WO2011054046A1

WO2011054046A1 - Controlled release particles and method for preparation thereof

Info

Publication number: WO2011054046A1
Application number: PCT/AU2010/001472
Authority: WO
Inventors: Gao Qing Lu; Shizhang Qiao; Amirali Akbarbhai Popat
Original assignee: The University Of Queensland And The State Of Queensland Acting Through Its Department Of Primary Industries And Fisheries
Priority date: 2009-11-06
Filing date: 2010-11-05
Publication date: 2011-05-12

Abstract

A process for preparing a particulate composition for controlled release of an active agent, the process comprising: forming a double emulsion comprising (i) an internal phase comprising droplets of a suspension in a first liquid of mesoporous silica particles and the active agent sorbed into the mesoporous silica particles; (ii) an intermediate dispersed phase within which the first liquid is dispersed comprising a second liquid; and an organic polymer or precursor thereof; and (iii) a continuous phase; and curing the polymer or precursor thereof to form microspheres comprising a coating of the polymer about the mesoporous silica particles.

Description

Controlled Release Particles and Method for Preparation Thereof Field

The invention relates to controlled release particles for controlled release of an active agent and a process for preparation of such controlled release particles.

Background

The controlled release, such as slow and/or sustained release, of an active ingredient is a highly desirable trait in many industries.

Targeting controlled release to the particular use, such as the nature and habits of a particular group of pests in the case of agrochemicals or a particular disease in the case of drugs, is desirable because it reduces the amount of active present in non-target location such as the environment in the case of agrochemicals or non-target tissue in the case of drugs.

While controlled release compositions are generally known there is a need for options which provide more targeted or precise control. Summary

There is provided a process for preparing a particulate composition for controlled release of an active agent, the process comprising:

forming a double emulsion comprising

(i) an internal phase comprising droplets of a suspension in a first liquid of mesoporous silica particles and the active agent sorbed into the mesoporous silica particles; (ii) an intermediate dispersed phase within which the first liquid is dispersed comprising a second liquid; and an organic polymer or precursor thereof; and (iii) a continuous phase; and

curing the polymer or precursor thereof to form microspheres comprising a coating of the polymer about the mesoporous silica particles.

In the preferred embodiments the double emulsion comprises the mesoporous silica dispersed in an aqueous internal phase, which is dispersed in a water immiscible solvent phase and which, in turn, is dispersed in a continuous aqueous phase. Such a system may be referred to as a suspension in the dispersed aqueous phase of a water-in oil-in water or S/W/O/W emulsion. Such an emulsion is prepared in one set of embodiments by a process comprising (a) mixing an organic solvent phase comprising a polymer or precursor thereof with an aqueous composition comprising dispersed mesoporous silica and the active agent sorbed into the mesoporous silica to form a first water-in-oil emulsion, (b) dispersing the first water-in-oil emulsion into an aqueous phase to form a second water-in-oil-in-water double emulsion. In a further set of embodiments the invention provides composition for controlled release of an active compound comprising an internal phase comprising a suspension in a first liquid of particles of mesoporous silica and the active agent sorbed into the mesoporous silica; and an organic polymer coating the particles of mesoporous silica. The process and particles may use a range of actives such as selected from agrochemicals, cosmetics, adhesives, inks, pharmaceuticals, neutraceuticals, fragrances, catalysts and flame retardants. However, in a particularly preferred set of embodiments the active comprises one or more agrochemicals, preferably pesticides, such as pesticides selected from the group consisting of pyrazole insecticides such as chlorantraniliprole, cyantraniliprole, dimetilan, tebufenpyram and tolfenpyram including phenylpyrazole insecticides such as acetoprole, ethiprole, fipronil, pyraclofos, pyrafluprole, pyriprole and vaniliprole; nicotinoid insecticides such as flonicamid and including nitroguanidine insecticides such as clothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethylene insecticides such as nitenpyram and nithiazine and pyridylmethylamine insecticides such as acetamiprid, imidacloprid, nitenpyram and thiacloprid and more preferable selected from fipronil and imidacloprid.

