Self-assembled micelle templated porous particles comprising silica and a metal oxide and their use in dental applications

Abstract

A composition having a porous amorphous framework containing silica and one or more metal oxide, in particular zirconia or titania or alumina. The pores of the framework are templated on micelles of one or more ionic or non-ionic surfactants. The framework may be templated by using an antimicrobial amphiphilic active agent such as octenidine or cetylpyridinium which will thereby be loaded in the pores of the porous framework. The framework may form a whole particle or a shell onto a particle. A composite material may be formed by dispersing the particles comprising the composition in a matrix material, such as a dental composite or restorative resin. A method of making the composition by way of a sol-gel technique which includes mixing an acid, water and one or more oxide precursors is also disclosed; the acid is preferably an organic and / or chelating acid such as acetic acid.

Description

SELF-ASSEMBLED MICELLE TEMPLATED POROUS PARTICLES COMPRISING SILICA AND A METAL OXIDE AND THEIR USE IN DENTAL APPLICATIONSRELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, US provisional application number 63 / 570,536 filed on March 27, 2024, Mesoporous Silica Particle with Zirconia and / or Titania and Use in Dental Applications, which is incorporated herein by reference.FIELD

[0002] The present disclosure relates to the particles containing oxides, optionally including zirconia and / or titania, a method of synthesis of the particles, and use of the particles for example as a filler in dental composites, adhesives or other matrix materials.BACKGROUND

[0003] Dental composites and adhesives typically include a filler. The filler is typically a silica-based nanoparticle or microparticle but silica-zirconia (zirconium dioxide) and titania (titanium dioxide) fillers have also been used. Zirconia is radiopaque and thereby allows composites filled with a zirconia-containing filler to be seen in standard dental X-ray images. Zirconia also has a different refractive index than silica. Combining zirconium dioxide and silica in a filler may allow the refractive index of the filler to match the refractive index of a resin matrix, thereby making a composite more nearly translucent. Titanium dioxide fillers also influence the color and strength of dental composites and are radiopaque.

[0004] US Patent 4,503,169 describes radiopaque, low visual opacity dental composites with non-vitreous microparticles dispersed in the composite matrix. The microparticles contain amorphous silica microregions interspersed with polycrystalline ceramic metal oxide microregions. An aquasol containing colloidal silica is mixed with a sol or solution containing a ceramic metal oxide (e.g. zirconium oxide) or a calcinable precursor (e.g. zirconium acetate). The mixture is initially acidic to inhibit non-uniform gelling. The mixture is then gelled, for example by raising the pH, by dehydration or by heating.

[0005] US Patent 4,764,497 describes a method of making spherical particles having a layer of an amorphous composition containing silica and a zirconia oxide. The zirconia is present at 0.01 -20 mol% based on silica. The particles are made in alcohol solutions. US Patent 10,758,457 describes similar particles having an average particle size in the range of 230-1000 nm and particular colorimetric values used as a filler in a curable composition.

[0006] US Patent 8,722,759 describes fillers containing silica-zirconia nanoclusters. The fillers are prepared by mixing a sol of silica nanoparticles with a sol of preformed crystalline nanozirconia particles. The fillers may provide desired optical properties in dental compositions.

[0007] US Patent Publication 20050123465 describes a mesoporous compound comprising a mineral phase of aluminum in which at least partially crystalline particles of cerium, titanium or zirconium compounds are dispersed.

[0008] US Patent 10,501 ,331 describes mesoporous zirconium oxide particles. The particles as made by way of a sol-gel synthesis in an alcohol solvent.SUMMARY

[0009] This specification describes a composition having an optionally porous (e.g. mesoporous) framework containing oxygen and one or more metals. In some embodiments, the one or more metals may include silicon (which is considered a metal herein) In some embodiments, one or more metals may be selected from Group 1 A (e.g. Na), IIA (e.g. Mg, Ca), IVB (e.g. Zr, Ti), VIIB (e.g. Mn), VIIIB (e.g. Fe), VIIIIB (e.g. Co), Villi (e.g. Ni), IB (e.g. Cu), IIB (Zn) and IIIA (e.g. Al) of the periodic table. In some embodiments, one or more metals may be selected from Groups I, II and III of the periodic table and transition metals. In some embodiments, one or more metals may be selected from zirconium, aluminum and titanium.

[0010] The composition is optionally in the form of particle (e.g. a nanoparticle or microparticle, optionally between 10 and 1000 nm in size), the shell of a particle or a coating. Without intending to be limited by theory, in embodiments having multiple metals the metals may be in the form of multiple oxides, which as used herein includes a complexoxide. In some embodiments, the framework may contain an SiO2 and ZrO2, SiO2 and TiC>2, AI2O3 and TiCh or SiC>2, ZrC>2 and TiCk glass wherein the multiple oxides (i.e. SiO2, ZrO2, AI2O3 and TiCh) are not present as distinct compounds but in an amorphous structure with oxygen linking silicon to zirconium, aluminum and / or titanium, optionally with some unbound oxygen, silicon, zirconium, aluminum and / or titanium atoms, optionally with other moieties present in the framework. Described differently, the framework may comprise, in some embodiments, a silicon zirconium oxide, a silicon titanium oxide, a silicon zirconium titanium oxide or a silicon aluminum oxide. In other embodiments, the framework has a single metal oxide, for example zirconium. The pores of the composition, if any, may be filled with a solid, liquid or a gas, or a combination of a liquid and a gas.

[0011] In embodiments containing sufficient zirconium and / or titanium, the composition is radiopaque. Adjusting the amounts of silicon relative to zirconium and / or titanium allows for adjustment of the colorimetric properties of the composition. Adjusting the porosity and selecting a material loaded in the pores of a porous framework allows further adjustment of the colorimetric properties of the composition.

[0012] In some embodiments, the composition is made by way of condensation in an aqueous solution, optionally around a templating agent, seed particle or substrate. The templating agent may be, for example, an amphiphilic compound, an ionic surfactant, or a non-ionic surfactant. The templating agent forms a micellar network prior to condensation of the oxide framework. The templating agent thereby provides an interconnected porous structure in the composition. The templating agent may remain in the composition in use, may be removed for example by calcination, or may be replaced with another compound after formation of the composition. Optionally, the templating agent is a useful biologically active agent, for example an antimicrobial agent. The seed particle is optionally porous. In some examples, there is both a seed particle and a templating agent.

