Multicompartmentalized material for the thermostimulated delivery of substances of interest, preparation process and applications

Abstract

The present invention relates to a material in the form of solid particles with a diameter varying from 1 m to 1 cm which are composed of a continuous shell E.sub.Ext comprising at least one silicon oxide, said shell E.sub.Ext imprisoning at least one fatty phase, said material being characterized in that said fatty phase is solid at the storage temperature of said material and predominantly comprises a crystallizable oil having a melting point (T.sub.M) of less than 100 C. and in that said fatty phase includes at least one lipophilic substance of interest S.sub.L and at least one inclusion comprising a continuous shell E.sub.Int comprising at least one silicon oxide, said shell E.sub.Int imprisoning an aqueous phase comprising at least one hydrophilic substance of interest S.sub.H. The invention also relates to a process for the preparation of said material, to its use for the thermostimulated delivery of active substances, and also to the compositions including it.

Claims

1. A material in the form of solid particles with a diameter varying from 1 m to 1 cm which are composed of a continuous shell E.sub.Ext comprising: at least one silicon oxide, said shell E.sub.Ext imprisoning at least one fatty phase, wherein in said material said fatty phase is solid at the storage temperature of said material and comprises from 50% to 99.9% by weight, with respect to the weight of said fatty phase, of a crystallizable oil having a melting point (T.sub.M) of less than 100 C. and in that said fatty phase includes at least one lipophilic substance of interest S.sub.L and at least one inclusion comprising a continuous shell E.sub.Int comprising at least one silicon oxide, said shell E.sub.Int imprisoning an aqueous phase comprising at least one hydrophilic substance of interest S.sub.H.

2. The material according to claim 1, wherein the crystallizable oil is chosen from fatty substances and mixtures of fatty substances, of natural or synthetic origin, the melting point of which is greater than 15 C.

3. The material according to claim 1, wherein the crystallizable oil is chosen from paraffin waxes, triglycerides, fatty acids, rosins, waxes, hydrogenated vegetable oils and their mixtures, synthetic bitumens, and their mixtures.

4. The material according to claim 1, wherein the material is provided in the form of a powder of spherical or substantially spherical particles.

5. The material according to claim 1, wherein the silica shell E.sub.Ext has a thickness of 0.1 to 2 m.

6. The material according to claim 1, wherein the silica shell or shells E.sub.Int have a thickness varying from 0.1 to 1 m.

7. The material according to claim 1, wherein the shells E.sub.Ext and/or E.sub.Int additionally comprise one or more metal oxides of formula MeO.sub.2 in which Me is a metal chosen from Zr, Ti, Th, Nb, Ta, V, W and Al.

8. The material according to claim 1, wherein the substance of interest is chosen from medicaments, active principles which can be used in cosmetics, chemical reactants, dyes, pigments and inks.

9. The material according to claim 1, wherein the substance or substances of interest S.sub.L represent from 0.001% to 50% by weight of the total weight of the fatty phase.

10. The material according to claim 1, wherein the substance or substances of interest S.sub.H represent from 0.001% to 50% by weight of the total weight of the aqueous phase present in the inclusion or inclusions present within the fatty phase.