The active is most preferably at least one termiticide such as imidacloprid or fipronil. The termiticide laiden particles increase the efficiency of delivery by targeting the whole termite colony and resulting in reduced release of the termiticide into the environment. The controlled release particles are gathered as food by termites at aggregation stations and carried back to the colony. Once ingested, the particle is orally transferred to nest mates and after controlled delay, release inside the body of the termites. In a further set of embodiments we therefore provide a method of controlling termites comprising applying the particles having a termiticide sorbed therein to soil, wood or other habitat of termites.

Detailed Description

The terms sorbed/sorption where used herein refers to the process in which one substance takes up or holds another (by either absorption or adsorption).

Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.

The term cure is used herein in the sense, for example, making (substances) harder to improve their usability. The curing may involve removal of solvent, reaction such as cross linking or polymerization or a combination thereof.

In general one of (a) the first liquid and continuous phase and (b) the intermediate phase, will be aqueous and the other of (a) and (b) will be water immiscible in the proportions used, that is they will form discrete phases. In one embodiment the double emulsion is a water-in -oil-in water (O/W/O) type double emulsion and in an alternative embodiment the double emulsion is an oil-in-water-in-oil type double emulsion. As the composition comprises a suspension of solid particles in the internal phase these types of systems may be referred to as S/W/O/W emulsions and S/O/W/O emulsions respectively. In a particularly preferred set of embodiments we provide a process for preparing a particulate composition for controlled release of an active agent, the process comprising: forming a double emulsion comprising (a) mixing an organic solvent phase comprising a polymer or precursor thereof with an aqueous composition comprising dispersed mesoporous silica and the active agent sorbed into the mesoporous silica to form a first water-in-oil emulsion, (b) dispersing the first water-in-oil emulsion into an aqueous phase to form a second water-in-oil-in-water double emulsion.

A process according to claim 3 wherein said aqueous phase comprises an emulsion stabiliser preferably a non-ionic emulsion stabiliser. Examples of suitable emulsion stabilizers include polyvinyl alcohol and hydrophilic low HLB surfactants such as alkylphenol ethoxylates such as Triton X-100, poloxymer surfactants such as the "PLURONIC" range, "ATLOX 4914", ATLAS G4989 and ATLAS G 4818. Ionic surfactants such as sodium lauryl sulfate may also be useful.

The process may further comprise a step of collecting and preferably also drying the microspheres having said active agent entrapped therein.

The organic solvent phase which is an intermediate or oil phase in a S/W/O/W type emulsion preferably comprises a volatile organic solvent. In this embodiment the polymer may be cured by a process comprising at least partly removing the solvent to form particles comprising a coating of the polymer on the mesoporous silica particles.

Examples of preferred solvents for use in the intermediate of an S/W/O/W system may be selected from the group consisting of chloroform, ethyl acetate, dichloromethane and acetone and more preferably dichloromethane and ethyl acetate.

Evaporation of a volatile solvent may be carried out to cause the polymer in the intermediate phase to cure and precipitate to form a coating on the particles. In one set of embodiments the polymer is selected from the group consisting of cellulose derivatives such as ethyl cellulose; polyvinyl pyrrolidone; polyvinyl acetate; chitosin; styresnics, poly(lactic acid), derivatives of poly(lactic acid), PEGylated poly(lactic acid), poly(lactic-co-glycolic acid), derivatives of poly(lactic-co-glycolic acid), PEGylated poly(lactic-co-glycolic acid), a polyanhydride, poly(ortho esters), derivatives of poly(ortho esters), PEGylated poly(ortho esters), poly(caprolactone), derivatives of poly(caprolactone), PEGylated poly(caprolactone), polyacrylates such as poly(acrylic acid), poly(Ci to C₄ alkyl)acrylate, polyacrylamides, derivatives of poly(acrylic acid), poly(urethane), derivatives of poly(urethane), and combinations thereof.