[0013] Mesoporous silica particles templated on a biocompatible agent are described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Self-assembly for Extended Biologically Active MoleculeRelease in Medical and Dental Applications”. This publication provides useful information on templating agents and is incorporated herein by reference. However, zirconia precursors typically react with water rapidly and hydrolysis and condensation are uncontrollably fast, leading to almost instantaneous zirconia precipitation. Accordingly, a zirconia precursor cannot be merely substituted for some of the silica precursor in the aqueous method exactly as described in this publication while producing some morphologies (e.g. generally monodisperse, spherical, submicron particles). In contrast, zirconia particles are most often prepared in alcohol solvents.

[0014] In a synthesis method described herein, a composition including zirconia and / or other metals, optionally in combination with silica, is condensed, optionally on a seed particle or substrate or around a surfactant or amphiphilic templating agent, for example octenidine dihydrochloride (OCT), in an aqueous solution. The solution is acidic, for example with a pH of 2-3. The acid may be an organic acid, for example acetic acid. The oxide (e.g. zirconia, titania, alumina and / or silica) precursors are optionally mixed with each other before being added to the solution. Condensation is initiated by raising the pH (for example by adding a base or a basic salt) or by adding a fluoride salt (for example ammonium fluoride), or by adding a basic fluoride salt (for example sodium fluoride), optionally without neutralizing the acidic solution. For example, adding a basic fluoride salt may cause the pH to rise to 4-5. In the absence of fluoride, the pH may be increased more, for example to 5-6.5.

[0015] Although the synthesis method may be varied, an organic and / or chelating acid such as acetic acid is preferable to some other acids such as HCI and HNO3. Without intending to be limited by theory, acetic acid may act as a chelating agent to inhibit hydrolysis and condensation of the zirconia precursor. While other surfactants might be used, OCT produces a good product yield and particle morphology without requiring an increase in pH beyond 5 to support condensation in the presence of fluoride ions. OCT is also a useful antimicrobial agent with a biocompatibility index greater than 1. Optionally, other surfactants such as cetylpyrindinium chloride (CPC), which can also be used as an antimicrobial agent, or cetyltrimethylammonium bromide (CTAB), or mixtures of surfactants, can be used. Although other basic salts might be used, an acidic or neutral salt without fluoride such as KCI does not result in solid formation.

[0016] This specification also describes a mesoporous particle (e.g. a nanoparticle or microparticle optionally between 10 and 1000 nm in size) containing silica and zirconia and / or titania. Optionally, the particle contains a biologically active templating agent in the pores of the particle. In some embodiments, the biologically active agent is an antimicrobial agent such as OCT. In some embodiments, zirconia and / or titania are in a shell of the particle.

[0017] This specification also describes a composition having a mesoporous framework including multiple oxides, for example metal oxides or organo-metal oxides, optionally including one or more zirconium compounds such as zirconia or organozirconia, in the framework and having a pore-loading capacity. In another aspect, the specification describes a porous particle containing silica and zirconia or a porous shell or coating containing zirconia, optionally loaded with an active agent.

[0018] This specification also describes a composition having a metal oxide framework that releases fluoride, for example when present in the mouth of a person.

[0019] This specification also describes a composition having a metal oxide framework coated on a particle or other substrate, for example a core-shell particle, optionally with zirconia in the shell.

[0020] This specification also describes a method of making a composition. The method includes preparing an acidic aqueous solution including one or more oxide precursors. A base, basic salt or fluoride salt is added to the solution to start (or accelerate) a condensation reaction. Optionally seed particles and / or a templating agent may be added to the solution. In some embodiments, a method includes preparing a first solution, the first solution being acidic and containing a surfactant and water. The method also includes preparing a second solution, the second solution containing silica and / or zirconia and / or titania and / or alumina precursors. The two solutions are mixed for a period of time. A salt is added to the mixture to start a condensation reaction. After a second period of time, particles of the composition are separated from mixture, and optionally washed and dried.

[0021] This specification also describes a composite product including a composition described herein, for example porous silica-zirconia and / or titania particlesor core-shell particles, dispersed in a matrix material. Optionally, the matrix material is a methacrylate resin. Optionally, the composite product is radiopaque, for example the composite product is detectable in a dental or medical X-ray. Optionally, the matrix material and the composition have similar, compatible and / or matched refractive indices, for example wherein the refractive index of the composition is closer (relative to the refractive index of silica or to the refractive index of similarly porous silica) to the refractive index of the matrix material.

[0022] The composite product may be used, for example, as a dental composite or adhesive or other dental material.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The description of drawings accompanying this disclosure is given below:

[0024] FIG. 1A is a schematic diagram showing a general method of synthesizing particles with a binary or ternary composition.

[0025] FIG. 1B is a schematic diagram showing an exemplary method of synthesizing particles with a binary or ternary silica - zirconia - titania composition.

[0026] FIG. 1C is a schematic diagram showing optional methods of synthesizing particles with a binary or ternary composition.

[0027] FIG. 1D is a schematic diagram showing an exemplary method of synthesizing core-shell particles with a binary or ternary composition in the shell.

[0028] FIG. 2A shows transmission electron microscope (TEM) images of (A and B) silica-zirconia particles of Example 1 , (C) silica-titania particles of Example 3, (D) silica- zirconia-titania particles of Example 4, (E) silica-zirconia particles of Example 5 and (F) silica-alumina particles of Example 6.

[0029] FIG. 2B shows transmission electron microscope (TEM) images of (A) silica-zirconia particles of Example 8, (B) silica-zirconia particles of Example 9, (C) silica- zirconia particles of Example 10, (D) silica-zirconia particles of Example 11 and (E) silica- zirconia particles of Example 12.

[0030] FIG. 2C shows transmission electron microscope (TEM) images of coreshell particles of (A) Example 14, (B) Example 15, (C) Example 16, and (D) Example 17.

[0031] FIG. 3 shows a release profile of octenidine dihydrochloride (OCT) at 37°C in PBS from the silica-zirconia particles of Example 1.

[0032] FIG. 4 shows TEM-energy dispersive X-ray (TEM-EDX) elemental analysis of the silica-zirconia particles of Example 1 at two different sites of the sample.

[0033] FIG. 5 shows TEM-EDX elemental analysis of the silica-zirconia particles of Example 2 at two different sites of the sample.

[0034] FIG. 6 shows TEM-EDX elemental analysis of the silica-zirconia-titania particles of Example 4 at two different sites of the sample.

