ° C, and the extremely high viscosity of silicate is fused with high SiO2 content. In another reference, the p > Attempt American no. 5,874,101 (the "patent '101") proposes a bioactive gel prepared by an improved process, a sol-ge process which includes a drying step for the treatment of hypersensitivity of the teeth. As with the existing bioactive glasses and glass / ceramics and as described in the '942 patent, the bioactive glasses in a' 101 patent are confined to a zone of specific composition in the Na2O-CaO-P2O5-SiO2 system defined primarily in silica content (Ogin, M., Ohuchi, F and Hench, LL, Compositional dependence of the formation of calcium phosphate films on bioglass (Compartment of formation of calcium phosphate films in bioglass), J. Biomed Mater. Res. 1980, 14, 55-64 and Ohtsuki, C, Kokubo, T., Taka atsuka, K and Yamamuro, T., Compositional dependence of bioactivity of glasses in the CaO-SiO2-P2O3 system: its in vitro evaluation (Composition dependence of glass bioactivity in the CaO-SiO2-P2O3 system: its in vitro evaluation), J. Ceram. Soc. Japn. 1991, 99, 1-6). The '101 patent describes a composition in weight percent of 40-90 SiO2, 4-45 CaO, 0-10 Na2O, 2-16 P2O5, 0-25 CaF2, 0-4 B2O3, 0-8 K2Oy 0-5 MgO . None of the references of the prior art provide bioactive particulates, which are simple and easy to prepare, and which promote the initiation of calcium containing material to restore and / or repair calcified mineral tissues.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to an inorganic or organic / inorganic compound composition, which consists essentially of CaO and SiO2 to restore defects in calcified tissues. The organic / inorganic compound material is preferably an amorphous binary oxide material of the CaO SiO 2 system having been prepared by the addition of a source of soluble calcium to a suitable silicon donor precursor, such as TEOS or sodium silicate. PREFERRED EMBODIMENT, the invention relates to an organic or organic / inorganic compound composition, which consists essentially of CaO and SiO2, which, when introduced into the tubules, initiates the formation of calcium-containing mineral within the tubules dentin for the relief of pain associated with sensitive teeth, Preferably, the compound composition should have a particle size in the size range of approximately 10 microns. or less, advantageously with the majority in the range of approximately 2 microns or less. The bioactive composition of the invention can be produced and / or obtained by various methods, including but not limited to: a) a modified low temperature sol-gel process that produces inorganic compounds; b) a modified low temperature sol gel process that produces organically modified silicates; c) analogously occurring analogs chemically or physically modified from the binary oxide material obtained from chemical supply companies, ie. Calcium silicate of wollastonite; and d) amorphous precipitation of inorganic materials.

IN THE DRAWINGS Figure 1 is a photographic electron micrograph of exploration or "SEM" (10 KV X 3200 magnification) of a sample of calcified tissues, an untreated dentin disc surface incubated in sterile saliva. Figure 2 is an SEM of a treated dentin disc surface (prepared in the same way as the untreated disc surface) after being treated (or repaired) by materials made by the process based on precipitation that produces inorganic particles . Figure 3 is an electronic scanning photomicrograph (20KV X 6000 magnification) of an untreated dentin disc surface. Figure 4 shows a superior dentin disc surface prepared in a similar manner after being treated with materials made by the dilution precipitation process.

Figure 5 is a scanning electron photomicrograph (magnification 10 KV X 1700) of an untreated dentin disc surface. Figure 6 shows a dentin disc surface prepared in a similar manner after being treated with materials made in Example 2 - modified sol-gel ORMOSILS process. Figure 7 is an electronic scanning photomicrograph (increase 10 KV X 1600) of the untreated control dentin disc sample. Figure 8 (10KV x 1700) shows a dentin disc surface prepared in a similar manner after being treated with materials prepared in Modified 4-core modified base-sol-gel reaction.

