WO2005110592A1

WO2005110592A1 - Mesoporous particles loaded with active substance

Info

Publication number: WO2005110592A1
Application number: PCT/SE2005/000700
Authority: WO
Inventors: Peter Alberius
Original assignee: Yki, Ytkemiska Institutet Ab
Priority date: 2004-05-17
Filing date: 2005-05-16
Publication date: 2005-11-24

Abstract

The invention refers to a mesoporous inorganic oxide particles having a pore size of 2-50 nm, loaded with an active substance, and multilayer polyelectrolyte coated. Said particles can be used for controlled release of the active substance.

Description

Mesoporous particles loaded with active substance

The present invention refers to mesoporous, optionally templated, inorganic oxide particles, which have been loaded with an active substance and polyelectrolyte coated in order to improve the control of the release rate of said substance.

BACKGROUND There is a need of systems for controlled release of a broad range of compounds like fragrances, flavours, drugs, biocides, enzymes, etc. in many different products. In certain applications it is advantageous that the carrier of said substances is composed of inert solid particles. Examples of such applications range from cosmetics, transdermal drug delivery to coatings formulations. Zeolites are crystalline inorganic oxides with well defined micro pores 0.5-1.5 nm in diameter, which consequently display huge surface areas, often >1000 m²/g. Zeolites therefore can adsorb big amounts of guest species. However, said materials are generally not well suited for controlled release applications due to their limited pore sizes and often irreversible adsorption of active ingredients small enough to enter the pores . Traditional porous inert materials with pore sizes in the mesoscopic 2-50 nm regime, like silica gel and activated carbon, have a disadvantage in that the pore structures are disordered. The disordered pore structures limit the accessibility of the internal surface to the adsorption of molecules with various functionalities like fragrances, flavours, biocides, drugs and other compounds that are attractive to immobilise for controlled release purposes. With the introduction of surfactant templated inorganic oxides in the early nineties this situation changed and a new class of materials was introduced with several advantages like bottle-neck free pores. These materials have great capacities for adsorbing active substances in an inert matrix, however, there is a limited control over release rates. The first mesoporous materials to be published were precipitated from dilute aqueous solutions with limited control over structure and stoichiometric composition. An important development was the so called "true liquid crystalline templa- ting" introduced by Attard et al . , Na ture 1995, 378, 366-368, which led to the development of methods producing thin films and powders with superior control over the internal mesostructures . In parallel with the development of mesoporous surfactant templated materials, the concept of Layer-by-Layer (LbL) polyelectrolyte coated materials was developed in order to incorporate various non-porous substrates within a polyelectrolyte coating.

PRIOR ART Inorganic carriers have been evaluated for the release of active substances. WO 00/11949 discloses porous inorganic carrier particles having a biocide adsorbed within the pore system. Said carrier particles are constituted by amorphous mesoporous silicas with disordered pores, as well as by crystalline zeolites, and are intended to be incorporated into a surface coating formulation, such as a paint or lacquer for controlled delivery of the biocide over an extended time period. Valet-Regi et al., Chem . Ma ter. 2001, 13, 308-311, refers to the use of a precipitated surfactant templated mesoporous material, MCM-41, showing hexagonal arrays of cylindrical mesopores, as the matrix in a controlled drug delivery system. Different pore sizes can be obtained as a result of templating with different surfactants. Common for the mentioned prior art systems is the lack of control over release rates, limited loading capacities and irreversible adsorption of active ingredients. WO 01/51196 describes a process for encapsulation of a solid particle material, such as a drug, nutrient, pesticide or preservative, comprising treatment with an amphiphilic substance and subsequent coating with one or more alternating layers of oppositely charged, polyelectrolytes . The solid particle material is in particular an organic crystalline template, such as a drug, creating a drug release system with a constant release rate over a long period of time. WO 02/09865 refers to -a method for producing nano or microcapsules into which an active ingredient may be incorporated. The capsules comprise a polyelectrolyte casing produced by precipitation on template particles. The active ingredient is either mixed with a templating, soluble polymeric colloid, precipitated and the particles coated, and then the polymeric template in a second step dissolved, or the active ingredient is introduced into the hollow capsule after dissolv- ing the templating polymeric core; neither of these techniques is trivial. The drawback of these materials is the difficulty in loading them with active substances and using and storing the encapsulated active materials over extended periods of time.