[0035] FIG. 7 shows TEM-EDX elemental analysis of the silica-zirconia particles of Example 7 at two different sites of the sample.

[0036] FIG. 8 shows a release profile of fluoride from silica-zirconia particles of Example 7 incubated in water at 37°C.

[0037] FIG. 9 shows TEM images of the silica-zirconia particles of Example 7 after 4 days of incubation in water at 37°C.

[0038] FIG. 10 shows normalized mean gray value of composites containing 10 wt% of silica particles, silica-zirconia particles of Example 1 and silica-zirconia-titania particles of Example 4 under X-ray.

[0039] FIG. 11 shows TEM-EDX elemental analysis of silica (core) and silica-titania (shell) particles of Example 13.

[0040] FIG. 12 shows TEM-EDX elemental analysis of silica (core) and silica- zirconia (shell) particles of Example 14.

[0041] FIG. 13 shows a TEM image of particles produced by adding a base rather than a fluoride salt.DETAILED DESCRIPTION

[0042] Various apparatuses or processes will be described below to provide an example of an embodiment of each claimed invention. No embodiment described belowlimits any claimed invention and any claimed invention may cover processes or apparatuses that differ from those described below. The claimed inventions are not limited to apparatuses or processes having all of the features of any one apparatus or process described below or to features common to multiple or all of the apparatuses or processes described below. It is possible that an apparatus or process described below is not an embodiment of any claimed invention. Any invention disclosed in an apparatus or process described below that is not claimed in this document may be the subject matter of another protective instrument, for example, a continuing patent application, and the applicants, inventors or owners do not intend to abandon, disclaim or dedicate to the public any such invention by its disclosure in this document.

[0043] Furthermore, it will be appreciated that for simplicity and clarity of illustration, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. In addition, numerous specific details are set forth in order to provide a thorough understanding of the embodiments described herein. However, it will be understood by those of ordinary skill in the art that the embodiments described herein may be practiced without these specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to obscure the embodiments described herein. Also, the description is not to be considered as limiting the scope of the embodiments described herein.

[0044] The following detailed description is merely exemplary in nature and is not intended to limit the described embodiments of the application and uses of the described embodiments. As used herein, the word “exemplary” or “illustrative” means “serving as an example, instance, or illustration.” Any implementation described herein as “exemplary” or “illustrative” is not necessarily to be construed as preferred or advantageous over other implementations. All of the implementations described below are exemplary implementations provided to enable persons skilled in the art to practice the disclosure and are not intended to limit the scope of the appended claims. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description.

[0045] It should also be noted that, as used herein, the wording “and / or” is intended to represent an inclusive-or. That is, “X and / or Y” is intended to mean X or Y or both X and Y, for example. As a further example, “X, Y, and / or Z” is intended to mean X or Y or Z or any combination thereof.

[0046] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree may also be construed as including a deviation of the modified term, such as by 1 %, 2%, 5% or 10%, for example, if this deviation does not negate the meaning of the term it modifies.

[0047] Furthermore, the recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1 , 1 .5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about” which means a variation of up to a certain amount of the number to which reference is being made if the end result is not significantly changed, such as 1 %, 2%, 5%, or 10%, for example.

[0048] Reference throughout this specification to “one embodiment”, “an embodiment”, “at least one embodiment” or “some embodiments” means that one or more particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, unless otherwise specified to be not combinable or to be alternative options.

[0049] Various aspects of the disclosure are described here with reference to the embodied figures. The aforementioned figures are presented exemplarily and are not intended to limit the disclosure to certain release patterns, morphology, particle sizes (for nanoparticle morphology), oxide(s) structure composition, etc.

[0050] As used herein, the term ‘oxides’ refers to metal (including metalloid) and optionally non-metal oxides and / or salts constituting the structure of the materials. The ‘oxides’ may have some unreacted and / or bridging organic groups.

[0051] As used herein, the term ‘biologically active agent’ refers to any natural or synthetic compound for preventing or treating a disease. This definition goes beyond themere drug and includes prodrugs, proteins, peptides, DNA and RNA and their derivatives and any compound which causes a determined biological response in the body.

[0052] As used herein, the term ‘amphiphilic’ refers to molecules having at least two groups with different solvent interaction properties. An amphiphilic molecule may be associated with a specific characteristic concentration named ‘critical micelle concentration (CMC)’ above which the amphiphilic molecules self-assemble to form micelles in solution.

[0053] The term “nanoparticles” is not used strictly, for example according to the IUPAC definition. For example, nanoparticles may have a size in the range of 1 -1000 nm. In some jurisdictions, nanoparticles having a size of more than 100 nm may be referred to as microparticles.

[0054] The term “solution” is not used strictly. For example, a solution may contain particles or precipitates.

[0055] This specification describes a composition, typically in the form of particles but optionally a coating, having a framework, wherein the framework is optionally porous. The framework may be an amorphous oxide or combination of oxides, or a multicomponent glass. The framework may be primarily silica, but also includes one or more other oxides such as zirconia and / or titania. In some embodiments, the framework may include only one oxide, for example zirconia.

[0056] Optionally, the pores of a porous framework may be loaded with at least one biologically active agent, for example an antimicrobial agent. In some examples, the biologically active agent is a micellizing amphiphilic molecule used as a templating agent during formation of the framework. Accordingly, the biologically active agent may be used both as a surfactant or templating agent as well as a therapeutic cargo to be delivered to a patient. Synthesis of the composition can optionally include loading the biologically active agent into the pores of the composition, without the need for post-synthesis calcination and absorption to load a biologically active agent. The amount of the templating agent may be below a threshold such that the framework retains structural properties sufficient for use in a composite material for the expected life of the compositematerial. Release of the biologically active agent may be driven mainly by diffusion from the pores rather than by dissolution or destruction of the framework.

[0057] Optionally, the composition may be produced in the form of porous (e.g. mesoporous) particles (e.g. nanoparticles or microparticles) or a porous coating. Optionally, the composition may be in the form of core-shell particles.

[0058] Optionally, the composition may be radiopaque. While silica is already radiopaque to some extent, the presence of zirconia and / or titania in the framework, and / or optionally in a shell or coating, may allow dental composites, adhesives or other composite material using the composition as a filler to appear more readily in X-ray images and have greater contrast with organic materials, tissues and structures, for example tooth or bone.