DETAILED DESCRIPTION OF THE INVENTION The inventors have found bioactive materials convenient to manufacture and surprisingly low cost that restore defects in calcified tissues, including relief of pain associated with hypersensitive teeth. The researchers have also found a bioactive glass that is conductive to mineralization by varying the processing parameters and the wet chemistry of the materials Bioactive particulate composition. Current bioactive materials, including glass, frequently depend on a complicated list of oxides, including P2O5, Na2O, B2O3, K2O, MgO, AI2O3, TiO2, Ta2O5 and fluoride salts, including CaF2. We found surprisingly that the growth of nucleating crystals can be initiated by using only one Basadc binary oxide system essentially exclusively in Si, O and Ca +. The bioactive materials prepared in accordance with the present invention, an inorganic compound or inorganic / organic hybrid containing CaO-SiO2 derived from naturally occurring analogs, are capable of depo > Place a layer of apatite or other mineral containing calcium, similar in composition and crystallinity to those mineral phases that predominate in normal dentine once the surface of the material is placed in conjunction with blood, saliva or simulated body fluid. We also find that by retaining bioactivity, even if these species are removed from the composition, they can decrease the cost of the material, allow greater freedom in processing and eliminate possible organoleptic and toxicological problems. The simplicity of the chemical composition of the present invention, which not only helps to facilitate processing and lower costs, but also allows flexibility to design the composition to the intended application. We found a material designed for nuclear mineral containing calcium for the treatment of a specific problem, sensitivity of teeth, and removed excipients that become a necessity of biological activity when used as an osteo-inductive material elsewhere in the body. Unlike most of the currently used bioactive materials that act in part by encouraging internal growth and tissue formation via osteoblasts and other hard tissue cells, the materials of the present invention surprisingly do not require auxiliaries cell phones. Additionally, the compositions according to the present invention are capable of inducing the precipitation of apatite and calcium-containing mineral from simulated body fluids without the aid of bone morphogenic proteins, dentine phosphoproteins, odontoblasts or their host cells, or a defined collagen matrix. . The ability to induce mineralization without the need for organic auxiliaries optimizes this material for use in the oral environment. In addition, many of these materials currently in use require highly specialized properties, such as porosity and mechanical strength suitable for their specific clinical use. For example, Li, Clark and Hench showed that there is a minimum rate of hydroxyapatite formation, which is necessary to be an effective mineralizing agent and that this velocity is a function of both the composition and the microstructure (Li et al., "An Investigation of Bioactive GlassPowders by Sol-Gel Processing ", (An Investigation of Bioactive Glass Powders by Sol-gel Processing), J. of Applied Biomaterials, Vol 2, 231-239 [1991].) The inventors have surprisingly found that the materials of the present invention do not need the porosity and mechanical strength of the prior art bioglasses to work in dental applications, so that when they are introduced into the tubules they initiate the formation of calcium-containing mineral within the dentinal tubules. inventors have also found, surprisingly, that the bioactive materials of the present invention are more bioactive beyond the composition limit for melting-derived glasses of the prior art with a less porous microstructure. Although other oxides are not necessary including P2O5, Na2O, B2O3, K2O, MgO, AI2O3, TiO2, Ta2O5 fluoride salts, including CaF2, as are commonly required in the compositions in the prior art, they can be used in conjunction with the oxide system binary of the present invention. A preferred and exemplary application for the bioactive materials of the present invention is in dentin hypersensitivity treatment. In the microscopic examination of exposed sensitive dentin surfaces, they show that they exist in clear differences between sensitive or non-sensitive dentine regions. Sensitive dentin is permeated by open tubules. AND? In contrast, surfaces of non-sensitive teeth are characterized by tubules that are sealed from the external environment by deposits or mineral coatings that occur naturally. We found that once it binds to the dentin surface or is introduced into the tubule, the amorphous material of the present invention initiates nucleation and stimulated meralization by the salivary environment, sealing the tubule of external stimuli by depositing a layer of apatite. or another mineral containing calcium, similar to the natural tooth mineral in composition and crystallinity. Suitable carriers for use in the composition for use in dentin hypersensitivity treatment are preferably hydroxylic materials, such as water, polyols and mixtures thereof. Polyols, sometimes referred to as humectants, include glycerol, sorbitol, propylene glycol, xylitol, polypropylene glycol, polyethylene glycol, hydrogenated corn syrup and mixtures thereof. Particularly preferred as the carrier is an acidic mixture of 3-30% water, 0-90% glycerol and 0-80% sorbitol In general, the amount of the carrier r will vary from about 25 to 99.9% by weight , preferably about 70-95% by weight When the compositions of this invention are in the form of a toothpaste or gel for the dentine hypersensitivity treatment, a natural or synthetic thickening agent will normally be included in a amount from about 0.1-10%, preferably about 0.5-5% by weight Thickeners may include hydroxypropyl methylcellulose, hydfoxethyl cellulose, sodium carboxymethylcellulose, xanthan gum, tragacanth gum, karaya gum, gum arabic, Irish moss, starch , algin ats and carrageenins L Looss ssuurrffaaccttaanntteess nnoorrmmallmmsnte are included in compositions for the treatment of hypersensitivity of dentin.These surfactants can be anionic type , non-ionic, cationic or amphoteric. Most preferred are hate lauryl sulfate, sodium dodecylbenzene sulfonate and sodium lauryl sarcosinate. The surfactants are usually present in an amount from about 0.5-80% by weight. For anti-caries protection, a fluoride ion source will normally be present in the oral compositions. Fluoride sources include sodium fluoride, potassium fluoride, stannous monofluorophosphate, calcium fluoride, stannous fluoride, and sodium onofluorophosphate. These sources should release from approximately 25 - 3500 ppm of fluoride ion.

