Cyclodextrin derivatives, their manufacturing process and their applications

Abstract

Cyclodextrin Derivatives, Their Manufacturing Process and Applications. The invention relates to a cyclodextrin derivative comprising: - glucoside subunits of chemical structure (4): (4), - optionally at least one glucoside subunit of chemical structure (5): (5), the total number of glucoside subunits of chemical structure (4) and chemical structure (5) is an integer n between 5 and 30, preferably between 6 and 8, at least 2 x among the x of the glucoside subunits of chemical structure (4) are different from each other. The invention relates to a manufacturing process for said CD derivative and its applications.

Description

Title of the invention: Cyclodextrin derivatives, their manufacturing process and their applications

[0001] The present invention relates to new cyclodextrin derivatives (hereinafter abbreviated as "CDs" in the plural or "CD" in the singular), and their applications in a wide variety of fields of application, including pharmaceutical, cosmetic, food, plant protection, agrochemical, textile and various industrial fields (e.g. paints, pigments).

[0002] In these different fields, it is perfectly known to encapsulate active substances (for example, active pharmaceutical or cosmetic ingredients, food additives, nutraceutical products, plant protection products, perfume essences, microorganisms, pigments, dyes) in individualized particles (micro- or nanoparticles).

[0003] In addition, the encapsulation of active substances is implemented in order to: - increase their activity time, due to the improvement of their chemical stability, by protecting them against light and / or interactions with other incompatible components (oxidation...), - mask a taste or an odor; - to ensure a prolonged and controlled release, for example in the dermis, in the case of cosmetic active compounds, or in the digestive tract, in the case of active substances in the agri-food industry.

[0004] Among the various encapsulation techniques, some use "host" molecules that have a cavity allowing the formation of inclusion complexes with "guest" molecules (e.g., active substances). "Host" molecules can be mineral molecules such as zeolites and kaolinites, as well as organic molecules such as crown ethers, cyclophanes, and CDs.

[0005] The encapsulation process, common to all these "host" molecules (also called "cage molecules"), is as follows: the "host" molecule admits one or more "guest" molecules into its cavity, partially or completely, through weak interactions but without any covalent bonds being formed. This also allows for easy dissociation of the inclusion complex formed. The complexation phenomenon results from numerous interactions involving the host molecule, the guest molecule, and the solvent, leading to the most thermodynamically stable state.

[0006] The encapsulation of active compounds using CDs through the formation of an inclusion complex is an encapsulation technique of choice.

[0007] Indeed, a CD is a cyclic oligosaccharide obtained by enzymatic degradation of amylose (a linear form of starch, which is therefore a renewable resource) using an enzyme, cyclodextrin glucosyltransferase (CGTase), of bacterial origin (Bacillus macerans, Alkalophylic bacillus). CDs thus have the advantage of being biodegradable.

[0008] More specifically, a CD is composed of n units of glucopyranose in chair conformation, which are linked together by alpha (1-4) glycosidic bonds.

[0009] The most abundant and therefore most commonly used CDs, known as natural or native CDs, are alpha-CDs (hexamers), beta-CDs (heptamers), and gamma-CDs (octamers), for which n is respectively equal to 6, 7, and 8. Other CDs exist for which: - n is smaller, for example n is equal to 5; - n is higher, and can reach values ​​from 9 to 30, or even more, for example delta-CD (n is equal to 9) and epsilon-CD (n is equal to 10).

[0010] By way of example, the chemical structures of alpha-CD (1) and beta-CD (2) are as follows:

[0011] [Chem.l] (1)

[0012] [Chem.2] OH HO (2)

[0013] Beta-CD is the CD which complexes the most molecules and whose derivatives are the most used.

[0014] CDs generally have (in particular alpha-, beta- and gamma-CDs) a three-dimensional structure in the shape of a conical cylinder (or in other words a "lampshade") whose wall is made up of glucopyranose units in chair conformation.

[0015] CDs have a central cavity, as can be seen in the chemical structure (3) below.

[0016] [Chem.3] (3)

[0017] The size of the cavity depends on the number of glucopyranose units contained in the CD.

[0018] The openings of the cavity are lined by hydroxyl groups.

[0019] More specifically, the secondary hydroxyl groups of the glucopyranose units attached to carbons C2 and C3 are located around the wider entrance of the cavity (also called the "secondary face"), or in other words, the larger side of the conical cylinder. The presence of these secondary hydroxyl groups gives the outer part of the CD a hydrophilic character (intended to be in contact with a polar solvent).

[0020] The primary hydroxyl groups, carried by the C6 carbons, are located around the other opening of the conical cylinder, also called the "primary face".

[0021] The wall of the central cavity of CDs is composed of carbon atoms, hydrogen atoms, and ether bonds. The lone pairs of electrons on the oxygen atoms forming glycosidic bonds are directed towards the interior of the cavity, where the electron density is therefore high. Consequently, the interior of the CD cavity, lined with hydrogen atoms on carbons C3 and C5, as well as oxygen atoms (O-4) participating in the glycosidic bond, is relatively nonpolar and hydrophobic.

[0022] Finally, the formation of hydrogen bonds between the hydroxyl groups located on the C2 and C3 carbons of two adjacent glucopyranose units contributes to the rigidity of the CD structure.

[0023] The CDs thus have a macrocyclic structure whose interior is hydrophobic and whose exterior is hydrophilic.

[0024] This amphiphilic character allows them to incorporate hydrophobic molecules into their cavity to form water-soluble inclusion complexes. Indeed, in aqueous solution, the nonpolar cavity of CDs is occupied by water molecules, which is energetically unfavorable (polar-polar interactions). These water molecules can be easily replaced by a suitable "guest" molecule that is less polar than water.

[0025] More generally, the cyclic structure and their cavity allow CDs to form inclusion complexes with a large number of highly varied molecules (neutral, charged, polar or nonpolar). The association of a CD with a guest molecule, as well as the dissociation of the complex formed, are governed by thermodynamic equilibrium.

[0026] Therefore, encapsulation in CDs makes it possible, in certain cases, to protect fragile molecules (for example, against ultraviolet rays, oxidation, or temperature), as well as to ensure their slow and controlled release in an aqueous medium according to this thermodynamic equilibrium. Furthermore, the formation of inclusion complexes of molecules that are poorly or not at all soluble in water (for example, cosmetic or pharmaceutical active ingredients) with CDs increases their apparent solubility and stability. These properties are notably used to improve the bioavailability of cosmetic or pharmaceutical active ingredients.

[0027] Furthermore, because each unit of glucopyranose has three reactive hydroxyl groups which are carried by the carbons C2, C3 and C6, it is known to synthesize a multitude of CD derivatives from so-called natural CDs and synthetic reagents, by replacing certain hydroxyl groups of the said natural CDs with a wide variety of groups, neutral or ionic such as alkyl, hydroxyalkyl, sulfobutyl, glucosyl, acetyl, amine, ether or ester groups from the said synthetic reagents.

[0028] CD derivatives are generally used to satisfy at least one of the following needs which are not always perfectly met by natural CDs: - the modulation of their solubility in different solvents; - the improvement of their complexation capacity; - the fixing of a specific group (for example for a vectorization application).

[0029] Just like CDs, certain water-insoluble CD derivatives are of industrial interest because they are particularly suitable for preparing dispersible systems in which CDs and their derivatives are in the form of particles (micro- or nanoparticles). Indeed, particles are used in a wide variety of applications.

[0030] For example, in the pharmaceutical field, such particles are useful for stabilizing or delivering active substances. Such particles can also have applications in plant protection products, where they can be used to deliver insecticides or pesticides. In the cosmetic and dermatological fields, these particles can transport active compounds to the dermis. In industrial sectors, such as paints, varnishes, and surface treatments, such particles provide dispersions useful for delivering pigments, reagents, and strippers in the form of very low-viscosity aqueous dispersions that are easy to spray or apply. Finally, the particles can also be used in printing, reprographics, and the surface treatment of textiles and fibers.

[0031] In order to obtain dispersible systems containing particles suitable for such applications, it is essential that: - CD derivatives are designed to self-organize in the aqueous phase to form said particles while also being able to accommodate at least one active substance within their cavity, - said particles remain stable over time.

[0032] As explained above, CDs and their derivatives have the advantage of being produced from compounds derived from natural resources, making them, in some cases, biodegradable. In order to limit the environmental impact of such particles obtained from CD derivatives and that they are as natural as possible, it is quite beneficial to limit the intake of surfactants which are classically used to promote the self-organization of CD derivatives but which are generally non-biodegradable products from synthetic chemistry.

[0033] Therefore, given all these needs, both in terms of improving solubility, forming an inclusion complex or self-organization in order to obtain particles that are stable over time, there is still a real interest in developing new bio-based CD derivatives that fully satisfy them.

[0034] The inventors of the present invention have succeeded in developing new CD derivatives which perfectly fulfill all these needs.

[0035] The invention relates to a CD derivative characterized in that it comprises: - glucosidic subunits of the following chemical structure (4):

[0036] [Chem.4]

[0037] in which x is an integer between 0 and 18, preferably between 0 and 12; - optionally at least one glucoside subunit of chemical structure (5):

[0038] [Chem.5] (5)

[0039] the total number of glucosidic subunits of chemical structure (4) and of chemical structure (5) is equal to an integer n between 5 and 30, preferably between 6 and 8, at least 2 x among the x of the glucosidic subunits of chemical structure (4) are different from each other.

[0040] The CD derivative must comprise at least 2 glucosidic subunits of chemical structure (4) which are different from each other, due to the fact that x is not the same integer in these at least 2 glucosidic subunits of chemical structure (4).

[0041] In embodiments of the invention, the CD derivative may not include a glucosidic subunit of chemical structure (5). The number of glucosidic subunits of chemical structure (5) is equal to 0 and the number of glucosidic subunits of chemical structure (4) is then equal to the integer n.

