FR3095966A1 - PROCESS FOR PREPARATION OF BIODEGRADABLE MICROCAPSULES AND MICROCAPSULES THUS OBTAINED - Google Patents

Abstract

Process for manufacturing microcapsules containing a so-called active substance, process in which: an aqueous solution of a surfactant is supplied, an oily phase comprising said active substance and at least one first monomer X, and a polar phase comprising at least one second monomer Y; an O / W type emulsion is prepared by adding said oily phase to said aqueous solution of the surfactant; said polar phase is added to said O / W emulsion, to enable a polymer to be obtained by polymerization of said X and Y monomers; said microcapsules comprising a wall formed by said polymer and containing said active substance are isolated from this reaction mixture; said process being characterized in that said polymer is a poly (beta-amino ester).

Description

METHOD FOR PREPARING BIODEGRADABLE MICROCAPSULES AND MICROCAPSULES THUS OBTAINED

Technical field of the invention

The present description concerns the field of microcapsules, and more particularly the processes for manufacturing microcapsules with a view to enclosing active substances such as essential oils. More specifically, it relates to a method for preparing biodegradable microcapsules. This method proceeds by interfacial polymerization of multifunctional compounds leading to poly(beta-amino ester)s. The invention also relates to the biodegradable microcapsules obtained by this method.

State of the art

Microencapsulation is a process making it possible to protect a reactive, sensitive or volatile substance (called here “active principle”) in a capsule whose size can vary from nanometer to micrometer. The core of the capsule is therefore isolated from its external environment. This makes it possible to delay its evaporation, its release or its deterioration; there are many applications that exploit these technical effects when the microcapsules are incorporated into a complex formulation or applied to a product.

By way of example, the microcapsules can be used to spread in a controlled manner the active principle that they contain, which can in particular be a biocidal active ingredient, an insecticide, a disinfectant, or a fragrance; this can be done by diffusion through the wall or under the influence of an external force which breaks the wall. In certain applications, the release of the active principle takes place under the influence of an external force which breaks the wall of the microcapsules; thus one can release a glue (see for example WO 03/016369 - Henkel), a reagent (see for example WO 2009/115671 - Catalysis).

In other applications, the contents of the microcapsule cannot escape but its color change under the effect of a variation in temperature (thermochromy) or UV irradiation (photochromy) is visible from the outside ( see for example WO 2013/114 025 – Gem Innov, or WO 2007/070118 – Kimberly-Clark, or EP 1 084 860 – The Pilot Ink Co.).

There are several techniques for preparing microcapsules. The main ones are atomization (in English: "spray-drying"), interfacial polymerization, solvent evaporation, self-assembly of polymers by the Layer by Layer (LbL) technique and the preparation of colloidosomes. All these techniques make it possible to obtain stable microcapsules with an average diameter of 10 μm. Interfacial polymerization is nevertheless the predominant technique because it allows the rapid preparation and in a single step of microcapsules whose wall is strong enough for them to be isolated and thus be used in many applications.

The formation of microcapsules by interfacial polymerization is usually done in 4 steps: (i) Preparation of a first phase containing the active principle (for example an essential oil) and an organosoluble monomer; (ii) Formation of an emulsion by dispersion of the first phase in an aqueous medium containing the surfactant, and which represents the second phase; (iii) Addition of the water-soluble monomer in the second phase; (iv) Formation and maturation of the membrane by reaction of monomers by polycondensation at the interface.

Several polymer families are conventionally used to manufacture the wall of microcapsules (Perignon, C. et al., Journal of Microencapsulation 2015, 32 (1), 1–15), such as polyamides (PA), polyurethanes (PU) or polyureas. The production of the walls of the microcapsules in PA generally uses monomers of the diamine type (hexamethylene diamine for example) and acyl chloride (sebacoyl chloride for example), while those in PU use monomers of the diamine type. -isocyanate (HDI, IPDI etc.) and diols. In the case of polyureas, monomers of the di-isocyanate and diamine type or di-isocyanates alone are used, the hydrolysis of which at the interface produces the amines allowing the synthesis of the urea function.

By way of example, the aforementioned document WO 2009/115671 describes the formation of microcapsule walls by interfacial polycondensation, from different mixtures of monomers: hexamethylene diisocyanate (HMDI) and ethylene diamine; tetraethylortosilicate (TEO) and 3-(trimethoxysilyl)propylmethacrylate (MPTS); 2,4-tolylenediisocyanate (TDI) and 1,3 phenylenediamine; 2,4-toluene diisocyanate and 1,3-phenylene diamine.

There are already some works reporting the preparation of microcapsules by interfacial polymerization using other types of polymers. We can cite, for example, the work of J. Bernard on the preparation of glyconanocapsules by azide-alkyne cycloaddition catalyzed by copper (R. Roux et al., J. ACS Macro Lett. 2012, 1 (8), 1074 –1078), or the work of K. Landfester (Siebert et al. Chem. Commun. 2012, 48, 5470-5472). L.Shi et al. (J. Appl. Polym. Sci. 2016, 133 (36), 168–7) as well as D. Patton et al. (ACS Appl. Mater. Interfaces 2017, 9 (4), 3288–3293) who were also able to prepare microcapsules by thiol-ene chemistry primed with a base and a photoinitiator respectively.