In one set of embodiments the polymer is an anionic polymer based on methacrylic acid such as a methacrylic acid homopolymer or methacrylic acid - methyl methacrylate copolymer. In another set of embodiments the polymer is a cellulose derivative such as an alkyl cellulose such as ethyl cellulose, cellulose acetate phthalate or carboxymethyl cellulose including salts such as sodium carboxymethylcellulose.

In one set of embodiments the intermediate phase is an oil phase comprising a polymerizable material and optionally also a solvent for the polymerisable material and the process of curing the polymer comprises polymerizing the polymerizable material to cure the polymer and cause it to condense onto the mesoporous particles. In certain embodiments of the invention it may be advantageous to for the polymer coating to be formed by in situ living free radical polymerization using, for example RAFT initiators, iniferters, nitroxides or the like. The particles of mesoporous silica may have an average particle size in the range of from 20 to 500 nanometres.

Examples of mesoporous silica particles suitable for use in the process are described in papers including CT, K., et al., A new family of mesoorous molecular sieves prepared with liquid crystal template. Journal of American Chemical Society, 1992. 1 14(27): p. 10834-10843; Wan, Y. and Y. Zhao, On the controllable soft templating Approcach to Mesoporous silicates. Chemcial Reviews, 2007. 1077(7): p. 2821 -2860; Trewyn, B.G., et al., Synthesis and Functionalization of a Mesoporous Silica nanopartice based on Sol- Gel Process and Application in Controlled Release, Accounts of Chemical Research, 2007. 40(9) : p. 846-853; and Vallet-Regi, M., F. balas, and D. Arcos, Mesoporous Materials for Drug Delivery. Angewandte Chemie International Edition2007. 46: p. 7548- 7558.

The amount of mesoporous silica particles with sorbed active may be in the range of from 0.1 to 30% by weight of the double emulsion composition, preferably fro 0.5 to 20%, more preferably from 1 to 1 0% and most preferably from 1 to 5 %.

The amount of active which can be sorbed into the mesoporous silica particles will depend on the specific active agent and structure of the mesoporous silica but in one set of embodiments the weight ratio of mesoporous silica to active agent is in the range of from 1 : 2 to 1 0: 1 .

In one set of embodiments the mesoporous silica has a surface modified with functional groups selected from the group consisting of phosphate and grafted organic compounds. The surface charge may be used together with the choice of polymer to assist in condensing the polymer about the mesoporous silica particles.

Each of the controlled release particles formed in accordance with the process will generally comprise one or more mesoporous silica particles laden with the active agent on which a coating of the polymer is formed. The mesoporous particles dispersed in the inner phase may aggregate during the process so that a proportion of particles may contain such aggregates of two or more mesoporous particles surrounded by a contiguous polymer coating.

In general, we have found that the process provides smaller discrete coated particles than generally available via the corresponding single emulsion method involving curing of polymer from a S/W/O system. This in turn provides more effective controlled release of active from the particles. The process further allows a wide range of polymer types to be used in coating to allow the release characteristics to be tailored to the desired end use and the nature of the active.

The invention will now be described with reference to the following examples. It is to be understood that the examples are provided by way of illustration of the invention and that they are in no way limiting to the scope of the invention. EXAMPLES

Brief Description of Drawings

The Examples are described in part with reference to the attached drawings. In the drawings:

Figure 1 is a graph of absorbed volume against relative pressure for a nitrogen adsorption isotherm of calcined sample MCM-41 of Example 2(a).

Figure 2 is a graph of the XRD pattern of MCM-41 from Example 2(a).

Figure 3 includes as Figure 3a an SEM image of MCM-41 and in Figure 3b a TEM image of MCM-41 , each Figure showing a 100nm scale bar.