[0042] In embodiments of the invention in which the CD derivative comprises at least one glucosidic subunit of chemical structure (5), the total number of glucosidic subunits of chemical structure (4) and of the at least one glucosidic subunit of chemical structure (5) is equal to the integer n.

[0043] In one embodiment of the invention, n is equal to 6. The derivative of CD is a derivative of alpha-CD.

[0044] In one embodiment of the invention, n is equal to 7. The derivative of CD is a derivative of beta-CD.

[0045] In one embodiment of the invention, n is equal to 8. The derivative of CD is a derivative of gamma-CD.

[0046] In one embodiment of the invention, the CD derivative comprises glucosidic subunits of chemical structure (4) with 2 different x.

[0047] In one embodiment of the invention, the CD derivative comprises glucosidic subunits of chemical structure (4) with 3 different x.

[0048] In one embodiment of the invention, x can be between 4 and 10, namely x can be equal to 4, 5, 6, 7, 8, 9 or 10.

[0049] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 2 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 2 glucosidic subunits of chemical structure (4) in which x is equal to 4; - 3 glucosidic subunits of chemical structure (5).

[0050] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 2 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 1 glucosidic subunit of chemical structure (4) in which x is equal to 4; - 4 glucosidic subunits of chemical structure (5).

[0051] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 3 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 1 glucosidic subunit of chemical structure (4) in which x is equal to 4; - 3 glucosidic subunits of chemical structure (5).

[0052] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 3 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 2 glucosidic subunits of chemical structure (4) in which x is equal to 4; - 2 glucosidic subunits of chemical structure (5).

[0053] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 4 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 2 glucosidic subunits of chemical structure (4) in which x is equal to 4; - 1 glucosidic subunit with chemical structure (5).

[0054] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 4 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 1 glucosidic subunit of chemical structure (4) in which x is equal to 4; - 2 glucosidic subunits of chemical structure (5).

[0055] In one embodiment of the invention, n is equal to 7 and the derivative of CD comprises: - 5 glucosidic subunits of chemical structure (4) in which x is equal to 10; - 1 glucosidic subunit of chemical structure (4) in which x is equal to 4; - 1 glucosidic subunit with chemical structure (5).

[0056] The invention also relates to a method for preparing a CD derivative according to the invention as described above, which is characterized in that it comprises at least the following steps: a) A mixture is prepared comprising at least: - a native CD comprising n glucopyranose units, n being an integer between 5 and 30, preferably between 6 and 8, - an enzyme configured to catalyze a transesterification reaction at the hydroxyl group carried by the C2 carbon of the glucopyranose units of native CDs and CD derivatives; b) a first vinyl ester of the following chemical structure (6) is added to said mixture:

[0057] [Chem.6] (6)

[0058] wherein x is an integer between 0 and 18, preferably between 0 and 12, said 1st vinyl ester being in nB stoichiometry ni being an integer less than n, to carry out a first transesterification reaction between the native CD and the 1st vinyl ester and so as to obtain at the end of this first transesterification reaction a 1st CD derivative called "intermediate" in the reaction medium, the CD derivative called "intermediate" corresponds to the native CD in which ni hydroxyl groups carried by the C2 carbons of the glucopyranose units of said native CD have reacted with said 1st vinyl ester; (c) at least a second vinyl ester of chemical structure (6) whose x value is different from the x value of the first vinyl ester is added to the reaction medium containing the so-called "intermediate" CD derivative, said second vinyl ester being added in n2 stoichiometry, n2 being an integer such that the sum of ni and n2 is less than or equal to n, to carry out, in the presence of said enzyme, at least a second transesterification reaction between the first so-called "intermediate" CD derivative and at least a second vinyl ester in which n2 hydroxyl groups among the hydroxyl groups carried by the C2 carbons of the glucopyranose units of said so-called "intermediate" CD derivative have reacted with said second vinyl ester so as to obtain at the end of at least a second transesterification reaction said CD derivative according to the invention; d) Optionally, step c) is repeated one or more times; all vinyl esters added to the reaction medium during said preparation process have chemical structure (6), all x of these vinyl esters are different from each other and the sum of the stoichiometries of all these vinyl esters is less than or equal to n.

[0059] As explained above, by "native CD" we mean a natural CD or in other words a CD that has not been chemically modified.

[0060] Preferably, the native CD is chosen from the group consisting of alpha-CD (n equals 6), beta-CD (n equals 7), and gamma-CD (n equals 8). Most preferably, the native CD is beta-CD.

[0061] In an advantageous embodiment, prior to step a), the native CD can be solubilized in a non-aqueous solvent, preferably a solvent preserving the integrity of the enzyme and in which native CD can be solubilized. This solvent can be an organic solvent or an ionic liquid that meets these criteria. For example, the organic solvent can be chosen from the group consisting of dimethyl sulfoxide (hereafter abbreviated as "DMSO"), dimethyl formamide (hereafter abbreviated as "DMF"), and pyridine. For example, the ionic liquid can be 1-n-butyl-3-methylimidazolium. The choice of a suitable solvent is perfectly within the capabilities of a person skilled in the art.

[0062] The x of the chemical structures (6) of all the vinyl esters used in the process for preparing the CD derivative according to the invention is an integer between 0 and 18, preferably between 0 and 12. Preferably, the vinyl esters used in this process are selected from the group consisting of vinyl butyrate, vinyl hexanoate, vinyl decanoate, vinyl octanoate, vinyl laurate, and vinyl myristate. Most preferably, these are vinyl butyrate and vinyl decanoate.

[0063] The enzyme is configured to catalyze a transesterification reaction at the hydroxyl groups attached to the C2 carbons of the glucopyranose units of: - any native CD and - any CD derivative, including at least one so-called "intermediate" CD derivative.

[0064] In other words, the enzyme is regioselective of the hydroxyl groups carried by the C2 carbons of the glucopyranose units of native CDs and of CD derivatives, in particular at least one so-called “intermediate” CD derivative.

[0065] The enzyme can be a protease or a lipase.

[0066] Preferably, the enzyme is thermolysin. Thermolysin is a protease. For example, it could be the enzyme marketed by Sigma Aldrich under the trade name P1512-250mg.

[0067] In an advantageous embodiment of the invention, the enzyme is immobilized on a support. The support may be diatomaceous earth (for example, Celite®). Immobilizing the enzyme on a support is a conventional procedure and therefore perfectly within the capabilities of a person skilled in the art.

[0068] Immobilizing the enzyme on a support (for example, Celite®) provides the following advantages: - the stabilization of the enzyme during transesterification reactions; - to facilitate the purification of the CD derivative following transesterification reactions; - the repeated use of the same enzyme for several transesterification reactions.

[0069] Without limiting the scope of the invention, the enzyme can be immobilized on a support in the following manner (the so-called "adsorption" method): - the enzyme is mixed, preferably at room temperature (e.g. 20°C), with a buffer solution (e.g. a 3-morpholino-l-propanesulfonic buffer solution with a pH of approximately 7) to obtain an enzyme suspension; - the enzyme suspension thus obtained is added to a support (for example celite®) in order to obtain a mixture; - the liquid phase of the mixture thus obtained is removed, for example under reduced pressure and preferably at room temperature, so as to obtain the immobilized enzyme.

[0070] During the first transesterification reaction, according to the stoichiometry of the first vinyl ester which is implemented, a part of the hydroxyl groups of the C2 carbons of the glucopyranose units is substituted to give glucosidic subunits of the chemical structure (4) as detailed above.

[0071] In other words, the degree of molecular substitution of the hydroxyl groups of the C2 carbons of the glucosidic subunits of chemical structure (4) with a determined x corresponding to the x of chemical structure (6) of the first vinyl ester depends on the stoichiometry of the first vinyl ester used in the first transesterification reaction. Depending on the desired degree of molecular substitution for the first transesterification reaction, it is perfectly within the capabilities of a person skilled in the art to determine the stoichiometry of the first vinyl ester to be used (or in other words, the amount of first vinyl ester to be used in the reaction medium).

[0072] In this regard, within the framework of the present invention, the "degree of molecular substitution" corresponds to the number of hydroxyl groups on the C2 carbons that are substituted to give glucosidic subunits of the chemical structure (4) with a determined x corresponding to the x of the chemical structure (6) of the vinyl ester determined for a specific transesterification reaction during the preparation process according to the invention, and this per molecule of native CD used. The degree of molecular substitution thus takes into account the number of glucopyranose units comprising the native CD.

[0073] The “total degree of molecular substitution” thus corresponds to the number of all the hydroxyl groups on the C2 carbons that are substituted to give glucosidic subunits of the chemical structure (4) with determined x values ​​corresponding to the x values ​​of the chemical structures (6) of the vinyl esters used for all the transesterification reactions carried out during the preparation process according to the invention, per molecule of native CD used in step a). The degree of Total molecular substitution is therefore less than or equal to n, which corresponds to the number of glucopyranose units in native CD.

[0074] The process for preparing the CD derivative according to the invention comprises at least 2 transesterification reactions which employ vinyl esters all different from one another, namely in the value of x of their chemical structure (6).

[0075] At least a second vinyl ester, different from the first vinyl ester in terms of the x values ​​of their chemical structures (6), is added to the reaction medium such that at least a second transesterification reaction is initiated. During this second transesterification reaction, all or part of the hydroxyl groups of the C2 carbons of the glucopyranose units of the so-called "intermediate" CD derivative (in other words, the hydroxyl groups of the C2 carbons of the glucopyranose units of the native CD that were not substituted during the first transesterification reaction) are substituted to give glucosidic subunits of the chemical structure (4) in which x corresponds to x of the chemical structure (6) of at least a second vinyl ester.