A fairly broad spectrum of polymeric materials is therefore available to those skilled in the art to select the type of microcapsule appropriate for a given use. Thus, microcapsules are already used in many technical applications, but their application potential has not yet been fully recognized, and it is a highly emerging sector set to grow significantly from the moment the microcapsule wall meets increasingly stringent criteria in terms of toxicity and recyclability.

However, microcapsules represent microparticles of polymeric materials. In recent years, microparticles of polymeric materials have been identified as an area of ecological concern, because of their wide dissemination in ecosystems, in soils, in aquatic and maritime ecosystems, to places far from their place of origin. introduction into the ecosystem. This wide spread not only generally harms the organisms present in these ecosystems, but could also have adverse consequences for human health. We are already seeing the announcement of increasingly stringent regulations which restrict the use of plastic materials liable to form microparticles during their degradation in a situation in a natural environment, and a fortiori plastic materials used from the outset in the form of microparticles .

For ecological reasons, it may seem contradictory to seek to develop a new product consisting of polymeric microparticles. It therefore appeared desirable to have microcapsules made of degradable polymeric material. It should be noted that the microcapsules, used in numerous special applications and capable of being incorporated into numerous products in common use (such as textiles, cosmetic or phytosanitary products) or for technical use (such as paints, varnishes, inks), will not normally be collected at the end of their life, and cannot therefore be subject to biodegradation by composting, as can be envisaged for collected plastic products. Thus, the degradability of the plastic materials that constitute the wall of the microcapsules cannot be based on the chemical mechanisms that take place during composting. In this context, the question of whether the degradability of the microcapsules involves a biological mechanism is relatively unimportant; what matters is their degradability in an ecosystem, regardless of the chemical mechanism of this degradation. For example, a fermentation would be a biodegradation, while a simple degradation in an ecosystem under the effect of light could be a photochemical reaction independent of the ecosystem; in reality the situation will often be mixed, especially if degradation proceeds in stages. In the following, we use the expression "(bio)degradable" to designate the characteristic of a material to degrade in a natural environment on a fairly short scale (of the order of weeks or a year), in depending on the characteristics of this natural environment and the exposure of the material to the various agents present in this natural environment.

It can be seen that all the microcapsules developed previously lead to the preparation of polymer chains (polyamide, polyurea, polyurethane, etc.) which will be either physically entangled in the case of a reaction between bifunctional compounds, or cross-linked in the case of one or more multifunctional compounds (functionality ≥ 3). In all cases, the walls are not (bio)degradable due to the nature of the polymer chain.

The problem that the present invention seeks to solve is to present a new type of microcapsule, easy to synthesize, without using toxic and/or expensive raw materials, which is (bio)degradable in the natural environment, which can be used with a large number of active ingredients, and which provides good external protection to the active ingredient that it is intended to contain.

Object of the invention

During their research work, the inventors found that one possibility for obtaining degradable microcapsules would be to prepare walls of polyester, which is a polymer known for its (bio)degradability. The literature shows that studies have already been conducted on this topic, and it has been shown that the reaction rate between acid chlorides and diols was very slow. This system is thus poorly suited to interfacial polymerization (see EM Hodnett and DA Holmer, J Polym Sci , 1962, 58, 1415–21). Special conditions such as the use of bisphenol A as diol and/or a very high pH reaction made it possible to obtain microcapsules (see W. Eareckson, J Polym Sci , 1959, 399–406; see also PW Morgan and SL Kwolek, J Polym Sci, 1959, 299–327) but these conditions are too restrictive for many internal phases and/or applications. In addition, the slowness of the polymerization reactions harms their industrial use in economic terms and short or even continuous production cycles.

Thus, the inventors did not pursue this path.

According to the invention, the problem is solved by using poly(beta-amino)ester (abbreviated here PBAE) microcapsules. According to the invention, these microcapsules are synthesized in a single reaction step by an addition reaction of the amine functions on the acrylate functions (reaction known as the “Michael addition”), by interfacial polymerization. This reaction leads to the micro-encapsulation of the organic phase without the formation of by-products (see the reaction scheme in Figure 6). The presence of ester functions in the backbone of the PBAE gives the polymer good degradation properties by hydrolysis.

Poly(beta-amino ester)s are known as such and have been widely used in recent years (Lynn, DM; Langer, R. J. Am. Chem. Soc . 2000, 122 (44), 10761–10768 .; Liu, Y.; Li, Y.; Keskin, D.; Shi, L. Adv. Healthcare Mater . 2018, 2 (2), 1801359–24) thanks to their biocompatibility and biodegradability properties, and they represent today Today is a family of materials which has numerous applications as biomaterials (for example as a vector of anticancer molecules, as an antimicrobial material, and for tissue engineering).

The fields of application of poly(beta-amino ester)s are very broad (see figure 9).

In general, it is known that aza-Michael addition type reactions can be carried out in a wide range of solvents ranging from halogenated apolar solvents (dichloromethane or chloroform for example) to polar solvents such as dimethylsulfoxide (DMSO) for example ( Liu, Y.; Li, Y.; Keskin, D.; Shi, L. Adv. Healthcare Mater . 2018, 2(2), 1801359–24). In practice, PBAEs are essentially prepared in solution and are then formulated to produce, for example, micelles, particles, gel/hydrogels, or films (so-called Layer by Layer technique). Oligo-PBAEs were also crosslinked in a second step either by photopolymerization (Brey, DM; Erickson, I.; Burdick, JA J. Biomed. Mater. Res. 2008, 85A (3), 731–741.7), or by presence of di-isocyanates.

