Method for preparing micron-sized polymer capsule

Abstract

The invention relates to a method for preparing polymer microcapsules, comprising the following steps: preparing an emulsion in the form of micro-droplets comprising an aqueous continuous phase and a dispersed phase by microfluidics control, said dispersed phase comprising a monomer or prepolymer A and a latent solvent at least partially miscible in the continuous phase; a step of partially or completely diffusing the latent solvent of the dispersed phase towards the continuous phase by diffusion and / or convection; a step of interfacial polymerization by polycondensation by bringing the microdroplets of the emulsion into contact with a polymerization solution comprising a second monomer or prepolymer B.

Description

Technical Field

[0001] The field of the invention relates to the field of methods for the preparation of microcapsules and the use of said microcapsules. Background Art

[0002] Polymer microcapsules, i.e. capsules with micrometer-sized dimensions, comprising a polymer shell and a core that can be solid or liquid, are found in many applications and in various fields, such as cosmetics, pharmaceuticals, phytosanitary products, paints, coatings, etc.

[0003] For example, in the medical field, encapsulation of active ingredients that are rapidly metabolized by degradative enzymes or degraded by the acidic pH of the stomach enables the protection, transport, targeting, and delivery of such substances to selected tissues or organs in a controlled and localized manner.

[0004] Common methods for preparing polymer microcapsules generally include a step of preparing an emulsion, followed by a step of interfacial polymerization (IFP) to form a polymer shell around the droplets of the dispersed phase.

[0005] According to this method, an emulsion is prepared in advance by mixing a solution of a dispersed phase and a solution of a continuous phase in a reactor to form an emulsion.

[0006] The dispersed phase solution comprises the first monomer A.

[0007] The interfacial polymerization step is carried out after contacting the droplets of the dispersed phase with a polymerization solution comprising the second monomer B. Polymerization by polycondensation of monomers A and B at the interface between the two phases enables the shell of the microcapsules to be formed in situ.

[0008] The shell obtained by interfacial polycondensation can be polyamide, polyurethane, polyurea, polyester or polycyanoacrylate obtained by polymerization of the monomers or prepolymers A and B shown in Table 1.

[0009] [Table 1]: Monomer or prepolymer

[0010]

[0011] These methods for standard mixing in batches under high shear result in poor control of the size distribution of the droplets and thus of the size distribution of the capsules formed.

[0012] Since the size of the droplets directly affects the properties of the microcapsules, such as the release profile of the active ingredient, the permeability of the microcapsules and the stability over time, methods for preparing smaller and more uniform microcapsules have been proposed, in particular methods for reducing and / or calibrating the droplet size.

[0013] In particular, the use of microfluidic devices enables the production of monodisperse microcapsules. Devices of this type are extensively described in the literature.

[0014] CN 111437895 describes a method and a microfluidic device for preparing nanocapsules and microcapsules.

[0015] Polenz et al. (Ingmar Polenz, David A. Weitz and Jean-Christophe Baret, Langmuir 2015, 31, 3, 1127-1134) describe the preparation of monodisperse polyurea microcapsules using a microfluidic device and interfacial polymerization. Their work shows that the properties of the polymer shell depend, in particular, on the presence of surfactants and the energy applied to the system to form the droplets.

[0016] Document WO 2007 / 150030 A2 describes a microfluidic system for producing nanoparticles for use as drug carriers.

[0017] The document Thorne et al. (Thorne, MF, Simkovic, F. & Slater, AG Production of monodisperse polyurea microcapsules using microfluidics. Sci Rep 9, 17983, 2019) describes the use of a microfluidic device to prepare polyurea microcapsules with a limonene core, the average diameters of the polyurea microcapsules being 27, 30, 32, 34 and 35 μm, and having a low dispersity of about ±2 μm.

[0018] Jiupeng Du's thesis, "Preparation of polyurea microcapsules calibrated in size and shell thickness by a microfluidic process for the absorption of ultraviolet," defended on March 13, 2022, concerned the development of polymer capsules with calibrated size and shell thickness using a microfluidic device. The target application involved the cosmetics field through the encapsulation of sunscreen agents.

[0019] However, these microfluidic emulsification methods have a major disadvantage in that the minimum diameter of the microdroplets formed is limited by the size of the channel used and the flow rate used. It is not possible to form microcapsules exceeding a certain size set by the equipment used.