[0076] As a result of at least a 2nd transesterification reaction, a CD derivative according to the invention is obtained in which all or part of the hydroxyl groups of the C2 carbons of the glucopyranose units of the so-called "intermediate" CD derivative have been substituted to give glucosidic subunits of the chemical structure (4) in which the length of the fatty chain is different.

[0077] Depending on the desired degree of substitution of the hydroxyl groups of the C2 carbons of the remaining glucopyranose units to give, from at least one 2nd vinyl ester, glucosidic subunits of the chemical structure (4), it is perfectly within the reach of a person skilled in the art to determine the stoichiometry of at least one 2nd vinyl ester to be used (or in other words the amount of at least one 2nd vinyl ester to be used in the reaction medium).

[0078] As explained above, the process for preparing a CD derivative according to the invention may include more than 2 transesterification reactions, for example 3 transesterification reactions, 4 transesterification reactions, 5 transesterification reactions, with respectively 3 different vinyl esters, 4 different vinyl esters, 5 different vinyl esters.

[0079] The vinyl esters used in the preparation of the CD derivative according to the invention must all be different from each other with respect to x of their chemical structure (6).

[0080] Furthermore, the vinyl esters must be added to the reaction medium in determined stoichiometries such that the sum of the stoichiometries of all the vinyl esters used during the process of preparing a CD derivative according to the invention is less than or equal to n (namely the number of units of glucopyranose which comprises the native CD used in step a) of said preparation process).

[0081] Because the hydroxyl groups of the C2 carbons of the glucopyranose units of all the native CD molecules present in the reaction medium are not all substituted to the same degree of molecular substitution during each of the transesterification reactions carried out during the preparation process, a complex mixture containing different CD derivatives according to the invention, the structure of which has been described above, is obtained at the end of this preparation process.

[0082] However, during the implementation of the process for preparing a CD derivative according to the invention, it was found that, because the enzyme (preferably thermolysin) was very regioselective, the number of different types of CD derivatives thus obtained was relatively small (about six) compared to the theoretical number expected considering all possible combinations of substitution of hydroxyl groups according to various degrees of molecular substitution.

[0083] All or part of the transesterification reactions of the process for preparing a CD derivative can be carried out simultaneously or sequentially.

[0084] In one embodiment of the invention, all transesterification reactions are carried out simultaneously. Thus, in this embodiment of the invention, steps b) and c) and, optionally d) are performed simultaneously.

[0085] In one embodiment of the invention, all transesterification reactions are carried out sequentially. In other words, in this embodiment of the invention, all transesterification reactions are carried out one after the other (i.e., successively).

[0086] In one embodiment of the invention, after step b) and before step c), the so-called "intermediate" CD derivative can be recovered after precipitation (for example, by centrifugation or filtration) of the reaction medium of the first transesterification reaction and, optionally, purified (for example, as described below). Step c) is then carried out in a reaction medium comprising at least the so-called "intermediate" CD derivative thus recovered (and optionally purified) and said enzyme configured to catalyze a transesterification reaction at the hydroxyl group on carbon C2 of the glucopyranose units of native CDs and CD derivatives, to which at least one second vinyl ester of chemical structure (6) is added so as to carry out at least one second transesterification reaction.

[0087] In other words, in this embodiment of the invention, the transesterification reactions are carried out sequentially and between each transesterification reaction, the so-called "intermediate" CD derivatives thus synthesized are recovered and possibly purified so that each new transesterification reaction is initiated with purified CD derivatives, known as "intermediate" derivatives. In other words, the CD derivatives are purified as they are obtained in the reaction medium to continue the transesterification reactions based on purified CD derivatives.

[0088] In another embodiment of the invention, the transesterification reactions are carried out sequentially by directly and progressively adding the other vinyl ester(s) to the reaction medium, without having recovered or possibly purified the so-called "intermediate" CD derivatives obtained as the vinyl ester(s) are added. In other words, in this embodiment of the invention, there is no intermediate purification of the CD derivatives obtained in the reaction medium.

[0089] In one embodiment of the invention, part of the transesterification reactions are carried out sequentially and the remaining transesterification reactions are carried out simultaneously.

[0090] In one embodiment of the invention, at the end of step c) or optionally at the end of step d), the CD derivative according to the invention thus obtained is recovered and optionally purified.

[0091] The conditions of the transesterification reactions implemented during the process of preparing a CD derivative according to the invention may advantageously be at least one of the following, taken alone or in combination thereof: - the temperature of the reaction medium can be between 20°C and 70°C, preferably between 40°C and 45°C; for example 45°C; - the reaction medium can be subjected to agitation, for example at an agitation speed of between 1 revolution / minute and 500 revolutions / minute, preferably between 200 revolutions / minute and 250 revolutions / minute.

[0092] Following the transesterification reactions, advantageously, the CD derivative thus prepared can be recovered and purified.

[0093] Indeed, at the end of the transesterification reactions, a synthetic product containing the unpurified CD derivative according to the invention is obtained.

[0094] Without limiting the scope of the invention, in a first embodiment of the invention, the recovery and purification of the CD derivative can be carried out in the following manner: 1) the enzyme is removed by centrifugation or filtration from the reaction medium thus obtained at the end of the last transesterification reaction and the supernatant or filtrate is recovered; 2) the synthesis product is precipitated from the supernatant (or filtrate) thus recovered by mixing in a non-solvent (i.e. a solvent in which the CD derivative according to the invention is not soluble) of the synthesis product (for example by adding a volume of an aqueous solution of methanol containing 35% by volume of methanol for a volume of supernatant); 3) in order to eliminate any possible traces of synthesis solvent (for example the solvent in which the native CD was optionally solubilized, in particular DMSO), the synthesis product is then isolated by solubilization cycles in a volatile organic solvent (for example tetrahydrofuran (hereafter abbreviated as "THF") or acetone) and then by precipitation in acetonitrile; 4) the isolated product obtained at the end of step 3) is then solubilized in a solvent (e.g. ethanol, acetone, THF), then filtered and dried (e.g. under reduced pressure or under vacuum) so as to obtain the CD derivative in a purified form.

[0095] Without limiting the scope of the invention, in a second embodiment of the invention, the recovery and purification of the CD derivative can be carried out in the following manner: 1) the enzyme is removed by centrifugation or filtration from the reaction medium thus obtained at the end of the last transesterification reaction and the supernatant or filtrate is recovered; 2) the supernatant or filtrate thus obtained is diluted 1 / 3 to 1 / 4 in water, preferably distilled water, which is then frozen (for example at -80°C); 3) The solvent in which the native CD and water were solubilized is removed by sublimation under reduced pressure (e.g. 0.002 mbar), e.g. at room temperature (20°C), so as to obtain the CD derivative in a purified form.

[0096] The implementation of the recovery and purification of the CD derivative according to the invention is perfectly within the reach of a person skilled in the art.

[0097] As explained above, the inventors discovered that the characteristics of the CD derivatives according to the invention as detailed above enabled them to spontaneously self-organize satisfactorily in a solvent (e.g. water) to obtain particles of the CD derivative.

[0098] Therefore, the invention also relates to a particle (micro- or nanoparticle) which is characterized in that it comprises at least one CD derivative according to the invention as described above or at least one CD derivative obtained according to the preparation process as described above.

[0099] Depending on its size, the particle according to the invention can be a microparticle or a nanoparticle.

[0100] In one embodiment of the invention, said particle may further comprise at least one active substance.

[0101] As mentioned above, CDs and CD derivatives are host molecules that can form inclusion complexes with at least one guest molecule such as an active substance.

[0102] In one embodiment of the invention, said CD derivative according to the invention and at least one active substance can form an inclusion complex.

[0103] In another embodiment of the invention, said particle further comprises at least one active substance that does not form an inclusion complex with said CD derivative according to the invention. In this embodiment, the active substance is encapsulated within the particle based on the CD derivative according to the invention.

[0104] The active substance may be chosen from the group consisting of pharmaceutical active ingredients (for human or animal use), cosmetic active ingredients, plant protection active compounds, food active compounds, food active compounds, biological active compounds, colorants and pigments.

[0105] The active substance may be any suitable molecule that may or may not form an inclusion complex with the CD derivative according to the invention. The choice of the active substance is perfectly within the capabilities of a person skilled in the art.

[0106] The particle according to the invention may comprise one or more different active substances.

[0107] In one embodiment of the invention, the particle comprises an active substance that may or may not form an inclusion complex with the CD derivative. In another embodiment of the invention, the particle comprises two different active substances that may or may not form an inclusion complex with the CD derivative.

[0108] The particle size according to the invention can be between 0.1 pm and 2 pm, preferably between 0.15 pm and 1 pm.

[0109] Advantageously, the particles according to the invention can be spheroidal.

[0110] The invention also relates to a method for manufacturing particles according to the invention which is characterized in that it comprises at least the following steps: a) a first mixture is prepared comprising at least one CD derivative according to the invention as described above or at least one CD derivative obtained according to the preparation process according to the invention as described above, a polar organic solvent and, optionally, at least one first surfactant and / or at least one first active substance; b) a second mixture is prepared comprising at least water and, optionally, at least one second surfactant and / or at least one second active substance; c) One of the 1st or 2nd mixture is added to the other mixture, so as to obtain a suspension of said particles.

[0111] In other words, in the first mixture, the presence of the first surfactant and the first active substance is optional. In the second mixture, the presence of the second surfactant and the second active substance is optional.

[0112] In one embodiment of the invention, said 1st mixture may comprise a first active substance.

[0113] In one embodiment of the invention, said 1st mixture may comprise two 1st active substances.

[0114] In step a), the polar organic solvent is advantageously miscible in any proportion with water, preferably distilled water.

[0115] In step a), the polar organic solvent can be chosen from the group consisting of acetone, methanol, ethanol, isopropanol and THF, taken alone or in mixtures thereof.

