WO2016005689A1

WO2016005689A1 - Use of an aminated homopolymer for encapsulating ingredients, method of synthesizing an aema homopolymer and method of encapsulating ingredients

Info

Publication number: WO2016005689A1
Application number: PCT/FR2015/051862
Authority: WO
Inventors: Frédérique PORTOLAN; Nicolas ESSELIN; Jean-François PILARD; David Rees; Osama M. Musa
Original assignee: Isp Investments Inc.
Priority date: 2014-07-10
Filing date: 2015-07-06
Publication date: 2016-01-14
Also published as: FR3023558B1; FR3023558A1

Abstract

The invention relates to the field of ingredient encapsulation. More particularly, the invention relates to the use of an aminated homopolymer for encapsulating active ingredients, in particular an aminoethyl methacrylate homopolymer (poly(AEMA)). The invention further relates to a method of synthesizing an aminoethyl methacrylate homopolymer, and the homopolymer produced by such a method. The invention also concerns a method of encapsulating ingredients using the aminoethyl methacrylate homopolymer as cationic polymer and the microcapsules produced by this encapsulation method.

Description

USE OF AN AMINE HOMOPOLYMER FOR THE ENCAPSULATION OF INGREDIENTS, METHOD FOR SYNTHESIZING A HOMOPOLYMER OF AEMA,

METHOD AND METHOD FOR ENCAPSULATION OF INGREDIENTS

Field of the invention

The present invention relates to the field of ingredient encapsulation. More particularly, the present invention relates to the use of an amine homopolymer for the encapsulation of active ingredients, in particular an aminoethyl methacrylate homopolymer (poly (AEMA)).

The invention also relates to a process for synthesizing an aminoethyl homopolymer methacrylate, and the homopolymer obtained by such a method.

The subject of the invention is also a process for the microencapsulation of ingredients using the aminoethyl methacrylate homopolymer, as cationic polymer, and the microcapsules produced by this encapsulation process.

Background of the invention

Encapsulation can be defined as the process of forming continuous layers of coating compounds, especially polymers or protein-polysaccharide complexes, around ingredients to be encapsulated, which can be, for example, solid particles, liquid droplets, gas or microbial cells. The fields of industrial applications of encapsulation are multiple. Examples include the pharmaceutical, cosmetics, food and beverage industries, the ink industry, but also biotechnology and, more recently, the textile industry. Encapsulation systems are as varied as their multiple applications: separating incompatible chemicals, improving the bioavailability of ingredients, masking unpleasant tastes or odors.

In the cosmetic field or in the pharmaceutical field, encapsulation or microencapsulation is used as much to obtain an aesthetic appearance in the formulations as to confine or protect the ingredients and / or control their release. Encapsulation can involve a wide variety of ingredients ranging from very simple to very complex molecules (flavors, drugs, DNA, whole viruses, etc.).

The field of the invention is more particularly microencapsulation which is a technique for coating microparticles of finely divided solids, droplets of liquids or gaseous compounds. The microparticles have a size of between approximately 1 μιη and 1 mm. The coating compounds may be polymers of natural or synthetic origin, or proteins or polysaccharides, or lipids. As part of the invention, the coating is more particularly carried out using a continuous layer of synthetic polymers.

The microencapsulation process must be adapted to the size and physicochemical properties of both the ingredients to be encapsulated and polymers forming the continuous coating layer.

There are different types of microencapsulation techniques, eg gelation, priling, nebulization, coacervation, emulsion-evaporation, emulsion-extraction, and their variants from dual water / oil / water emulsions .

The present invention more particularly relates to a complex coacervation microencapsulation process which involves the use of an anionic polymer and a cationic polymer. The ingredient to be encapsulated is in a discontinuous phase emulsified into fine droplets in a continuous phase.

The principle of complex coacervation is based on the liquid-liquid phase separation resulting from the formation of complex electrostatic interactions between the polymers. The aggregation of these initially soluble complexes, induced by the addition of a coacervation agent of the polymers, leads to the formation of liquid droplets called "coacervates" or "aggregates". Coacervates subjected to gravity flocculate and coalesce to achieve a macroscopic phase separation.

The coacervation agent of the polymers can be a salt or a solvent but it can also consist of the modification of the pH or the temperature. The coacervation agent may be added before, during or after the emulsification step.

The coacervates are gradually deposited on the surface of each droplet comprising the ingredient, until a continuous layer is formed.

Finally, the addition of a hardener or a crosslinking agent allows the crosslinking and thus the hardening of the continuous layer of coacervates of polymers around the droplet comprising the ingredient to be encapsulated.

The polymers are generally proteins of animal origin for the cationic polymer and polysaccharides for the anionic polymer. The parameters influencing the interactions between the polymers and therefore the formation of the coacervates are, on the one hand, physico-chemical parameters such as the pH, the ionic strength, the molar mass of the polymers, the charge density of the polymers, the ratio mass between the polymers and the total polymer concentration and, on the other hand, physical parameters involving a set of forces that can influence the structure and stability of the coacervates, such as temperature, pressure, speed and agitation time.

An essential step in coacervation is the initial formation of polymer coacervates via electrostatic interactions between the charged polymers. Generally, the establishment of electrostatic bonds results in a reduction of the electrostatic free energy of the system by reducing the mobility and flexibility of the polymers. Two types of coacervates can be obtained by electrostatic interactions. On the one hand, soluble coacervates when the number of charges between the interacting polymers do not fully balance, the overall load carried by the coacervate obtained then allowing it to remain soluble by interacting with the solvent molecules. On the other hand, insoluble or precipitated coacervates when the neutralization of the charges borne by the two polymers is total, the total charge of the complex obtained being zero. Other types of interactions occur in the formation of coacervates, including hydrogen bonds or hydrophobic interactions.

Hydrophobic bonds are generally established during changes in the conformation and structure of the polymers. These modifications allow the hydrophobic zones of the polymers to come into contact and interact. In some cases, the hydrophobic interactions may be the driving force for the coacervation of the polymers, even if the two polymers are oppositely charged, while in other cases, the intensity of the hydrophobic interactions may be such that it counterbalances the electrostatic interactions, limiting or suppressing the phenomenon of complex coacervation.

Microencapsulation by complex coacervation makes it possible to obtain microcapsules of various sizes between 5 and 1000 μιη at low cost, which makes it a method of choice widely used in industry, for example the food industry, the pharmaceutical industry, or even cosmetic.

In the prior art, the microcapsules are conventionally obtained according to the complex coacervation process and most often use as cationic polymer gelatin of porcine or marine origin, and as anionic polymer gum acacia, pectin, chitosan, or the agar.