[0020] Therefore, although the use of microchannels with small cross-sections could be a solution for producing microcapsules with smaller diameters, this is not an effective solution in practice, as it would require the use of much lower flow rates in the microchannels, thus limiting productivity. In addition, the potential for clogging of microchannels would make their use more difficult.

[0021] Therefore, there remains an unmet need for improved methods for preparing microcapsules or microparticles of micrometer-sized diameter, uniform size and shape, i.e., low polydispersity (coefficient of variation less than 15%, or even less than 7%), and whose shells have a controlled, constant and uniform thickness.

[0022] The work carried out by the researchers made it possible to develop a method that meets this need while avoiding the shortcomings of existing technologies. Summary of the Invention

[0023] In order to further reduce the size of the microcapsules compared to those obtained by microfluidic emulsification, the inventors have developed a method comprising an additional step enabling the control and reduction of the size of the microcapsules.

[0024] In a general aspect, the present invention relates to a method for preparing polymer microcapsules, the method comprising the steps of:

[0025] - preparing by microfluidics an emulsion in the form of microdroplets comprising an aqueous continuous phase and a dispersed phase comprising a monomer or prepolymer A and a cosolvent at least partially miscible in the continuous phase;

[0026] - a step of partially or completely diffusing the latent solvent of the dispersed phase towards the continuous phase by diffusion and / or convection;

[0027] a step of interfacial polymerization by polycondensation by bringing the microdroplets of the emulsion into contact with a polymerization solution comprising a second monomer or prepolymer B.

[0028] In a general aspect, the present invention relates to a method for preparing polymer microcapsules, the method comprising the steps of:

[0029] - preparing by microfluidics an emulsion in the form of microdroplets comprising an aqueous continuous phase and a dispersed phase comprising a monomer or prepolymer A and a latent solvent at least partially miscible in the continuous phase;

[0030] - a step of diffusing the latent solvent of the dispersed phase towards the continuous phase by diffusion and / or convection;

[0031] a step of interfacial polymerization by polycondensation by bringing the microdroplets of the emulsion into contact with a polymerization solution comprising a second monomer or prepolymer B.

[0032] The method according to the invention comprises the steps of preparing an emulsion in the form of microdroplets by a microfluidic method from an aqueous continuous phase and a dispersed phase, said dispersed phase comprising a monomer A or a prepolymer A, a solvent and a cosolvent, said cosolvent being at least partially miscible in the continuous phase;

[0033] - a step of partial or total diffusion of the latent solvent of the dispersed phase towards the continuous phase by diffusion and / or convection, which step can be carried out during the flow of the emulsion through the microchannels;

[0034] - a step of interfacial polymerization by polycondensation by contacting the microdroplets of the emulsion with a polymerization solution comprising a second monomer B or prepolymer B, which polymerization step can be performed continuously or batchwise in a microfluidic device.

[0035] According to another aspect, the present invention relates to a preparation of microcapsules obtainable by the process according to the invention, characterized in that the coefficient of variation is less than 7%.

[0036] According to a general aspect, the present invention relates to a method for preparing polymer microcapsules, the method comprising the following steps:

[0037] - preparing by microfluidics an emulsion in the form of microdroplets comprising an aqueous continuous phase and a dispersed phase comprising a monomer or prepolymer A and a latent solvent at least partially miscible in the continuous phase;

[0038] - a step of partially or completely diffusing the latent solvent of the dispersed phase towards the continuous phase by diffusion and / or convection;

[0039] a step of interfacial polymerization by polycondensation by bringing the microdroplets of the emulsion into contact with a polymerization solution comprising a second monomer or prepolymer B.

[0040] According to one aspect, the process according to the invention is characterized in that monomer A or prepolymer A is an acyl chloride or an isocyanate, monomer B or prepolymer B is an amine, or in that monomer A or prepolymer A is an isocyanate or a carboxylic acid, monomer B or prepolymer B is an alcohol, advantageously monomer A or prepolymer A is an isocyanate and monomer B or prepolymer B is an amine.