11. A process for the preparation of a material as defined in claim 1, wherein said process comprises the following stages: 1) in a first stage, bringing a fatty phase comprising from 50% to 99.9% by weight, with respect to the weight of said fatty phase, of a solid crystallizable oil (CO) having a melting point T.sub.M of less than 100 C. to a temperature T.sub.CO such that T.sub.CO is greater than T.sub.M, in order to obtain a crystallizable oil in the liquid state; 2) in a second stage, incorporating, in the fatty phase in the liquid state, at least one lipophilic substance of interest (S.sub.L) and solid colloidal particles P1; 3) in a third stage, bringing said fatty phase in the liquid state into contact with a first aqueous phase (AP1) brought beforehand to a temperature T.sub.AP1 such that T.sub.AP1 is greater than T.sub.M, said aqueous phase additionally including at least one hydrophilic substance of interest (S.sub.H); 4) in a fourth stage, subjecting the liquid mixture resulting from the third stage to mechanical stirring in order to obtain a water-in-oil (W/O) emulsion formed of droplets of aqueous phase dispersed in the continuous fatty phase in the liquid state and in which the solid colloidal particles P1 are present at the interface formed between the continuous fatty phase and the dispersed droplets of aqueous phase AP1; 5) in a fifth stage, adding the W/O emulsion obtained above in the preceding stage to a second aqueous phase (AP2) brought beforehand to a temperature T.sub.AP2 such that T.sub.AP2 is greater than T.sub.M and additionally including solid colloidal particles P2, said W/O emulsion representing at most 20% by weight with respect to the weight of the second aqueous phase; 6) in a sixth stage, subjecting the liquid mixture resulting from the fifth stage to mechanical stirring in order to obtain a water-in-oil-in-water (W/O/W) double emulsion formed of a continuous aqueous phase (AP2) including droplets of fatty phase in the liquid state, each of said droplets of fatty phase in the liquid state including at least one droplet of aqueous phase AP1, in which double emulsion the solid colloidal particles P2 are present at the interface formed between the continuous aqueous phase AP2 and the dispersed droplets of fatty phase in the liquid state; 7) in a seventh stage, bringing said W/O/W double emulsion to a temperature T.sub.W/O/W such that T.sub.W/O/W is less than T.sub.M in order to bring about the solidification of the fatty phase and to obtain a W/O/W double emulsion formed of globules of fatty phase in the solid state, each of said globules including at least one droplet of aqueous phase AP1, said globules being dispersed in the aqueous phase AP2; 8) in an eighth stage, adding, to the aqueous phase AP2 of the double emulsion and with mechanical stirring, at least one silicon oxide precursor and a sufficient amount of at least one acid to bring the aqueous phases AP1 and AP2 to a pH of less than or equal to 4; 9) in a ninth stage, leaving the W/O/W triple emulsion standing, in order to allow the silicon oxide precursor to hydrolyse and to condense in the form of a silicon oxide shell around said droplets of aqueous phase AP (mineralization of the emulsion) and to thus obtain the expected material; and 10) in a tenth stage, separating said material from the aqueous phase AP2.

12. The process according to claim 11, wherein the solid colloidal particles P1 and P2 are metal oxides chosen from the group consisting of oxides of silicon, titanium, zirconium and iron, and their salts.

13. The process according to claim 11, wherein the solid colloidal particles P1 and P2 are identical in chemical nature and are chosen from silicon oxide nanoparticles.

14. The process according to claim 11, wherein the amount of solid colloidal particles P1 varies from 0.01% to 10% by weight, with respect to the total weight of the aqueous phase AP1.

15. The process according to claim 11, wherein the amount of solid colloidal particles P2 varies from 0.01% to 5% by weight, with respect to the total weight of the W/O emulsion.

16. The process according to claim 11, wherein the solid colloidal particles P1 and P2 are functionalized by adsorption of surfactant molecules at their surface.

17. The process according to claim 11, wherein the silicon oxide precursors are chosen from silicon alkoxides.

18. The process according to claim 17, wherein the silicon alkoxides are chosen from tetramethoxyorthosilane, tetraethoxyorthosilane, dimethyldiethoxysilane, (3-mercaptopropyl)trimethoxysilane, (3-aminopropyl)triethoxysilane, N-(3-trimethoxysilylpropyl)pyrrole, 3-(2,4-dinitrophenylamino)propyltriethoxysilane, N-(2-aminoethyl)-3-aminopropyltrimethoxysilane, phenyltriethoxysilane, methyltriethoxysilane and their mixtures.

19. The process according to claim 11, wherein the amount of silicon oxide precursor varies from 0.005 to 4 M/m.sup.2 of surface area of the globules of the dispersed phase of the emulsion and of the droplets of aqueous phase AP1 of the emulsion.