Figure 4 is a graph showing plots of the weight of adsorption of active agent Imidacloprid on to silica particles with contact time in acetone solutions of concentration from 2 to 20mg Inl. As reported in Example 4.

Figure 5 is a graph showing plots of the percent cumulative release of active agent Imidacloprid from particles in water with time as reported in Example 4.

Figure 6 is a graph with plots of the adsorption of active agent Fipronil with time on to silica particles from solutions in acetone of various concentrations from 2 to 20mg/ml with time as reported in Example 4.

Figure 7 is a graph with plots of the release of active agent Fipronil from particles prepared from various acetic solutions as per Figure 6 with time as reported in Example 4.

Figure 8 is an SEM image showing ethyl cellulose coated controlled release particles prepared according to Example 5. Figure 9 is a graph showing the cumulative release of active agent Fipronil from ethyl cellulose coated particles and from control uncoated particles reported in Example

EXAMPLE 1 - Part (a) MCM-41 Nanospheres

Typically, 0.6g of Ci₆TAB quaternary ammonium type surfactant is mixed with 288ml of water and 2.1 ml of 2M sodium hydroxide. The mixture it then heated to 80°C in a water bath for 30 minutes. Then 3g of TEOS are added. The solution is stirred vigorously for two hours. White precipitate is collected, centrifuged and washed twice with ethanol. After overnight drying, particles are calcined at 550°C for five hours to remove surfactant completely.

EXAMPLE 1 - Part (b)

Sorption of biocides (Imidacloprid and Fipronil)

100mg of MCM-41 is suspended into 2, 5, 7.5, 1 0 and 20 mg/l solution of Imidacloprid and Fipronil in acetone. The mixture is sonicated for two minutes and stirred for 48 hours. Samples are collected at specified time, centrifuged and filtered before analysis. Imidacloprid and Fipronil are analysed by High performance liquid chromatography (HPLC) and Gas chromatography (GC) respectively.

EXAMPLE 1 - Part (c) Coating using Ethyl cellulose

Ethyl cellulose is dissolved in an organic solvent. 100mg of biocide-loaded particles are suspended in 3ml of 1 % polyvinyl alcohol (PVA) and mixture sonicated for one minute using probe sonicator to form an emulsion. It is then added to solution of ethyl cellulose drop wise and again sonicated to form S/W/O emulsion. This in turn is added to 1 00ml of 1 % PVA solution (S/W/O W) and stirred for four hours to remove the organic solvent. EXAMPLE 2 - Part (a)

MCM-41 Nanospheres with Phosphonate functional group

Phosphonate group functionalised Mesoporous silica nanoparticles were prepared by the following method from Lu J. :"Mesoporous nanoparticles as delivery system for hydrophobic anteesnor drugs", Small, 2007, 3(8) 1341 -1346. Briefly, 0.5g of Ci₆TAB was mixed with 240ml of water and 1 .7ml of 2M sodium hydroxide. The mixture was then heated to 80°C in a water bath for 30 minutes. Then 2.5ml of TEOS was added. After 15 minutes of stirring, 0.63ml of 3-trihydroxy silylpropyl methylphosphonate was added to the mixture and solution was stirred vigorously for two hours. White precipitates were collected, centrifuged and washed twice with ethanol. The particles were dried at room temperature. Surfactant removal of these particles was done by using ethanol-acid mixture.

EXAMPLE 2 - Part (b)

Sorption of Biocides is carried out according to Example 1 , Part (b).

EXAMPLE 2 - Part (c)

Coating of the biocide sorbed particles may be carried out according to Example 1 Part (c) or other polymer coating processes described hereafter.

EXAMPLE 3 - Part (a)

Nitrogen adsorption is performed on a Quantachrome Quadrasirb SI at the liquid nitrogen temperature of 77K. Surface area is calculated by the Brunauer-Emmet-Teller (BET) method. Pore diameter distribution is determined by Barrett-Joyner-Halenda (BJH) method and pore volume is estimated from the amount of nitrogen adsorbed at relative pressure of 0.99.