[0041] According to one aspect, the process according to the invention is characterized in that the isocyanate is a diisocyanate, advantageously the isocyanate is a diisocyanate selected from the group consisting of toluene 2,4-diisocyanate (TDI), hexamethylene 1,6-diisocyanate (HDI), isophorone diisocyanate (IPDI), polydiphenylmethane diisocyanate (PMDI), hexamethylene diisocyanate biuret (HBD-LV), hexamethylene diisocyanate trimer (HDT-LV (low-viscosity aliphatic polyisocyanate based on hexamethylene diisocyanate trimer)), aliphatic pentamethylene diisocyanate (PDI), combinations of these diisocyanates, advantageously the isocyanate is hexamethylene diisocyanate biuret (HBD-LV).

[0042] According to one aspect, the process according to the invention is characterized in that the amine is chosen from hexamethylenediamine (HMDA), polyethyleneimine (PEI), ethylenediamine (En), diethylenetriamine (DETA), triethylenetetramine (TETA), aromatic polyamines (XDA), aliphatic polyamines (TEPA), polyetheramines, guanidine carbonate, combinations of these amines, advantageously the amine is En or guanidine carbonate.

[0043] According to one aspect, the method according to the invention is characterized in that the solubility of the latent solvent in water at 20° C. is between 1 g / L and 100 g / L.

[0044] According to one aspect, the process according to the invention is characterized in that the cosolvent is chosen from butyl acetate, ethyl acetate, amyl acetate, butyl stearate, advantageously the cosolvent is butyl acetate or ethyl acetate.

[0045] According to one aspect, the process according to the invention is characterized in that the dispersed phase comprises at least 60% by weight of said latent solvent relative to the total weight of the dispersed phase.

[0046] According to one aspect, the process according to the invention is characterized in that the dispersed phase comprises at least one excipient and / or active ingredient and / or solvent.

[0047] According to one aspect, the process according to the invention is characterized in that the dispersed phase comprises, relative to the total weight of the dispersed phase:

[0048] - 60 to 90% by weight of a latent solvent;

[0049] - 3 to 12% by weight of monomers and / or prepolymers A;

[0050] - 7 to 30% by weight of solvents;

[0051] - Active ingredient and monomer or prepolymer A in a ratio of 3:7.

[0052] According to one aspect, the process according to the invention is characterized in that the continuous phase comprises, relative to the total weight of the continuous phase:

[0053] - 0.1% to 5% of a surfactant, advantageously the surfactant is SDS;

[0054] -Suitable amount of water.

[0055] According to one aspect, the method according to the invention is characterized in that the diffusion step is performed by flowing the emulsion through a microfluidic microchannel.

[0056] According to one aspect, the method according to the invention is characterized in that the polymerization step is carried out continuously or batchwise in a microfluidic microchannel.

[0057] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method according to the invention.

[0058] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method according to the invention, which microfluidic device comprises a microchip or a cascade micromixer, which is connected to a microfluidic microchannel, for example a microfluidic microchannel with a diameter between 500 μm and 2000 μm.

[0059] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method according to the invention, which microfluidic device comprises a microchip or a cascade micromixer, which is directly connected to a microfluidic microchannel, for example a microfluidic microchannel with a diameter between 500 μm and 2000 μm.

[0060] According to another aspect, the present invention relates to a microfluidic device suitable for implementing any embodiment of the method according to the invention, which microfluidic device comprises a microchip or a cascade micromixer directly connected to a microfluidic microchannel made of PTFE and having a diameter between 500 μm and 2000 μm.

[0061] According to another aspect, the present invention relates to a microfluidic device comprising a microchip or a cascade micromixer to which a microfluidic microchannel made of PTFE and having a diameter between 500 μm and 2000 μm is connected.

[0062] According to another aspect, the invention relates to a microfluidic device comprising a microchip or a cascade micromixer connected to a microfluidic microchannel made of PTFE and having a diameter between 500 μm and 2000 μm.

[0063] According to another aspect, the invention relates to a microfluidic device comprising a microchip or a cascade micromixer directly connected to a microfluidic microchannel made of PTFE and having a diameter between 500 μm and 2000 μm.

[0064] Depending on the desired properties of the polymer, the monomers and / or prepolymers A and B may be selected from:

[0065] [Table 2]: Examples of monomers and / or prepolymers A and B

[0066]

[0067] Without being bound by any theory, it is assumed that the microdroplets are formed during the preparation step of an emulsion containing a solvent and / or a co-solvent (droplets before diffusion), and then the co-solvent is extracted from the dispersed phase of the emulsion towards the continuous phase by diffusion and / or convection phenomena during the flow through the microchannels to obtain microcapsules with small size and low polydispersity and with uniform shell thickness after the interfacial polymerization step.