SUMMARY OF THE INVENTION The invention describes an inert inorganic mesoporous carrier material and modifications thereof to be used in a controlled release system with superior control over release rates. More specifically, the invention refers to mesoporous carrier materials loaded with active substances, the release rate of which can be controlled by encapsulation of the loaded materials within a polyelectrolyte coating. The product of the invention will be an easily stored, and easily dispersable, dry powder.

DESCRIPTION OF THE INVENTION The present invention refers to mesoporous inorganic oxide particles having a pore size of 2-50 nm, loaded with active substance, and subsequently multilayer polyelectrolyte coated. Multilayer coated mesoporous inorganic oxide particles Mesoporous inorganic oxide particles Inorganic porous oxide particles, which can be used according to the invention are particles wherein the inorganic oxide is selected from the group consisting of silica, titanium dioxide or any other transition metal- oxide. As opposed to zeolites, the inorganic matrices do not display any long range orders and are often completely amorphous, e.g. Si0₂. Some oxides (e.g. Ti0₂ after some heat treatment) do however display icro- crystalline wall materials with randomly ordered crystallites.

However, the templated mesoporous materials are different in one important aspect to mesoporous silica materials having a disordered pore structure. The templated mesoporous materials posses wall materials with no long range order but well defined crystalline pore structures with long range order. This well ordered pore structure ensures that all internal surface area is accessible for the adsorption of active substances. There are many commercially available mesoporous silica materials having a disordered pore structure or in other words amorphous silica gels that may be used as an alternative to the well ordered templated mesoporous silicates described above. The amorphous silicates generally adsorb less amounts of active components than the well ordered materials, but this disadvantage may be tolerable. Examples of amorphous mesoporous silica gels include series produced by Grace Davison, e.g. the Syliod series manufactured for use in the coating of ink jet papers or the Davisil chromatographic silicates e.g. grade 710 with internal surface areas comparable to the surfactant templated materials . Templated mesoporous particles are prepared by mixing solubilised inorganic precursors with amphiphilic substances. Inorganic precursors used for making the mesoporous particles typically consist of alkoxides that are hydrolysed prior to the synthesis. Examples of alkoxides include tetraethyl orthosili- cate (TEOS) , tetramethyl orthosolicate (TMOS) , tetra-propyl orthosilicate (TPOS) , titanium (IV) tetraethoxide . The mesoporous structure is obtained by templating with amphiphilic substances selected from the group consisting of ionic surfactants, non- ionic surfactants, and amphiphilic block copoly ers . Amphiphilic substances self assembling with the hydrolysed inorganic precursors include, but are not limited by, ionic surfactants such as the alkyl ammonium halogenides, such as trialkyl ammonium halogenides (e.g. Cι₆TAB) , alkyl pyridinium salts, alkylsulphates (e.g. SDS) , alkanesulphonates, alkylarene- sulfonates, nonionic polyoxyethylene alkyl ether surfactants (e.g. belonging to the Brij family, like Brij56), poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) block copolymers (e.g. belonging to the Pluronic® family, like P104), lipids and phospholipids, monoglycerides, sugar based surfactants, block copolypeptides . The pore structures formed when removing the organic templating materials are typically 2-50 nm in diameter and can be well ordered, that is crystalline. Examples of the well ordered pore-structures include, but are not limited to, the lamellar "onion like", 2D hexagonal, 3D hexagonal, and various cubic mesostructures . Each structure type can be formed from various types of amphiphilic molecules and the pore diameter is directly related to the size of the templating molecules. The resulting structures are determined by the ratio of amphiphilic molecules to hydrolysed inorganic components (Alberius et al., Chem . Ma ter. 2002, 14, 3284-3294) . The invention especially refers to particles, wherein the internal pore structure of the surfactant templated particles is lamellar, cubic or hexagonal. Templated mesoporous materials generally display accessible pore diameters between 2 and 30 nm and BET surface areas of 100-1500 m²/g. A mesoporous material templated by the cationic surfactant Cι₆TAB typically has a pore diameter of 2.5 nm with a BET surface area of 1100 m²/g. Particles templated by block copolymer P104 have pores with a diameter of around 6 nm and a BET surface area of 300 m²/g. The choice of amphiphilic substance together with process parameters enables a precise control over pore-arrangment and pore diameters independently of each other, allowing for tailor made pore structures optimised for each application. According to a preferred aspect the invention refers to particles, wherein the inorganic oxide is a templated silica and the internal pore structure is 2D-hexagonal . According to another aspect of the invention the esaporous particles can also have an amorphous, that is disordered pore structure. Mesoporous silicates having an ordered pore structure may be prepared by co-precipitation of amphiphilic substances and hydrolysed silica from aqueous acidic or basic solutions, at elevated or at ambient temperatures (Kresge et al . , Nature 1992, 