[0059] Optionally, the composition may have a refractive index or other colorimetric properties matching, or nearly matching, a selected polymeric resin. The refractive index of the nanoparticles can be tuned by selecting the amount of zirconia and / or titania included in the composition. ZrO2 has a refractive index of about 2.159. TiO? has a refractive index of about 2.45 to 2.7. Silica has a refractive index of about 1.47. Optionally, the framework may contain 5-35 mol% zirconia. Optionally, the framework may contain 3-35 mol% or 3-15 mol% titania. Optionally, the framework of a shell or coating may be entirely zirconia or titania.

[0060] The refractive index of the composition can also be tuned by varying the porosity and by selecting a composition filling the pores. Optionally, the pores may be filled with a solid, a liquid or a gas, for example air. The porosity of the composition may be about 25-75% by volume.

[0061] A process of making the composition may be primarily aqueous. Specifically, alcohol is 10 wt% or less, or 5 wt% or less, or 2 wt% or less during condensation of the framework. Relative to a primarily alcohol-based method, this can provide a number of benefits such as decreased manufacturing costs or decreased environmental impact. In at least some examples, the composition may also have increased porosity and / or increased drug loading relative to some prior silica-zirconia nanoparticles which are prepared in alcohol.

[0062] The process is conducted in an acidic solution. An organic acid, such as acetic acid, may be used during the process of creating the nanoparticles. In addition to reducing the pH, acetic acid or another organic acid may act as a chelating agent to inhibit hydrolysis and condensation of a zirconia, titania, alumina or other metal oxide precursor upon contact with water. Other chelating organic acids such as glycolic acid, gluconic acid, lactic acid, citric acid tartaric acid, oxalic acid or glacial acetic acid may be used.

[0063] The metal oxide precursor may be a metal alkoxide. For example, a zirconia precursor may be a zirconium alkoxide such as zirconium propoxide or zirconium butoxide, which is highly reactive in water. Accordingly, zirconium alkoxides such as zirconium propoxide is typically provided in an alcohol solution, for example 70 wt% in propanol. Tetraethyl orthosilicate (TEOS) is also soluble in propanol, which facilities preparing a mixture of TEOS and zirconium propoxide. However, both TEOS and zirconium propoxide react upon exposure to water. Transferring the TEOS and zirconium propoxide into an acidic solution, optionally with the presence of a chelating agent, inhibits condensation relative to hydrolysis sufficiently to permit mixing and later condensation of the framework on the micellar network. Propanol or another alcohol may be transferred into the aqueous templating agent solution if already present in the TEOS and / or zirconium propoxide (or other metal alkoxide) solution provided that the resulting templating agent solution remains primarily aqueous.

[0064] Condensation is initiated by adding a base, basic salt, or fluoride salt. A basic fluoride salt, such as sodium fluoride, may be used. Adding the basic salt or a base increases the pH of the solution, but the solution optionally remains acidic. Alternatively, a non-basic fluoride salt, for example ammonium fluoride may be used, optionally with minimal or no increase in pH.

[0065] Particles of the composition, optionally core-shell particles, may be incorporated in a number of different polymer matrix composites through any number of standard techniques used to incorporate solid phases in liquid phases including orbital mixer, shear mixer, sonication and stirring.

[0066] Octenidine dihydrochloride, optionally included in the present composition, includes tertiary amine structures. Some dental resin systems have well known color stability issues related to their photoinitiator systems, especially in the presence ofaromatic amines. The addition of MEHQ and / or BHT as color stabilizers in the presence of tertiary or aromatic amines in dental materials is well established and understood, and could be expanded to systems containing the materials disclosed herein. Alternatively, photoinitiator systems may be used that do not have documented color stability problems or do not themselves contain additional tertiary amines, such as those used commercially with the tertiary-amine-containing monomer methacryloyloxydodecylpyridinium bromide (MDPB).

[0067] Particles of the composition, optionally core-shell particles, may be incorporated, for example at up to 85% by weight of polymeric resin, into a composite resin, for example a methacrylate resin. One possible use of the composition is to provide a radiopaque and / or antimicrobial and / or color matching and / or fluoride releasing filler for dental composites, adhesives or other products.

[0068] Compared to stand-alone particles, incorporation of particles in a methacrylate-based polymeric matrix (resembling the particles in a potential final application as an antimicrobial dental filler) reduces the release rate of biologically active agent or fluoride ions due to the increase of diffusion path as well as the hydrophobicity of the matrix. However, this reduced release rate enhances the longevity of the release from the polymeric matrix containing the particles.

[0069] Figure 1A shows steps in a method of making a composition.

[0070] In one step, water, one or more oxide precursors, and an acid are combined. The acid may be an inorganic or organic acid and / or a chelating agent. In some embodiments, the acid is acetic acid. In some embodiments, the acid is added in an amount sufficient to produce a pH of 2-3. In some embodiments, the one or more precursors include a silica precursor and one or more other metal oxide precursors, In some embodiments, only one metal oxide precursor, for example a zirconia precursor, is used.

[0071] In another step, the combination is mixed. In some embodiments, mixing continues for about 30-60 minutes.

[0072] In other step, fluoride is added to the combination and / or the pH of the combination is increased. In some embodiments, a non-basic fluoride salt, for exampleammonium fluoride, is added. In some embodiments, a basic fluoride salt, for example sodium fluoride is added. In some embodiments, a base, for example sodium hydroxide is added. In the presence of fluoride, the pH does not need to be raised, but the pH may optionally increase, for example to about 4-5. In the absence of fluoride, the pH may be increased to more than 5, for example about 5-6.5.

[0073] In another step, seed particles and / or a templating agent are added to the combination. The seed particles and / or templating agent can be added during any of the steps described above. The seed particles can be porous or non-porous particles. Alternatively, a substrate may be provided to make a coating in a non-particle form. The templating agent can be a surfactant amphiphilic molecule added at above its critical micelle concentration. Optionally, the surfactant may be a biologically active agent, for example an antimicrobial agent such as OCT. Other useful surfactants include CPC and CTAB, among others.

[0074] The step of adding fluoride and / or increasing the pH induces or accelerates condensation of an oxide framework. In another step mixing continues, for example for about 30-60 minutes. After a period of mixing, particles may be separated and optionally washed and dried.

[0075] Figure 1 B shows steps in a method of making a composition according to certain embodiments.