[0116] In step a), the first surfactant may be a non-ionic lipophilic surfactant, preferably with an HLB between 4 and 8. HLB is the English acronym for "Hydrophilic-Lipophilic Balance". Said first surfactant may be a sorbitan ester (for example, sorbitan oleate).

[0117] In step a), the first active substance is preferably a molecule soluble and / or miscible in the first mixture. Said first active substance is insoluble in water. Thus, the first active substance is preferably lipid-soluble. The first active substance may be chosen from pharmaceutical (for human or animal use) or cosmetic active ingredients, plant protection product active compounds, food active compounds, food processing active compounds, biological active compounds, colorants, and pigments. It may, for example, be a derivative of vitamin C, vitamin E, curcumin, or a lipophilic preservative.

[0118] In step a), the first mixture may further comprise at least one lipophilic compound. This may be a vegetable oil (e.g. olive oil, sunflower oil), a synthetic oil (e.g. Miglyol®), an essential oil (e.g. tea tree essential oil), a butter, or any other lipophilic compound (e.g. benzyl benzoate, isopropyl myristate, a hydrocarbon).

[0119] In this embodiment of the invention, namely when the first mixture further comprises at least one lipophilic compound, a suspension of capsular-type particles is obtained. These particles comprise: - an outer envelope containing at least one CD derivative according to the invention as described above or obtained according to the preparation process as described above, as well as optionally the 1st surfactant and the 2nd surfactant; - a core based on the lipophilic compound in which the first active substance is optionally dispersed or solubilized, said core is surrounded by the outer envelope.

[0120] If a 2nd active substance is present in the 2nd mixture, it is found in the aqueous phase of the particle suspension.

[0121] The outer envelope is in the form of a wall of very regular thickness.

[0122] Capsular-type particles have the advantage that their nucleus allows a greater support for active substances.

[0123] In this regard, it should be noted that when the first mixture is devoid of lipophilic compound, a suspension of matrix-type particles is obtained. These particles are dense and constitute a matrix, or in other words, a network. In other words, these matrix-type particles do not have a cell wall.

[0124] In step b), the 2nd surfactant may be a non-ionic hydrophilic surfactant, preferably with an HLB greater than or equal to 10. Said 2nd surfactant may for example be chosen from the group consisting of sugar-derived surfactants, for example alkyl glucosides such as decyl glucoside.

[0125] In step b), the 2nd active substance is preferably a molecule soluble in the 2nd mixture. The 2nd active substance may be chosen from among pharmaceutical active compounds (for human or animal use), cosmetic active compounds, plant protection active compounds, food active compounds, food processing active compounds, biological active compounds, colorants, pigments and preservatives that are hydrophilic.

[0126] In step b), the water can be distilled, salted, acidified or alkalized water.

[0127] The particle preparation process according to the invention can be carried out at a temperature that has little or no effect on its proper execution. This temperature can be any temperature at which the first and second mixtures are liquid. The choice of temperature is perfectly within the capabilities of a person skilled in the art. The temperature can be ambient temperature (approximately 20°C).

[0128] The ratio of the volume of the 1st mixture to the 2nd mixture can be between 3 / 1 and 1 / 5, preferably between 1 / 2 and 2 / 1.

[0129] The mass percentage of at least one 1st surfactant and / or at least one 2nd surfactant (if used during the particle preparation process according to the invention), expressed in relation to the total mass of the particle suspension obtained at the end of step c), may be between 0.1% and 10%, preferably between 0.2% and 2%.

[0130] Preferably, step c) is carried out under stirring, for example at a stirring speed of between 50 revolutions / minute and 1000 revolutions / minute, preferably between 250 revolutions / minute and 500 revolutions / minute.

[0131] Agitation can be obtained by means of a magnetic stir bar.

[0132] In step c), the particle suspension forms almost instantaneously. In other words, in the aqueous phase, the CD derivatives according to the invention spontaneously self-organize.

[0133] In one embodiment of the invention, at the end of step c), all or part of the polar organic solvent can be removed. The removal of all or part of the polar organic solvent can, for example, be carried out under reduced pressure. This step of removing the polar organic solvent is perfectly within the capabilities of a person skilled in the art.

[0134] Furthermore, at the end of step c), or possibly at the end of this polar organic solvent removal step if this step is performed, all or part of the water can be removed under vacuum until a suspension of particles according to the invention is obtained at a desired concentration, or particles in solid form. This step of concentrating the particle suspension is perfectly within the capabilities of a person skilled in the art.

[0135] The particle suspension obtained at the end of step c), or possibly at the end of the polar organic solvent removal step, or possibly at the end of the particle suspension concentration step if this or these steps are carried out, can be filtered. The filtration of the particle suspension is perfectly within the capabilities of a person skilled in the art.

[0136] Following step c), the suspension of particles thus obtained can also be sterilized, buffered (for example at physiological pH), and lyophilized.

[0137] The particles according to the invention, whether matrix or capsular, have the advantage of allowing a high incorporation rate of the first active substance. This is due to the possibility of two incorporation systems (i.e., molecular or particulate encapsulation) of the active substances in said particles: - firstly, loading the first active substance into the matrix in the case of matrix-type particles or into the nucleus in the case of capsular-type particles, and - secondly, a possible charge of the first active substance in the cavity of the CD derivative, due to the fact that said first active substance may have a conformation suitable with respect to the cavity of the CD derivative.

[0138] Thanks to the particles according to the invention, the active substances exhibit improved physico-chemical stability due to their integration within particles remaining stable over time which are obtained by spontaneous and durable self-organization of CD derivatives according to the invention and which can further form inclusion complexes with said first active substances.

[0139] Advantageously, no surfactant is used during the manufacturing process of particles according to the invention so that said particles are as natural and biodegradable as possible.

[0140] Because the particles according to the invention comprise CD derivatives capable of forming inclusion complexes with one or more active substances, they offer the following advantages: - they allow the bioavailability of said active substances to be modulated; - they improve the chemical stability of said active substances, by protecting them from light and / or interactions with other incompatible components; - they ensure a prolonged and controlled release of said active substances, for example in the dermis, in the case of cosmetic active compounds.

[0141] The particles according to the invention are therefore particularly suitable for incorporation into compositions requiring the encapsulation of active substances for the reasons detailed in particular in the introduction to the description of the present invention.

[0142] Therefore, the invention also relates to a composition, preferably a composition chosen from pharmaceutical, cosmetic, food, agri-food, phytosanitary, paint, varnish, textile dye compositions, which is characterized in that it comprises at least particles according to the invention as described above or obtained according to the manufacturing process as described above.

[0143] The invention and its advantages are illustrated in the examples below.

[0144] Synthesis of products: comparative CD derivatives and CD derivatives according to the invention:

[0145] For all the syntheses described below, the enzyme used was thermolysin, more specifically, the type X protease isolated from Bacillus thermoproteolyticus rokko marketed by the company Sigma Aldrich under the trade name P1512-250mg.

[0146] Regeneration of celite ® (diatomaceous earth):

[0147] The thermolysin immobilization support was celite®, which was regenerated as follows: 10 g of celite® were regenerated over 6 hours at 80°C in 100 mL of a nitric acid solution (with a nitric acid volume percentage of 69.5%) using a reflux setup. The nitric acid was then removed by filtration, and the celite® was washed with distilled water until a pH of stable of 6.5-7. The regenerated celite® was oven-dried at 80°C before being stored in an airtight bottle.

[0148] Immobilization of thermolysin on celite®:

[0149] Thermolysin was immobilized on celite® as follows: 100 mg of thermolysin was mixed at 20°C in 5 mL of a 3-morpholino-l-propanesulfonic acid buffer solution (concentration of 50 mmol / L and pH of 7.5). The resulting preparation was added to 1 g of regenerated celite®. The liquid phase of this preparation was slowly removed at 25°C under reduced pressure to obtain 100 mg of thermolysin immobilized on 1 g of celite®.

[0150] Synthesis of comparative product 1: derivative of comparative CD 1:

[0151] 1.00015 g (782 pmol) of native beta-CD was solubilized in 9.0981 g of DMSO, then mixed with 100.08 mg of thermolysin immobilized on 1 g celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the thermolysin immobilized on celite® in suspension in the reaction medium.

[0152] Next, with a view to a single transesterification reaction with a degree of molecular substitution of 4, 0.63007 g (313 mmol) of vinyl decanoate was introduced into the reaction medium.

[0153] The reaction medium thus obtained was incubated at a temperature of 45°C during which the transesterification reaction took place.

[0154] The transesterification reaction of CD was monitored by thin-layer chromatography by comparison with native beta-CD dissolved in DMSO. The mobile phase consisted of 2-propanol / pure ethyl acetate / distilled water / 30% ammonia (6 / 1 / 3 / 1 v / v / v / v) and was detected with a developer comprising 5 g of potassium dichromate in 100 mL of an aqueous sulfuric acid solution containing 40% by volume of said sulfuric acid.

[0155] Following the transesterification reaction, the comparative product 1 thus synthesized was recovered in the following way from the reaction medium: it was separated from the thermolysin immobilized on celite® by recovering the centrifugation supernatant from the reaction medium.

[0156] The CD derivatives synthesized in solution in the supernatant were precipitated by mixing a volume of this supernatant with an equal volume of a methanol solution (more precisely a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution).

[0157] The precipitate obtained was isolated (centrifugation) and traces of DMSO were removed by 3 cycles of solubilization of the product in THF / precipitation in acetonitrile and filtration.

[0158] The product thus recovered was solubilized in ethanol, filtered and dried under reduced pressure. It was a first derivative of comparative CD 1 (i.e. comparative product 1).

[0159] Synthesis of product invention 1: CD derivative according to invention 1;

[0160] 200.2 mg (20.6 pmol) of comparator product 1 were solubilized in 5.1035 g of DMSO, then mixed with 83.33 mg of thermolysin immobilized on 1 g of celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a solution of comparative product 1 in the presence of the immobilized thermolysin.