[0068] In order to facilitate diffusion and / or convection phenomena, the latent solvent must be at least partially miscible in water.

[0069] The co-solvent may be selected from compounds having a solubility in water at 20°C between 1 and 100 g / L.

[0070] Examples of particularly suitable cosolvents for use in the present invention are butyl acetate, ethyl acetate, amyl acetate and / or butyl stearate; more particularly suitable cosolvents are butyl acetate or ethyl acetate.

[0071] The microcapsules thus prepared have a diameter smaller than that of the pre-diffusion microdroplets (before the latent solvent diffuses toward the continuous phase), are uniform in size, have low polydispersity (coefficient of size variation less than 7%), and have a shell with a constant and uniform thickness. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] [ Figure 1 ]:[ Figure 1 a]: Schematic diagram of the device according to the present invention. A-reservoir of dispersed phase; B-reservoir of continuous phase; C-pressure pump; D-valve; E-three-way connector; F-microchip; [ Figure 1 b]: Schematic representation of the method for preparing microcapsules according to the invention.

[0073] [ Figure 2 ]:[ Figure 2 a]: Image of microdroplets during emulsion preparation before diffusion of the latent solvent (microdroplets before diffusion); [ Figure 2 b]: Histogram of the diameter distribution of microdroplets; [ Figure 2 c]: Image of the microdroplet after the latent solvent of the microdroplet diffuses toward the continuous phase (microdroplet after diffusion); [ Figure 2 d]: Histogram of the diameter distribution of microdroplets after latent solvent diffusion; [ Figure 2 e]: Image of microcapsules after interfacial polymerization; [ Figure 2 f]: histogram of the diameter distribution of microcapsules;

[0074] [ Figure 3 ]: Diameter of microdroplets before diffusion as a function of flow rate - butyl acetate (BA) BA-60% system.

[0075] [ Figure 4 ]: (a) Image of microdroplet formation in the “dripping” state in a microchannel (Qc and Qd are 40.0 μL / min and 3.0 μL / min, respectively); (b) Image of microdroplet formation in the “jetting” state in a microchannel (Qc and Qd are 110.0 μL / min and 3.0 μL / min, respectively).

[0076] [ Figure 5 ]: The diameter of the microdroplets after diffusion as a function of the diameter of the microdroplets before diffusion - BA-60% system.

[0077] [ Figure 6 ]: Changes in microdroplet diameter as a function of time for various organic phase systems.

[0078] [ Figure 7 ]: Microcapsules of BA-60% system observed under a scanning electron microscope.

[0079] [ Figure 8 ]: Diameter of microdroplets before diffusion as a function of flow rate - BA-90% system.

[0080] [ Figure 9 ]: (a) Image of microdroplet formation in the “dripping” state in a microchannel (Qc and Qd are 60.0 μL / min and 3.0 μL / min, respectively); (b) Image of microdroplet formation in the “tip-streaming” state in a microchannel (Qc and Qd are 100.0 μL / min and 5.0 μL / min, respectively).

[0081] [Figure 10]: Diameter of microdroplets after diffusion as a function of diameter of microdroplets before diffusion - BA-90% system.

[0082] [Figure 11] Microcapsules of the BA-90% system observed under a scanning electron microscope.

[0083] [Figure 12]: Diameter of microdroplets as a function of the flow rate of the aqueous phase - 60% system.

[0084] [Figure 13]: Diameter of microdroplets as a function of the flow rate of the aqueous phase - 90% system.

[0085] Figure 14: Image of microdroplets before diffusion. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min.

[0086] Figure 15: Size distribution of droplets before diffusion. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 40.7% Average diameter: 19.3 μm.

[0087] Figure 16: Size distribution of droplets before diffusion. Continuous phase flow rate: 60 mL / min - Continuous phase flow rate: 10 mL / min CV: 36.5% Average diameter: 16.6 μm.

[0088] Figure 17: Effect of continuous phase flow rate on the average size of microdroplets before diffusion. Continuous phase flow rate: 10 mL / min.