[0076] In one step, a solution is prepared having a surfactant, an acid and water. The surfactant is an amphiphilic molecule added at above its critical micelle concentration. Optionally, the surfactant may be a biologically active agent, for example an antimicrobial agent. In some examples described further below, the surfactant is OCT. The acid may be an inorganic or organic acid and / or a chelating agent. In the examples described further below, the acid is acetic acid. The acid is added in an amount sufficient to produce a pH of 2-3.

[0077] In another step, a mixture is prepared containing a silica precursor and one or more of a zirconia precursor and a titania precursor. The silica precursor may be TEOS. The zirconia precursor may be zirconium propoxide. The titania precursor may be titanium butoxide. The precursor mixture may be in an alcohol, for example propanol, solvent.

[0078] In another step, the precursor mixture and the surfactant solution mentioned above are combined. Alternatively, the silica precursor and one or more of the zirconia precursor and the titania precursor may be separately combined with the surfactant solution. The precursors and the surfactant solution are mixed for a first period of time, for example about 30 minutes to 1 hour.

[0079] After the first period of time, a basic salt is added to the solution. In examples described further below, the basic salt is sodium fluoride. Enough of the basic salt is added to raise the pH of the solution without neutralizing the solution. For example, the pH of the solution may be raised to 4-5. Adding the basic salts initiates a condensation reaction. The condensation reaction is allowed to proceed for a period of time, for example about 30 minutes.

[0080] In another step, the composition is collected, i.e. separated from the solution. Optionally, the composition may be washed and dried.

[0081] Figure 1 C shows steps in a method of making a composition according to certain other embodiments.

[0082] In one step, a mixture is prepared having a surfactant, an acid and water, water and an acid, or water and a surfactant. The surfactant may be an amphiphilic molecule, in some embodiments added at or above its critical micelle concentration. Optionally, the surfactant may be a biologically active agent, for example an antimicrobial agent. In some examples described further below, the surfactant is OCT. The acid may be an inorganic or organic acid and / or a chelating agent. In the examples described further below, the acid is acetic acid. The acid is optionally added in an amount sufficient to produce a pH of 2-3.

[0083] In another step, a mixture is prepared containing oxide precursors or oxide precursors and an acid. The acid is typically not added if an acid was added in the previous step. In some embodiments, the one or more oxide precursors includes a silica precursor and one or more of a zirconia precursor and a titania precursor and an alumina precursor. The silica precursor may be TEOS. The zirconia precursor may be zirconium propoxide. The titania precursor may be titanium butoxide. The precursor mixture may be in an alcohol, for example propanol, solvent.

[0084] In another step, the two solutions mentioned above are combined. Alternatively, the silica precursor and one or more of the zirconia precursor and the titania precursor may be separately combined with the first solution. The precursors and the surfactant solution are mixed for a first period of time, for example about 30 minutes to 1 hour.

[0085] After the first period of time, a fluoride salt is added to the solution. The fluoride salt may be pre-dissolved in water or in a powder form. In examples described further below, the fluoride salt is sodium fluoride or ammonium fluoride. Adding the fluoride salts initiates a condensation reaction. The condensation reaction is allowed to proceed for a period of time, for example about 30 minutes.

[0086] In another step, the composition is collected, i.e. separated from the solution. Optionally, the composition may be washed and dried.

[0087] Figure 1 D shows steps in a method of making a composition according to certain other embodiments. The methods of Figures 1 B and 1 C are typically used to produce homogenous particles. The method of Figure 1 D is used to produce core-shell particles.

[0088] In one step, a first mixture is prepared having water, a surfactant, and a base. The surfactant may be as described above. In another step, silicon alkoxide or another core precursor is added. Mixing may continue, for example for about 30 minutes. These two steps may be as described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Self-assembly for Extended Biologically Active Molecule Release in Medical and Dental Applications", which is incorporated herein by reference. Porous core particles form in the first solution. Alternatively, this first mixture could be made with porous or non-porous particles formed separately, optionally include or not include the surfactant, and optionally replace the base with a fluoride salt or a basic salt.

[0089] In another step, a second mixture is prepared containing shell oxide precursors (or optionally one shell oxide precursor) and an acid. In some embodiments, the shell oxide precursors include a silica precursor and one or more of a zirconia precursor and a titania precursor and an alumina precursor. Some or all of the precursorsmay be alkoxides. In some embodiments, the silica precursor may be TEOS. The zirconia precursor may be zirconium propoxide. The titania precursor may be titanium butoxide. In some embodiments, the single shell oxide precursor is zirconium propoxide.

[0090] In another step, the first and second mixtures are combined. Alternatively, multiple shell oxide precursor mixtures (each having one or more oxide precursors) may be separately combined with the first mixture. Alternatively, the components of the first and second mixtures might be combined in other ways. For example, the particles and a base, basic salt or fluoride salt could be added to the second mixture.

[0091] Combining the second mixture (comprising one or more shell precursors) and the first mixture causes an increase in pH (relative to the prior shell precursor solution) due to the base in the first solution. The increase in pH causes the shell precursors to condense onto the particles of the first solution. The precursors and the first solution may be mixed for a period of time, for example about 30 minutes to 1 hour, while condensation continues. Alternatively, a basic salt or fluoride salt in the first mixture may cause the shell precursors to condense onto the particles.

[0092] In another step, the product (i.e. core-shell particles) is collected, i.e. separated from the solution. Optionally, the product may be washed and dried.

[0093] The following examples are non-limiting and provided to further enable the description of the invention. Examples 1 to 5 and 7 are examples of making binary or ternary silica-zirconia-titania particles by the method shown in Figure 1 B. Example 6 expands the method in Figure 1 B to making silica-alumina particles. Example 7 is used to make particles for a fluoride release study. Example 8 shows the use of a mixture of surfactants, in this embodiment a mixture of CPC and OCT, as an alternative to using a single surfactant system of either OCT or CTAB as used in other examples, or as alternative to using CPC alone. Example 9 shows the use of a reduced amount of surfactant. Example 10 shows synthesis of particles in the absence of a surfactant. Example 11 shows an alternative sequence for adding the acid. Example 12 shows the use of an alternative salt. Examples 13-17 provide examples of making core-shell particles.

[0094] Example 1 : Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia.

[0095] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT and 1 ml acetic acid. OCT is an amphiphilic surfactant with antimicrobial properties and a biocompatibility index of more than 1 .