Anti-caries agents will be present in an amount from about 0.05-3.0% by weight, preferably about 0.5-1.0%. The flavors that are normally present in compositions for oral care are those based on oils of spearmint and mint. Examples of other flavoring agents include menthol, wintergreen clove, eucalyptus and anise seed. The flavors can vary in concentration from about 0.1 - 5.0%. Sweetening agents, such as saccharin, sodium cyclamate, aspartame, ssaaccaarroossae and ssiimmiillaarreess can be included in the nivivveness from about 0.1-5.0 wt%. Other additives may be incorporated including preservatives, silicones, other synthetic or natural polymers, anti-gingivitis actives, anti-tartar agents, bleaching agents and other desirable products frequently found in a conventional toothpaste, such as baking soda and peroxide. It is also advantageous that these materials are compatible with conventional de-sensitizing agents, such as potassium nitrate, potassium chloride and potassium bicarbonate, as well as novel de-sensitizing agents, such as those described in US Patent No. 5,589,159. . Numerous vehicles are present for the oral delivery of active agents in dentin hypersensitivity treatment, including but not limited to pastes, gels, rinses, powders, gums, dental floss, pastes and solutions, and although each is not described, finds within the scope of the present invention.

In compositions for use as bone implants or for forming implantable surfaces, other materials may be added to the bioactive materials of the present invention, including antibiotics, structural fibers and / or polymeric resins, depending on the application.