[0089] [Figure 18]: Image of microdroplets after diffusion of ethyl acetate (EA) 90% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min.

[0090] Figure 19: Size distribution of microdroplets after diffusion in the EA 60% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min - CV: 41.2%.

[0091] Average diameter: 6.0μm.

[0092] [Figure 20]: Size distribution of microdroplets after diffusion in the EA 90% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 45.0%.

[0093] Average diameter: 3.2μm.

[0094] [Figure 21]: Image of microcapsules of EA 60% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min.

[0095] [Figure 22]: Size distribution of microcapsules in the EA 60% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 36.9% Average diameter: 6.3 μm.

[0096] [Figure 23]: Size distribution of microcapsules in the EA 90% system. Continuous phase flow rate: 50 mL / min - Continuous phase flow rate: 10 mL / min CV: 33.1% Average diameter: 4.4 μm.

[0097] [Fig. 24] An image of microdroplets before diffusion in a system of ethyl acetate (EA) 90% EA and 2% SDS. Continuous phase flow rate: 200 mL / min - Continuous phase flow rate: 200 mL / min.

[0098] [Fig. 25] Images of microdroplets after diffusion in a system of ethyl acetate (EA) 90% EA and 2% SDS. Continuous phase flow rate: 200 mL / min - Continuous phase flow rate: 200 mL / min.

[0099] [Figure 26] Size distribution of microdroplets after diffusion in EA90% and 2% SDS systems. Continuous phase flow rate: 200 mL / min - Continuous phase flow rate: 200 mL / min. DETAILED DESCRIPTION

[0100] Other advantages, features and details of the invention will become apparent from the following detailed description.Each of the described subjects or embodiments or examples is a specific subject of the present invention.

[0101] For the purposes of this invention, the following definitions apply:

[0102] - Emulsion: A mixture of two immiscible liquids, one forming the dispersed phase in the form of microdroplets dispersed throughout the continuous phase.

[0103] o The terms internal phase, dispersed phase and discontinuous phase will be used indiscriminately to refer to the dispersed phase.

[0104] o The terms external phase, dispersion medium and continuous phase will be used indiscriminately to refer to the continuous phase.

[0105] o Emulsions in which the dispersed phase is lipophilic (e.g., vegetable oil or mineral oil) and the dispersion medium is aqueous (e.g., water) are called O / W emulsions; emulsions in which the dispersed phase is aqueous and the dispersion medium is lipophilic are themselves called W / O oil-containing emulsions.

[0106] - Micron-sized polymer microcapsules: capsules with a size of less than 65 microns, preferably between 5 and 65 microns, and having a uniform shell covering the surface of the capsule.

[0107] - Granules: solid particles.

[0108] - Microdroplets: droplets with an average diameter less than or equal to 80 micrometers, preferably between 0.5 and 80 micrometers. The microdroplets before and after diffusion correspond to the microdroplets of the invention before and after diffusion of the solvent from the dispersed phase towards the continuous phase.

[0109] - Prepolymer: a polymerizable oligomer comprising 2 to 5 monomer units.

[0110] - Microfluidics: Systems for the flow of fluids through a network of microchannels having at least one dimension on the micrometer scale.

[0111] The step of preparing the emulsion can be carried out by bringing a solution corresponding to the dispersed phase into contact with a second solution corresponding to the continuous phase in a microfluidic device of microchip type (advantageously a glass-bonded microchip), which comprises a cross-shaped, T-shaped or Y-shaped mixer or a cascade or lamination micromixer, the microchip advantageously being hydrophilic.

[0112] The use of the microfluidic device according to the present invention enables the formation of microdroplets of a dispersed phase within a continuous phase. Within the microchip, the size of the microdroplets depends on the fluid dynamics. Four states are distinguished and described below: "dripping," "squeezing," "jetting," or "tip streaming." Of these four states, the dripping state is particularly advantageous.

[0113] "extrusion"

[0114] When the flow rate of the continuous phase is low, larger droplets block the cross section of the channel downstream of the junction and eventually separate due to the pressure increase of the upstream continuous phase.

[0115] This flow regime produces droplets that are generally large in diameter, on the order of 150 microns in diameter, making it unsuitable for the present invention.