Gelatin is a polymer derived from the hydrolysis of collagen, which is generally positively charged at a pH below its isoelectric pH. It is commonly used for coacervation in combination with anionic polymers such as pectin, alginate, gum arabic, carboxymethylcelluloses (CMC). Gelatin, whose molecular weight is between 100 and 300 kDa, has many advantageous properties for complex coacervation process: it is water-soluble, has emulsifying properties due to its amphoteric character, has many chemically crosslinkable functions including its amine and hydroxyl functions, or ionizable and finally has a variable steric conformation.

Although gelatin has the advantage of being perfectly biocompatible and biodegradable, its use is increasingly controversial because of the health risks of its animal origin. Thus, it requires a more thorough purification to be rid of its impurities and endotoxins that could cause pathologies. Moreover, depending on its variable origins, gelatin may present problems of stability and reproducibility.

It is therefore desirable to provide alternatives to the use of gelatin in the microencapsulation process by coacervation.

In this context, bovine serum albumin (BSA) and beta-lactoglobulin (BLG) have been proposed as alternatives to gelatin. However, the bovine origin of these proteins does not solve the problem of health risks. More generally, all of the natural polymers currently described in the literature to replace gelatin do not make it possible to obtain stable, reproducible microcapsules of controllable size.

On the other hand, certain synthetic polymers have been proposed for microencapsulation by coacervation, such as, for example, polyvinyl alcohol (PVA) (Bachtsi A.R. et al., J. Control.Release, (1996), 38, 49-58). Nevertheless, PVA is a very unstable polymer and is very sensitive to changes in temperature and the amount of salt added during encapsulation. On the other hand, the control of the PVA crosslinking rate is very delicate when it is desired to reproduce this protocol on a large scale.

Considering the foregoing, a problem to be solved by the present invention is to replace gelatin in the microencapsulation process by complex coacervation.

Thus, the inventors have demonstrated that a homopolymer of amino monomers, in particular a homopolymer of aminoethyl methacrylate (poly (AEMA)), can be effectively used, as cationic polymer, for the encapsulation of ingredients. The inventors have also developed a process for synthesizing an aminoethyl methacrylate homopolymer particularly suitable for this application.

The primary amine polymers are polymers synthesized from monomers comprising an amine function, such as aminoethyl methacrylate polymers, for example as vectors of pharmacologically active molecules, as particles. functional colloidal compounds for biomedical applications, for the preparation of sterically stabilized polyaniline particles, for the preparation of cationic latexes, for the synthesis of polypeptide and micelle vesicles, or for the localized biomineralization of calcium carbonate and silica ( Mortada SAM et al., J. Microencapsulation, (1987), 4, 23-37, Peters H., W. et al., Drug Dev., Ind. Pharm., (1992), 18, 123-134).

However, no one has heretofore described the use of synthetic polymers containing amine functions, particularly aminoethyl methacrylate homopolymers, for the microencapsulation of ingredients by coacervation.

The invention and the advantages thereof will be better understood on reading the description and examples of embodiments which follow given by way of illustration, with reference to the appended figures;

Figure 1: schematic representation of the coacervation process;

Figure 2: general formula of poly (AEMA);

Figure 3: Residual level of AEMA monomers as a function of time during the polymerization process of poly (AEMA) according to Example 1;

FIG. 4: Nuclear Magnetic Resonance (NMR) analysis of the carbon of the poly (AEMA-MAA) obtained according to Example 4;

Figure 5: Assessment of turbidity as a function of pH and poly (AEMA) / CMC ratio; and

Figure 6: Zeta potential evaluation as a function of pH and poly (AEMA) / CMC ratio

Presentation of the invention

The subject of the present invention is a process for the synthesis of homopolymers of polyaminoethyl methacrylate (poly (AEMA)), by uncontrolled radical polymerization, characterized in that the steps of the synthesis are carried out at an acidic pH of between 3 and , 5 and 5.5.

In the remainder of the description, "AEMA" refers to the monomers of aminoethyl methacrylate and the monomers derived from AEMA of general formula (I):

in which

R 1 can be indifferently hydrogen or methyl;

R2 is an alkyl chain of the formula - (CH ₂ ) n- wherein n is 1 to 10, with or without hetero elements, for example aminoethoxyethyl methacrylate, or aminoethoxypropyl methacrylate;

R ₃ can be indifferently hydrogen, methyl, ethyl, isopropyl, propyl or a tertiary butyl group.

For example, ΓΑΕΜΑ is preferably:

tert-butylaminoethylmethacrylate in which R 1 = CH ₃ , R ₂ = CH ₂ CH ₂ when n = 2 and R ₃ = (CH ₃ ) ₃ , or

methylaminobutyl methacrylate wherein R 1 = CH ₃ , R ₂ = CH ₂ CH ₂ CH ₂ CH ₂ when n = 4 and R ₃ = CH ₃ , or

aminopropyl methacrylate wherein R 1 = CH ₃ , R ₂ = CH ₂ CH ₂ CH ₂ when n = 3 and R ₃ = H, or

Γ aminoethylmethacrylate wherein R 1 = CH ₃ , R ₂ = CH ₂ CH ₂ when n = 2 and R ₃ = H.

In the remainder of the description, "poly (AEMA)" refers to the homopolymer of aminoethyl methacrylate synthesized indifferently from AEMA monomers and monomers derived from AEMA.

Advantageously, ΓΑΕΜΑ makes it possible to obtain not only homopolymers having a molecular weight and a polymolecularity index close to those of gelatin, but also homopolymers capable of forming coacervates and of crosslinking in order to stabilize the microcapsules during the encapsulation process. ingredients. As a result, The microcapsules obtained will have acceptable stability and breaking strength with regard to the applications envisaged.

By "microcapsule breaking force" is meant the maximum force that the microcapsules can withstand when applying a mechanical stress measured in Newton per unit weight (Ng ¹ ).

It is the evaluations of the stability of Sodium Dodecyl Sulfate (SDS) capsules and the breaking strength that help to validate a gelatin-replaceable polymer in the complex coacervation encapsulation process. Depending on the applications envisaged, the microcapsules will have to meet different criteria of breaking strength and stability. It is generally accepted in the field of encapsulation of ingredients that the microcapsules must have a breaking force of greater than 3 μg- ¹ and a stability in the SDS of greater than 1 h, for certain applications, for example in the food or some cosmetic creams, a breaking strength greater than 3 Ng- ¹ and a stability in the SDS greater than 10 h are required. For other applications, in media more concentrated in surfactants, for example shampoos, an acceptable minimum breaking force is 6 μg ^-1 and acceptable stability is stability in the SDS greater than 12 hours.

Advantageously, AEMA provides a primary amine function such as lysine and also arginine in gelatin.

Poly (AEMA) is a non-toxic homopolymer with many primary amino functions. The AEMA monomers carry primary amine functions that are positively charged when the pH of the solution is below the isoelectric pH (pHi) of 4.5. These primary amine functions are also reactive with crosslinking agents used in encapsulation in the microcapsule stabilization step, to form intermolecular covalent bonds.