Preparation. It is an advantage of the present invention that the materials are easy to manufacture, eliminating the costly and slow processing processes involved with the bioactive materials derived from melting and sol-gel derivatives in the prior art, the bioactive materials of the present invention. The invention can be prepared by various processes and with various chemical modifications designed to engineer the composition for a specific application, due to advanced processing and to engineer the wet chemistry to intensify the bioactivity of the material. The processes of the present invention can be used to prepare the bioactive materials of the present invention, which are based exclusively on Si, O and Ca + 2. 1. Modified sol-gel process that produces inorganic glasses The synthesis of sol-gel with conventional glass is achieved by combining a precursor of alkoxide of rr etal with water and a catalyst with "polymerization" consistent with the species of metal alkoxide and the production of a gel followed by the steps below: 1) sintering with heat at temperatures fr < between 600 - 900 degrees Celsius, 2) heat treatments for calcination, and frequently 3) supercritical drying to maintain the integrity of the nanostructured material. Unlike glasses prepared by the melting process, glasses prepared by the sol-gel process ("sol-gel-derived glasses") maintain the bioactivity for the compositions up to pure silica gels A particular feature of sol-gel processing is the production of microporous materials.As a result, two advantageous consequences follow: 1) The large surface area associated with the gel gives. silica containing porous calcium leads to a rapid increase in the concentration of Ca + 2 ions in the surrounding solution, and 2) The teixture produced by the sol-gel process results in a uniform porcsa gel layer with the exchange of ions and dissolution rates reduced as the SiO2 content increases. It is thought that these two factors are responsible for the high velocity of mineral formation and the extension of the composition bioactivity range in the sol-gel derived glasses. Studies have shown that pre-fixed silica sol-gel, unlike melting glass, has a highly hydrolyzed silica surface, which facilitates and initiates apatite nucleation from metastable simulated body fluids. The inventors have been able to surprisingly incorporate the favorable porosity and the increased surface area associated with the sol-gel derived materials in a "modified sol-gel process" that does not require the additional processing steps of sintering with heat, treatment of calcination heat and supercritical drying for maintain the integrity of the nanostructured material, these steps are not easily adaptable to production, but are necessary to achieve "a properly formed sol-gel glass". In this modified sol-gel process of the invention for producing inorganic materials, a precursor of calcium alkoxide, tetraethoxysilane (TEOS) and optionally tri-3-io-os-a-te (TEP), is hydrolyzed under acidic conditions and low temperatures to form a gel. Other appropriate ingredients will also be apparent to those of ordinary skill in the art. The process can also be carried out using conditions to chases for the hydrolysis reaction. It has been found that this controls both the morphology and the size of the powders produced. 2. Modified sol-gel process that produces organically modified silicates ("Ormosils") In this Ormos s process, a hydrolysis reaction as described in the modified sol-gel process is first used to prepare hybrid organic / inorganic materials, followed by the formation of an inorganic network. During the formation of this network, the appropriately functionalized organic portions also undergo a condensation reaction and are incorporated into the network that is being formed. In this second manifestation, organic / inorganic hybrids are prepared from silanol-terminated poly (dimethylsiloxane) [PDMS] and tetraethoxysilane precursors [TEOS] (a source of silicon) as described by Hu and MacKenzie (Journal of which arises from the ability to serve as a source of reactive primary silica species. The ability of this inorganic material to easily form the reactive silica species is the key to its ability to nuclear mineral containing calcium. The dissolution rate of soluble silicates depends on the proportion of glass, solids concentration, production temperature, pressure, particle size and surface area g bal. Dissolution normally occurs in a two-step mechanism involving ion exchange and network breakdown. Ion exchange: = Si-OCa + H2O = Si-OH + Ca + 2 + OH 'Rupture of the network: = Si-O-Sii = + OH < - > = Si-O '+ HO-Si = As supplied, the calcium silicate may not conform to the specifications or possess the desired functionality and certain modifications, i.e., surface alterations, particle size adjustment, and / or other necessary treatments may be implemented. When received first, Alfa Aesar's commercial material was moderately active in our evaluation. However, after grinding balls of the material to an average size of 5μm, the material p prrooppoorrcciioonnóó bbiiooaaccttiivviiddaadd iinntteennssii each. The naturally occurring calcium silicate obtained from wollastonite has shown bioactivity in our in vitro evaluations. These materials that include calcium silicate, (meta (CaSiO3), ortho Ca2SiO), etc., can be obtained commercially through suppliers of major chemicals, such as Alfa Aesar and Aldrich. 4. Precipitation-based process that produces inorganic particles The fourth manifestation of the present invention is our most preferred process. In this process based on precipitation, the sol-gel procedure is modified to a precipitation method to remove the difficult processing parameters inherent to a sol-gel (or the "sol-gel modified" method) simply by precipitating an amorphous oxide and not go through the "sun-cel" stage. In this process, the inorganic particles are produced as previously described in the sol-gel process, by the controlled hydrolysis of TEOS and resulting condensation incorporating reactive ions donated from a calcium source, either a calcium salt, such as calcium nitrate or an alkoxide derivative, such as calcium methoxide in a precipitation method. Inorganic particles contain specific agents, ions, polymers or colloidal particles that make the materials of the present invention bioactive. In a traditional sol-gel process (or our "modified" sol-gel), silicate gels are often synthesized by hydrolyzing monomeric tetrafunctional alkoxide precursors that employ a mineral acid (eg, HCl) or a base (e.g. , NH3) as a catalyst. At the functional group level, three reactions are usually used to describe the sol-gel process: Hydrolysis = Si-OR + H2O < ? = Si-OH + ROH Esterification Condensation of alcohol = Si-OR + HO - Sis - > = Si-O-Si = + ROH Alcohó lisis 3. Hydrolis' = Si-O-Si = + H2O < - > = Si-OH + HO - SU Water condensation where R is an alkyl group, C, | H2x + 1. The hydrolysis reaction replaces the alkoxide (OR) groups with hydroxyl (OH) groups. Subsequent condensation reactions involving the silanol groups produce siloxane (Si-O-Si) bonds plus alcohol byproducts (ROH) or water. Under most conditions, condensation begins before the hydrolysis is complete. D Deebbiiddoo aq queue eell aaqguuaa v and alkoxysilane are immiscible, a mutual solvent such as alcohol, is not usually used as a homogenizing agent in a sol-gel process. However, the gels can be prepared from mixtures of silicon alkoxide-water without added solvent, because the alcohol produced as the by-product of the hydrolysis reaction is sufficient to homogenize the separate system of phase initially. We have found that, if after the step of hydrolysis, a reactive species ie calcium nitrate is added to the mixing vessel, the silica will precipitate due to the destabilization of surface charge within the sun. This precipitated material that when tested in our model, surprisingly achieves superior results as an occluder of dentinal tubules and, as is judged Dor scanning electron microscopy ("SEM"), a superior dentin mineralizing agent as shown in the Figures, comparing two samples of calcified tissue or two dentin disc surfaces, one untreated (Figure 1) and one treated (Figure 2) with the materials prepared by this preferred process.

In the most preferred method of the precipitation process, a "diluted precipitation process", an amorphous CaO-SiO2 inorganic material, is produced by I e? reaction of a diluted silicate source, ie, aqueous solutions of potassium or sodium silicate with a source of soluble calcium as previously described. This procedure allows the manipulation of both the composition of the final precipitate, as well as physical characteristics, such as the final size or concentration. It is found that the materials prepared by this dilution process work very well both in aqueous dispersion and prototype dentifrice compositions, as confirmed by hydraulic conductance tests and SEMs as shown in Figures 3 and 4 (two dentin surfaces). prepared in a similar way, untreated and treated).

Without wishing to join a theory, it is postulated in our invention, that Ca (ll) and other key species for bioactivity, can be introduced in silica sol in formation, resulting in a particulate hybrid material.