[0096] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0097] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0098] TEM images of the particles are shown in panels A and B of Figure 2A. Figure 3 shows the release profile of OCT from the particles at 37°C in PBS. Figure 4 shows elemental mapping by energy dispersive x-ray analysis (EDX) for the nanoparticles. Uniform distribution of silica and zirconia can be seen in the particles. Moreover, nitrogen distribution shows the presence of OCT in the particles.

[0099] Fig. 10 shows normalized mean gray value of a composite containing 10 wt% of the particles under X-ray. As shown in the figure, the particles have increased radiopacity relative to silica particles.

[0100] Example 2: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 70% silica and 30% zirconia.

[0101] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT and 1 ml acetic acid.

[0102] In a separate vial (solution # 2), mix 867.17 pl of TEOS with 746 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour. After 1 hour, prepare a solution of 40mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0103] Figure 5 shows elemental mapping by energy dispersive x-ray analysis (EDX) for the nanoparticles. Uniform distribution of silica and zirconia can be seen in the particles. Moreover, nitrogen distribution shows the presence of OCT in the particles.

[0104] Example 3: Silica-Titania nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% titania.

[0105] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT and 1 ml acetic acid.

[0106] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 138.8 pl of titanium butoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour. After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml of NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0107] TEM images of the particles are shown in panel C of Fig. 2A.

[0108] Example 4: Silica-Zirconia-Titania nanoparticles (ternary composition) with nominal molar composition of 85% silica, 7.5% zirconia, 7.5% titania.

[0109] In a vial (solution # 1 ), mix 14 ml of water with 0.1036 g of OCT and 1 ml of acetic acid.

[0110] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 186.5 pl of zirconium propoxide and 141 .6 pl of titanium butoxide. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour. After 1 hour, add 320 mg NaF to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0111] TEM images of the particles are shown in panel D of Fig. 2A. Fig. 6 shows TEM-EDX elemental analysis of the particles. Fig. 10 shows normalized mean gray value of a composite containing 10 wt% of the particles under X-ray. As shown in the figure, the particles have increased opacity relative to silica particles.

[0112] Example 5: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia and with cetyltrimethylammonium bromide (CTAB) as surfactant.

[0113] In a vial (solution # 1 ), mix 6 ml of water with 0.062 g of CTAB and 1 ml acetic acid.

[0114] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0115] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0116] TEM images of the particles are shown in panel E of Fig. 2A.

[0117] Table 1 shows the refractive index of nanoparticles with different oxide compositions in the framework made according to Examples 1 and 2. These results show the effect of framework composition in combination with the surfactant on the refractive index. The silica nanoparticles in Table 1 are templated on OCT with similar porosity to the nanoparticles of Examples 1 and 2.Table 1 : Refractive index of particles (as synthesized)Sample Nominal molar Refractive_ Composition of framework indexSilica nanoparticles 100% Silica 1.50Silica-Zirconia nanoparticles 92% Silica - 8% Zirconia 1 .51(Example 1)Silica-Zirconia nanoparticles 70% Silica - 30% Zirconia 1 .53(Example 2)

[0118] Table 2 shows the refractive index of nanoparticles with different oxide compositions of framework made according to Examples 1 and 2 after removal of the surfactant. The results in Table 2 show the effect of framework composition alone on the refractive index. Comparing the results in Table 1 to the results in Table 2 shows the effect of the surfactant on the refractive index.Table 2: Refractive index of particles (after removal of surfactant)Sample Nominal molar Refractive_ Composition of framework indexSilica nanoparticles 100% Silica 1.46Silica-Zirconia nanoparticles 92% Silica - 8% Zirconia 1 .47(Example 1)Silica-Zirconia nanoparticles 70% Silica - 30% Zirconia 1 .49(Example 2)

[0119] Example 6: Silica-Alumina nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% alumina.

[0120] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT and 1 ml acetic acid.

[0121] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 104.5 pl of Aluminum-tri-sec-butoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0122] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0123] TEM images of the particles are shown in panel F of Fig. 2A

[0124] Example 7: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 85% silica and 15% zirconia

[0125] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT and 1 ml acetic acid.

[0126] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 373 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0127] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0128] Fig. 7 shows TEM-EDX elemental analysis of the particles which indicates, among other things, that fluoride was incorporated into the particles. Fig. 8 shows a fluoride release profile of the particles incubated in water at 37°C. Fig. 9 shows TEM images of the silica-zirconia particles after 4 days of incubation in water at 37°C. The arrows point to areas where the middle of the particles or their edges became more transparent. The presence of these transparent areas is believed to indicate the release of fluoride ions from the particle. Fluoride release can be beneficial in dental applications to inhibit caries, although the amount of fluoride incorporated and released from the particle may be limited if required to preserve any required structural qualities of the particles.

[0129] Example 8: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia and with a mixture of octenidine dihydrochloride (OCT) and cetylpyridinium chloride (CPC) as surfactants.

[0130] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT, 15 mg of CPC and 1 ml acetic acid.

[0131] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0132] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0133] TEM images of the particles are shown in panel A of Fig. 2B.

[0134] Example 9: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia and with minimal amount of surfactant.

[0135] In a vial (solution # 1 ), mix 6 ml of water with 0.03 g of OCT and 1 ml acetic acid.

[0136] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0137] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 ml NaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0138] TEM images of the particles are shown in panel B of Fig. 2B.

[0139] Example 10: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia and in the absence of a surfactant.

[0140] In a vial (solution # 1 ), mix 14 ml of water with 1 ml acetic acid.

[0141] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0142] After 1 hour, add 588 mg NaF powder and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0143] A TEM image of the particles is shown in panel C of Fig. 2B.

[0144] Example 11 : Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia and with different sequence of precursors addition.

[0145] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT.

[0146] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 l of zirconium propoxide and 1 ml acetic acid to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0147] After 1 hour, prepare a solution of 40 mg / ml NaF in water. Then, add 8 mlNaF solution to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0148] A TEM image of the particles is shown in panel D of Fig. 2B

[0149] Example 12: Silica-Zirconia nanoparticles (binary composition) with nominal molar composition of 92% silica and 8% zirconia and with NH4F as fluoride salt.

[0150] In a vial (solution # 1 ), mix 6 ml of water with 0.1036 g of OCT and 1 ml acetic acid.

[0151] In a separate vial (solution # 2), mix 1.053 ml of TEOS with 182.8 pl of zirconium propoxide to have a homogenous clear solution. Add solution 2 to 1 dropwise while mixing. Continue mixing for 1 hour.