[0116] "Dripping"

[0117] By increasing the flow rate of the continuous phase, higher shear stress is achieved through the continuous phase. Microdroplets form near the junction of the microchannels due to the pinching of the dispersed phase caused by absolute stability. The microdroplets formed under this flow state are monodisperse and generally have a size between 50 and 100 microns.

[0118] Examples of flow rates for this flow regime:

[0119] For the system with 60% cosolvent (butyl acetate)

[0120] Dispersed phase: 1 μL / min

[0121] Continuous phase: 40 to 110 μL / min

[0122] or

[0123] Dispersed phase: 3 μL / min

[0124] Continuous phase: 40 to 90 μL / min

[0125] or

[0126] Dispersed phase: 5 μL / min

[0127] Continuous phase: 40 to 60 μL / min

[0128] For 90% BA system

[0129] Dispersed phase: 1 μL / min

[0130] Continuous phase: 40 to 100 μL / min

[0131] or

[0132] Dispersed phase: 3 μL / min

[0133] Continuous phase: 40 to 100 μL / min

[0134] or

[0135] Dispersed phase: 5 μL / min

[0136] Continuous phase: 40 to 80 μL / min.

[0137] "injection"

[0138] By increasing the flow rate of the dispersed phase and / or the continuous phase, a jet is formed ( Figure 4 ), and due to convective instabilities, the continuous phase contracts downstream of the junction. When the inertial forces of the dispersed phase and the shear forces of the continuous phase are high enough to overcome the interfacial tension (the only force holding the dispersed phase within the junction), the dispersed phase is entrained downstream before the instability reaches the critical value required to break the droplets. The size of the microdroplets in this "jetting" state will be close to that of the "dripping" state, but with the disadvantage of higher polydispersity than in the "dripping" state.

[0139] Examples of flow rates for this flow regime:

[0140] For the system with 60% cosolvent (butyl acetate)

[0141] Dispersed phase: 3 μL / min

[0142] Continuous phase: 110 μL / min or higher

[0143] or

[0144] Dispersed phase: 5 μL / min

[0145] Continuous phase: 90 μL / min or higher.

[0146] "Cutting-edge flow"

[0147] This is a transient flow state between "dripping" and "jetting." In this state, the convection effect of the continuous phase causes the surfactant to move toward the end of the dispersed phase. This movement of the end of the dispersed phase creates an "over-concentration" of the surfactant. Due to the much lower interfacial tension than at equilibrium, the smallest microdroplets with a diameter of less than 50 microns are formed.

[0148] The flow rate of this flow state is:

[0149] For the system with 90% cosolvent (butyl acetate)

[0150] Dispersed phase: 5 μL / min

[0151] Continuous phase: 100 μL / min.

[0152] The preferred state is the dripping state, which enables the formation of droplets of defined and controlled size according to the selected flow rate.

[0153] Therefore, controlling the flow rates of the continuous and dispersed phase solutions can form micron-sized droplets of uniform size.

[0154] The microdroplets thus obtained have a micrometer-scale diameter, which may be less than 100 μm, advantageously less than 90 μm, more advantageously less than 80 μm, more advantageously less than 70 μm, and more advantageously less than 60 μm, or 50 μm, or 40 μm, or 30 μm, or 10 μm. The diameter may also be between 0.1 and 100 μm, or between 15 and 50 μm, or between 1 and 50 μm.

[0155] For example, the microfluidic device according to the present invention can be used ( Figure 1 ) to obtain a droplet diameter of approximately 65 μm with a continuous phase flow rate of 70 to 80 μL / min and a dispersed phase flow rate of 1 μL / min.

[0156] Droplet diameters of approximately 50 μm can be achieved using flow rates of the continuous phase between 140 μL / min and 150 μL / min and a dispersed phase flow rate of 1 μL / min.

[0157] In a second step, the diameter of these microdroplets decreases during a step of diffusion of the latent solvent contained in the microdroplets towards the continuous phase by diffusion and / or convection phenomena, this latent solvent having the property of being at least partially miscible with the continuous phase.

[0158] This diffusion of the latent solvent results in a reduction in the diameter of the microdroplets.

[0159] This step can be carried out, for example, in a microchannel made of polytetrafluoroethylene, the diameter of which is between 500 and 2000 μm and the length of which is preferably greater than 30 cm and advantageously between 30 cm and 1 m, the flow rate of the emulsion in which microchannel is between 0.002 m / s and 0.1 m / s.