In general, the stabilization of colloids by electrostatic repulsion is successfully described by the DLVO theory (the Derjaguin theory, Landau, Ververy and Overbea k which describes stability suspensions), well known for colloidal chemicals. Silicas do not conform to the DLVA theory, because it is apparently stabilized by a layer of adsorbed water that prevents coagulation even at the isoelectric point. The addition of cations to aqueous silica sol can reduce the degree of hydration / destabilize the silica. Alien and Matijevic (J. Colloid and Interface Sci, 3 1 [3] 1969 287-296, 33 [3] (1970) 420-429, 35 [1] (1971) 66-76) showed that adding a salt to the sun would produce ion exchange in the following way = Si-OH + Mz +? = Si-OM (2'1) + + H + where Mz + is a non-hydrogenated cation of charge z. Because the silanol groups are the water adsorption sites, the removal of SiOH med in ion exchange reduces the amount of hydration and decreases the stability of the colloid. The reaction precipitates a Ca (ll) -containing silicate which can be easily removed from the solution by filtration and can be resuspended in a suitable vehicle for application as a dental material. The remaining solutions can be reused by facilitating both the cost and the production of the material. In the process based on the precipitation of the present invention, sodium silicate [CAS # 1344-09-8] can be substituted as the source of silicon. The addition of an appropriate amount of a calcium source Soluble, that is, Ca (NO3) 2, to a sodium silicate solution, precipitates a silicate containing calcium, whose composition is similar to previously described materials. The amount of C ++ to be added to the silicate solution was determined by both stoichiometric calculations and experimental design. The precipitation-based process of the present invention has several advantages over other processes. This process does not produce by-products that can contaminate the final product after incorporation into a standard dentifrice, that is, ethanol or residual TEOS. In addition, the chemistry of the reaction in this process is such that the particle size can be controlled more easily during the reaction, thus eliminating the need for additional steps of size reduction and grinding, which are not only costly but also they can also increase the possibility of contamination of the final product. In addition, the reaction only requires two ingredients, sodium silicate and the appropriate calcium source. Both chemicals are readily available from chemical companies and are relatively inexpensive compared to other processes. In this process, the material, once precipitated and separated from the remaining solvent, does not require any special processing, including washing, drying at high heat or supercritical drying; nor does the material involve a procedure for calcination or extraction of organic solvent. Additionally, it is preferred, although not critical, that in the process, the precipitated material be chemically controlled to produce amorphous material of particle size range sufficiently small in size. as it does not require additional furniture, crushing or reduction. In this way, one avoids the possibility of sample contamination and additional processing costs. The preferred process of chemical reactions carried out under ambient conditions, produces a highly porous calcium-containing silica, similar to bioactive glass prepared by the sun process. - Traditional gel in biological activity. This inorganic material does not resemble the heat-activated bioactive glass material currently available in other ways. It is much preferred that the reaction produces a calcium-containing oxide material, based only on a two-component system, CaO-SiO2; and that the reaction occurs at room temperature in familiar solvents for the field of health care, as well as safe and well known to the personnel of production facilities. The bioactive materials prepared in the examples that follow are suitable for various applications, including but not limited to: a) the enhancement of binding of bone cells and activity when the materials are placed in a tissue culture medium for repair of defects bone, so that when inoculated with cells, the formation of bone tissue begins; b) implant compositions for filling cavities in bones and channels in the teeth; c) compositions for oral care to be used to re-crystallize the teeth; c) compositions for oral care for repairing periodontal bone defects; and compositions for oral care for use in the treatment of dentine hypersensitivity. The bone defects contemplated include, but are not limited to, the following: repairs of cystic defects, sites of benign and malignant tumors on resection, bone loss, fracture repair sites including delayed or non-union sites, joint repair sites, osteoporosis-related defects and periodontal defects Examples The following examples are provided for illustrative purposes only, and changes or alterations may be made that are not described herein. In examples designed to treat dentine hypersensitivity, experiments were conducted using a modified in vitro dentin sensitivity model described in US Pat.270,031. In this method, intact human molars free of caries or restorations are sectioned perpendicular to the long axis of the tooth with a metallurgical saw in sections of approximately 1 mm in thickness. The dentin-free and varnish-free sections are retained for testing. These sections are etched with a solution of EDTA (ethylenediamine tetraacetic acid) to remove the smear layer. The disk is mounted on a split camera device as reported in Journal of Dental Research 57: 187 (1978). This special leak-proof chamber is connected to a pressurized fluid reservoir containing a tissue culture fluid intended to mimic the osmolality of human body fluid. By using a mixture of pressurized N2 or CO2 gas, the fluid can be maintained at physiological pH. The apparatus includes a tube Glass capillary mounted on a ruler or other measuring instrument, An air bubble is injected into the capillary glass tube and by measuring the displacement of the bubble as a function of time, the flow of fluid through the disc dent ina can be measured. It has been reported that the fluid actually flows out of the dentine tubules inside a normal tooth. Following measurements of the baseline fluid flow in the dentin disc, the expiratory mix, dentifrice, gel or mouthwash is applied to the external diiscus surface in a manner that would mimic its clinical use. After a defined application period, the experimental material is rinsed and the post-application hydraulic conductance (Ipacute) is measured. In this way, several experimental materials can be tested both alone and as components of final products, for the ability to obstruct the flow of fluid in the dental tubules. The percentage of flow reduction induced by the application of the experimental material can then be calculated. For all the examples given, it was necessary to incubate saliva to achieve flow reductions. In order to study the mineralizing potential of novel agents, a prolonged period is necessary as well as a modification of a standard dentin hydraulic conductance measurement. After initial post-application measurements are taken, the divided chamber is removed from the apparatus and a deposit of sterile filtered human saliva is attached to the chamber which allows the fluid to bathe the occlusion dentin surface treated. The outside of the camera is wrapped in parapelle cord to avoid contact with air and that results Subsequently, they are refluxed while stirring at 80 ° C for 30 minutes. After reflux, the mixture was quenched at 25 ° C with ice water, emptied into containers and allowed to gel under ambient conditions. After gelification, irregular, flat-shaped fragments were ground into sizes in the range of about 10 microns or less, with the majority in the range of about 2 microns or less. Grinding can be performed by several methods including, but not limited to, ball milling, air impact grinding, MICROS super fine milling, rotary cutter grinding, hammer milling and cage milling. This material, now of known particle size, was dispersed in glycerin and was tested in our in vitro model as a paste at various concentrations. In the current modality of the invention, the repeated applications of a 20% paste showed good. ability to reduce dentin fluid flow as seen in Table 1.