[0152] After 1 hour, dissolve 282.3 mg NH4F in 8 ml of water and add it to the mixture and continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0153] A TEM image of the particles is shown in panel E of Fig. 2B

[0154] NaF is a basic salt and fluoride has catalytic effects in sol-gel processes involving silica. NH4F is a slightly acidic salt and caused only a small increase in pH, from 2.4 to 2.7, after mixing the two solutions. These results indicate the fluoride ions, even in the absence of an increase in pH, can still lead to particle formation.

[0155] In another example, a base (without fluoride ions) was used in place of NaF. Mixing the 2 solutions resulted in a pH increase from 2.3 to 5.2. Spherical particles were formed, but the morphology of the particles was not as good as when fluoride ions were present. For example, more irregular-shaped particles were formed (Figure 13).

[0156] Example 13: Silica-Titania core-shell nanoparticles with silica core and nominal molar composition of 70% silica and 30% titania for the shell.

[0157] Core particles were prepared as described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Selfassembly for Extended Biologically Active Molecule Release in Medical and Dental Applications". In a vial (solution # 1 ), mix 14.856 ml of water with 0.1036 g of OCT and 0.144 ml of 2M NaOH. Then, add 1.239 mL of TEOS. The reaction proceeds for 30 minutes.

[0158] In a separate vial (solution # 2), mix 867.17 pl of TEOS with 566.42 pl of Titanium butoxide and 1 ml acetic acid for 30 minutes.

[0159] Add solution 2 to 1 dropwise while mixing. Continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0160] Fig. 11 shows TEM-EDX elemental analysis of the particles.

[0161] Example 14: Silica-Zirconia core-shell nanoparticles with silica core and nominal molar composition of 70% silica and 30% zirconia for the shell.

[0162] Core particles were prepared as described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Selfassembly for Extended Biologically Active Molecule Release in Medical and Dental Applications". In a vial (solution # 1 ), mix 14.856 ml of water with 0.1036 g of OCT and 0.144 ml of 2M NaOH. Then, add 1.239 mL of TEOS. The reaction proceeds for 30 minutes.

[0163] In a separate vial (solution # 2), mix 867.17 pl of TEOS with 746 pl of zirconium propoxide and 1 ml acetic acid for 30 minutes.

[0164] Add solution 2 to 1 dropwise while mixing. Continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0165] A TEM image of the particles is shown in panel A of Fig. 2C. Fig. 12 shows TEM-EDX elemental analysis of the particles.

[0166] Example 15: Silica-Zirconia core-shell nanoparticles with silica core and nominal molar composition of 50% silica and 50% zirconia for the shell.

[0167] Core particles were prepared as described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Selfassembly for Extended Biologically Active Molecule Release in Medical and Dental Applications". In a vial (solution # 1 ), mix 14.856 ml of water with 0.1036 g of OCT and 0.144 ml of 2M NaOH. Then, add 1.239 mL of TEOS. The reaction proceeds for 30 minutes.

[0168] In a separate vial (solution # 2), mix 619.4 pl of TEOS with 1243.4 pl of zirconium propoxide and 1 ml acetic acid for 30 minutes.

[0169] Add solution 2 to 1 dropwise while mixing. Continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0170] A TEM image of the particles is shown in panel B of Fig. 2C.

[0171] Example 16: Silica-Zirconia core-shell nanoparticles with silica core and zirconia shell.

[0172] Core particles were prepared as described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Selfassembly for Extended Biologically Active Molecule Release in Medical and Dental Applications". In a vial (solution # 1 ), mix 14.856 ml of water with 0.1036 g of OCT and 0.144 ml of 2M NaOH. Then, add 1.239 mL of TEOS. The reaction proceeds for 30 minutes.

[0173] In a separate vial (solution # 2), mix 2486.8 pl of zirconium propoxide and 1 ml acetic acid for 30 minutes.

[0174] Add solution 2 to 1 dropwise while mixing. Continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0175] A TEM image of the particles is shown in panel C of Fig. 2C.

[0176] In this example, the shell is entirely of zirconia rather than being a binary or ternary structure. In nanoparticles, a relatively thin core can provide a large volume fraction of the whole particles. Accordingly, it is predicted that silica-zironia core shell particles may be made with a large mass or volume percentage of zirconia, for example more than 30%, while still having good morphology.

[0177] Example 17: Silica-Zirconia-Titania core-shell nanoparticles with silica core and nominal molar composition of 70% silica, 15% zirconia, and 15% titania for the shell.

[0178] Core particles were prepared as described in International Patent Publication Number WO 2017 / 197510 A1 , "Highly Loaded Metal Oxide Materials by Selfassembly for Extended Biologically Active Molecule Release in Medical and Dental Applications". In a vial (solution # 1 ), mix 14.856 ml of water with 0.1036 g of OCT and 0.144 ml of 2M NaOH. Then, add 1.239 mL of TEOS. The reaction proceeds for 30 minutes.

[0179] In a separate vial (solution # 2), mix 867.17 pl of TEOS with 373.02 pl of zirconium propoxide and 283.21 pl of Titanium butoxide and 1 ml acetic acid for 30 minutes.

[0180] Add solution 2 to 1 dropwise while mixing. Continue mixing for 30 minutes. Collect the particles with centrifugation followed by a washing step. Dry the product at 60°C.

[0181] A TEM image of the particles is shown in panel D of Fig. 2C.

[0182] Considering examples 13 to 17, the presence of seed particles in the form of mesoporous silica particles provided good morphology (e.g. generally monodisperse spherical submicron particles) even in the absence of fluoride ions and even without silicain the shell. Mixing the two solutions causes an increase of the pH of the mixture (relative to the acidic solution) which causes the shell material to condense on the core particle producing spherical particles of a consistent size. Alternatively other seed particles, for example non-porous colloidal silica particles, could be used as seed particles, with or without a surfactant also present.

[0183] The shell in examples 13 to 17 is porous as indicated by the release of OCT from the core-shell particles. Without intending to be limited by theory, some surfactant (e.g. OCT) is expressed on the surface of the core particles. Excess surfactant may branch out from the surface. The surfactant thereby functions as a templating agent to form pores in the shell. However, the presence of a surfactant is not predicted to be necessary to cause shell formation. The surfactant could be reduced or eliminated, for example by washing the surfactant-templated core particles, or by using other core particles such as colloidal silica, to produce a less porous shell or a non-porous shell.