The synthesis process according to the invention comprises a first step of dissolving the AEMA monomer in a solvent.

For the implementation of the synthesis method, any solvent known to those skilled in the art for dissolving the monomers can be used.

In particular embodiments of the synthesis process according to the invention, the solvents are chosen from water, ethanol, methanol, isopropanol, propanol or any mixture of these solvents, preferably from water, isopropanol and ethanol or a mixture of these solvents. The use of these solvents, in particular water, makes it possible to obtain a high degree of conversion of monomers into homopolymers and a good repeatability of the molecular weights.

In particular embodiments of the synthesis method according to the invention, the solvent is a mixture of isopropanol and water in a ratio of between 10:90 and 90:10.

In a particularly preferred mode, the solvent is a mixture of isopropanol and water in a ratio of 80:20.

In the synthesis process according to the invention, it is essential that the steps of the synthesis are carried out at an acid pH of between pH 3.5 and 5.5. Preferably, the acidic pH is pH 4.

In basic medium, under standard synthesis conditions, the amino function of AEMA is very nucleophilic. During the polymerization, the amine function of the AEMA is thus secondarily subjected to intramolecular or intermolecular amidation reactions, or to an undesired saponification reaction.

The inventors have shown, by comparing the synthesis of the random amino copolymers at different pH, that when the synthesis process is carried out in an acidic medium, at a pH of between 3.5 and 5.5, this makes it possible to obtain a homopolymer of which the percentage of modification by saponification is less than 10% (m / m). Thus, in acidic medium, the amine functions of AEMA are advantageously not involved in a saponification reaction and are available for reacting with a crosslinking agent during the encapsulation process of the ingredients.

Preferably, the steps of the synthesis are carried out at a temperature of between 50 to 100 ° C, and even more preferably at a temperature of between 70 and 85 ° C.

For the initiation of the radical polymerization reaction, the radical initiators of the reaction are preferably chosen from azo initiators or peroxides.

In a particularly preferred embodiment, the radical initiator is (2,2'-Azobis (2-methylbutyronitrile) commercially available for example under the name VAZO ™ 67 or Azobisisobutyronitrile, also called AIBN.

In alternative embodiments, the radical initiator of the reaction is benzoyl peroxide.

Preferably, the azo initiators are used, such as VAZO ™ 67 which is an initiator conventionally used to carry out the polymerization in water. Azo initiators allow faster reactions than with peroxides. In addition, the reaction initiators used in the process according to the invention, in particular VAZO ™ 67 or benzoyl peroxide are inexpensive, do not require intense purification at the end of the reaction, and have low risks. of toxicity.

The d'homopolymerization process most commonly used in the prior art is the Atom transfer radical polymerization ("ATRP") technique. ATRP uses tert-butyl aminoethyl methacrylate monomers, that is, AEMA monomers whose amino function is protected by a tert-butyl protecting group. In addition to the use of a priming agent, the ATRP requires the joint use of a transfer agent which is generally a copper type transition metal. This technique requires performing at the end of the synthesis reaction one or more additional purification steps to remove the potentially toxic and allergenic metal before using the encapsulating polymers. These steps represent an additional cost.

Advantageously, this problem does not arise with the synthesis method according to the invention which does not use transfer agent in addition to the initiator of the reaction. The method for synthesizing poly (AEMA) by non-controlled radical polymerization according to the invention is less complex to implement and less expensive than the ATRP technique.

In addition, the reaction initiators used in the process according to the invention, in particular VAZO ™ 67 or benzoyl peroxide are inexpensive, do not require intense purification at the end of the reaction, and have low risks. of toxicity.

The propagation step is the step of lengthening the macromolecular chain by successive additions of monomeric units on the "macro-radical" in growth.

The termination of the reaction is uncontrolled depending on the time and the conditions of the reaction. In the process according to the invention, the reaction time is 6 to 15 hours of reaction depending on the temperature and the solvent used. At the end of this reaction time, the polymerization reaction is considered complete, since the residual level of each of the monomers is less than 1%.

Poly (AEMA) obtained by the process according to the invention has an average molecular weight between 50,000 and 150,000 g.mol ^-1, preferably between 80,000 and 100,000 g.mol ^1, and the polydispersity index ( Ip) is between 4 and 5.

In a particular example of the synthesis process, the AEMA monomers solubilized in demineralized water, isopropanol, ethanol or a combination of these solvents are introduced into a reactor at room temperature, with stirring. The H of the solution is adjusted to a pH of between 3.5 and 5.5 using an acid, for example 99% acetic acid, or hydrochloric acid, or sulfuric acid. The solution is then heated and a radical initiator, for example VAZO ™ 67, is added for 9 hours.

At the end of this period, the reaction mixture is further stirred at a temperature between 70 and 85 ° C for an additional hour.

The reaction is stopped as soon as the residual level of the monomers becomes less than 100 mg.kg- ¹ which is a tolerated threshold for the methacrylic monomers by the specificities given by the regulatory affairs in industry.

At this point, the residual level of AEMA monomers is quantified by gas chromatography (GC). The homopolymers obtained are suspended in the final solution. Advantageously, the process according to the invention does not require any purification of the poly (AEMA) obtained contrary to the polymerization of AEMA by the ATRP route known in the state of the art.

Using the method described above, a monomer of the polymerization rate AEMA 98.5% was reached after 10 h with a PI between 4 and 5. average molecular weight from 80 000 to 90 000 g mol ^{" 1} , in particular 87,000 g ^/ ml, was determined by size exclusion chromatography (CES).

The poly (AEMA) obtained by the process according to the invention is a cationic homopolymer with physico-chemical characteristics close to those of gelatin, for example the molar mass, or the polymolecularity index (Ip), which gives them similar behavior during encapsulation.

Among the advantages of the process of the invention, the following advantages can be cited:

at the end of the polymerization, the residual monomer level is lower than the tolerated threshold for the methacrylic monomers (threshold: <100 mg ^/ kg- ¹ of residual monomer), when measured by chromatography, therefore the poly (AEMA ) obtained comply with regulatory and toxicological requirements, without the need for additional purification steps, which is a major advantage in the cosmetics, pharmaceutical or food industry;

the poly (AEMA) according to the invention allow encapsulation carried out under standard conditions, comprising both the efficient production of the coacervation and crosslinking steps; and

the microcapsules formed after encapsulation with the poly (AEMA) according to the invention have a satisfactory stability and a breaking force; for example, a force of rupture of 3 to 12 Ng- ¹ , a stability in water higher than 24 hours, and a stability in the SDS greater than 1 hour.