Table 1 Percentage of flow reduction with glycerin dispersions of an organic / inorganic compound material Treatment Post-treatment Deviation Average size (40 h) standard sample (N =) % compound paste 61.5% ± 12.9 organic / inorganic in glycerin It should be noted that the cycle of repeated applications and filtered saliva incubations did not produce significant fluid flow reductions when non-bioactive materials were evaluated.

In addition, the integrity of an untreated dentin surface and a dentin surface treated with placebo, exposed to this cyclic method, was confirmed by SEM. Occlusion was not observed when a cinder surface treated with finely ground pumice was examined in this manner. Similarly, the morphology of untreated dentin surfaces that were exposed to single cyclic sterile saliva treatments, as in this mineralization model, does not differ significantly from freshly cut dentin specimens prepared after SEM evaluation.

Example 2 (modified sol-gel - ORMOSILS) The second embodiment of the present invention is prepared from the same precursors co rh or in Example 1 and processed in a similar manner. However, in this example, the amount of calcium nitrate (1.25 g), the source of calcium ions, was significantly increased in the mat srial. Although this increase reduced the unusual mechanical strength and flexibility of the original material, the resulting composition showed better dentin fluid flow reducing capacity (Table 2) at various concentrations in glycerin dispersions.

Table 2: Percentage of flow reduction with glycerin dispersion of an organic / inorganic material with high incorporation of calcium ions Treatment Post-treatment Deviation Average size (40 h) standard sample (N =) . 0% of material 100% 0.0 organic / inorganic in glycerin 20% of material 100% 0.0 organic / inorganic in glycerin This material resulted in a faster and more complete occlusion than the material described in Example 1, as shown in Figure 6, which shows a disc surface of dentin after being treated with materials prepared by this sol-gel process. modified ORMOSILS. Figure 5 shows a dentin surface prepared in a similar manner that is not treated.

Example 3 (modified sol-gel - inorganic materials) A completely inorganic material is produced by a sol-gel process under ambient conditions. The material uses precursors similar to the mplo 2 axis, but PDMS and tetrahydrofuran were omitted. 2-propanol is a solvent for TEOS and is not used in this example. The TEOS is simply a silicon source in this example. The procedure is the same as in Examples 1 and 2. Without However, the product of this example contains only calcium, silicon and oxygen. Although this material has poor mechanical strength, it is very effective as an agent or tubule luster. In addition, the absence of PDMS and tetrahydrofuran is favorable for the toxicological profile.