It is also known that linear or cross-linked PBAEs are relatively stable in an acid medium but degrade more rapidly by hydrolysis of the ester functions at neutral and/or basic pH. This hydrolysis phenomenon leads to the release of small molecules such as bis(β-amino acid)s and diols when linear PBAEs are used; these molecules are known to be non-toxic with respect to mammalian cells, and of little influence on the metabolism of healthy cells.

According to an essential characteristic of the present invention, the microcapsules having a PBAE wall are synthesized by interfacial polymerization.

More specifically, according to the invention, the problem is solved by a process in which the Michael polycondensation reaction is used between amine functions and acrylate functions to obtain Poly(Beta-Amino Esters) (PBAE) by interfacial polymerization. The inventors have found that this process, applicable to various active ingredients to be encapsulated, makes it possible to prepare stable microcapsules which can be isolated by drying and which have the property of being (bio)degradable.

The microencapsulation process according to the invention comprises the following steps:

1. Dispersion of one or more compounds having at least two acrylate functions in an organic solution constituting the phase to be encapsulated (and comprising, where appropriate, the active principle);
2. Addition of an excess relative to the previous volume of an aqueous phase comprising one or more surfactants, followed by emulsification;
3. Addition to the emulsion obtained in step (b) of one or more compounds comprising at least one primary amine function and/or two secondary amine functions and polymerization reaction at a temperature between approximately 20° C. and 100° C. VS ;
4. Collection, washing and drying of the microcapsules.

Thus, a first object of the invention is a process for manufacturing microcapsules containing a so-called active substance, process in which:

• an aqueous solution of a surfactant, an oily phase comprising said active substance and at least one first monomer X, and a polar phase comprising at least one second monomer Y are supplied;
• an emulsion of O/W type is prepared by adding said oily phase to said aqueous solution of the surfactant;
• said polar phase is added to said O/W emulsion, to enable a polymer to be obtained by polymerization of said monomers X and Y;
• said microcapsules comprising a wall formed by said polymer and containing said active substance are isolated from this reaction mixture;

said process being characterized in that said polymer is a poly(beta-amino ester).

Said first monomer X is selected from (multi)acrylates, in particular (multi)acrylates of formula X'-(-O(C=O)-CH=CH ₂ ) _n with n ≥ 2 and where X' represents a molecule on which is grafted n acrylate units.

Said first monomer X is preferably selected from (multi)acrylates of formula X'-(-O(C=O)-CH=CH ₂ ) _n with n ≥ 4 and where X' represents a molecule on which is grafted n acrylate units. More specifically, it is advantageously selected from the group formed by:

• diacrylates, and preferably those described in the article by Nayak et al. (Polymer-Plastics Technology and Engineering, 2018, 57, 7, 625-656);
• triacrylates, in particular C ₁₅ O ₆ H ₂₀ (CAS No. 15625-89-5, ie trimethylolpropane triacrylate), tetraacrylates, pentaacrylates, hexaacrylates, mixtures between these different O[CH ₂ C type acrylates (CH ₂ OR) ₃ ] ₂ where R is H or COCH=CH ₂ ;
• the (multi)acrylates described in the article by Nayak et al. (Polymer-Plastics Technology and Engineering, 2018, 57, 7, 625-656);
• polymers bearing pendant acrylate functions;
• functional oligo PBAEs, prepared for example by reacting diacrylate compounds with a functional primary amine and/or a functional secondary diamine;
• the mixture of different compounds described above.

Said second monomer Y is selected from amines. More specifically, it is advantageously selected from the group formed by:

• primary amines R—NH ₂ ;
• primary diamines of the NH ₂ (CH ₂ ) _n NH ₂ type where n is an integer which can typically be between 1 and 20, and which is preferably 2 or 6;
• primary (multi)amines such as tris(2-aminoethyl)amine;
• secondary diamines such as piperazine;
• polymers having primary and/or secondary amines such as polyethylene imine.

In one embodiment, said polymerization of said monomers takes place with stirring at a temperature of between 20°C and 100°C, and preferably between 30°C and 90°C.

Another object of the invention is a microcapsule containing a so-called active substance, characterized in that its wall is formed of poly(beta-amino ester).

Yet another object of the invention is a microcapsule obtainable by the process according to the invention.

tricks

Figures 1 to 14 illustrate certain aspects of the invention, but do not limit their scope. Figures 2 to 5 relate to Example 1. Figure 7 relates to Example 2, Figure 8 to Example 3, Figure 8 to Example 3, Figure 10 to Example 6 , Figure 11 to Example 7, Figure 12 to Example 10, Figure 13 to Example 11, and Figure 14 to Example 13. Figures 2 to 5 and 10 to 14 are micrographs optics; the horizontal bar at the bottom left of the image represents a length of 50 µm.

shows the general scheme of the process according to the invention. The four-digit numerals designate steps in this process.

shows an optical micrograph of microcapsules obtained according to example 1, after 5 hours of reaction.

shows an FTIR spectrum of the wall of the microcapsules isolated in the slurries after 6 hours of reaction.

shows an optical micrograph of microcapsules obtained according to Example 1, after drying on a glass slide.

shows two optical micrographs of microcapsules obtained according to example 1, after drying on a glass slide. The micrograph on the left was obtained in grazing light, the micrograph on the right under fluorescent light after adding a few drops of a fluorescent dye.

illustrates the reaction scheme of the reaction according to the invention.