[0184] While the invention has been illustrated and described with reference to preferred embodiments thereof, it will be recognized by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

CLAIMS:WHAT IS CLAIMED IS:1 . A composition having a porous amorphous framework including silica and one or more oxides of metals selected from Group 1A (e.g. Na), HA (e.g. Mg, Ca), IVB (e.g. Zr, Ti), VIIB (e.g. Mn), VIIIB (e.g. Fe), VIIIIB (e.g. Co), Villi (e.g. Ni), IB (e.g. Cu), IIB (Zn), 11 IA (e.g. Al) of the periodic table, selected from one or more oxides of metal from Groups1. II or III of the periodic table and transitions metals, or selected from zirconia and titania.

2. The composition of any of claim 1 having one or more ionic or non-ionic surfactants in the pores of the framework.

3. The composition of claim 1 or 2 wherein the pores of the framework are templated on micelles of the one or more ionic or non-ionic surfactants.

4. The composition of any of claims 1 to 3 comprising one or more of titania and zirconia.

5. The composition of any of claims 1 to 4 comprising alumina.

6. The composition of any of claims 1 to 5 being spherical particles or part thereof.

7. The composition of any of claims 1 to 6 comprising fluoride, optionally incorporated into the framework.

8. The composition of any of claims 1 to 7 wherein the one or more ionic or non-ionic surfactants comprise an amphiphilic molecule.

9. The composition of any of claims 1 to 8 wherein the one or more ionic or non-ionic surfactants comprise a biologically active agent.

10. The composition of claim 9 wherein the biologically active agent is an antimicrobial agent.11 . The composition of claim 9 or 10 that releases the biologically active agent without dissolution of the framework.

12. The composition of any of claims 1 to 11 wherein the pores are templated on micelles formed in an aqueous solution of one or more of octenidine dihydrochloride, polyhexamethylene biguanide, cetylpyridinium chloride, lauric arginate, and Benzalkonium chloride.

13. The composition of any of claims 1 to 12 wherein the pores comprise one or more of octenidine and cetylpyridinium.

14. The composition of any of claims 1 to 13 wherein the composition forms a shell on a silica core15. A method of making a porous composition including one or more metal oxides by way of a sol-gel technique performed in one or more aqueous solutions in the presence of a chelating and / or organic acid.

16. The method of claim 15 wherein the acid is acetic acid.

17. The method of claim 15 or 16 wherein the one or more metal oxides comprise zirconia or titania or both.

18. The method of any of claims 15 to 17 wherein the one or more metal oxides comprise alumina.

19. The method of any of claims 15 to 18 wherein the one or more metal oxides comprise silica.

20. The method of any of claims 15 to 19 wherein pores of the composition are templated on micelles or a surfactant, optionally a biologically active agent.

21. The method of any of claims 15 to 20 comprising adding a first aqueous solution comprising the acid and one or more metal oxide precursors to a second aqueous solution containing silica particles, a surfactant and a base.

22. The method of any of claims 15 to 21 comprising adding a fluoride salt.

23. The method of any of claims 15 to 22 comprising adding a base or a basic salt.

24. A composition comprising a core particle and a shell, wherein the core particle is a silica particle and the shell comprises another oxide.

25. The composition of claim 24 wherein the core particle is porous.

26. The composition of claim 24 or 26 wherein the shell is porous.

27. The composition of claim 26 wherein the pores of the shell are templated on an amphiphilic molecule, optionally a biologically active agent.

28. The composition of any of claims 25 to 27 wherein the shell comprises a) silica and b) one or more other metal oxides such as zirconia and / or titania and / or alumina.

29. The composition of any of claims 25 to 27 wherein the shell comprises one or more other metal oxides such as zirconia and / or titania and / or alumina without silica.

30. The composition of claim 29 wherein the shell consists essentially of zirconia.31 . A method of making a composition in the form of a coating or shell and including one or more metal oxides by way of a sol-gel technique using an aqueous solution comprising a chelating and / or organic acid and precipitation of the composition on particles or another substrate.

32. The method of claim 31 wherein the acid is acetic acid.

33. The method of claim 31 or 32 wherein the one or more metal oxides comprise zirconia or titania or both.

34. The method of any of claims 31 to 33 wherein the one or more metal oxides comprise alumina.

35. The method of any of claims 31 to 33 wherein the one or more metal oxides comprise silica.

36. The method of any of claims 31 to 34 comprising forming pores in the composition wherein the pores are templated on micelles of a surfactant, optionally a biologically active agent.

37. The method of any of claims 31 to 36 comprising adding a first aqueous solution comprising the acid and the one or more metal oxide precursors to a second aqueous solution containing silica particles and optionally a surfactant.

38. The method of any of claims 31 to 37 comprising adding a fluoride salt.

39. The method of any of claims 31 to 38 comprising adding a base or a basic salt.

40. A method of making a composition including one or more metal oxides by way of a sol-gel technique using an aqueous solution comprising a chelating and / or organic acid and precipitation of the composition one or more of a) particles or another substrate and b) micelles of an amphiphilic molecule, wherein condensation of the composition is initiated or accelerated by the addition of a fluoride salt.41 . The method of claim 40 wherein the acid is acetic acid.

42. The method of claim 40 or 41 wherein the one or more metal oxides comprise one or more of zirconia, titania and alumina.

43. The method of any of claims 40 to 42 wherein the one or more metal oxides comprise silica.

44. The method of any of claims 40 to 43 wherein the fluoride salt is a basic salt.

45. The method of any of claims 40 to 44 comprising forming pores in the composition wherein the pores are templated on micelles of a surfactant, optionally a biologically active agent.

46. The method of any of claims 40 to 45 wherein the micelles are formed in a solution of OCT and / or CPC.

47. A composite material comprising particles including the composition defined in any other claim, or made by the process of any other claim, dispersed in a matrix material.

48. The composite material of claim 47 wherein the matrix material is a dental or medical methacrylate resin or adhesive.

49. The composite material of claim 47 or 48 wherein the composite material comprises zirconia and / or titania and is radiopaque.

50. The composite material of any of claims 47 to 49 wherein the refractive index of the composition is closer (relative to the refractive index of silica or to the refractive index of similarly porous silica) to the refractive index of the matrix material.51 . The composite material of any of claims 47 to 50 wherein the matrix material and the composition have similar, compatible and / or matched refractive indices.

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