Table 3: Percentage of flow reduction with glycerin dispersion of an inorganic derivative or sol-gel compound Treatment ost-treatment Deviation Average size (40 h) is idar sample (N =) . 0% compound 97.4% ± 3.7 inorganic sol-gel derivative in glycerin Example 4 (ribaded sol-gel process - base catalyzed reaction). A base catalyzed sol-gel process is used to control the shape and size of the resulting particulate suspisions. The starting materials are as follows: 50 ml of TEOS, 75 ml of ethanol, 70 ml of water, 0.575 g of ammonium hydroxide (30%) and 3.6 g of calcium nitrate. For these reactions, ammonia is used as a catalyst that causes the formation of spherical particles. This procedure is based on an article by Stóber and Fink from 1968, "Controlled Growth of Monodisperse Silica Spheres ii the Micron Size Range" (Controlled growth of monodisperse silica spheres in the micron size range) (Journal of Colloid and nterface Science , 26, 62-69, 1968). The resulting particulate composition proved to be a very mineralizing agent effective (Table 4). The electronic scanning micrographs showed a complete coverage of the dentinal tubules that is inferred to be due to the mineralization of the tubule orifice in samples treated with the composite material. Untreated samples are marked by numerous patent tubules indicative of hypersensitive regions of the tooth. Furthermore, our ability to chemically control the shape and morphology of the particulate material makes this example easier to formulate and process. In addition, the elemental analysis of this material confirms large amounts of C + 2 and Si in a conductive proportion to bioactivity. Figures 7 and 6 compare two surfaces of dentin prepared in a similar manner to one untreated and one treated with the composition of Example 8.

Table 4: Percentage of flow reduction with glycerin dispersion of an inorganic compound Treatment Post-treatment Deviation Average size (40 h) standard sample (N =) . 0% of compound 98.0% ± 3.4 inorganic in glycerin 10.0% of compound 97.7% ± 3.4 17 inorganic in glycep Example 5 (naturally occuring minerals) A calcium ortho-silicate [(CaO) 2-SiO2, FW: 0.088-0.044 mm (17.24, - US 325 mesh)] was used derived from the Wollastonite ore. from Alfa Aesar Published studies Hian indicated that the pseudowollastoninta, synthesized at 1500 ° C, lasted for 2 hours from a stoichiometric mixture of calcium carbonate and silica, is bioactive in a simulated body fluid environment (De Aza PN et al., Bioactivity of Pseudowollastonite in Human Saliva, Journal of Dentistry, 27 (1999), 107-113). As supplied from Alfa Aesar, the particle size was not suitable for such application and the material was ball milled in glycerol at a favorable average particle size for the mineralization of a microporous substrate. As shown in Table 5, the resulting particulate composition proved to be an effective mineralizing agent Table 5: Percentage of flow reduction with dispersions of calcium ortho-silicate derived from wollaston (a Treatment ost-treatment Deviation Average size (40 h) standard sample (N =) 205 of calcium ortho-silicate 74.3% ± 30.0 derived naturally, provided by Alfa Aesar Example 6 (Process based on precipitation that produces inorganic particles). A precipitate was prepared using a commercially available solution of sodium silicate and calcium nitrate. To 72.8% by weight of a 40% sodium silicate solution, 27.2% by weight of a 75% calcium tetrahydrate solution in deionized water, with the mixer running at high speed to provide maximum agitation to the partner silicate solution. The precipitation occurred immediately. The precipitate (calcium silicate, inorganic precipitate or "CSIP") was dried at 60 ° C for 40 hours. In Example 6, the particle size of CSIP was reduced by milling (e.g., using an air impact mill, simple ball mill, etc.). However, it is possible to alter the particle size by altering the pH or diluting the sodium silicate solution, while maintaining the high concentration of calcium nitrate to decrease the final particle size of the precipitate. The superior tubule occlusion efficiency was judged by both hydraulic conductance and SEMs as shown in Figs. 3-4 (untreated and treated with the composition of Example 6).

Example 7 A tooth past composition which further aids in pain relief, when used on hypersensitive teeth, was prepared using the following formulation. The de-sensitizing agent in this example may be any of the above-mentioned inorganic compounds, Ormosil, synthetically derived inorganic material, or sol-gel derived materials, or sodium silicate derived materials, in a suitable composition. The given percentage by weight of each ingredient is based on a value of 100% for the total formulation.

Ingredient% by weight Water 48.4 Calcium silicate (derived from a solution of 5.0 sodium silicate [1344-09-8] and Ca (NO3) 2 [13477-34-4]) Laurel sodium sarcosinate 0.4 Sodium saccharin 0.3 Sodium fluoride 0.2 Hydroxyethyl alcohol 2.3 Hydrated silica abrasive 6.0 Lauryl sulfate and sodium 1.2 Glycerin 23.0 Hydrated silica thickener 8.0 Membrane oil 0.2 EXAMPLE 8 A second formulation of toothpaste comprising a deactivating agent consisting of either an Ormosil, inorganic compound, synthetically derived inorganic material or sol-gel derived materials was prepared. The percentage basis by weight and the preparation process are the same as those described in previous examples. , dispenses each phase sim ultáne amenté, or can be packed in separate tubes that are intended to be applied sequentially Phase A Phase B Ingredient% by weight Inorganic compound catalyzed with base 3.0 Laurel sodium sarcosinate 0.6 0.6 Hydroxyethylcellulose 2.3 Sodium lauryl sulfate 1.2 Glycerin 82.8 Hydrous silica thickener 8.0 8.0 Methylated salicylate 0.1 Sodium fluoride 0.3 Sodium saccharine 0.3 Water 84.6 Oil Mint green 0.2 Hydrated silica abrasive 6.0 The active ingredient can also be formulated in a variety of dental rinse formulations designed to alleviate tooth sensitivity. An extremely fine particle size is needed to ensure homogenous dispersion of either Ormosil, inorganic compounds, inorganic material, or synthetically derived, sol-gel derived materials or calcium silicate naturally derived from mineral precursors. This can be achieved either by chemical modification or mechanical milling of material.