shows that the thermochromic microcapsules are stable after being placed in the oven for 30 min and that their thermochromic function is preserved.

illustrates the degradability of the walls of the microcapsule by an accelerated degradation test.

illustrates the different fields of application of poly(beta-amino ester)s.

shows that the microcapsules are stable after 24 h, and their mean diameter is between 10 μm and 30 μm.

shows an image similar to Figure 10, and leads to the same conclusion, for another example.

mount the result of the use of the microcapsules according to the invention in carbonless paper.

shows a photograph of microcapsules according to yet another example of the invention.

shows a photograph of microcapsules according to yet another example of the invention.

detailed description

In the following detailed description of embodiments of this specification, numerous specific details are set forth in order to provide a more thorough understanding of the present invention, and to enable those skilled in the art to carry out the invention. . However, it will be apparent to those skilled in the art that the present description can be implemented without these specific details. In other cases, well-known characteristics have not been described in detail to avoid unnecessarily overloading the description.

Figure 1 shows a general diagram of the process according to the invention. The aqueous solution of the surfactant ( 1000 ) is prepared. An organic solution is also prepared comprising the phase to be encapsulated (which comprises the so-called active substance) and the monomer X ( 1002 ). In step 1010 , this organic solution 1002 is added to said aqueous solution 1000 and, in step 1020 , an emulsion 1022 of the O/W type (oil in water, in English Oil in Water, according to a known designation of the skilled in the art). In step 1030, an aqueous solution of monomer Y 1024 is added to said emulsion 1022 . In step 1040 the polymerization reaction leads to a reaction mixture 1042 from which then forms in step 1050 a heterogeneous mixture 1052 called slurry which comprises, in aqueous-based suspension, the microcapsules containing the phase to be encapsulated.

Step 1050 typically involves a temperature of reaction mixture 1042 above about 20°C, typically between 20°C and 100°C. A temperature between about 30°C and about 90°C is preferred, and even more preferably between about 40°C and about 80°C.

This process can be applied to different monomers X and Y. According to the invention the monomer X is a (multi)acrylate, and the monomer Y is an amine, preferably a primary amine and/or a (multi)primary amine and /or a secondary diamine and/or a compound having primary and secondary amines.

By (multi)acrylate is meant any compound of formula X'-(-O(C=O)-CH=CH ₂ ) _n with n≥2 and where X' represents a molecule on which n acrylate units are grafted.

By primary (multi)amine is meant any compound comprising at least two primary amine functions.

As acrylate, it is possible to use, for example, triacrylates (such as C ₁₅ O ₆ H ₂₀ , CAS No. 15625-89-5); tetraacrylates; pentaacrylates; hexaacrylates; the mixtures between these various acrylates mentioned. Molecules of the O[CH ₂ C(CH ₂ OR) ₃ ] ₂ type can be used, for example, where R can be H or COCH=CH ₂ .

As an amine, molecules of the NH ₂ (CH ₂ ) _n NH ₂ type can be used, for example, where n is an integer which can typically be between 1 and 20, and which can be for example 2 (ethylene diamine ) or 6 (hexamethylene diamine, CAS number: 124-09-4). One can also use piperazine, tris(2-aminoethyl)amine (TREN) or polyethylene imine (PEI).

The nature and concentration of amines and acrylates can be varied.

The ratio of the reactive functions of the monomers Y (-NH) and X (acrylate) is advantageously greater than 1, and typically between 1 and 5, preferably between 1.2 and 3.8.

According to a particular embodiment of the invention, the monomers X (acrylate) and/or Y (amine) are biosourced.

Figure 6 shows the reaction scheme of the aza-Michael addition reaction between a secondary amine and an acrylate (reaction (a)) and the polyaddition reaction between a multifunctional acrylate compound and a multi-amine compound leading to a polymer cross-linked (reaction (b)).

The organic core of the microcapsules may consist of an organic phase comprising an active substance. During the formation of the microcapsule, this organic phase will be enclosed by the polymeric wall of the microcapsule, which protects it from the environment. Said organic phase may consist of said active substance, or said active substance may form part of said organic phase, in which it may in particular be dissolved. The expression “active substance” here refers to the specific purpose for which the microcapsules are intended to be used; as a general rule, given the specificity of the microcapsule product, this purpose is always known during their manufacture.

The active substance can be selected in particular from oils (pure or possibly containing other molecules in solution or in dispersion), such as essential oils, natural and edible oils, vegetable and edible oils, liquid alkanes, esters and fatty acids, or also from dyes, inks, paints, thermochromic and/or photochromic substances, fragrances, products with a biocidal effect, products with a fungicide effect, products with an antiviral effect, products with a phytosanitary effect , active pharmaceutical ingredients, products with cosmetic effects, glues; these active principles possibly being in the presence of an organic vector.

Can be used for example and in a non-limiting way extracts of distillation of natural products such as essential oils of eucalyptus, lemongrass, lavender, mint, cinnamon, camphor, anise, lemon, orange, which may have been obtained by extraction from plant material, or by synthesis.

One can also use other substances such as long chain alkanes (for example tetradecane), which can contain lipophilic molecules in solution.

In general, and depending on the function sought for the microcapsules, it is possible to use any hydrophobic compound, which will thus be naturally dispersed in the form of an emulsion of hydrophobic drops suspended in an aqueous phase.