Low angle X-ray powder diffraction is carried out using a Rigaku miniflex diffractometer using co radiation (λ= 1 .792A) and operated at 30kv with a variable slit width. The scanning rate is set at 1 degree/minute over 2Θ from 1.5-10 degree. Transmission electron microscopy is done by using JEOL-1010 with an accelerated voltage of 100kV. Scanning electron microscopy is done by using JEOL 6400 with an accelerated voltage of 8-12kV.

FTIR is done with NICOLET 6700 by Thermo Electron Corporation. Zeta potential is measured using Malvern Zeta seizer (Zeta nano ZS).

HPLC is carried out by Waters HPLC system. Sunfire (hydrophilic) column is used for separation of Imidacloprid. UV visible detector is used at wavelength of 230-270nm range and injection volume is 10μιη due to small size of the column.

GC is carried out using AGILENT gas chromatography, with electron conductivity detector (ECD). ECD was chosen due to its high sensitivity towards halogen compounds present in Fipronil. EXAMPLE 3 - Part (b)

Structural Characterisation of MSN's

As shown in Figure 1 , the calcined MSN shows a type IV isotherm. A steep increase in nitrogen uptake due to capillary condensation inside mesopores occurs at a relative partial pressure of (roughly) 0.2<P/P_o<0.3 whilst an evident nitrogen adsorption above P/Po =0.9 should be caused by the interstices among the nanospheres. The prepared MSN exhibit a high BET specific surface area of 1020 m²/g, and a large pore volume of 1 .02. The BJH pore-size distribution plot (inset of Figure 10) shows a sharp peak at mean diameter of 2.4 nm, which indicates the present of uniform mesopores. Figure 2 shows XRD pattern of calcined MCM-41 type silica structure. It shows three resolved peaks which can be indexed as 100, 1 10 and 200 reflections associated with 2D hexagonal symmetry. Reflection peaks at d1 1 0 and d200 confirm the highly ordered structure.

Figure 3 shows the SEM and TEM images of MCM-41 . SEM showed particles had smooth surface and the particle size was about 1 00nm. TEM image shows porous nature of the particles and confirms the hexagonal porous structure of MCM-41 .

EXAMPLE 4

Adsorption and release of Imidacloprid and Fipronil using MCM-41

Adsorption of Imidacloprid was carried out using acetone as solvent, due to its high solubility in acetone. It is evident from the graph shown in Figure 4 that about 14mg of Imidacloprid can be adsorbed into 1 00mg of silica particles. By increasing the concentration of Imidacloprid solution, the adsorbed amount is increased maximum up to 14%. In-vitro release of Imidacloprid was carried out in deionised water. Release kinetics shows initial burst release in first few hours followed by plateau. Initial burst is attributed to the solubility of Imidacloprid in water (~ 500 mg/l). It can be assumed from this that Imidacloprid is physically adsorbed inside the pores and can be easily removed upon mild release conditions. Additionally, from the release kinetics curves (Figure 5) it can be observed that after 7.5mg/ml concentration the release rate becomes faster in first few hours, which is possibly because after that most of the biocides are onto the particle surface and not inside the pores. This leads to faster release rate.

Fipronil was chosen as a second model biocide due to its solubility in water. It's practically insoluble in water, but it is soluble in Acetone, Hexane and other organic solvents. Adsorption of Fipronil shows similar results as Imidacloprid and Figure 6 shows the corresponding adsorption of Fipronil from acetone at concentrates of from 2 to 20 mg/ml. Interestingly, adsorbed amount is slightly higher than Imidacloprid (16mg/100mg of MCM-41 ). The release kinetics of Fipronil shows different picture, however, it shows slow and low release in water than Imidacloprid. But, it does have that initial burst release for first few hours (Figure 7). EXAMPLE 5

Ethyl cellulose encapsulated MSNs and biocide release from the same

By looking at the release curve of both Imidacloprid and Fipronil it is evident that silica particles are good carrier for adsorption and release of biocides. However, release is very fast in first few hours. To achieve the targeted and controlled biocide delivery, particles needs a barrier layer. This layer can provide control over the burst release and at the same time can serve as carrier for targeting the termite gut.