Example 10 Formulations of a medicinal type mouthwash and fluoride oral rinse are as follows in weight percent (adjusted to pH 6):

Claims (20)

1. A composition for removing defects in calcified tissues comprising an amorphous bioactive particulate material, consisting essentially of calcium, silicon and oxygen.

A composition according to claim 1, wherein said amorphous material is selected from the group consisting of. a) a reaction product from an organic silicate source and a calcium source; b) a hydrolysis product containing calcium of tetraethylorthosilicate, c) a sol-gel of silica containing calcium d) a calcium oxide bina rio and precipitated silicate material; e) a synthetic analogue of a calcium silicate similar to wollastonite, which occurs naturally; and f) a reaction product precipitated from a source of soluble calcium and a solution of silicat b.

3. A composition according to claim 2, wherein said amorphous material is a precipitated reaction product of a soluble calcium source and a dilute sita- cate source selected from an aqueous potassium solution or a sodium silicate solution. .

4. A composition according to any of claims 1 to 3, wherein said material has a particle size in the range of about 10 microns or less.

A composition according to claim 4, in which the material mostly comprises particles in the size range of about 2 microns or less.

A composition according to any one of claims 1 to 5 in a dental product for relieving the sensitivity of the teeth due to the presence of exposed tooth sce and open dentinal tubules, by causing the formation of calcium-containing mineral within the teeth. dentinal tubules of sensitive teeth.

7. A composition according to claim 6, comprising a carrier and about 1-25% of said amorphous material.

8. A composition according to claim 7, wherein the carrier comprises 0-30% water, 0-90% glycerol and 0-80% sorbitol.

9. A composition according to claim 7 or claim 8, wherein said morpho material is about 5-10% of the composition and the composition is a dentifrice

10. The use of an amorphous bioactive particulate consisting essentially of calcium, silicon and oxygen, in the preparation of product to restore defects in calcified tissues.

11. A use according to claim 10 in the preparation of a product to alleviate the sensitivity of teeth due to the presence of exposed dentinal sce and open dentinals, by causing the formation of calcium-containing mineral within dentinal tubules of the sensitive teeth.

12. A use according to claim 10 or claim 11, wherein said amorphous material is selected from the group consisting of: a) a reaction product from an organic silicate source and a calcium source; b) a hydrolysis product containing calcium of tetraethylorthosilicate; c) a silica sol-gel containing calcium; d) a binary calcium oxide and precipitated silicate material; e) a synthetic analogue of a calcium silicate similar to wollastonite, which occurs naturally; and f) a reaction product precipitated from a soluble calcium source and a silicate solution.

13. An amorphous bioactive particulate consisting essentially of calcium, silicon and oxygen, to restore defects in calcified tissues.

14. A bioactive particulate according to claim 13, for use in the de-sensitization of the teeth.

15. An amorphous bioactive particulate according to claim 13 or claim 14, selected from the group consisting of: a) a reaction product of an organic silicate source and a calcium source; b) a hydrolysis product containing calcium of tetraethylorthosilicate; c) a silica sol-gel containing calcium; d) a binary calcium oxide and precipitated silicate material; e) a synthetic analogue of a calcium silicate similar to wollastonite, which occurs naturally; Y f) a reaction product precipitated from a source of soluble calcium and a solution of silica

16. A process for producing an amorphous bioactive particulate to restore defects in calcified tissues, said process essentially consisting of adding a sufficient amount of a solution from a source of soluble calcium to a silicate solution or silicate precursor to cause a precipitate of silicate particulates containing calcium.

17. A process of agreement is claim 16, wherein said source of soluble calcium is selected from the group consisting of calcium salts and alkoxide derivatives and mixtures thereof.

18 A process according to claim 16 or claim 17, wherein said solution of a silicate or silicate precursor is a source of dilute silicate selected from the group of aqueous potassium solution and aqueous solution of sodium silicate.

19. A process for the production of an amorphous bioactive particulate for the treatment of sensitive teeth, said process essentially consisting of combining a metal slxide with water and a catalyst and the polymerization of a silicate ester for the production of said amorphous bioactive particulate. .

20. A process according to claim 19, wherein said metal alkoxide is prepared from tetraethoxysilane and pol? (D? Methylsiloxane) terminated in silanol.