Many additives can be incorporated into the microcapsule allowing better protection of the organic phase to be encapsulated, against infrared radiation, ultraviolet radiation, the involuntary penetration of a specific gas or oxidation.

As surfactant, it is possible in particular to use those which are cited in Encyclopedia of Chemical Technology, volume 8, pages 912 to 915, and which have a hydrophilic-lipophilic balance (according to the HLB system) equal to or greater than 10.

Other macromolecular surfactants can also be used. Mention may be made, for example, of polyacrylates, methylcelluloses, carboxymethylcelluloses, polyvinyl alcohol (PVA) optionally partially esterified or etherified, polyacrylamide or synthetic polymers possessing anhydride or carboxylic acid functions such as ethylene/maleic anhydride copolymers. Preferably, polyvinyl alcohol can be used as surfactant.

It may be necessary, for example in the case of aqueous solutions of a cellulosic compound, to add a little alkaline hydroxide such as sodium hydroxide, in order to facilitate its dissolution; it is also possible to use such cellulosic compounds directly in the form of their sodium salts, for example. Amphiphilic copolymers of the Pluronics type can also be used. Generally, aqueous solutions containing from 0.1 to 5% by weight of surfactant are used.

The size of the droplets is a function of the nature and the concentration of the surfactant and of the speed of agitation, the latter being chosen all the greater as smaller average diameters of the droplets are desired.

In general, the stirring speed during the preparation of the emulsion is 5,000 to 10,000 revolutions per minute. The emulsion is usually prepared at a temperature between 15°C and 95°C.

Generally when the emulsion has been obtained, the agitation by turbine is stopped and the emulsion is agitated using a slower agitator of the usual type, for example of the frame agitator type, typically at a speed of order of 1500 to 1500 revolutions per minute.

The method according to the invention thus leads to homogeneous and fluid suspensions containing, depending on the fillers introduced, generally from 20% to 80% by weight of microcapsules having an average diameter of 100 nm to 100 μm. The diameter of the microcapsules can preferably be between 1 μm and 50 μm, and even more preferably between 10 μm and 40 μm.

The microcapsules according to the invention are (bio)degradable. The biodegradation can be determined for example by one of the methods described in the document “OECD Guidelines for the Testing of Chemicals: Ready Biodegradability” (adopted by the Council of the OECD on July 17, 1992). In particular, the manometric respirometry test (method 301 F) can be used. Preferably, this test is carried out on emptied and washed microcapsules, so that the biodegradation of the content of the microcapsules does not interfere with the test, the purpose of which is to characterize the biodegradation of the material forming the wall of the microcapsules. Preferably, the microcapsule according to the invention shows a biodegradation of at least 80%, and preferably of at least 85%, measured after incubation for 10 days using said 301 F method. With this same method , after an incubation of 28 days, the microcapsules according to the invention preferably show a biodegradation of at least 90%, preferably of at least 95%, and even more preferably of at least 98%.

Examples

To enable those skilled in the art to reproduce the invention, examples of implementation are given here; they do not limit the scope of the invention.

Example 1 : Preparation of perfumed microcapsules based on a diamine (HMDA)

1. Preparation of the emulsion

11.0 g of essential oil (Eucalyptus) was placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (0.39 g, 0.71 mmol) was dispersed in the essential oil under magnetic stirring (350 rpm). Stirring was maintained until the solution became homogeneous; a heating step has been added if necessary. The essential oil/organic monomer combination was added gradually to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by mass); the mixture was homogenized using an Ultraturrax™ IKA T10 at 9500 rpm for 3 min at room temperature to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, preheated to 50°C, the previously prepared emulsion was introduced and stirred at a speed of 250 rpm. When the emulsion reached 50°C, the solution of diamine (Hexamethylene diamine HMDA) (0.17 g, 1.46 mmol) in 5 g of 2 wt% PVA solution was added dropwise using of a syringe and with stirring (250 rpm). During the reaction, samples at different reaction times were taken and analyzed by optical microscopy and Fourier transform infrared spectroscopy (FTIR) in order to monitor the formation of the microcapsules.

The total amount of monomers used was ~0.56 g. The amine was used in excess relative to the acrylate monomer so as to have a ratio of –NH/acrylate functions = 1.6. The essential oil/water mass ratio is equal to 0.24.

The analysis of the microcapsules can be done by microscopy after a drying step. This analysis makes it possible to ensure the stability of the microcapsules once isolated. A second analysis consists of adding a few drops of a fluorescent dye (Nile Red) to the dried microcapsules. Nile Red, a lipophilic chromophore which fluoresces only in an organic phase, makes it possible to verify that the core of the microcapsule still contains organic phase and that the microcapsules are filled.

Figure 2 shows an optical microscopy image of the reaction medium after 5 h of reaction. The microcapsules are spherical, with a diameter between about 10 µm and about 25 µm. FIG. 3 shows the FTIR spectrum of the microcapsules isolated from a slurry after 6 h of reaction (after washing with acetone, followed by three cycles of centrifugation and drying in an oven). There are characteristic vibrations of NH bonds around 3300 cm ^-1 to 3400 cm ^-1 , as well as a narrow band characteristic of a C=O bond around 1727 cm ^-1 .

Figure 4 shows an optical micrograph of microcapsules dried on a glass slide. Their diameter is about 30 µm to 35 µm. Figure 5 shows a micrograph of microcapsules dried on a glass slide in raking light (left) and in fluorescent light (right) after adding a few drops of the fluorescent dye Nile Red. Intense emission under fluorescent light shows that the core of the microcapsule contains an organic phase.