Termites eat cellulose as their basic food, by coating with the cellulose or its derivative with mesoporous silica can be advantageous. In addition, termite gut consists of enzymes like cellulose and chitinase, cellulose or its derivative can become a potential substrate for the enzyme leading to enzyme specific release in the gut. Due to the solubility limitations with cellulose, we used ethyl cellulose. SEM image shows that particles are almost spherical and has particle size about Ι ΟΟμιη, and smooth surface (Figure 8). To study the release kinetics Fipronil was used as a model biocide. Imidacloprid on the other hand, can be leaked through the silica nanoparticles because of its high water solubility and the coating method uses large amount of water. Release results shows that Fipronil release was inhibited by the large particle size and polymer characteristics of ethyl cellulose (Figure 9). The slow release is attributed to the distance travelled by Fipronil molecules from micro particles, solubility of Fipronil in water and solubility of ethyl cellulose in water.

MCM-41 was successfully used as a carrier for adsorption and release of biopesticide. It is shown that both water soluble (Imidacloprid) and water insoluble (Fipronil) molecules can be loaded into pores of MCM-41 type of material. Release of biopesticide was dependent on the type of coating and inherent solubility of the compound.

Ethyl cellulose coated composite microparticles can be effectively formed by using S/W/O/W method. Coated particles are around Ι ΟΟμιη in size. Due to insolubility of ethyl cellulose in water and increased diffusion path length, composite microparticle shows very low release rate of Fipronil in water. Thus, this technique can be utilised to study the targeted release of biopesticide inside the termite gut as well.

Example 7 and Example 8

Preparation of Coated particles using S/W/O/W technology

50mg of Mesoporous silica nanoparticles MSN was added into 2ml of 1 -5%PVA

(Polyvinyl alcohol) and stirred for few seconds. To this solid particle in water S/W suspension 4ml of a 2%w/v polymer solution, in accordance with Table 2 below, was added drop wise and mixture was sonicated for a minute to provide a solid-in-water-in-oil type emulsion. This emulsion was poured into 50-100ml of 0.3-1 %W/V PVA solution to form a S/W/O/W and was stirred for 3 hours to evaporate solvent. Solid particles generated were centrifuged, washed with water and dried under vacuum.

This method was conducted with each of the polymers Ethyl cellulose and poly(lactic-co- glycolic acid) (PLGA). It was noticed that when the polymer was PLGA a smaller particle size was obtained (~500nm) compared to Ethylcellulose (1 -20micrometer). Table 2 below shows particle size and seta potential of MSN coated polymeric particles using S/W/O/W method. It is to note here that MSN were MCM-41 type with particle size of about 1 50nm and Zeta potential in water was -4mV.

Table 2

A similar process can be used with other polymers such as PLGA, PLA, Poly- caprolactone, and "Eudragit".

Various parameters can be optimised depending upon polymer characteristics and solvent used. We found that this method can be used for various water insoluble polymers such as PLGA, poly(lactic acid) (PLA), Poly-caprolactone and polymethacrylate polyacrylate type polymers such as the poly(meth)acrylate sold under the registered trademark "Eudragit" by Evonik Industries.

Claims

1 . A process for preparing a particulate composition for controlled release of an active agent, the process comprising :

forming a double emulsion comprising

(i) an internal phase comprising droplets of a suspension in a first liquid of mesoporous silica particles and the active agent sorbed into the mesoporous silica particles;

(ii) an intermediate dispersed phase within which the first liquid is dispersed comprising a second liquid; and an organic polymer or precursor thereof; and

(iii) a continuous phase; and

2. A process according to claim 1 wherein the double emulsion is a water-in-oil-in- water emulsion comprising the particulate mesoporous silica suspended in the internal water phase.