359, 710-712) . However, there are several disadvantages with the precipitation route since there is a poor control over the relative composition of the precipitated materials and thus a poor control over internal mesostructures . Another route generating mesostructured materials is the so called "evaporation induced self assembly" of surfactant- silica hybrid materials (Lu et al., Na ture 1999, 398, 223-226). These materials are prepared by evaporating a solvent in which amphiphilic substances together with hydrolysed silica are dissolved. The non-volatile components self-assemble in inter- mediate liquid crystalline structures that subsequently solidify as the inorganic precursors solidify. Powders are typically prepared by spraying the precursor solution into a carrier gas where the solvents are evaporated. In a second part of the continuous process the aerosol is heated in order to speed up the cross-linking of the inorganic oxide and permanent the mesostructure. The hybrid material is in a final step calcined in air order to remove the templating amphiphilic materials. The diameter of the mesoporous particles can be up to 50 μm, however the size of the particles is preferably up to 10 μm, varying between 2 and 8 μm, thus giving an outer surface area of these materials of the order 2-4 m²/g. Active substances The active substances introduced into the mesoporous hosts are generally non-water soluble organic substances. The active substance can for instance be a liquid, paste or solid material. If the active substance is a liquid, such as an oil, the formulation into particles will bring about the additional advantage of obtaining a final product in the form of a solid powder. Examples of active substances include, but are not limited to, biocides, perfumes, fragrances, flavours, drugs, vitamins, preservatives, enzymes, and hormones, which substances can be synthetic or natural organic compounds, such as proteins, and oils . The invention especially refers to mesoporous inorganic oxide particles loaded with an active substance selected from the group consisting of a biocide, a fragrance, a flavour, a drug, an enzyme or a hormone. The active substance may be incorporated into the particles by several different methods . The substances may be adsorbed from the gaseous phase, from different solvents, such as water, ethanol, cyclohexane, dichloromethane, acetone, or even compressed gases, like carbon dioxide. The solvents should, however, at least partly solve the active ingredients, and wet but not adsorb strongly to the inorganic carrier material. The spontaneous adsorption from a solvent requires a relatively strong interaction between guest molecules and the inorganic porous carrier materials. Examples of substances adsorbing strongly on silica include aromatic organic or amine-containing compounds . The substances may also be introduced into the carrier particles by evaporating the solvent into which the particles were added. By capillary action the pores are the last part of the particles to dry and in that way the dissolved material is enriched in the pores. The loaded particles are generally hydrophobic and not easy dispersible in aqueous formulations. Polyelectrolyte coating The layer-by-layer (LbL) precipitation of polyelectrolytes is a well established technique (see for instance Decher et al., Thin Solid Films 1992, 210-211, part 2, 831-835, describing the build-up of ultrathin multilayer films by consecutively alternating adsorption of anionic and cationic polyelectrolytes on charged surfaces) . The method includes the successive adsorption of differently charged polyelectrolytes on to the loaded mesoporous particles . The LbL coated loaded particles are easily dispersed in aqueous media. More specifically the loaded mesoporous inorganic particles are dispersed in saline aqueous solutions with a salt content of 0. OK [NaCl] <10 M, preferably 0.1 M NaCl. The dispersion of the loaded materials is facilitated by the addition of an ionic surfactant, typically SDS (sodium dodecyl sulphate) or C₁₆TAB (cetyl trimethyl ammonium bromide) . After the dispersion, the first polyelectrolyte solution is added, cationic if an anionic surfactant is added in order to disperse the particles, anionic if cationic surfactants are used in the dispersion process. The subsequent polyelectrolyte layers are added with subsequent rinsing in order to adsorb each polyelectrolyte layer. If substantial amounts of the active substance to be loaded into the particles leach out during the encapsulation process, this problem can be solved by saturating all solutions used in the encapsulation processes with the active substance. This reduces the problem with leakage of actives to a minimum. Polyelectrolytes are generally understood to mean polymers having ionically dissociable groups, which may be a component or substituent of the polymer chain. Polyelectrolytes are divided into polyacids or polybases depending on the type of dissociable groups. Polyanions are formed from polyacids when they dissociate with cleavage of protons. Suitable polyanions include naturally occurring polyanions, such as alginate, carboxymethylcellulose, carboxymethyldextran, and synthetic polyanions, such as polyacrylates, polystyrene sulfonate, polyvinyl phosphate, polyvinyl sulfonate. Polycations are formed from the protonation of polybases, including naturally occurring polycations, such as chitosan, and synthetic polycations, such as polyethylene imine, polyamines, polyallylamine hydrochloride . Specific examples of said poly-electrolytes are for instance listed in WO 02/09865. The final thickness of the polyelectrolyte