[0160] Under these conditions, the transit time of the microdroplets in the microchannel ranged from 1 to 120 seconds.

[0161] These diffused microdroplets are then converted into microcapsules during an interfacial polymerization step by polycondensation, by contacting the microdroplets comprising monomer and / or prepolymer A with a polymerization solution comprising a second monomer and / or prepolymer B added to the emulsion.

[0162] Preferably, the amount of monomer or prepolymer A does not exceed 30% by weight relative to the total weight of the dispersed phase.

[0163] For example, the dispersed phase may comprise 12% by weight of prepolymer A (HDB-LV), 28% by weight of the active ingredient octyl salicylate (OS), and 60% by weight of the cosolvent (ethyl acetate).

[0164] The molar amount of monomer or prepolymer B in the polymerization solution is adjusted according to the amount of monomer or prepolymer A, and the amount of monomer or prepolymer B exceeds the amount of monomer or prepolymer A by 5 times or more.

[0165] The following is a calculation example for an amount of monomer B and / or prepolymer B (in this case ethylenediamine) of about 0.01% by weight relative to the total weight of the polymerization solution:

[0166] Total volume of solution: 1kg

[0167] Molar mass of ethylenediamine: 60.1 kg / kmol

[0168] Number of moles of ethylenediamine in the solution:

[0169]

[0170] The number of moles of amine functional groups (-NH2) in the solution: 1.7×10 -6 kmol×2=3.4×10 -6 kmol

[0171] Maximum flow rate of the dispersed phase of the system with 60% cosolvent (butyl acetate): 5 μL / min

[0172] Collection time: 210 minutes (or 3 hours)

[0173] Density of dispersed phase: 0.937 kg / L

[0174] Mass percentage of HDB-LV in the dispersed phase: 12%

[0175] The mass percentage of isocyanate functional groups (-NCO) in HDB-LV molecules is 23%

[0176] Molar mass of isocyanate group: 42 kg / kmol

[0177] Moles of isocyanate functional groups in solution:

[0178]

[0179] Ratio between the number of amine functional groups and the number of isocyanate functional groups:

[0180]

[0181] This example is given because in this case the amount of monomer B in the solution is at its minimum and the amount of monomer A is at its maximum. In other words, for other chemical compositions the ratio between the number of amine functional groups and the number of isocyanate functional groups can only be greater than 5.

[0182] For example, the amount of monomer and / or prepolymer B is about 0.01 to 1% by weight relative to the total weight of the polymerization solution.

[0183] [Table 3]:

[0184]

[0185] The capsules thus prepared exhibited:

[0186] The coefficient of variation of the diameter of the microcapsules is less than or equal to 7%, and the coefficient of variation of the diameter of the microdroplets is less than or equal to 2%.

[0187] - For capsules with a diameter between 25 μm and 50 μm, the thickness of the microcapsule shell is between 700 nm and 1500 nm.

[0188] Advantageously, the diameter of the capsule according to the invention is between 50 μm and 90 μm, more advantageously between 10 μm and 50 μm.

[0189] dispersed phase

[0190] The solution of the dispersed phase comprises at least one monomer or prepolymer A, a cosolvent and may comprise further solvents, excipients and active ingredients which are soluble in the solvent and / or cosolvent.

[0191] The amount of monomer A or prepolymer A is less than or equal to 30% by weight of the composition of the dispersed phase, preferably between 3% and 12% by weight of the composition of the dispersed phase.

[0192] Co-solvents suitable for the present invention must be at least partially miscible in the aqueous continuous phase. Preferably, the amount of co-solvent used is at least 60% by weight of the dispersed phase, preferably 90% by weight of the dispersed phase.

[0193] The use of a latent solvent in an amount greater than 90% by weight relative to the weight of the dispersed phase makes it possible to reduce the diameter of the microdroplets from an initial 50 to 80 μm to a diameter of about 24 to 40 μm after transfer of the solvent to the continuous phase, i.e. by about 50%.

[0194] When an additional solvent is used, this solvent is immiscible or barely miscible in the (aqueous) continuous phase.The amount of solvent in the dispersed phase is less than or equal to 30% or even between 7% and 30% by weight of the dispersed phase.

[0195] Additional excipients (eg, surfactants, etc.) and active ingredients that are soluble in the solvent may be added to the dispersed phase solution.