3. A process according to any one of the previous claims wherein the process of forming a double emulsion comprises (a) mixing an organic solvent phase comprising a polymer or precursor thereof with an aqueous composition comprising dispersed mesoporous silica and the active agent sorbed into the mesoporous silica to form a first water-in-oil emulsion, (b) dispersing the first water-in-oil emulsion into an aqueous phase to form a second water-in-oil-in-water double emulsion.

4. A process according to claim 3 wherein said aqueous phase comprises an emulsifier.

5. A process according to claim 4 wherein said emulsifier is a non-ionic emulsifier.

6. The process of claim 3 or claim 4, wherein said first water-in-oil emulsion additionally comprises at least one surfactant.

7. A process according to any one of the previous claims further comprising collecting the microspheres having said active agent entrapped therein.

8. A process according to any one of claims 3 to 7 wherein the organic solvent phase comprises a volatile organic solvent and the polymer is cured by a process comprising at least partly removing the solvent to form a coating of the polymer on the mesoporous silica particles and collecting the particles.

9. A process according to any one of the previous claims wherein the intermediate phase is an oil phase comprising a polymerizable material and the process of curing the polymer comprises polymerizing the polymerizable material.

10. A process according to many one of the previous claims wherein the active agent is selected from agrochemicals, cosmetics, adhesives, inks, pharmaceuticals, neutraceuticals, fragrances, catalysts and flame retardants.

1 1 . A process according to any one of the previous claims wherein the active agent is at least one pesticide selected from the group consisting of pyrazole insecticides such as chlorantraniliprole, cyantraniliprole, dimetilan, tebufenpyram and tolfenpyram including phenylpyrazole insecticides such as acetoprole, ethiprole, fipronil, pyraclofos, pyrafluprole, pyriprole and vaniliprole; nicotinoid insecticides such as flonicamid and including nitroguanidine insecticides such as clothianidin, dinotefuran, imidacloprid and thiamethoxam ; nitromethylene insecticides such as nitenpyram and nithiazine and pyridylmethylamine insecticides such as acetamiprid, imidacloprid, nitenpyram and thiacloprid and more preferable selected from fipronil and imidacloprid.

12. A process according to any one of the previous claims wherein the particles of mesoporous silica have an average particle size in the range of from 20 to 500 nanometres.

13. A process according to any one of the previous claims wherein the polymer is a controlled release polymer selected from the group consisting of cellulose derivatives such as ethyl cellulose; polyvinyl pyrrolidone; polyvinyl acetate; chitosin; styresnics, poly(lactic acid), derivatives of poly(lactic acid), PEGylated poly(lactic acid), poly(lactic-co-glycolic acid), derivatives of poly(lactic-co-glycolic acid), PEGylated poly(lactic-co-glycolic acid), a polyan hydride, poly(ortho esters), derivatives of poly(ortho esters), PEGylated poly(ortho esters), poly(caprolactone), derivatives of poly(caprolactone), PEGylated poly(caprolactone), polyacrylates such as poly(acrylic acid), poly(Ci to C₄ alkyl)acrylate, polyacrylamides, derivatives of poly(acrylic acid), poly(urethane), derivatives of poly(urethane), and combinations thereof.

14. A process according to any one of the previous claims wherein the weight ratio of mesoporous silica to biologically active agent is in the range of from 1 : 2 to 10: 1 .

15. A process according to any one of the previous claims wherein the mesoporous silica has a surface modified with functional groups selected from the group consisting of phosphate and grafted organic compounds.

16. A composition for controlled release of an active compound comprising an internal phase comprising a suspension in a first liquid of particles of mesoporous silica and the active agent sorbed into the mesoporous silica; and an organic polymer coating the particles of mesoporous silica.