The subject of the present invention is thus a homopolymer of polyaminoethyl methacrylate (poly (AEMA)) obtainable by the non-controlled radical polymerization synthesis method according to the invention.

Poly (AEMA) obtained by the process according to the invention have an average molecular weight between 50,000 and 150,000 g.mol ^-1, preferably between 80,000 and 100,000 g.mol ^1, and the Ip is between 4 and 5.

The poly (AEMA) according to the invention is a cationic polymer capable of replacing gelatin in the encapsulation of ingredients.

The third subject of the present invention is the use of an aminated homopolymer for the microencapsulation of at least one ingredient by complex coacervation, wherein the aminated rhomopolymer is synthesized from aminoethyl methacrylate monomers (AEMA) or monomers derived from AEMA. of general formula (I):

in which

R 1 can be indifferently hydrogen or methyl;

R2 is an alkyl chain of the formula - (CH ₂ ) _n - in which n is between 1 and 10, with or without hetero elements, for example aminoethoxyethyl methacrylate, or aminoethoxypropyl methacrylate;

R3 may be indifferently hydrogen, methyl, ethyl, isopropyl, propyl or a tertiary butyl group.

In a particularly preferred embodiment, the aminated rhomopolymer used for microencapsulation of ingredients by complex coacervation is a homopolymer of polyaminoethyl methacrylate (poly (AEMA)). The present invention relates more particularly to statistical cationic copolymers capable of allowing microencapsulation by coacervation.

The term "microencapsulation" according to the invention encompasses all of the microencapsulation and encapsulation techniques known to those skilled in the art.

By "microcapsules" is meant capsules which have a size of between about 1 μηι and 1 mm and contain between 5 and 90% of encapsulated ingredients.

By "ingredients" is meant molecules or molecular or fluid complexes of interest that can be liquid or solid, hydrophilic or hydrophobic. For example, molecules that are active in cosmetics or in pharmacology, or pigments or additives, or any compound already known for its interest in being encapsulated.

The use of microencapsulation, and more particularly poly (AEMA) for the microencapsulation of ingredients, is advantageous for a wide range of products.

Among the ingredients that can be encapsulated by the poly (AEMA) according to the invention, mention may be made of:

useful ingredients in biomedicine, including pharmacologically active molecules, vitamins, steroids, amino acids, peptides, proteins, vaccines, genes, bacteria and viruses, living cells, active enzymes, agents ingestible contrast for medical diagnostics (eg magnetite and barium sulfate), etc. Among the pharmaceutical active molecules include antibiotics, anti-inflammatories, anti-psoriasis agents, anti-seborrhoeic agents, enzyme inhibitors, for example a phospholipase A2 inhibitor, antifungal agent, an anti-cancer agent, an antiviral agent; ingredients useful in agri-food, including food additives, for example vitamins, minerals, oils, flavors, flavoring agents, sweeteners, sweeteners, colorants, preservatives, antioxidants, nutrients, probiotic bacteria and amino acids;

- agricultural ingredients, such as fertilizers, herbicides, pesticides, biopesticides (natural toxins), insecticides, fungicides, anti-fouling agents, insect repellents;

ingredients that are useful in the cosmetic field, in particular ingredients such as enzymes or vitamins (mention may be made of vitamin F which will advantageously be encapsulated to mask its odor), emollients, active substances for tanning the skin, skin, for the hydration of the skin, and for the depigmentation of the skin, hair care products, nail polish, nail removers and make-up removers, cosmetic coloring compositions (for example pigments), sunscreens (there may be mentioned: octyl methoxycinnamate, camphorous methylbenzylidene, isoamylmethoxy-cinnamate, PABA, octyl salicylate), enzymes (eg, for depilatory creams proteases or keratinases to protect them from inactivation that could be caused by surface active agents such as sodium stearate or sodium lauryl sulfate), oils (eg mineral oils, castor oil, jojoba oil, vegetable oils, octyl hydroxystearate, benzoates, isopropyl palmitate, isopropyl myristate), amino acids (such as glycine, antioxidants such as tocopherol). These encapsulated ingredients are capable of being incorporated into a large number of cosmetic preparations, such as skin care products, UV protective creams, depilatory creams, cleansing creams, deodorants and perfumes. bath powders, hair creams and ointments, shampoos, UV protection lotions, lipsticks, blushes and eye shadows, face powders, skin cleansing lotions;

- the ingredients useful in the field of printing, sound recording and image, for example color precursor, photocurable oils;

- ingredients useful in the field of pigments and fillers, for example organic and inorganic pigments and fillers or fillers, especially for applications in the production of plastics, inks, coatings and materials magnetic;

- ingredients useful in the field of detergents and cleaning products, perfumes, etc. ;

ingredients useful in the field of adhesives, for example adhesives based on natural or synthetic polymers mixed with a polymerization agent, a polymerization initiator, solvents and other additives;

- the ingredients useful in the textile field for the lasting application of perfumes and softeners. Other ingredients encapsulated in this field are for example dyes, cosmetic ingredients, repellents, insecticides, polychromic and thermochromic materials, flame retardants (organic, for example phosphorus derivatives, or minerals, for example silicas ), vitamins, antimicrobial agents, and phase change materials. Thus, the invention relates to the use of an aminoethyl homopolymer methacrylate, for the microencapsulation of ingredients in the cosmetic field.

The invention further relates to the use of an aminoethyl methacrylate homopolymer for the microencapsulation of ingredients in the pharmaceutical and biomedical fields.

The invention further relates to the use of an aminoethyl methacrylate homopolymer for the microencapsulation of ingredients in the field of home hygiene.

The invention further relates to the use of an aminoethyl methacrylate homopolymer for the microencapsulation of ingredients in the field of textiles.

The invention further relates to the use of an aminoethyl methacrylate homopolymer for the microencapsulation of ingredients in the field of nutritional supplements.

The fourth subject of the present invention is a process for the microencapsulation of at least one ingredient by complex coacervation comprising the following steps:

- preparation of two phases, a hydrophilic phase and a lipophilic phase, said phases being immiscible with each other,

dissolving at least one cationic polymer and at least one anionic polymer in the hydrophilic phase,

pH adjustment and addition of a coacervation agent of the polymers, dissolution of the ingredient in the hydrophilic phase or in the lipophilic phase, dispersion of the phase comprising the ingredient in the other phase, by emulsification,

moderate agitation for a time of between 30 minutes and 3 hours, in order to allow the adsorption of the aggregates around the droplets of the emulsion, at the interface between the two phases, and

- crosslinking of the microcapsules,

characterized in that said cationic polymer is an aminated homopolymer synthesized from monomers derived from AEMA, of general formula (I):

R 1 can be indifferently hydrogen or methyl;

R2 is an alkyl chain of the formula - (CH ₂ ) n- in which n is between 1 and 10, with or without hetero elements, for example aminoethoxyethyl methacrylate, or aminoethoxypropyl methacrylate;

Coacervation is a physico-chemical method of constitution and stabilization of microcapsules. Complex coacervation is an encapsulation process that involves the use of an anionic polymer and a cationic polymer under pH conditions such that the two polymers are of opposite charge, allowing their combination into co-aggregates. .