shell is determined by the number of subsequent coatings adsorbed on the outer surface. The thickness of each double layer of cationic and anionic polyelectrolytes is influenced by the salt concentration and is typically 1 nm at a salt concentration of around 0.1 M NaCl. The polyelectrolyte coating can also be applied by so called "surface precipitation" (see WO 02/09865) . Using the latter approach, both the anionic and cationic polyelectrolytes may for example be dissolved in the same solution without gelling, provided that pH is adjusted in order to neutralize either the cationic or anionic polyelectrolytes. In a subsequent step the pH is slowly increased or decreased in order to charge the neutralized polyelectrolyte and thus start the precipitation (or coacervation) of the polyelectrolyte complexes on the surface of the loaded inorganic carrier materials. One example includes the dissolution of PAH (PolyAllylamine Hydrochloride) and PSS (Poly sodium 4-Styrene-Sulfonate) in an aqueous solution at high pH (pH>ll) with a sodium chloride concentration of 0.1 M. A reduction of pH will induce the precipitation of PAH-PSS complexes on the particles generating the polyelectrolyte encapsulation. Another example includes the dissolution of PAA (polyacrylic acid) and PAH in acidic water (pH<1.5) with a salt concentration of 0.1 M. An increase of pH induces the precipitation of PAH-PAA complexes on the particles. The final thickness of the polyelectrolyte coating is determined by the relative amounts of polyelectrolyte and particles. Preferred particles of the invention have a polyelectrolyte coating comprising differently charged polyelectrolytes in a thickness of 1-50 nm, preferably 5-15 nm, measured in dry state by TEM (transmission electron microscope) . Process for preparing multilayer coated mesoporous silica particles The invention also refers to a process for preparing multilayer polyelectrolyte coated mesoporous inorganic oxide particles loaded with active substance, which process is characterised in that mesoporous inorganic oxide particles having a pore size of 2-50 nm are loaded with an active substance, and that said loaded particles are coated layer by layer with alternating polyacids and polybases. The invention also refers to a process for preparing multilayer coated templated mesoporous silica particles loaded with an active substance, comprising the following steps forming a precursor solution of a hydrolysed silane and a templating amphiphilic substance; spray drying the precursor solution into spherical mesostructured silica particles at ambient temperature; heating said spherical particles to 150-290°C in order to condense the silica particles; calcining the mesostructured silica particles in air at a temperature of 400-700°C in order to remove the templating amphiphilic substance; loading said calcined silica particles with an active substance; and layer-by-layer coating of said loaded silica particles with polyelectrolytes . According to a preferred aspect the process described also comprises the additional step of adding an amphiphilic substance after the loading of the calcined silica particles with a hydrophobic active substance, in order to improve the dispersibility of the loaded particles. The mesoporous materials can be prepared as follows: The precursor solutions (Example 1) were sprayed in an aerosol based process with great care taken in order to make sure that all solvents were evaporated at ambient temperatures in the first part of the reactor. This was possible to achieve thanks to the individual regulation of carrier gas flow and liquid flow respectively. The dried aerosol was then passed trough a heating stage of the reactor, where the inorganics condensed without disrupting the mesoscopic ordering present in the individual particles after dried at ambient temperature. The aerosol was finally cooled to 30-100°C, more preferably 30-50°C before being passed through a teflon tube filter. The heating stage was set to 150-290°C, preferably 200-290°C and most preferably 270- 280 °C. In order to generate a porous material, the hybrid mesostructured materials can be calcined in air at 400-600 °C, preferably at 550 °C, for several hours, more preferably 4 hours, which removes the templating organics. The loading of the active ingredients can be done as follows: Silica particles (see Example 2) were dried at 120°C in a vacuum furnace to evacuate eventual humidity. A solution of the active substance in cyclohexane was prepared and mixed with the templated particles. The coating of loaded particles can be performed as described (see Example 3) . Release properties of loaded, polyelectrolyte coated particles The release of the loaded active substances, i.e. the permeability of the polyelectrolyte shell, can be modified by changing several different parameters. Most important is the thickness of the shell, and type of polyelectrolytes used for the encapsulation. Other parameters include, but are not limited to, the inclusion of lipids and/or amphiphilic polyelectrolytes in the polyelectrolyte shells, variations in pH, salinity or temperature. The release of biocides as the active substance has been monitored by following the increasing concentration over time in cyclohexane. A clear reduction of the release kinetics could be observed for LbL-coating with 10 and 16 layers of polyelectrolytes, respectively. The invention also refers to the use of a multilayer polyelectrolyte coated surfactant templated mesoporous inorganic oxide particle loaded with an active substance, as previously described, for the controlled release of said active substance.