[0161] Next, 0.0623 g (103 pmol) of vinyl butyrate were introduced into the comparator product 1 solution in the presence of immobilized thermolysin.

[0162] The reaction medium thus obtained was incubated at a temperature of 45 °C for a period of 96 hours during which a transesterification reaction took place.

[0163] The transesterification reaction was monitored by thin-layer chromatography in the same manner as for comparator product 1. The mobile phase consisted of 2-propanol / pure ethyl acetate / distilled water / 30% ammonia (by volume in the proportions 9 / 1 / 2 / 1 v / v / v / v) and was detected with a developer comprising 5 g of potassium dichromate in 100 mL of an aqueous sulfuric acid solution containing 40% by volume of said sulfuric acid.

[0164] Following the transesterification reaction, the product of invention 1 thus synthesized was recovered and purified in the same way as for the comparative product 1. It was a 1st derivative of CD according to the invention.

[0165] Synthesis of comparative product 2: derivative of comparative CD 2:

[0166] 1.00018 g (881 pmol) of beta-CD was solubilized in 8.4681 g of DMSO, then mix with 83.16 mg of thermolysin immobilized on 1 g of celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the immobilized thermolysin.

[0167] Next, 1.2647 g (3.13 mmol) of vinyl decanoate was introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0168] The reaction medium thus obtained was incubated in the microwave at a temperature of 45°C for a period of 6 hours during which the transesterification reaction took place.

[0169] The transesterification reaction was monitored by thin-layer chromatography in the same manner as for comparator product 1.

[0170] Following the transesterification reaction, the comparative product 2 thus synthesized was recovered from the reaction medium as follows: it was separated from the thermolysin immobilized on celite® by collecting the centrifugation supernatant from the reaction medium. The centrifugation supernatant was precipitated in 30 mL distilled water. The resulting precipitate was washed in approximately 70 mL of distilled water, then solubilized in approximately 50 mL of ethanol, and then filtered through pleated filter paper.

[0171] The filtrate was dried under reduced pressure to remove the ethanol in order to obtain the comparative product 2 in a purified form. This was a second comparative CD derivative.

[0172] Synthesis of product invention 2: CD derivative according to invention 2:

[0173] 1 g (881 pmol) of native beta-CD was solubilized in 9.5233 g of DMSO, then mix with 83.33 mg of immobilized thermolysin on 1 g celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the immobilized thermolysin.

[0174] Next, 0.1893 g of vinyl butyrate (1.65 mmol) was introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0175] The reaction medium thus obtained was incubated at a temperature of 45°C under stirring at 250 rpm for a period of 25 days during which the first transesterification reaction took place.

[0176] The first transesterification reaction was monitored by thin-layer chromatography in the same manner as for comparator product 1.

[0177] Following the first transesterification reaction, the intermediate product thus synthesized was recovered in the reaction medium as follows: it was separated from the thermolysin immobilized on celite® by recovering the centrifugation supernatant from the reaction medium.

[0178] An extemporaneous preparation of 83.33 mg of thermolysine immobilized on 1 g of celite® was added to the centrifugation supernatant.

[0179] Then 0.9703 g (4.89 mmols) of vinyl decanoate was added.

[0180] The reaction medium thus obtained was again incubated at 45 °C under stirring at 250 rpm for a period of 144 hours during which the 2nd transesterification reaction took place.

[0181] Following the 2nd transesterification reaction, the synthesis product present in the reaction medium was precipitated by mixing a volume of said reaction medium with an equal volume of a methanol solution (more precisely a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution).

[0182] The precipitate obtained was isolated (centrifugation) and traces of DMSO were removed by 3 cycles of solubilization of the product in THF / precipitation in acetonitrile and filtration.

[0183] The product thus recovered from invention 2 was purified as follows: it was solubilized in ethanol, filtered, and dried under reduced pressure. This was a second CD derivative according to the invention.

[0184] Synthesis of product invention 3: CD derivative according to invention 3:

[0185] 1 g (881 pmol) of native beta-CD was solubilized in 9.5233 g of DMSO, then mix with 83.33 mg of immobilized thermolysin on 1 g celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the immobilized thermolysin.

[0186] Next, 0.3645 g of vinyl butyrate (3.19 mmol) was introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0187] The reaction medium thus obtained was incubated at a temperature of 45°C under stirring at 250 rpm for a period of 25 days during which the first transesterification reaction took place.

[0188] The first transesterification reaction was monitored by thin-layer chromatography in the same manner as for comparator product 1.

[0189] Following the first transesterification reaction, the intermediate product thus synthesized was recovered in the following way from the reaction medium: it was separated from the thermolysin immobilized on celite® by recovering the centrifugation supernatant from the reaction medium.

[0190] An extemporaneous preparation of 83.33 mg of thermolysine immobilized on 1 g of celite® was added to the centrifugation supernatant.

[0191] Then 0.9821 g (4.95 mmols) of vinyl decanoate was added.

[0192] The reaction medium thus obtained was again incubated at 45 °C under stirring at 250 rpm for a period of 144 hours during which the 2nd transesterification reaction took place.

[0193] Following the second transesterification reaction, the synthesis product present in the reaction medium was precipitated by mixing a volume of said reaction medium with an equal volume of a methanol solution (more precisely, a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution). Then, the DMSO was removed by solubilization / precipitation in a THF / acetonitrile system.

[0194] The product thus recovered from invention 3 was purified as follows: it was solubilized in ethanol, filtered, and dried under reduced pressure. This was a third CD derivative according to the invention.

[0195] Synthesis of the product invention 4 l derivative of CD according to invention 4:

[0196] 1 g (881 pmol) of native beta-CD was solubilized in 9.1070 g of DMSO, then mixed with 83.33 mg of thermolysin immobilized on 1 g of celite® under stirring (250 revolutions / minute) at a temperature of 45°C in order to obtain a beta-CD solution in the presence of immobilized thermolysin.

[0197] Next, 0.4522 g (3.96 mmol) of vinyl butyrate was introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0198] The reaction medium thus obtained was incubated at a temperature of 45°C under stirring at 250 rpm for a period of 3 days during which the first transesterification reaction took place.

[0199] Then, after these 3 days of incubation, 0.6309 g of vinyl decanoate (3.18 mmols) was added to the reaction medium.

[0200] The reaction medium thus obtained was again incubated at 45 °C under stirring at 250 rpm for a period of 114 hours during which the 2nd transesterification reaction took place.

[0201] Following the 2nd transesterification reaction, the synthesis product present in the reaction medium was precipitated by mixing a volume of said reaction medium with an equal volume of a methanol solution (more precisely a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution).

[0202] The precipitate obtained was isolated (centrifugation) and traces of DMSO were removed by 3 cycles of solubilization of the product in THF / precipitation in acetonitrile and filtration.

[0203] The product thus recovered according to invention 4 was purified as follows: it was solubilized in ethanol, filtered, and dried under reduced pressure. This was a 4th CD derivative according to the invention.

[0204] Synthesis of the product of invention 5: CD derivative according to invention 5:

[0205] 1.00017 g (881 pmol) of native beta-CD was solubilized in 8.2855 g of DMSO, then mixed with 83.33 mg of thermolysin immobilized on 1 g celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the immobilized thermolysin.

[0206] Next, 0.1810 g (1.58 mmol) of vinyl butyrate and 1.2560 g (6.33 mmol) of vinyl decanoate were introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0207] The reaction medium thus obtained was incubated at a temperature of 45°C under stirring at 250 rpm for a period of 114 hours during which 2 transesterification reactions took place with the 2 aforementioned vinyl esters.

[0208] Following these two transesterification reactions, the synthesis product present in the reaction medium was precipitated by mixing a volume of said reaction medium with an equal volume of a methanol solution (more precisely, a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution).

[0209] The precipitate obtained was isolated (centrifugation) and traces of DMSO were removed by 3 cycles of solubilization of the product in THF / precipitation in acetonitrile and filtration.

[0210] Synthesis of product invention 6: CD derivative according to invention 6 j.

[0211] 1.00111g (881 pmol) of native beta-CD was solubilized in 9.0665 g of DMSO, then mixed with 83.33 mg of thermolysin immobilized on 1 g celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the immobilized thermolysin.

[0212] Next, 0.3244 g (2.84 mmol) of vinyl butyrate and 0.6397 g (3.22 mmol) of vinyl decanoate were introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0213] The reaction medium thus obtained was incubated at a temperature of 45°C under stirring at 250 rpm for a period of 114 hours during which 2 transesterification reactions took place with the 2 aforementioned vinyl esters.

[0214] Following these 2 transesterification reactions, the synthesis product present in the reaction medium was precipitated by mixing a volume of said reaction medium with an equal volume of a methanol solution (more precisely a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution).

[0215] The precipitate obtained was isolated (centrifugation) and traces of DMSO were removed by 3 cycles of solubilization of the product in THF / precipitation in acetonitrile and filtration.

[0216] Synthesis of product invention 7: CD derivative according to invention 7:

[0217] 1 g (881 pmol) of native beta-CD was solubilized in 9.0915 g of DMSO, then mixed with 83.33 mg of thermolysin immobilized on 1 g celite® under agitation (250 rpm) at a temperature of 45°C so as to obtain a beta-CD solution in the presence of the catalyst in suspension.

[0218] Next, 0.6293 g (3.17 mmol) of vinyl decanoate was introduced into the beta-CD solution in the presence of immobilized thermolysin.

[0219] The reaction medium thus obtained was incubated at a temperature of 45 °C under stirring at 250 rpm for a period of 3 days during which the first transesterification reaction took place.