The aggregates of cationic polymers and anionic polymers forming at the coacervation stage are referred to interchangeably as "coaggregates" and "coacervates".

In the context of the invention, "encapsulation" can be defined as the process of forming a continuous layer of cationic polymer and anionic polymer around ingredients to be encapsulated.

The inventors have developed a novel microencapsulation process using amine homopolymers synthesized from AEMA-type monomers or its derivatives, of general formula (I), as cationic polymer.

The aminated homopolymer used can be obtained according to a standard radical polymerization technique known in the art, for example by Atom transfer radical polymerization ("ATRP"). In this case, the homopolymer will have to be purified to remove the residual metals before encapsulation. In particularly preferred embodiments of the encapsulation process according to the invention, the aminated homopolymer synthesized from monomers derived from AEMA is a homopolymer produced by the uncontrolled radical polymerization process according to the invention.

In a particularly preferred embodiment, the homopolymer is a homopolymer of polyaminoethyl methacrylate.

The anionic polymer may be any anionic polymer known to those skilled in the art of complex coacervation encapsulation.

In particular embodiments, the anionic polymers used are selected from Carboxymethylcellulose (CMC) or gum arabic.

In particular embodiments, the mass ratios between the poly (AEMA) and the anionic polymer are between 1/0, 1 and 1/2.

In a first step, two phases, a hydrophilic phase and a lipophilic phase, immiscible with each other, are prepared.

The hydrophilic phase may be a protic polar solvent, for example water, ethanol, methanol, or an aprotic polar solvent, for example acetone or ethyl acetate. Preferably, the hydrophilic phase is water.

The lipophilic phase can be an oil, for example a mineral oil, olive oil, rapeseed oil, or sunflower oil or an organic solvent, for example chloroform, ethyl acetate, hexane, heptane.

In a second step, the cationic amine homopolymer and the anionic polymer are dissolved in the first hydrophilic phase.

A next step is to dissolve the ingredient to be encapsulated in the phase to be dispersed in the continuous phase by emulsification so as to form dispersed droplets. Depending on the hydrophilic or lipophilic nature or insoluble particles of the ingredient, the dispersed phase will be the hydrophilic or lipophilic phase. The ingredient is always in the disperse phase.

The encapsulation process according to the invention is adapted to the encapsulation of a single ingredient or of several ingredients.

Thus, three particular embodiments of the dissolution step of the ingredient to be encapsulated in the process according to the invention are possible depending on the insoluble, hydrophilic or lipophilic nature of the ingredient to be encapsulated. When the ingredient to be encapsulated is of insoluble nature, an embodiment of the encapsulation process according to the invention then comprises the steps of:

dispersion of the ingredient in one of the hydrophilic or lipophilic phases, said ingredient remaining in the solid state,

emulsification so as to obtain an emulsion of the "oil-in-water" or "water-in-oil" type from one of the phases to the other.

If the ingredient is dispersed in the hydrophilic phase, a "water-in-oil" emulsion is made, whereas if the ingredient is dispersed in the lipophilic phase, an "oil-in-water" emulsion is made. ".

When the ingredient to be encapsulated is of a lipophilic nature, another embodiment of the encapsulation process according to the invention then comprises the steps of:

dissolution of the ingredient in the lipophilic phase,

emulsification of the lipophilic phase in the hydrophilic phase so as to obtain an "oil-in-water" type emulsion. After this step, the droplets of lipophilic solution containing the ingredient are dispersed in the hydrophilic phase containing the dissolved polymers.

When the ingredient to be encapsulated is hydrophilic in nature, an embodiment of the encapsulation process according to the invention then comprises the steps of:

dissolution of the ingredient in the same hydrophilic phase,

emulsification of the first hydrophilic phase in the lipophilic phase so as to obtain a "water-in-oil" type emulsion. After this step, the droplets of hydrophilic solution containing the ingredient and the dissolved polymers are dispersed in the lipophilic phase.

The emulsification step is intended to form droplets and thus the heart of the microcapsules comprising the ingredient to be encapsulated. This step is carried out by emulsion or by microemulsion with stirring. The stirring speed and the inclination angle of the stirrer are chosen according to the desired size of the microcapsules.

The microencapsulation can be done indifferently by oil-in-water or water-in-oil emulsification depending on the nature of the ingredients to be encapsulated.

Emulsions and microemulsions are a particular form of mixing two immiscible liquid phases. Emulsification is a low shear dispersion of the phase containing the ingredient to be encapsulated in another immiscible solution.

After emulsification, the solution containing the ingredient to be encapsulated should be in the form of droplets dispersed in the immiscible continuous phase. The emulsion can be stabilized with a surfactant. The microemulsion follows the same principle but does not require shearing forces to form and is formed by simple mixing. The microemulsion is a fine dispersion essentially based on the interfacial properties, stabilized by a surfactant, to form droplets with dimensions of between 1 μιη and 1 mm.

Any surfactant or surfactant known in the art can be used to stabilize the emulsion. However, advantageously, the use of the aminated homopolymer according to the invention, preferably poly (AEMA), makes it possible to stabilize the emulsion by virtue of the electrostatic interactions between the primary amine functions of the polymers dissolved in the phase, by playing the role of a surfactant.

In particular embodiments, the emulsion is carried out at a temperature between 25 ° C and 80 ° C.

In another step, the pH is adjusted and the coacervation is induced by the addition of a coacervation agent of the polymers.

It is possible that pH adjustment is sufficient to cause coacervation. In this case the addition of a separate coacervation agent is not necessary.

The pH must be adjusted so that it is less than the isoelectric point of the aminated homopolymer according to the invention, and greater than the isoelectric pH of the anionic polymer used, so that both are in charge ionic form. reversed which allows the formation of coacervates. The interactions involved between the two polymers during the formation of the coacervates are of electrostatic, hydrogen or hydrophobic nature.

In particular embodiments, the pH is adjusted to a pH of between 3 and 6, more preferably at pH 4.5. Advantageously, this pH corresponds to the pH for obtaining coacervates soluble in the reactive medium and which do not precipitate. In a particular embodiment, the capsules were obtained after the formation of coacervates at pH 4.5 in the presence of a poly (AEMA) according to the invention and CMC in a weight ratio of 1 / 0.4 to 50 ° C.

The coacervation step can be indifferently carried out before, during or after the emulsification step. Coacervation here refers to the process of formation of the microcapsules following the addition of a coacervation agent of the polymers. This step is preferably carried out with stirring, which advantageously allows the coacervates to be distributed in a uniform manner around the droplets comprising the ingredient.