EXAMPLES Example 1. Production of mesoporous silicates The precursor solution was prepared from a pre-hydro- lysed solution by mixing 10.4 g of tetraethoxysilane, TEOS, (Puru >98 %) in 5.4 g diluted hydrochloric acid (pH 2) and 12 g ethanol (99.7 %) under vigorous stirring at room temperature during 20 minutes. The templating amphiphilic molecules (see Table 1) were dissolved in 8 g ethanol (99.7 %) before being mixed with the hydrolysed TEOS solution. As the templating amphiphilic molecules have been used the cationic surfactant hexadecyl trimethyl ammonium bromide, Ciε AB, Aldrich, and two triblock copolymers of the Pluronics series (BASF) : P123, EO₂₀PO₇₀EO₂₀, and P104, E0₂₇P0₆ιE0₂₇.

Table 1. Mesostructures as a function of various amphiphiles at different concentrations

The well ordered mesostructured silica particles were produced in a reactor, which consists of a spraying chamber combined with a tube furnace and a filter. Droplets of the precursor solution were generated in the spraying chamber using a two-flow spray-nozzle with a replaceable orifice with a diameter of 1.5 mm. The liquid and gas flows were varied between 0 and 3 ml per minute and 10-20 litres (STP) per minute, respectively. The liquid-to-gas flow ratio was in all experiments tuned so that all solvents evaporated in the vertical spraying chamber, which was kept at room temperature. Nitrogen or dried air was used as carrier gas and the relative humidity (RH) was relatively low (<20 %) in all experiments. The produced hybrid particles were calcined at 550 °C for 4 hours in air to remove the surfactant templates and generate the mesoporous colloidal material.

Example 2. Loading of active substance, spontaneous adsorption Silica particles, Cι₆TAB templated with the 2D hexagonal pore structure, were dried at 120 °C in a vacuum furnace to evacuate eventual humidity. Solutions of the biocide DCOIT (Dichloro-2-n-octyl-4-isothiazolin-3-one, melting point 40.0°C) in cyclohexane of different concentrations (0.1 wt%, 0.25 wt%, 0.5 wt%, 1 wt%, 2 wt% and 5 wt%) were prepared. 10 g of each type of DCOIT-solution was mixed with 0.25 g of the powder. The mixtures were left under stirring over night. The adsorbed amount was determined using temperature gravimetry methods in combination with an analysis of DCOIT left in the supernatants, see Table 2.