Example 2 : Preparation of perfumed microcapsules based on a diamine (HMDA)

1. Preparation of the emulsion

11.0 g of a thermo-chromic solution (blue 10°) were introduced into a beaker, placed in an oil bath and heated to 130° C with magnetic stirring (350 rpm). Stirring was maintained until the thermo-chromic solution became homogeneous and transparent. The thermo-chromic solution was cooled, and when its temperature reached 50°C, the (multi)acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (0.39 g, 0.71 mmol) was dispersed under magnetic stirring (350rpm). Stirring is maintained until the solution becomes homogeneous. The thermochromic/organic monomer combination was gradually added to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by mass); the mixture was homogenized using an Ultraturrax™ IKA T10 at 9500 rpm for 3 min at room temperature to form an emulsion

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, preheated to 50°C, the previously prepared emulsion was introduced and stirred at a speed of 250 rpm. When the emulsion reached 50°C, the solution of diamine (Hexamethylene diamine HMDA) (0.17 g, 1.46 mmol) in 5 g of 2 wt% PVA solution was added dropwise using of a syringe and with stirring (250 rpm). During the reaction, samples at different reaction times were taken and analyzed by optical microscopy.

The total amount of monomers used was ~0.56 g. The amine was used in excess relative to the acrylate monomer so as to have a ratio of –NH/acrylate functions= 1.6. The thermochromic solution/water mass ratio is 0.24.

The dried microcapsules show a reversible color change with a reversible color change at a temperature of 10°C. These same capsules can, moreover, be heated in an oven at 130° C. for 30 min without modifying their thermochromic properties ( FIG. 7 ).

Example 3 : Degradability test of a poly(beta-amino ester)

A first degradability test was carried out according to the following procedure:

1. Synthesis of poly(beta-amino ester)

In a beaker, Hexamethylene diamine HMDA monomer (1.0 g, 8.6 mmol) was dissolved in THF (4.0 g) and added to a solution of (multi)acrylate monomer (trimethylolpropane triacrylate) (1.8 g, 6.1 mmol) dissolved in 2.5 g of THF. The mixture was placed in a pillbox then placed in an oil bath at 50°C.

The amine was used in excess relative to the acrylate monomer in such a way as to have a function ratio –NH/acrylate= 2.

The polymer recovered after 5 hours of reaction was washed three times with acetone and dried in an oven.

1. Degradation of poly(beta-amino ester)

The degradation of the poly(beta-aminoester) was carried out according to the following protocol:

20 mg of the polymer dissolved in 1 mL of a solution of sodium hydroxide (3M, in deuterated water D ₂ O, pH~14) is introduced into a flask fitted with a magnetic stirrer. Since the polymer is crosslinked, it is not soluble in the aqueous phase.

Figure 8 shows that the poly(beta-amino ester) dissolved in the aqueous phase, characterizing efficient degradation of the polymer under these accelerated degradation conditions.

Example 4 : Preparation of perfumed microcapsules based on a triamine (TREN)

1. Preparation of the emulsion

11.0 g of essential oil (Eucalyptus) was placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (0.39 g, 0.74 mmol) was dispersed in the essential oil under agitation. The essential oil/organic monomer combination was added gradually to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by mass); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, the previously prepared emulsion was introduced. An aqueous solution of tris(2-aminoethyl)amine TREN (0.145 g, 0.99 mmol) in 5 g of 2 wt% PVA solution was added with stirring at a temperature between 50°C and 60°C.

Example 5 : Preparation of thermochromic microcapsules based on a triamine (TREN)

1. Preparation of the emulsion

11.0 g of a thermochromic solution were introduced into a beaker and stirred hot, the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (0.39 g, 0.74 mmol) was dispersed therein under hustle. The thermochromic/organic monomer combination was gradually added to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by mass); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, the previously prepared emulsion was introduced at a temperature of approximately 50°C to 60°C. An aqueous solution of tris(2-aminoethyl)amine TREN (0.145 g, 0.99 mmol) in 5 g of 2 wt% PVA solution was added with stirring at a temperature between 50°C and 80°C.

Example 6 : Preparation of microcapsules based on a biosynthetic monomer

1. Preparation of the emulsion

11.0 g of essential oil (Eucalyptus) was placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (0.39 g, 0.74 mmol) was dispersed in the essential oil under agitation. The essential oil/organic monomer combination was gradually added to the aqueous solution of the surfactant prepared beforehand (40 g PVA 2% by weight); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with a mechanical stirring system with IKA blades, the emulsion prepared previously was introduced, the aqueous solution of diamine (Butane-1,4-diamine (Putrescine) (0.13 g , 1.47 mmol) in 5 g of 2 wt% PVA solution was added with stirring at a temperature between 50°C and 60°C.

Figure 10 shows an optical microscopy image of the capsules after 24 h of reaction. The microcapsules are spherical, with an average diameter between about 10 µm and about 30 µm.

Example 7 : Preparation of microcapsules based on polyethylene imine (PEI)

1. Preparation of the emulsion

11.0 g of essential oil (Eucalyptus) was placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (0.39 g, 0.74 mmol) was dispersed in the essential oil under agitation. The essential oil/organic monomer combination was added gradually to the aqueous solution of the surfactant prepared beforehand (40 g PVA 2% by mass); the mixture was homogenized using an IKA Ultraturrax™ to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, the previously prepared emulsion was introduced. A solution of polyethylene imine (PEI) (1.78 g, 1.48 mmol) in 5 g of 2 wt% PVA solution was added with stirring at a temperature between 50°C and 60°C.