The principle of coacervation is based on the gentle desolvation of a solution containing one or more polymers dissolved in a solution and one or more ingredients to be encapsulated, induced by the addition of a coacervation agent of the polymers.

The coacervation agent of the cationic and anionic polymers may be, for example, the modification of the pH or of the temperature, the addition of salts or solvents.

Advantageously, in the coacervation method of the invention, the modification of the pH is sufficient to induce coacervation.

The addition of an agent for coacervation of cationic and anionic polymers then generates electrostatic attraction forces between molecules, which are greater than the molecular-solvent bonding forces. This imbalance between the forces results in the formation of aggregates of cationic and anionic polymers, which are called coacervates.

The solubility of the polymers in the hydrophilic phase is lowered and polymer coacervates are formed in the hydrophilic phase which becomes cloudy. Advantageously, the electrostatic interactions generated by the amine functions of the copolymer according to the invention, positively charged when the pH of the solution is lower than the isoelectric pH of the cationic polymer, promote the formation of aggregates and allow the formation of microcapsule walls.

The polymer aggregates are deposited progressively at the interface of the two immiscible phases on the surface of the droplets containing the ingredient to be encapsulated, to form a continuous layer of polymers around the droplet.

A final crosslinking step includes the addition of a hardener or a crosslinking agent which allows the formation of a continuous film of polymers around the ingredient to be encapsulated. The crosslinking agent is chosen from the crosslinking agents known to those skilled in the art, for example glutaraldehyde, ethylene glycol diglycidil ether, transglutaminase, and sodium tripolyphosphate. In preferred embodiments, the crosslinking agent used is glutaraldehyde.

The crosslinking is to stiffen the capsule formed by the formation of covalent bonds between the primary amines or secondary coacervates of polymers and the aldehyde function of the crosslinking agent.

Preferably, the crosslinking agent is added at low temperature, between 5 and 10 ° C, in order to stiffen the membranes of the microcapsules.

Advantageously, the amine functions of the AEMA monomers included in the random cationic copolymer according to the invention are very reactive with glutaraldehyde.

The encapsulation process according to the invention makes it possible to obtain microcapsules from 5 to 1500 μιη, more particularly from 100 to 900 μιη, and even more particularly from 500 to 800 μιη.

The ingredient encapsulation process makes it possible to obtain stable, biocompatible microcapsules of reproducible sizes.

Thus, a fourth subject of the invention is microcapsules obtained by the encapsulation process according to the invention, preferably having a size of from 5 to 1500 μιη, more particularly from 100 to 900 μιη, and more particularly from 500 to 800 μιη. .

Other particular embodiments of this method for synthesizing the cationic cationic copolymers according to the invention and the use of rh-derived amine rhomopolymer for the encapsulation of ingredients also result from the previous description. Other advantages and characteristics of the invention will appear better on reading the examples given by way of illustration and not limitation.

Example 1; Preparation of poly (AEMA) homopolymers by the process according to the invention

The AEMA monomer is commercially available with about 90% purity in the form of 2-aminoethyl methacrylate hydrochloride. It is in powder form.

In a 1 L reactor, at room temperature, 75 g (0.454 mol) of AEMA monomers are dissolved in the presence of 170 g of demineralized water.

The pH of the solution is adjusted to pH 4 using 99% acetic acid. The solution is heated and maintained at 83 ° C.

The radical initiator VAZO ™ 67 (1.25 g, 6.5 mmol) is added at regular time intervals, every hour, in 10 equal fractions (0.125 g, 0.65 mmol) during the first 9 hours. hours. At the end of this period, the reaction mixture is stirred at 83 ° C for an additional hour and then heating and initiator injections are stopped.

The final solution comprising the statistical cationic copolymers obtained does not then require any purification.

A conversion of the monomer AEMA of 98.5% was obtained within 10 h with a molecular weight of 87 000 g.moi ¹ and Ip of 4.7.

The poly (AEMA) modification rate obtained is from 0 to 10% over time only by saponification.

Figure 2 illustrates the general formula of poly (AEMA) obtained according to this example. In this FIG. 2, the index "m" represents the number of units of AEMA monomers constituting this chain, regardless of the order of sequence of these units in the chain. "M" is between 600.degree. 800.

Example 2; Preparation of poly (AEMA) homopolymers by ATRP

The monomers of AEMA (9.58 g, 57.8 mmol) are introduced into the reactor under nitrogen and the initiator which is 2- (4-morpholino) ethyl 2-bromoisobutyrate ME-Br [20,21] ( 0.32 g, 1.2 mmol, 2.20-bipyridine (0.37 g, 2.3 mmol) is added.

Cu (I) Cl is then added as a catalyst (0.1 g, 1.2 mmol) in a mixture of 19.8 mL 80/20 IPA / H 2 O at a concentration of 33% (w / v) to 50 ° C. After 6 hours of reaction, the solution is diluted in deionized water and purified by dialysis for 3 days to remove Cu (II). The solution is finally concentrated on a rotary evaporator to remove the water.

An AEMA monomer conversion of 80% was reached within 10 hours.

The modification rate of poly (AEMA) obtained is 20 to 41.6% over time, of which 18.5% by saponification and 1.5% by internal rearrangements.

Example 3; Analysis of Residual AEMA Monomer Levels by Gas Chromatography

Purpose: The residual AEMA monomer level as a function of time was quantified by gas chromatography (GC) for the synthesis method according to Example 1.

Protocol:

Gas chromatography is performed on an AGILENT® 7890 A (Agilent, France). The column used is an AGILENT® Capillary DB-624 of fused silica 30 m long, internal diameter 0.53 mm and film thickness 3.0 μιη. Elution is ensured by a helium flux and the detection is carried out by a flame ionization detector (FID).

The injector is at a constant temperature of 250 ° C in split mode with a 5: 1 ratio. The oven temperature is initially 80 ° C, then a temperature ramp is performed (5 .min ^_1 ) up to 130 ° C. This level is maintained for 40 minutes at this temperature. Finally, the temperature ramp (5 ° C.min ^-1 ) is increased to 250 ° C. and then maintained for 15 minutes.

The carrier gas used is helium at a pressure of 4.4 psi and a constant flow rate of 33 ml.min- ¹ . Finally, the detection temperature (FID) is 250 ° C. The volume of the sample to analyze is 2 μί.

Results:

At this stage, the residual level of ΓΑΕΜΑ was measured as 70 mg.kg- ¹ . As shown in Figure 3, we observe that only 1.5% (w / w) of AEMA has not polymerized There is 98.5% polymerization rate.