Table 2. Adsorption isotherm for DCOIT in mesoporous silica in cyclohexabe

Example 3. Layer-by-layer (LbL) coating of polyelectrolytes Step 1: 1 g of mesoporous Cι₆TAB templated silica particles were dispersed in 40 ml of 100 mM NaCl solution using an ultrasonic probe during one minute. pH was adjusted at 8.0 by addition of NaOH solution. Step 2: Then 20 ml of an aqueous solution of PEI, concentration: 1 mg/ml, (Polyethylene Imine, high molecular weight, Aldrich) , containing 100 mM NaCl, were added to the silica colloids dispersion. The sample was left under stirring during 15 in to adsorb the polyelectrolyte. Step 3: This dispersion was then centrifuged at 3500 rpm during 5 min, the supernatant was removed and the particles were washed with 50 ml 100 mM NaCl. The suspension was centrifuged again at the same conditions as the first time, and the sediment was redispersed with 40 ml 100 ml NaCl. Step 4: 20 ml of an aqueous solution of PSS, concentration: 1 mg/ml, (Poly sodium 4-Styrene-Sulfonate, Mw = 70000 g/mole, Aldrich) containing 100 mM NaCl, was added. The suspension was left under stirring for 15 minutes. Step 5: Same washing step as step 3. Step 6: 20 ml of an aqueous solution of PAH, concentration: 1 mg/ml, (PolyAllylamine Hydrochloride, Mw = 15000 g/mole, Aldrich) containing 100 mM NaCl, was added. The suspension was left under stirring for 15 minutes. Step 7: Same washing step as step 3. Steps 4-7 were repeated as many times as required in order to achieve the desired polyelectrolyte layer thickness. Finally the particles were washed in deionised water and dried in air. The polyelectrolyte coatings typically grew 1 nm for each polyelectrolyte layer added. The encapsulations were characterised using transmission electron microscopy (TEM) methods, which showed that the PE-layers were relatively homogeneous in both thickness and density. Example 4. Release of biocide (DCOIT) into cyclohexane from non- coated and LbL coated mesoporous silica particles A proof-of-principle study demonstrating the influence of the polyelectrolyte coatings on release rates was performed for DCOIT in LbL coated Cι₆TAB mesoporous silica particles. The release kinetics of DCOIT were evaluated in cyclohexane for analytical reasons. 0.1 g loaded silica particles (35 % DCOIT by weight) were added to 100 ml cyklohexane. Samples were extracted and the concentration of DCOIT in the supernatant was measured by UV-VIS spectroscopy as a function of release time, see Table 3 below.

Table 3. Relative amount of released DCOIT over time in cyclohexane

The obtained results, stated in Table 3, show that the release rate of DCOIT into cyclohexane is significantly reduced by the LbL encapsulation of the loaded materials. Although the release into cyclohexane may not be relevant for practical applications, the relative change in release kinetics can be extrapolated to other solvents and/or chemical environments, including water. This indicates the viability of PE-coatings for reducing the release rate of active substances. Example 5. Loading of particles with ibuprofen and LbL coating Mesoporous silica particles, Cι₆TAB templated with the 2D hexagonal pore structure, were dried at 120 °C in a vacuum furnace to evacuate humidity. A 4 % ibuprofen cyclohexane solution was mixed with the dried mesoporous silica powder (1:1 weight ratio silica: ibuprofen) . After spontaneous adsorption for 12 h the powder was separated and the loading was determined by temperature gravimetry to be 25 %. The loaded particles were polyelectrolyte coated as described in Example 3 with 6 and 12 layers, respectively. The first layer was PEI, and then followed alternating layers of PSS and PAH, the last layer being PSS. In order to minimise the leaching the coating took place at a low temperature.