[0220] Then, after these 3 days of incubation, 0.5781 g of vinyl butyrate (5.06 mmoles) was added to the reaction medium.

[0221] The reaction medium thus obtained was again incubated at 45 °C under stirring at 250 rpm for a period of 114 hours during which the 2nd transesterification reaction took place.

[0222] Following the 2nd transesterification reaction, the synthesis product present in the reaction medium was precipitated by mixing a volume of said reaction medium with an equal volume of a methanol solution (more precisely a mixture of methanol and distilled water, the volume of methanol representing 30% of the volume of the methanol solution).

[0223] The precipitate obtained was isolated (centrifugation) and traces of DMSO were removed by 3 cycles of solubilization of the product in THF / precipitation in acetonitrile and filtration.

[0224] The product thus recovered from invention 7 was purified as follows: it was solubilized in ethanol, filtered, and dried under reduced pressure. This was a 7th derivative of CD according to the invention.

[0225] Characterization of the synthesized products j.

[0226] All synthesized products were characterized by a MALDLTOF type mass spectrometry method (abbreviated "MS", as it is the English acronym for "mass spectrometry"): - "MALDI" being the English acronym for "Matrix Assisted Laser Desorption Ionisation"; - "TOF" being the English acronym for "Time-Of-Flight".

[0227] This method is generally referred to by the English acronym "MALDL TOF-MS" and can be translated as "matrix-assisted laser desorption-ionization time-of-flight mass spectrometry analysis method". It is therefore a mass spectrometer coupling a matrix-assisted laser ionization source and a time-of-flight analyzer.

[0228] We describe below the implementation of the characterization of comparative product 1. All other synthesized products were characterized in the same way.

[0229] Comparative product 1 was solubilized in THF (10 pg / pL) to obtain a solution of comparative product 1.

[0230] A matrix solution was prepared by solubilizing 2,5-dihydroxybenzoic acid (hereinafter abbreviated "DHB") in THF (20 mg / mL).

[0231] For the analysis, a mixture of 0.5 pL of the comparator product 1 solution and 0.5 pL of the matrix solution was deposited on a MALDI plate and dried in cold air to crystallize the product on the sample holder (analysis in vacuum).

[0232] The mass spectra were acquired using a time-of-flight mass spectrometer equipped with a reflectron (namely an electrostatic mirror or "ion mirror") which deflected the positive ions with an electric field, thus doubling the ion's flight path length and increasing the spectrometer's resolution. The time-of-flight spectra were generated by averaging the signals from 10 repetitions of 10 different points (non-homogeneous deposition and desorption of the material at the location of the previous shot) with a frequency of 1000 shots / second.

[0233] The MALDLTOF-MS method has the advantage of achieving resolutions of 20,000 and thus being able to visualize molecules of similar masses.

[0234] MALDI / TOF analysis of all synthesized products showed for each of them a set of signals confirming the presence of a statistical mixture of differently acylated CD derivatives.

[0235] Indeed, as explained above, the synthetic products obtained at the end of the process of preparing a CD derivative according to the invention are in reality a complex mixture of different CD derivatives because the hydroxyl groups of the C2 carbons of the glucopyranose units of all the native CD molecules present in the reaction medium have not all been substituted according to the same degree of molecular substitution.

[0236] The identification of the different CD derivatives was carried out by comparison with the theoretical molecular masses of native β-CD, 1 to 7 times substituted at the hydroxyl groups of the C2 carbons of its glucopyranose units by the aliphatic chains provided by vinyl decanoate and / or vinyl butyrate, taking into account the stoichiometries of these two vinyl esters used in the transesterification reactions of the syntheses of the products according to the invention and the comparative products. Subsequently, the relative intensity of the different CD derivatives was calculated.

[0237] Table 1 below details for comparative product 1, as a function of the number of substitutions of the hydroxyl groups of the C2 carbons of the glucopyranose units of native beta-CD to give glucosidic subunits of chemical structure (4) with x equal to 10 (because it is derived from vinyl decanoate): - the theoretical molecular masses of CD derivatives; - the molecular masses of CD derivatives determined by MALDI-TOF analysis; - the relative intensities of CD derivatives determined by MALDI-TOF analysis.

[0238] [Tables] Degree of substitution Theoretical molecular weight (g / mol) Molecular weight determined by MAL DLTOF (g / mol) Relative intensity (%) 2 1443.5 1466.5 33.4 3 1597.8 1620.8 96 4 1752.1 1775.1 100 5 1906.4 1929.4 52.7 6 2060.6 2083.6 12.4

[0239] Table 2 below details for product invention 1, as a function of the number of substitutions of the hydroxyl groups of the C2 carbons of the glucopyranose units of native beta-CD to give glucosidic subunits of chemical structure (4) with x equal to 10 (because derived from vinyl decanoate and noted "CIO") or with x equal to 4 (because derived from vinyl butyrate and noted "C4"), the molecular masses of the CD derivatives determined by MALDI-TOF analysis.

[0240] [Tables2] Degrees of substitution of CIO and C4 Molecular mass determined by MAL DLTOF (g / mol) 2 CIO + 1 C4 1535.7 2C10 + 2C4 1605.7 3 CIO + 1 C4 1689.8 3C10 + 2C4 1759.8 4 CIO + 1 C4 1843.9 4C10 + 2C4 1914.9 5 CIO + 1 C4 1999.062

[0241] Table 3 below details the average molecular masses in g / mol calculated from the results of the MALDI-TOF analyses for comparative products 1 and 2, as well as for invention products 1 to 7. The average molecular mass of a given product thus corresponds to the average of the molecular masses of all the CD derivatives present in said given product.

[0242] [Tables3] Product Average molecular weight (g / mol) Comparative product 1 1721.69 Invention product 1 2081.71 Comparative product 2 1632.7 Invention product 2 1561.0426 Invention product 3 1601.9733 Invention product 4 2029.0763 Invention product 5 1759.860 Product invention 6 2069.096 Product invention 7 1829.898

[0243] Preparation of particles from comparative product 2 and invention products 2 and 4:

[0244] 1 — p repair of particles from the product of invention 2 _ (acetone solvent);

[0245] 2.51 mg of product of invention 2 were solubilized at 25°C in 2.5 mL of acetone to to obtain an organic solution with a concentration of 1 mg / mL. This organic solution was kept at 25°C and then poured into 2.5 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0246] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.

[0247] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0248] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the acetone.

[0249] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0250] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0251] 2 — preparation of particles from the product of invention 4 (acetone solvent):

[0252] 2.52 mg of product of invention 4 were solubilized at 25°C in 2.5 mL of acetone to to obtain an organic solution with a concentration of 1 mg / mL. This organic solution was kept at 25°C and then poured into 2.5 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0253] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.

[0254] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0255] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the acetone.

[0256] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0257] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0258] Characterization of the particles obtained from the products of invention 2 and 4 j.

[0259] The size of the particles was measured by quasi-elastic scattering of light, using an instrument marketed by the company Malvem Panalytical under the trade name Zetasizer Nano ZS, after appropriate dilution of the samples.

[0260] Three analyses of the same sample were carried out. The experimental conditions were as follows: temperature 25 ± 0.1 °C, reference angle 173°, viscosity 0.899 x 10-3 Pa.s and refractive index 1.330.

[0261] Table 4 below details, according to the storage time (i.e., at the initial time "T=0"), then after 1 day, 4 days, 5 days, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks and 13 weeks) of the particles obtained from the product of invention 2, the 3 measurements of their size (nm) obtained, as well as the polydispersity index (hereinafter abbreviated "PDI" because it is an English acronym for "PolyDispersity Index") calculated from these measurements.

[0262] The PDI is the ratio between the standard deviation and the mean particle size obtained from the 3 measurements taken. A low polydispersity index indicates a narrow particle size distribution, while a high polydispersity index indicates a wide distribution with a broad range of particle sizes.

[0263] [Tables4] Size (nm) PDI Duration 1st measurement 2nd measurement 3rd measurement T=0 86.54 86.12 86.61 0.093 1 day 84.90 84.54 84.12 0.095 4 days 85.32 84.82 84.67 0.106 5 days 84.92 84.82 84.58 0.126 4 weeks 88.76 87.06 86.78 0.131 5 weeks 89.44 88.36 88.29 0.117 6 weeks 95.21 96.70 96.03 0.203 7 weeks 91.92 90.27 89.65 0.140 8 weeks 92.58 91.50 90.56 0.129 9 weeks 96.09 95.40 96.51 0.170 13 weeks 106.6 106.9 105.5 0.130

[0264] In view of the results detailed in Table 4 above, it can be noted that the particles obtained from the product of invention 2 remain stable at room temperature over time (namely at least up to 13 weeks).

[0265] Table 5 below details the 3 measurements of the size (nm) of the particles obtained from the product of invention 2 and the product of invention 4 at T= 0, as well as the PDI calculated from these measurements.

[0266] [Tables5] Size (nm) PDI 1st measurement 2nd measurement 3rd measurement Particles of product invention 2 86.54 86.12 86.61 0.093 Particles of product invention 4 77.72 78.08 77.44 0.148

[0267] In view of the results detailed in Table 5 above, it is possible to obtain particles in acetone from products of the invention having different substitutions.

[0268] 3 — _ preparation of particles from the product of invention 2 (ethanol solvent):

[0269] Next, particles were prepared in the same way as for the first particle preparation except that acetone was replaced by ethanol.

[0270] 5.09 mg of product of invention 2 were solubilized at 25°C in 5 mL of ethanol to to obtain an organic solution with a concentration of 1 mg / mL. This organic solution was kept at 25°C and then poured into 10 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0271] The ratio of the volume of the aqueous phase to the volume of the organic phase was 2 / 1.

[0272] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0273] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the ethanol.

[0274] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0275] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0276] 4 — preparation of particles from the product of invention 4 (ethanol solvent):

[0277] Next, particles were prepared in the same way as for the 2nd particle preparation except that acetone was replaced by ethanol.