20. A thermostimulated and simultaneous delivery of at least one lipophilic substance of interest and of at least one hydrophilic substance of interest, said delivery comprising the step of: delivering said at least one lipohilic substance of interest and of at least one hydrophilic substance of interest via the material of claim 1 in either one of a powder form or a dispersion in a solvent.

21. The thermostimulated and simultaneous delivery of at least one lipophilic substance of interest and of at least one hydrophilic substance of interest according to claim 20, wherein the delivery of the lipophilic and hydrophilic substances of interest is obtained by thermal expansion of the fatty phase, bringing about rupture of the shell surrounding the fatty phase as well as rupture of each of the silica shells surrounding each of the droplets of aqueous phase AP1 dispersed in the fatty phase, under the effect of a rise in the temperature of the material to a delivery temperature T.sub.D such that T.sub.D>T.sub.M.

22. A pharmaceutical, cosmetic or food product, comprising: as an ingredient, at least one material as defined in claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1a-1d are optical microscopy photographs of various emulations prepared during preparation of the material in accordance with one embodiment;

(2) FIGS. 2a-2b are images taken in epifluoroescence confocal microscopy of the material at ambient temperature in accordance with one embodiment; and

(3) FIGS. 3a-3d are images taken in confocal microscopy of the material at ambient temperature in accordance with one embodiment.

DETAILED DESCRIPTION

(4) The present invention is illustrated by the following implementational examples, to which, however, it is not limited.

EXAMPLES

(5) The starting materials used in the examples which follow are listed below: Icosane, 99% pure (melting point=37 C.), sold by Sigma-Aldrich; Tetraethoxyorthosilane, more than 99% pure (TEOS); Rhodamine B: Sigma-Aldrich; Cetyltrimethylammonium bromide (CTAB): ChemPur; Silica nanoparticles with a diameter of 12 nm, sold under the name Aerosil AR 816, and silica nanoparticles with a diameter of 16 nm, sold under the name Aerosil AR 972: Evonik Degussa.

(6) These starting materials were used as received from the manufacturers, without additional purification.

(7) The critical micelle concentration (CMC) of the CTAB in pure water at ambient temperature is 0.92 mM.

(8) The materials obtained were characterized using an inverted optical microscope sold under the trade name Axiovert X100 by Zeiss and equipped with a heating stage from Mettler which makes it possible to control the temperature and also the heating and cooling rates.

(9) The size distribution of the emulsions was studied using a particle sizer sold under the trade name Mastersizer Hydro MS2000 by Malvern Instrument. The particle size measurements were carried out at 25 C. in pure water. The intensity of the scattering as a function of the angle which was collected was converted using the Mie-Lorenz theory. The distribution in the size of the particles was expressed by their weighted mean diameter (D) and their polydispersity (P) by applying the following equations (1) and (2):

(10) $\begin{array}{cc}D=\frac{\underset{i}{\overset{}{.Math.}}{N}_i{D}_i^3}{\underset{i}{\overset{}{.Math.}}{N}_i{D}_i^2}& \left(1\right)\\ \mathrm{and}& \\ P=\frac{1}{\stackrel{\_}{D}}\frac{\underset{i}{\overset{}{.Math.}}{N}_i{D}_i^3.Math.\stackrel{\_}{D}-D_i.Math.}{\underset{i}{\overset{}{.Math.}}{N}_i{D}_i^3}& \left(2\right)\end{array}$

(11) in which: D.sub.i is the diameter of the particles, N.sub.i is the total number of droplets with the diameter D.sub.i, D is the median diameter, that is to say the theoretical opening of the sieve such that 50% of the particles, by weight, have a greater diameter and 50% have a smaller diameter.

(12) These formulae are applied in the particle sizers from Malvern Instrument.

(13) The materials were observed using a confocal microscope sold by Leica under the name True Confocal Scanner Leica TCS SP2.