Conclusion:

We observe that the conversion rate of monomers to homopolymers is greater than 98%

the residual rate of methacrylic monomers after homopolymerization according to Example 1 is less than <lOOmg.kg ^"1 is less than <100mg.kg ^_1, which is which is acceptable by the regulations in force in the industry for residues of methacrylate monomers

Example 4; ¹³ C-carbon nuclear magnetic resonance (NMR) analysis of the poly (AEMA) obtained according to Example 1

Objective: to verify that during the process of synthesis of the copolymers according to the invention, the primary amine functions of the monomers of (AEMA) do not undergo modifications, for example saponification type.

Protocol:

The purity of the samples was verified by ¹³ C-carbon NMR. A solution of each 20% (w / w) polymer was prepared in D2O. This concentration has been used to obtain an optimal signal-to-noise ratio, which also makes it possible to reduce the number of necessary accumulations. The device used is a BRUKER® AM400 high-resolution spectrometer equipped with an Aspect computer interface. The NMR spectrum obtained results from the accumulation of 1024 spectra made with carbon decoupling at 400.13 MHz. The measurement sequence consisted of a series of 90 ° pulses spaced 2.5 s apart. The external reference is a sodium salt of (3- (trimethylsilyl-2,2,3,3) propionic acid, the resonance of methyl being at a chemical shift of 0 ppm.

Results:

The ¹³ C NMR analysis of the carbon, by the interpretation of the chemical shifts shown in FIG. 4, shows all the functions of the homopolymer. The presence of carbon at 42 ppm and 63 ppm shows the modification of poly (AEMA) by saponification and the formation of ethanolamine and methacrylic acid (MAA). By integrating the peak at 53-57 ppm of the O-CH 2 ester function and the peak at 62-65 ppm of ethanolamine, we observe that about 9% (m / m) of the AEMA is saponified to poly ( AEMA-MAA).

These carbon NMR results are confirmed by proton NMR analysis and observable NH bands by infra-red spectroscopy at 2400 - 3400 cm ^-1 .

Conclusion:

Although 9% (m / m) of the poly (AEMA) obtained according to Example 1 is modified by saponification over time, we have been able to obtain a polymer of low Ip and having a molar mass sufficiently close to that of gelatin which can be used for the encapsulation of ingredients.

After acid synthesis, the absence of the 64 ppm doublet which corresponded to the oxygen-linked carbon of the alcohol function and the absence of the 47 ppm doublet which corresponded to the nitrogen-bound carbon of the amine ethanolamine indicate that saponification does not take place in an acid medium.

Example 5; Evaluation of coacervate formation by turbidity analysis

Objective: To evaluate the coacervate formation yield of polymers for different poly (AEMA) ratios according to Example 1 and CMC by measuring the turbidity as a function of the pH and to determine the ratio of the polymers and the optimal pH to obtain a yield maximum in soluble coacervates.

Principle:

In the complex coacervation encapsulation process, pH adjustment is an essential parameter that determines the formation of coacervates. The formed coacervates create a haze in the solution. This disorder can be measured; it is directly correlated to the amount of coacervates formed. The measurement of turbidity thus allows us to quantify the formation efficiency of the coacervates from an anionic polymer and a cationic polymer as a function of the pH. It is thus possible to determine the pH of formation of soluble coacervates (or pHc) pHc is the pH for which a maximum yield of soluble coacervates is obtained. The pHc is determined by calculating the pH or peak of the turbidity curve is maximum.

The poly (AEMA) obtained according to Example 1 and the CMC are placed in solution in acidic medium at pH 3. Then the solution is alkalinized by the addition of sodium hydroxide at 0.01 N. Samples are taken at regular intervals and turbidity is measured as a function of pH throughout the test.

Results:

Figure 5 shows that the optimal coacervation yield is obtained for a polymer (m / m) ratio of poly (AEMA) / CMC of 1 / 0.4.

The pHc of the poly (AEMA) obtained according to Example 1 / CMC for the different ratios tested is between 3 and 7.

Conclusions:

A maximum turbidity value is obtained for a poly (AEMA) / CMC polymer ratio of 1 / 0.4, with a soluble coacervate formation pHc of between 4 and 5. In other words, the efficiency of the formation soluble coacervates is maximal under these conditions.

The pH allowing the formation of soluble coacervates capable of encapsulating is an acidic pH between pH 4 and 6. In a basic medium, at a pH of between 8 and 10, the turbidity is low, which corresponds to the absence of formation of coacervates. both polymers remaining dissolved in the medium.

Example 6; Evaluation of the pH of electrical equivalence (PEE) by analysis of the Zeta potential of the coacervates formed from poly (AEMA) obtained according to Example 1

Objective: evaluation of the Zeta potential as a function of the pH for different ratios of poly (AEMA) obtained according to Example 1 / CMC, anionic polymer, so as to determine the PEE of the coacervates formed. The evaluation of the zeta potential as a function of the pH informs us of the charge density at the surface of the coacervates coming from two polymers and thus makes it possible to determine the value of the pH of electrical equivalence (or PEE). The PEE is the pH where the positive charge density of the cationic polymer and the negative charge density of the anionic polymer are neutralized thereby forming coacervates of zero charge density. PEE is also the pH for which the intensity of electrostatic interaction between the polymers is maximum. In the case of synthetic polymers, the coacervates formed precipitate, whereas in the case of natural polymer, the coacervates remain soluble.

Protocol: The solutions were prepared at a total polymer concentration of 5% (w / w) with different ratios of cationic / anionic polymers (1 / 0.75, 1 / 0.4, 1 / 0.2, 1/1). .

The cationic and anionic polymers are placed in solution in an acid medium at pH 3. Then the solution is alkalinized by the addition of sodium hydroxide at 0.01 N. Samples are taken at regular intervals and the zeta potential is measured as a function of the pH throughout the test.

The electrical equivalence pH of the coacervates formed with different acid polymer ratios is determined to be the value measured when the value of the zeta potential is zero.

Results:

Figure 6 shows the results of the potential zeta-based pH and different polymer ratios

The results show that as the poly (AEMA) ratio obtained according to Example 1 / CMC increases, the pH of electrical equivalence increases and the charge density of the coacervates decreases. It is observed for all the polymer ratios analyzed that the PEE is between 9 and 11.

Conclusion:

In the case where the formation of the microcapsules is at a pH below the PEE, the microcapsules formed will be positively charged; on the other hand, if the formation of the capsules is at a pH higher than the PEE, the microcapsules formed will be negatively charged. The overall charge of the microcapsules is important in particular for adjusting the pH according to the applications envisaged for the microcapsules.

At PEE, the coacervates precipitate. Thus, in order to optimize the formation efficiency of the coacervates while having soluble coacervates which do not precipitate and therefore which are capable of forming microcapsules in encapsulation, the encapsulation process must be carried out at a pH below the PEE and higher than the pHc forming soluble coacervates therefore at a pH between pH 3 and 10.