[0278] 2.52 mg of product of invention 4 were solubilized at 25°C in 2.5 mL of ethanol to to obtain an organic solution with a concentration of 1 mg / mL. This organic solution was kept at 25°C and then poured into 2.5 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0279] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.

[0280] Particles formed spontaneously upon the addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0281] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the ethanol.

[0282] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0283] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0284] Characterization of particles obtained from products of invention 2 and 4 j.

[0285] The particle size was measured in the same way as for the 1st e particle preparation.

[0286] Table 6 below details the 3 measurements of the size (nm) of the particles obtained, as well as the PDI calculated from these measurements.

[0287] [Tableauxô] Size (nm) PDI 1st measurement ^th 2 measurement 3rd measurement particles of product invention 2 119.8 119.2 120.1 0.082 particles of product invention 4 214.4 214.3 211.6 0.112

[0288] In view of the results detailed in Table 6 above, it is possible to obtain particles in ethanol from products of the invention having different substitutions. The particles obtained in ethanol are larger than those obtained in acetone.

[0289] 5 — _ preparation of particles from the product of invention 4 (acetone solvent and by varying the ratio of the volume of the aqueous phase to the volume of the organic phase U

[0290] 5 — preparation A: ratio of the volume of the aqueous phase to the volume of the phase organic (1 / 2)

[0291] 2.55 mg of product of invention 4 were solubilized at 25°C in 2.5 mL of acetone to to obtain an organic solution with a concentration of 1 mg / mL. This organic solution was kept at 25°C and then poured into 1.25 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0292] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 2.

[0293] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0294] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the acetone.

[0295] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0296] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0297] 5 — preparation B: ratio of the volume of the aqueous phase to the volume of the phase organic (1 / 3)

[0298] 2.50 mg of product of invention 4 were solubilized at 25°C in 2.5 mL of acetone to to obtain an organic solution with a concentration of 1 mg / mL. This organic solution was kept at 25°C and then poured into 0.835 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0299] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 3.

[0300] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0301] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the acetone.

[0302] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0303] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0304] Characterization of the particles obtained from the product invention 4 j.

[0305] The particle size was measured in the same way as for the first particle preparation.

[0306] Table 7 below details the 3 measurements of the size (nm) of the particles obtained, as well as the PDI calculated from these measurements.

[0307] [Tables7] Size (nm) PDI 1st measurement 2nd measurement 3rd measurement 5th preparation A 266.1 269.4 264.5 0.140 5th preparation B 427.7 425.5 431.3 0.132

[0308] In view of the results detailed in Table 7 above, an increase in the size of the particles prepared from the product of invention 4 in acetone is possible by decreasing the ratio of the volume of the aqueous phase to the volume of the organic phase.

[0309] 6 — preparation of particles (variation of the concentration of the invention product (in the organic phase):

[0310] 6 — preparation A: concentration of 1 mg / mL of the product of invention 4 in the organic phase

[0311] The 6th particle preparation A corresponds to the 2nd particle preparation as detailed above.

[0312] 6 — preparation B: concentration of 2 mg / mL of the product of invention 4 in the organic phase

[0313] 5.16 mg of product of invention 4 were solubilized at 25°C in 2.5 mL of acetone to to obtain an organic solution with a concentration of 2 mg / mL. This organic solution was kept at 25°C and then poured into 2.5 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0314] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.

[0315] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0316] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the acetone.

[0317] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0318] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0319] 6 — preparation C: concentration of 3 mg / mL of the product of invention 4 in the organic phase

[0320] 7.53 mg of product of invention 4 were solubilized at 25°C in 2.5 mL of acetone to An organic solution with a concentration of 3 mg / mL was obtained. This organic solution was kept at 25°C and then poured into 2.5 mL of distilled water subjected to magnetic stirring at a speed of 420 revolutions per minute.

[0321] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.

[0322] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said particles of matrix type.

[0323] The suspension of particles was then subjected to evaporation under reduced pressure (40°C) to remove the acetone.

[0324] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0325] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0326] Characterization of the particles obtained from the product of invention 4;

[0327] The particle size was measured in the same way as for the first particle preparation.

[0328] Table 8 below details the 3 measurements of the size (nm) of the particles obtained, as well as the PDI calculated from these measurements.

[0329] [Tables8] Size (nm) PDI 1st measurement 2nd measurement 3rd measurement 6th preparation A 77.72 78.08 77.44 0.148 6th preparation B 124.6 119.6 117 0.113 6th preparation C 106.1 106.4 106 0.095

[0330] In view of the detailed results in Table 8 above, it is possible to vary the particle size by varying the concentration of the invention product in the organic phase.

[0331] 7 — preparation of particles with a lipophilic compound (essential oil (tea tree)

[0332] 6.12 mg of product of invention 2 were solubilized at 25°C in 1.5 mL of ethanol to obtain an organic solution with a concentration of 4 mg / mL. Then, 25 pL of tea tree essential oil and 20 mg of sorbitan oleate (Montané® 80, namely a non-ionic lipophilic surfactant) were added to this mixture to obtain an organic solution.

[0333] This organic solution was stored at 25°C and then poured into 0.860 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0334] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0335] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said capsular-type particles.

[0336] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0337] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0338] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0339] Characterization of the particles obtained from the product of invention 2:

[0340] The particle size was measured in the same way as for the first particle preparation.

[0341] Table 9 below details, according to the storage duration (namely initially at T=0, then after 1 day, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 12 weeks and 18 weeks) of the particles, the 3 measurements of their size (nm) obtained, as well as the PDI calculated from these measurements.

[0342] [Tables9] Size (nm) PDI Duration 1st measurement 2nd measurement 3rd measurement T=0 321.9 323.7 320.9 0.228 1 day 309.5 305.4 310.4 0.178 3 weeks 307.1 310.7 315.6 0.242 4 weeks 289.3 294.0 295.0 0.274 5 weeks 293.0 293.6 292.0 0.218 6 weeks 283.0 286.6 298.2 0.224 7 weeks 272.9 272.7 273.4 0.177 8 weeks 281.2 287.9 ​​283.6 0.224 12 weeks 286.2 290.0 281.7 0.201 18 weeks 355.1 343.8 343.9 0.272

[0343] In view of the results detailed in Table 9 above, it is noted that the capsular-type particles remain stable over time (at least up to 18 weeks).

[0344] 8 — preparation of particles (variation in the nature of the lipophilic compound)

[0345] 8 — preparation A: 25 pL of tea tree essential oil:

[0346] The 8th particle preparation A corresponds to the 7th particle preparation as detailed above.

[0347] 8 — preparation B: 50 pL of tea tree essential oil:

[0348] 6.09 mg of product of invention 4 were solubilized at 25°C in 3 mL of ethanol to to obtain an organic solution with a concentration of 2 mg / mL. Then, 50 pL of tea tree essential oil and 20 mg of sorbitan oleate (Montané® 80) were added to this mixture to obtain an organic solution.

[0349] This organic solution was stored at 25°C and then poured into 1.72 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0350] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0351] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said capsular-type particles.

[0352] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0353] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0354] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0355] 8 — preparation C: 25 pL of benzyl benzoate:

[0356] 12.09 mg of product of invention 4 were solubilized at 25°C in 3 mL of ethanol to to obtain an organic solution with a concentration of 4 mg / mL. Then, 25 pL of benzyl benzoate and 20 mg of sorbitan oleate (Montané® 80) were added to this mixture to obtain an organic solution.

[0357] This organic solution was stored at 25°C and then poured into 1.72 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0358] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0359] Particles formed spontaneously upon the addition of the organic solution to the distilled water so as to obtain a suspension of said capsular-type particles.

[0360] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0361] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0362] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0363] 8 — preparation D: 50 pL of sunflower oil:

[0364] 12.09 mg of product of invention 4 were solubilized at 25°C in 3 mL of ethanol to to obtain an organic solution with a concentration of 4 mg / mL. Then, 50 pL of sunflower oil and 20 mg of sorbitan oleate (Montané® 80) were added to this mixture to obtain an organic solution.

[0365] This organic solution was stored at 25°C and then poured into 1.72 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0366] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0367] Particles formed spontaneously upon the addition of the organic solution to the distilled water so as to obtain a suspension of said capsular-type particles.

[0368] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0369] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0370] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0371] Characterization of the particles obtained from the products of invention 2 and 4 j.

[0372] The particle size was measured in the same way as for the first particle preparation.

[0373] Table 10 below details the 3 measurements of the size (nm) of the particles obtained, as well as the PDI calculated from these measurements.

[0374] [TableauxlO] Size (nm) PDI 1st measurement 2nd measurement 3rd measurement 8th preparation A 321.9 323.7 320.9 0.228 8th preparation B 355.0 365.4 402.1 0.355 8th preparation C 559.1 573.4 561.8 0.241 8th preparation D 364.9 366.2 359.2 0.323

[0375] In view of the results detailed in Table 10 above, it is possible to obtain particles with different kinds of lipophilic compound.

[0376] 9 — preparation of particles encapsulating or not an active substance (the Vitamin C palmitate) solubilized in tea tree essential oil:

[0377] The active substance vitamin C palmitate is a derivative of vitamin C.

[0378] In these experiments, vitamin C palmitate was first solubilized in tea tree essential oil at a concentration of 100 mg / mL.

[0379] 9 — preparation A:

[0380] 6.14 mg of product of invention 4 were solubilized at 25°C in 1.5 mL of ethanol to obtain an organic solution with a concentration of 4 mg / mL. Then, 25 pL of tea tree essential oil and 20 mg of sorbitan oleate (Montané® 80) were added to this mixture to obtain an organic solution.