Example 1

Preparation, Characterizations and Study of a Material in Accordance with the Invention

(14) In this example, the preparation, the characterization and the study of a material in accordance with the invention, composed of a silica shell including a crystallizable oil comprising dispersed droplets of aqueous phase, each of said droplets being itself surrounded by a silica shell, are illustrated.

(15) It should be noted that, in this example, the oily and aqueous phases do not include substances of interest, this example being given to demonstrate the structural feasibility of the compartmentalized material according to the process in accordance with the invention.

(16) It is easy to extrapolate the process below to oily and aqueous phases respectively including at least one lipophilic substance of interest and at least one hydrophilic substance of interest. The Rhodamine B used below in the aqueous phase in order to demonstrate the formation of the droplets of aqueous phase surrounded by a silica shell within the oily phase can furthermore be regarded as a hydrophilic substance of interest.

(17) 1) Preparation of the Material

(18) i): Functionalization of the Silica Particles

(19) 5 g of Aerosil AR 816 silica nanoparticles were dispersed in 100 ml of distilled water using an ultrasonic bath. 9 mg of CTAB/g of particles were subsequently added to this dispersion, this amount representing approximately 1.35 times that of the critical micelle concentration (CMC=0.92 mM). As the surface of the silica nanoparticles is negatively charged, the CTAB (cationic surfactant) is adsorbed at the surface of the silica particles and thus makes it possible to confer on them an amphiphilic nature. An aqueous phase AP1 including a dispersion of silica nanoparticles functionalized at the surface was obtained.

(20) The amount of CTAB was adjusted to the weight of the silica particles in order to obtain a specific coverage of 12 nm.sup.2/CTAB molecule at the silica/water interface, all the CTAB used being regarded as adsorbed at the surface of the silica particles.

(21) ii) Preparation of the W/O Emulsion

(22) 20% by weight of an aqueous phase AP1 comprising 0.02% by weight of Rhodamine B and 0.1 M of NaCl, preheated to a temperature of 45 C., were introduced into the fatty phase (icosane), also preheated to 45 C. and including a dispersion of AR 972 silica particles. The amount of AR 972 silica particles to be dispersed in the fatty phase is calculated as a function of the amount of aqueous phase, in a proportion of 50 mg of silica particles per gram of aqueous phase.

(23) The emulsification of the fatty phase and of the aqueous phase was carried out using a stirrer sold under the name Ultra-Turrax T25 by Janke & Kunkel, equipped with an S25 KV-25F dispersing device, ending by stirring at 12 000 revolutions/min for 1 minute. The resulting emulsion was maintained at 45 C. in a thermostatically controlled bath without stirring in order to allow the phenomenon of limited coalescence to occur (adsorption of the silica particles at the surface of the dispersed droplets of aqueous phase, which makes it possible to improve the homogeneity of the distribution in the size of the water droplets dispersed in the oil).

(24) iii) Preparation of the W/O/W Double Emulsion

(25) 20% by weight of the W/O emulsion obtained above in the preceding stage were subsequently added to an aqueous phase AP2 comprising 0.1 M of NaCl and the functionalized AR 816 silica particles as prepared above. The amount of functionalized particles depends on the total weight of the W/O emulsion used. In this example, the aqueous phase AP2 included 8 mg of functionalized particles per gram of W/O emulsion introduced into the aqueous phase AP2.

(26) The emulsification of the W/O emulsion in the aqueous phase AP2 was carried out using the same stirrer as above in stage ii), finishing by stirring at 8000 revolutions/min for 2 minutes. The W/O/W double emulsion thus obtained was subsequently kept in a thermostatically controlled bath at 45 C. without stirring for a few minutes in order to allow the phenomenon of limited coalescence to occur (adsorption of the silica particles at the surface of the dispersed droplets of fatty phase).

(27) The emulsion was subsequently removed from the thermostatically controlled bath and then allowed to return to ambient temperature in order to bring about the solidification of the fatty phase.