Figure 11 shows optical microscopy images of the capsules after 24 h of reaction. The microcapsules are spherical, with an average diameter between about 10 µm and about 30 µm

Example 8 : Preparation of scented microcapsules (shell/PI ratio=3.4%)

1. Preparation of the emulsion

193.6 g of essential oil (Eucalyptus) was placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (4.5 g, 8.5 mmol) was dispersed in the essential oil under agitation. The essential oil/organic monomer combination was gradually added to the aqueous solution of the surfactant prepared beforehand (255.9 g PVA 2% by mass); the mixture was homogenized using a Homomixer to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, the previously prepared emulsion was introduced. A solution of diamine (Hexamethylene diamine HMDA) (2.01 g, 17.2 mmol) in 44.1 g of a 2 wt% PVA solution was added with stirring at a temperature between 50°C and 60°C . It was left to react for 2 h at 50°C and for 5 h at 60°C.

Example 9 : Preparation of scented microcapsules

1. Preparation of the emulsion

11.0 g of a mixture of 80% Papaya Pineapple perfume (reference RS42370 from Technicoflor in Allauch (France)) and 20% methyl myristate were placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta- /hexa-acrylate) (0.39 g, 0.74 mmol) was dispersed into the fragrance with stirring. The fragrance/organic monomer combination was added gradually to the aqueous solution of the surfactant prepared beforehand (40 g PVA 2% by mass); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, the previously prepared emulsion was introduced. A solution of diamine (Hexamethylene diamine HMDA) (0.17 g, 1.49 mmol) in 5 g of a 2 wt% PVA solution was added with stirring at a temperature between 50°C and 60°C. It was left to react for 2 h at 50°C and for 5 h at 60°C.

Example 10 : Preparation of microcapsules for carbonless copies (shell/PI ratio=3.4%)

1. Preparation of the emulsion

193.6 g of an internal phase (Dye) was placed in a beaker, and the multi acrylate monomer (Dipentaerythritol penta-/hexa-acrylate mixture) (4.5 g, 8.5 mmol) was dispersed in the internal phase with stirring. The whole was added gradually to the aqueous solution of the surfactant prepared beforehand (255.9 g, PVA 2% by weight); the mixture was homogenized using a Homomixer to form an emulsion.

1. Microencapsulation

In a double-walled reactor, equipped with an IKA mechanical blade stirring system, the previously prepared emulsion was introduced. An aqueous solution of diamine (Hexamethylene diamine HMDA) was added, with stirring at a temperature between 50°C and 60°C.

1. Use of microcapsules in carbonless paper

These microcapsules were applied to a sheet of paper, according to known methods, and used in a self-copying system. Figure 12 shows the result, which is quite satisfactory.

Example 11 : Preparation of thermochromic microcapsules based on the POSS@octa(acrylate) monomer

1. Preparation of the emulsion

20.0 g of thermochromic, and eight-function ported polyoctahedral silsesquioxanes acrylate (POSS@octa(acrylate), CAS # 1620202-27-8, purchased from Hydridplastics, 1.48 g, 1.12 mmol) and the thermal inhibitor Butylated HydroxyToluene (BHT, 5.0 mg), were placed in a beaker. The mixture was solubilized hot with magnetic stirring. Stirring was continued until the solution became homogeneous. The thermochromic / POSS@octa(acrylate) assembly was gradually added to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by weight); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a reactor, the previously prepared emulsion was introduced. The solution of Hexamethylene diamine (HMDA, 0.35 g, 3.01 mmol) in water was added drop by drop using a syringe and with stirring. The reaction was carried out at 50°C for 1 hour and at 80°C for 23 hours.

Figure 13 shows a ce photograph of the microcapsules.

Example 12 : Preparation of thermochromic microcapsules based on the POSS@octa(acrylate) monomer with meta-xylylenediamine

1. Preparation of the emulsion

10.0 g of thermochromic, and polyoctahedral silsesquioxanes carried eight acrylate function (POSS@octa(acrylate), CAS # 1620202-27-8, purchased from Hydridplastics, 1.50 g, 1.12 mmol) and the thermal inhibitor Butylated HydroxyToluene (BHT, 5.0 mg), were placed in a beaker. The mixture was solubilized hot with magnetic stirring. Stirring was continued until the solution became homogeneous. The thermochromic / POSS@octa(acrylate) assembly was gradually added to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by weight); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a reactor, the previously prepared emulsion was introduced. The solution of meta-xylylenediamine (n^ohCAS 1477-55-0, 0.60g, 3.01mmol) in 3 mL of water was added dropwise using a syringe and with stirring. The reaction was carried out at 65°C for 1 hour and at 80°C for 17 hours.

Example 13 : Preparation of thermochromic microcapsules based on the POSS@octa(acrylate) monomer with POSS@octammonium and hexamethylene diamine (HDMA)

1. Preparation of the emulsion

10.0 g of thermochromic, and polyoctahedral silsesquioxanes carried from eight acrylate functions (POSS@octa(acrylate), n^ohCAS 1620202-27-8, purchased from Hydridplastics, 1.40 g, 1.06 mmol) and the thermal inhibitor Butylated HydroxyToluene (BHT, 5.0 mg), were placed in a beaker. The mixture was solubilized hot with magnetic stirring. Stirring was continued until the solution became homogeneous. The thermochromic / POSS@octa(acrylate) assembly was gradually added to the aqueous solution of the surfactant prepared beforehand (40 g, PVA 2% by mass); the mixture was homogenized using an Ultraturrax™ IKA T10 to form an emulsion.