[0381] This organic solution was stored at 25°C and then poured into 0.860 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0382] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0383] Particles formed spontaneously upon the addition of the organic solution to the distilled water so as to obtain a suspension of said capsular-type particles.

[0384] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0385] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0386] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0387] 9 “ preparation B:

[0388] 6.06 mg of product of invention 4 were solubilized at 25°C in 1.5 mL of ethanol to obtain an organic solution with a concentration of 4 mg / mL. Then, 25 pL of tea tree essential oil (in which 2.5 mg of vitamin C palmitate were solubilized), as well as 20 mg of sorbitan oleate (Montané® 80) were added to this mixture to obtain an organic solution.

[0389] This organic solution was stored at 25°C and then poured into 0.860 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0390] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0391] Particles formed spontaneously upon the addition of the organic solution to the distilled water so as to obtain a suspension of said capsular-type particles.

[0392] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0393] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0394] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0395] 9 — preparation C:

[0396] 6.08 mg of product of invention 4 were solubilized at 25°C in 1.5 mL of ethanol to to obtain an organic solution with a concentration of 4 mg / mL. Then, 12.5 pL of tea tree essential oil (in which 1.25 mg of vitamin C palmitate were solubilized), as well as 20 mg of sorbitan oleate (Montané® 80) were added to this mixture to obtain an organic solution.

[0397] This organic solution was stored at 25°C and then poured into 0.860 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0398] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0399] Particles formed spontaneously upon the addition of the organic solution to the distilled water so as to obtain a suspension of said capsular-type particles.

[0400] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0401] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0402] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0403] Characterization of the particles obtained from the product invention 4 j.

[0404] The particle size was measured in the same way as for the first particle preparation

[0405] Table 11 below details the 3 measurements of the sizes (nm) of the particles obtained with these 9th preparations A to C, as well as the PDI calculated from these measurements.

[0406] [Tables 11] Size (nm) PDI 1st measurement 2nd measurement 3rd measurement 9th Preparation A without active substance 213.1 212.5 212.9 0.167 9th Preparation B 220.2 216.9 216.5 0.202 with active substance 9th Preparation C with active substance 332.8 328.0 326.2 0.320

[0407] In view of the results detailed in Table 11 above, it can be noted that it is possible for the particles according to the invention to simultaneously carry a lipophilic compound (tea tree essential oil) and an active substance (vitamin C palmitate).

[0408] 10 — preparation of particles manufactured in the absence of the decyl surfactant glucoside in the aqueous phase:

[0409] The objective of this 10th particle preparation was to show that: - the particles according to the invention prepared from the product according to the invention 4 remained perfectly stable over time, even in the absence of the decyl glucoside surfactant in the aqueous phase during their manufacture, - unlike particles prepared from the comparative product 2.

[0410] 10 — preparation A: particles according to the invention manufactured in the absence of decyl glucoside:

[0411] The 10th preparation A of particles corresponds to the 9th preparation A of particles.

[0412] IQ — preparation B: comparative particles produced in the absence of decyl glucoside

[0413] 6.17 mg of comparator product 2 were solubilized at 25°C in 1.5 mL of ethanol to obtain an organic solution with a concentration of 4 mg / mL. Then, 25 pL of tea tree essential oil and 20 mg of sorbitan oleate (Montané® 80) were added to obtain an organic solution.

[0414] This organic solution was stored at 25°C and then poured into 0.860 mL of distilled water. The resulting mixture was subjected to magnetic stirring at a speed of 420 rpm.

[0415] The ratio of the volume of the aqueous phase to the volume of the organic phase was 1 / 1.75.

[0416] Particles formed spontaneously upon addition of the organic solution to distilled water so as to obtain a suspension of said capsular-type particles.

[0417] The suspension of particles was then subjected to vacuum evaporation (40°C) to remove the ethanol.

[0418] The suspension of particles was concentrated until a final aqueous volume was obtained corresponding to approximately 50 to 80% of the initial volume of distilled water used.

[0419] The suspension of particles thus obtained was stored in closed bottles at room temperature.

[0420] Characterization of particles _ j.

[0421] The particle size was measured in the same way as for the first particle preparation

[0422] Table 12 below details the 3 measurements of the sizes (nm) of the particles obtained with these 10th preparations A and B, as well as the PDI calculated from these measurements.

[0423] [Tables 12] Size (nm) PDI Stability over time 1st measurement 2nd measurement 3rd measurement 10th Preparation A 213.1 212.5 212.9 0.167 Stable at 18 weeks 10th Preparation B 468.9 479.1 475.2 0.335 Formation of a second particle population at 4 days

[0424] The particles obtained from product of invention 4 remain stable over time, even though they were obtained in the absence of the decyl glucoside surfactant. Conversely, the size of the particles obtained from comparative product 2, also in the absence of the decyl glucoside surfactant, is more polydisperse and changes over time. These particles are not stable over time.

[0425] This 10th particle preparation demonstrates that with the particles according to the invention prepared from CD derivatives according to the invention, it is possible to avoid adding a surfactant to the aqueous phase during their manufacture.

[0426] This demonstrates the great advantage of CD derivatives according to the invention which make it possible to manufacture particles that are as natural as possible.

Claims

Demands

1. Cyclodextrin derivative (hereinafter abbreviated as "CD"), characterized in that it comprises: - of glucosidic subunits of the following chemical structure (4): [Chem.4] in which x is an integer between 0 and 18, preferably between 0 and 12; - optionally at least one glucoside subunit of chemical structure (5): [Chem. 5]

2. (5), the total number of glycosidic subunits of chemical structure (4) and chemical structure (5) is equal to an integer n between 5 and 30, preferably between 6 and 8, at least 2 x among the x of the glucosidic subunits of chemical structure (4) are different from each other. Derivative of CD according to claim 1, characterized in that n is equal to 6, 7 or 8.

3. A process for preparing a CD derivative according to claim 1 or 2, characterized in that it comprises at least the following steps: a) a mixture is prepared comprising at least: - a native CD comprising n glucopyranose units, n being an integer between 5 and 30, preferably between 6 and 8, - an enzyme configured to catalyze a transesterification reaction at the hydroxyl group carried by the C2 carbon of the glucopyranose units of native CDs and CD derivatives; b) a first vinyl ester of the following chemical structure (6) is added to said mixture: (6) in which x is an integer between 0 and 18, preferably between 0 and 12, said 1st vinyl ester being in nH stoichiometry ni being an integer less than n, to carry out a 1st transesterification reaction between the native CD and the 1st vinyl ester and so as to obtain at the end of this 1st transesterification reaction a 1st CD derivative called "intermediate" in the reaction medium, the CD derivative called "intermediate" corresponds to the native CD in which ni hydroxyl groups carried by the C2 carbons of the glucopyranose units of said native CD have reacted with said 1st vinyl ester; (c) At least one second vinyl ester of chemical structure (6) is added to the reaction medium containing the so-called "intermediate" CD derivative. This second vinyl ester has a different x-value than the x-value of the first vinyl ester. The second vinyl ester is added in n2 stoichiometry, where n2 is an integer such that the sum of n1 and n2 is less than or equal to n. In the presence of the enzyme, at least one second transesterification reaction is carried out between the first "intermediate" CD derivative and the at least one second vinyl ester. During this reaction, n2 hydroxyl groups from among those on the C2 carbons of the glucopyranose units of the so-called "intermediate" CD derivative have reacted with the second vinyl ester. vinyl ester so as to obtain at least a second transesterification reaction of said CD derivative; d) optionally, step c) is repeated one or more times; all vinyl esters added to the reaction medium during said preparation process have chemical structure (6), all x of these vinyl esters are different from each other and the sum of the stoichiometries of all these vinyl esters is less than or equal to

4. n. Method for preparing a CD derivative according to claim 3, characterized in that the native CD is chosen from the group consisting of alpha-CD, beta-CD and gamma-CD.

5. A method for preparing a CD derivative according to claim 3 or 4, characterized in that the vinyl esters are selected from the group consisting of vinyl butyrate, vinyl hexanoate, vinyl decanoate, vinyl octanoate, vinyl laurate and vinyl myristate.

6. A method for preparing a CD derivative according to any one of claims 3 to 5, characterized in that the enzyme is thermolysin.

7. A method for preparing a CD derivative according to any one of claims 3 to 6, characterized in that all or part of the transesterification reactions are carried out simultaneously or sequentially.

8. A process for preparing a CD derivative according to any one of claims 3 to 7, characterized in that at the end of step c) or optionally at the end of step d), said CD derivative thus obtained is recovered and optionally purified.

9. Particle, characterized in that it comprises at least one CD derivative according to any one of claims 1 to 2 or at least one CD derivative obtained according to the preparation process according to any one of claims 3 to 8.

10. Particle according to claim 9, characterized in that it further comprises at least one active substance.

11. Particle according to claim 9 or 10, characterized in that the size of said particle is between 0.1 pm and 2 pm, preferably between 0.15 pm and 1 pm.

12. A process for manufacturing particles according to any one of claims 9 to 11, characterized in that it comprises at least the following steps: a) a first mixture is prepared comprising at least one CD derivative according to any one of claims 1 to 2 or at least one CD derivative obtained according to the preparation process according to any one of claims 3 to 8, a polar organic solvent and, optionally, at least one first surfactant and / or at least one first active substance; b) a second mixture is prepared comprising at least water and, optionally, at least one second surfactant and / or at least one second active substance; c) one of the first or second mixture is added to the other mixture, so as to obtain a suspension of said particles.

13. A method for manufacturing particles according to claim 12, characterized in that the 1st mixture further comprises at least one lipophilic compound.

14. Composition, preferably a composition selected from pharmaceutical, cosmetic, food, agri-food, phytosanitary, paint, varnish, textile dye compositions, characterized in that it comprises at least particles according to any one of claims 9 to 11 or particles obtained according to the manufacturing process according to any one of claims 12 to 13.

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