(28) iv) Mineralization of the Emulsion: Formation of the Silica Shells

(29) The W/O/W double emulsion obtained above in the preceding stage was diluted down to 7% by weight by addition of an aqueous solution comprising 0.5% by weight of CTAB, 46% by weight of 37% by volume hydrochloric acid (HCl) and 0.1 M of NaCl, under cold conditions, that is to say at a temperature of 4 C.

(30) The pH of the mixture thus formed was approximately 0, which subsequently makes it possible to carry out the hydrolysis and the condensation of the TEOS at the oil/water interfaces.

(31) The mineralization of the emulsion was thus carried out by introducing 10 ml of the acidified double emulsion into test tubes and by then adding thereto 0.3 g of TEOS per tube.

(32) The tubes were subjected to continuous stirring on a rotating wheel at the rate of 9 revolutions per minute in a chamber thermostatically controlled at 25 C. After one hour, the expected material was recovered by centrifuging and washed several times with water comprising 0.1 M of NaCl.

(33) The material obtained was stored in pure water for several months. No detrimental change in the capsules was observed during this period.

(34) 2) Results and Characterizations

(35) The appended FIG. 1 represents an optical microscopy photograph of the various emulsions prepared during the preparation of the material in accordance with the invention: FIG. 1a): W/O emulsion; FIG. 1b): W/O/W double emulsion at ambient temperature before the mineralization stage; FIG. 1c): W/O/W double emulsion at ambient temperature after the mineralization stage; FIG. 1d): curve showing the size distribution of the particles of the final material (percentage by volume (%) as a function of the diameter of the particles (mm)).

(36) It was subsequently confirmed that an increase in the temperature brought about rupture of the silica shells and the release of the molten fatty phase and also of the aqueous phase AP1.

(37) The appended FIG. 2 is an image taken in epifluorescence confocal microscopy of the material at ambient temperature, that is to say at a temperature at which the fatty phase is in the solid state, and at two different magnifications. In this figure, the white arrow denotes the water/oil interface of the inclusions of droplets of aqueous phase AP1, each encapsulated by a silica shell. The structure of the material in accordance with the invention is clearly seen, by virtue of the Rhodamine B added to the aqueous phase AP1. The Rhodamine B is exclusively present in the droplets of water encapsulated by a silica shell, the concentration of Rhodamine furthermore being higher as the water/oil interface is approached, said encapsulated drops of water being dispersed in the fatty phase, itself encapsulated by a silica shell.

(38) The material was subsequently brought to a temperature of 65 C. by gradually raising the temperature at the rate of 2 C. per minute. The material was subsequently again observed in confocal microscopy after returning to ambient temperature. The corresponding photos are given in the appended FIG. 3, in which FIGS. 3a and 3c are views taken without fluorescence and FIGS. 3b and 3d are views taken with fluorescence, at two different magnifications. In this figure, the thick broken white lines indicate the presence of the fatty phase devoid of fluorescence, the thin broken white lines indicate the impression of the water droplets, these now being devoid of fluorescence, and the white arrow indicates the presence of a few mineralized droplets of water outside the external shell after rupture thereof. It can thus be seen that the heat treatment results in the expulsion of the fatty phase devoid of Rhodamine B by rupture of the silica shell initially surrounding each globule of fatty phase. It is also possible to observe, in FIGS. 3a and 3c, a few droplets without fluorescence corresponding in fact to the impressions left by the water droplets which were initially encapsulated in the internal silica shells and which were scattered after rupture of these internal silica shells. This proves that the TEOS has migrated inside the globules of fatty phase of the W/O/W double emulsion up to the oil/water interface in order to form an internal silica shell around each of the droplets of aqueous phase AP1 which are dispersed in the fatty phase and that the thermal expansion of the fatty phase by raising its temperature brings about both rupture of the external silica shell surrounding the globules of fatty phase and also rupture of the internal silica shells surrounding the droplets of aqueous phase AP1 which are dispersed in the fatty phase.

(39) It is thus possible to simultaneously release lipophilic and hydrophilic substances which would be respectively present in the fatty phase and in the aqueous phase AP1 by simple raising of the temperature of the materials in accordance with the invention.