Example 6. Release of ibuprofen into water from non-coated and LbL coated mesoporous silica particles This study demonstrates the influence of the polyelectrolyte coatings on the release rate of the active substance ibuprofen from the LbL coated particles prepared in Example 5. The release kinetics of ibuprofen was evaluated in water. 0.04 g loaded silica particles (25 % ibuprofen by weight) were added to 1000 ml deionised water. 10 ml samples of the colloidal dispersion obtained were collected after the stated periods of time, the samples were centrifugated, the particles discarded and the concentration of ibuprofen in the supernatant was measured by UV-VIS spectroscopy as a function of release time, see Table 4 below. Table 4. Relative amount in % of released ibuprofen over time in water Time (mitiinn)) NNoonn--ccooaatteedd LbL 6 1.lyers LbL 12 layers 10 8888,,55 65,5 31,0 20 9922,,22 77,3 41,2 30 9944,,88 82,3 50,0 40 83,7 60,3 50 88,7 62,9 60 9966,,00 90,2 69,0 75 95,8 72,2 90 94,3 78,8 105 96,0 83,1 120 9977,,44 96,6 85,0 150 96,0 88,1 180 9977,,88 100,2 92,1 210 98,9 93,0 240 9977,,88 98,5 93,5 300 9966,,22 99,6 98,1 360 9988,,77 100,0 100,0 1440 110000,,00 100,0 100,0

The obtained results show that the release rate of ibuprofen into water is dependent on the number of layers of the LbL encapsulated loaded particles.

CONCLUSION The above examples show that the process of the invention is a suitable method for immobilising hydrophobic organic substances into inorganic particles, and that the release rate of said substances can be controlled by subsequent encapsulation of the particles.

Claims

1. Mesoporous inorganic oxide particles having a pore size of 2- 50 nm, loaded with active substance, characterised in being multilayer polyelectrolyte coated.

2. The particles according to claim 1, wherein the inorganic oxide is selected from the group consisting of silica, titanium dioxide or any other transition metal oxide.

3. The particles according to claim 1 or 2, wherein the pore structure has been templated by amphiphilic substances selected form the group consisting of ionic and non-ionic surfactants, and amphiphilic block copolymers .

4. The particles according to any of claims 1-3, wherein the pore structure has been templated by surfactants, such as an alkyl ammonium halogenide.

5. The particles according to any of claims 1-3, wherein the pore structure has been templated by an amphiphilic block copolymer .

6. The particles according to any of claims 1-5, wherein the internal pore structure of the templated particles is lamellar, cubic or hexagonal.

7. The particles according to any of claims 1-6, wherein the inorganic oxide is an amorphous silica and the internal pore structure is 2D-hexagonally ordered.

8. The particles according to claim 1 or 2, wherein the pore structure is amorphous.

9. The particles according to any of claims 1-8, wherein the polyelectrolyte coating comprises differently charged polyelectrolytes in a thickness of 1-50 nm.

10. The particles according to any of claims 1-9, wherein the active substance is selected from the group consisting of a biocide, a fragrance, a flavour, a drug, an enzyme, and a hormone .

11. A process for preparing multilayer polyelectrolyte coated mesoporous inorganic oxide particles loaded with active substance, characterised in that mesoporous inorganic oxide particles having a pore size of 2-50 nm are loaded with an active substance, and that said loaded particles are coated layer by layer with alternating polyacids and polybases.

12. A process according to claim 11 for preparing multilayer coated templated mesoporous silica particles loaded with an active substance, comprising the following steps - forming a precursor solution of a hydrolysed silane and a templating amphiphilic substance; spray drying the precursor solution into spherical mesostructured silica particles at ambient temperature; heating said spherical particles to 150-290 °C in order to condense the silica particles; calcining the mesostructured silica particles in air at a temperature of 400-700 °C in order to remove the templating amphiphilic substance; loading said calcined silica particles with an active substance; and layer-by-layer coating of said loaded silica particles with polyelectrolytes .

13. Process according to claim 12, also comprising the additional step of adding an amphiphilic substance after the loading of the calcined silica particles with a hydrophobic active substance.

14. Use of a multilayer polyelectrolyte coated optionally surfactant templated mesoporous inorganic oxide particle loaded with an active substance according to any of claims 1-10, for controlled release of said active substance.