1. Microencapsulation

In a reactor, the previously prepared emulsion was introduced. Afterwards, the solution of Hexamethylene diamine (HMDA, 0.70 g, 6.02 mmol), POSS@(octa)ammonium (n^ohCAS 150380-11-3, purchased from Hydridplastics, 0.30 g, 0.26 mmol), and potassium carbonate (0.16 g, 1.16 mmol) in the water was added drop by drop using a syringe, with stirring. The reaction was carried out at 65°C for 1 hour and at 80°C for 17 hours.

Figure 14 shows a ce photograph of the microcapsules.

Example 14 : Biodegradation test

A batch of microcapsules prepared according to Example 8 was supplied. The microcapsules were opened, emptied and washed. They were then subjected to the biodegradability test described in the OECD 301 document ( “OECD Guideline for the Testing of Chemical Products: Easy Biodegradability” ) using the 301 F method (manometric respirometry test). After an incubation period of ten days the percentage of biodegradation was 82%.

Claims (12)

Process for manufacturing microcapsules containing a so-called active substance, process in which:

• an aqueous solution of a surfactant, an oily phase comprising said active substance and at least one first monomer X, and a polar phase comprising at least one second monomer Y are supplied;
• an emulsion of O/W type is prepared by adding said oily phase to said aqueous solution of the surfactant;
• said polar phase is added to said O/W emulsion, to enable a polymer to be obtained by polymerization of said monomers X and Y;
• said microcapsules comprising a wall formed by said polymer and containing said active substance are isolated from this reaction mixture;

said process being characterized in that said polymer is a poly(beta-amino ester). Process according to Claim 1, characterized in that the said first monomer X is selected from the (multi)acrylates, and preferably the (multi)acrylates of formula X'-(-O(C=O)-CH=CH ₂ ) _n with n≥4 and where X' represents a molecule on which n acrylate units are grafted. Process according to Claim 2, characterized in that the first monomer X is selected from the group formed by:

• diacrylates;
• triacrylates, in particular trimethylolpropane triacrylate, tetraacrylates, pentaacrylates, hexaacrylates, mixtures of these different acrylates of the O[CH ₂ C(CH ₂ OR) ₃ ] ₂ type where R is H or COCH=CH ₂ ;
• polymers bearing pendant acrylate functions;
• functional oligo PBAEs, prepared for example by reacting diacrylate compounds with a functional primary amine and/or a functional secondary diamine;
• the mixture of different compounds described above.

Process according to any one of Claims 1 to 3, characterized in that the said second monomer Y is selected from amines. Process according to Claim 4, characterized in that the second monomer Y is selected from the group formed by:

• primary amines R—NH ₂ ;
• primary diamines of the NH ₂ (CH ₂ ) _n NH ₂ type where n is an integer which can typically be between 1 and 20, and which is preferably 2 or 6;
• primary (multi)amines such as tris(2-aminoethyl)amine;
• secondary diamines such as piperazine;
• polymers having primary and/or secondary amines such as polyethylene imine.

Process according to any one of Claims 1 to 5, characterized in that the said polymerization of the said monomers is carried out with stirring at a temperature of between 20°C and 100°C, and preferably between 30°C and 90°C. Process according to any one of Claims 1 to 6, characterized in that the said surfactant is selected from the group formed by macromolecular surfactants, preferably in that the said surfactant is selected from the group formed by polyacrylates, methylcelluloses, carboxymethylcelluloses, polyvinyl alcohol optionally partially esterified or etherified, polyacrylamide, synthetic polymers having anhydride or carboxylic acid functions, ethylene/maleic anhydride copolymers and in that said surfactant is even more preferably polyvinyl alcohol. Process according to any one of Claims 1 to 7, characterized in that the said active substance is selected from the group formed by:

• essential oils, fragrances,
• inks, paints, thermochromic and/or photochromic substances, dyes, glues,
• products with a biocidal effect, products with a fungicidal effect, products with an antiviral effect, products with a phytosanitary effect, products with a cosmetic effect, active pharmaceutical ingredients,
• natural and edible oils, vegetable and edible oils, liquid alkanes, esters and fatty acids.

Microcapsule containing a so-called active substance, characterized in that its wall is formed of poly(beta-amino ester). Microcapsule according to Claim 9, characterized in that it has an average diameter of between 100 nm and 100 µm, preferably between 1 µm and 50 µm, and even more preferably between 10 µm and 40 µm. Microcapsule according to Claim 9 or 10, characterized in that it shows a biodegradation of at least 80%, and preferably of at least 85%, measured by a manometric respirometry test according to method 301 F of the "Guidelines OECD for the Testing of Chemicals: Ready Biodegradability” after a ten-day incubation. Microcapsule according to any one of Claims 9 to 11, characterized in that it shows a biodegradation of at least 90%, preferably of at least 95%, and even more preferably of at least 98%, measured by a manometric respirometry test according to method 301 F of the "OECD Guidelines for the Testing of Chemical Products: Easy Biodegradability" after incubation for 28 days.