In the case of poly (AEMA) -CMC with a ratio of 1 / 0.4 (m / m) to a pH of 4.5 coacervates are formed with optimal yield via the polymer charge density .

Example 7; Evaluation in encapsulation of polv (AEMA) obtained according to example 1 with the CMC

Objective: Analyze the ability of the poly (AEMA) obtained according to Example 1 to encapsulate, and evaluation of the microcapsules obtained. Figure 1 schematically illustrates some steps of the complex coacervation encapsulation process.

In step a) the amine homopolymer derived from AEMA obtained according to Example 1 and the CMC are dissolved in the continuous phase, the ingredient is contained in the discontinuous phase which is emulsified in the continuous phase; step b) illustrates the formation of the coacervates of polymers by adjusting the pH and / or adding a coacervation agent; step c) illustrates the adsorption of the coacervates at the surface of the discontinuous phase droplets; step d) shows the formation of the uniform layer of polymers around the droplets, this layer being stiffened by crosslinking, which makes it possible to obtain microcapsules.

Protocol:

In this study, 2.5 g of CMC form complexes with 6.6 g of poly (AEMA) obtained according to Example 1, dissolved in 330 g of distilled water at 45 ° C. in the presence of 0.2 g of sodium hydroxide (20% NaOH (m / m)) with vigorous stirring (120 rpm).

As soon as the polymers are completely solubilized, we adjust the pH using acetic acid at 20% (m / m) at pH = 4.75 determined by turbidity analysis as being the optimal pH for obtaining the coacervates. .

Once the coacervates are observed under a microscope, we add 200 g of lipophilic phase which consists of mineral oil in which an ingredient is dissolved, in this case 0, 1% of colored pigment (green dry).

In order to obtain homogeneous and sufficiently stable droplet formation during the complex coacervation step, a pale with a stirring angle of 15 ° relative to the vertical is used. The temperature should be close to 45 ° C and the rotation speed should go from 120 rpm to 170-180 rpm.

After emulsification, the adsorption of the coacervates around the oil droplets which form a continuous layer of polymer aggregates is observed under a microscope (objective X5). It is necessary to add as much acetic acid as is useful for observing thin walls on the coacervates. It is necessary to leave the stirring for 2 hours at room temperature in order to allow the coacervates to adsorb and form the walls.

As soon as the walls are formed, the reaction is progressively cooled to a temperature of 10 ° C.

2 g of glutaraldehyde are added and then the reaction is left overnight under stirring at room temperature. After decantation, unreacted excess coacervates precipitate and the microcapsules present in the supernatant are filtered using a plastic filter with a porosity of 60 μιη.

Subsequently the microcapsules are rinsed with water three times and then filtered to remove unreacted crosslinking agent.

Finally, the microcapsules are placed in a solution comprising a preservative.

The structure of the capsules obtained by the polymer / CMC complexes is qualitatively studied by a binocular microscope. Dispersions were observed by placing 500 μΐ of mixture on a slide using a Nikon Eclipse 200 optical microscope (Nikon, Japan) equipped with a 41 W LED direct light device (halogen model 6V20W / 6V30W, Compilant multi-voltage (100 V-240 V)) and a Nikon camera specially adapted for artificial light.

The microcapsules formed are analyzed with respect to different parameters: their size, their breaking strength, their stability in water and the SDS.

The breaking force is measured on 10 different capsules by an LFRA texture analyzer (Brookfield Viscosimeter, United Kingdom). It allows to expose the capsules to a force between 0 and 100 g. The measurements are made with an uncertainty of 0, 1% of the mass exerted.

The size and distribution of microcapsules were measured by static light scattering in aqueous medium diluted to 0.1% (w / v). The granulometer used was a Malvern Mastersizer 2000 equipped with a red laser with a power of 5 mW emitting at a wavelength of 632.8 nm. The absorbance is from 470 nm to 632 nm and the reading is done by Fourier transform.

Results: The microcapsules formed have a water stability greater than 24 h, and a stability in sodium dodecyl sulphate (SDS) greater than 1 hour.

The microcapsules formed have a breaking force of 3 to 5 μg ^-1 and a size of between 500 μιη and 800 μιη.

Conclusion:

The poly (AEMA) obtained according to Example 1 allows effective encapsulation of ingredients and to obtain microcapsules having a breaking force and stability satisfactory for the intended applications.

Claims

1. Process for the synthesis of homopolymers of polyaminoethyl methacrylate (poly (AEMA)), by uncontrolled radical polymerization, characterized in that the steps of the synthesis are carried out at an acid pH of between 3.5 and 5.5.

2. The method of claim 1, wherein the solvent is selected from water, ethanol, methanol, isopropanol, or a mixture of these solvents.

3. Method according to one of claims 1 to 2, wherein the steps of the synthesis are carried out at pH 4.

4. Homopolymer of polyaminoethyl methacrylate (poly (AEMA)) obtained by the radical polymerization synthesis method according to one of claims 1 to 3.

5. Use of an amino homopolymer for the microencapsulation of at least one ingredient by coacervation, the amino homopolymer being synthesized from monomers derived from aminoethyl methacrylate (AEMA), neral (I):

in which,

R1 is hydrogen or methyl;

R2 is an alkyl chain of the formula - (CH ₂ ) _n - wherein n is 1 to 10, with or without hetero elements, for example aminoethoxyethyl methacrylate, or Γ aminoethoxypropyl methacrylate; and

R3 is a hydrogen, a methyl, an ethyl, an isopropyl, a propyl or a tertiary butyl group.

6. Use according to claim 5, characterized in that the amino homopolymer used for the microencapsulation of ingredients by complex coacervation is a homopolymer of polyaminoethyl methacrylate (poly (AEMA)).

A method of microencapsulating at least one ingredient by complex coacervation comprising the steps of:

- crosslinking of the microcapsules,

in which,

R1 is hydrogen or methyl;

R2 is an alkyl chain of the formula - (CH ₂ ) _n - wherein n is 1 to 10, with or without hetero elements, for example aminoethoxyethyl methacrylate, or Γ aminoethoxypropyl methacrylate; and R3 is a hydrogen, a methyl, an ethyl, an isopropyl, a propyl or a tertiary butyl group.

The microencapsulation process according to claim 7, wherein the amino homopolymer is a homopolymer of polyaminoethyl methacrylate (poly (AEMA)) obtained by the synthesis method according to one of claims 1 to 3.

9. microencapsulation process according to one of claims 7 to 8, wherein the pH is adjusted to a pH between 3 and 6.

10. Microencapsulation process according to one of claims 7 to 9, wherein the mass ratio between the cationic polymer and the anionic polymer is between 1/0, 1 and 1/2.

1. Microcapsules obtained by the microencapsulation process according to one of claims 7 to 10.