[0196] Advantageously, the proportion of monomer A or prepolymer A in the dispersed phase is less than 12% by weight, preferably less than 3% by weight, preferably 0.3% by weight.

[0197] The composition of the dispersed phase according to the invention may, for example, comprise:

[0198] 60% to 90% by weight of a cosolvent;

[0199] 3 to 12% by weight of monomers and / or prepolymers A;

[0200] 7 to 30% by weight of a solvent;

[0201] The ratio of active ingredient and monomer or prepolymer A is 3:7.

[0202] Solvents and cosolvents

[0203] The term "solvent" or "cosolvent" is understood to mean a liquid that has the property of dissolving other substances.

[0204] According to the process of the present invention, the dispersed phase comprises a latent solvent which is at least partially miscible in the aqueous continuous phase and may comprise an additional solvent which is immiscible or barely miscible in the aqueous continuous phase.

[0205] For the purposes of the present invention, partial miscibility is understood to mean that the solubility of the cosolvent in water at 20°C is at least 1 g / L, preferably at least 100 g / L at 20°C.

[0206] Completely miscible means that 100% of the cosolvent is miscible in water.

[0207] For purposes of the present invention, partially miscible means that at least 10% of the cosolvent is miscible in water, at least 20% of the cosolvent is miscible in water, or at least 30% of the cosolvent is miscible in water, or at least 40% of the cosolvent is miscible in water, or at least 50% of the cosolvent is miscible in water, or at least 60% of the cosolvent is miscible in water, or at least 70% of the cosolvent is miscible in water, or at least 80% of the cosolvent is miscible in water, or at least 90% of the cosolvent is miscible in water.

[0208] Examples of particularly suitable cosolvents for the present invention are selected from dibutyl adipate, n-butyl acetate, ethyl acetate, amyl acetate and butyl stearate.

[0209] The co-solvent is preferably n-butyl acetate.

[0210] Examples of solvents suitable for the present invention are cyclohexane, cycloheptane, cyclohexanone, hexane, heptane, octane, toluene, benzene, xylene, m-cresol or p-cresol, benzaldehyde, ethyl acetate, ether, chloromethane, dichloromethane, chloroform, carbon tetrachloride, trifluoromethane, difluoromethane, haloalkanes, haloalkenes, dichloroethane, trichloroethane, tetrachloroethane, trifluoroethane, trichloroethylene, tetrachloroethylene or mixtures thereof.

[0211] Examples of particularly suitable solvents for the present invention are selected from hexadecane, octyl salicylate, dibutyl adipate and dibutyl adipate or Cetiol B.

[0212] The solvent is preferably octyl salicylate.

[0213] Active ingredient

[0214] The dispersed phase may contain one or more active ingredients, such as a phase change material (hexadecane, heptadecane, octadecane, nonadecane, or eicosane), a sunscreen (octyl salicylate or benzyl salicylate), a fragrance (lavender, ethyl salicylate, or limonene), or an insecticide (pirimiphos-methyl or pyrethroids).

[0215] Since the active ingredient is completely soluble in the solvent and / or cosolvent of the dispersed phase, the solubility (or miscibility) of the active ingredient in the aqueous phase must not be greater than 0.1 g / L. Among the above active ingredients, esters (e.g., the adipate family) have the highest solubility (or miscibility) in the aqueous phase, which is about 0.1 g / L.

[0216] The amount of active ingredient contained in the dispersed phase may be between 0% and 28% of the composition of the dispersed phase, for example between 0% and 28% by weight, and corresponds to a final amount of active ingredient in the microcapsules of between 0% and 70% by weight.

[0217] continuous phase

[0218] The continuous phase is an aqueous phase comprising water and at least one surfactant, the amount of surfactant preferably being less than or equal to 1% of the total weight of the continuous phase.

[0219] The surfactant may be selected from natural surfactants, or synthetic ionic, nonionic or amphoteric surfactants. As an ionic surfactant, for example, sodium lauryl sulfate (SDS) may be used. Depending on the phase in which the nonionic surfactant is used, it is preferred to use a surfactant with a high hydrophilic / lipophilic balance or "HLB" as the nonionic surfactant, for example ( Type) polyoxyethylene sorbitan derivatives, ( or, on the contrary, surfactants with a low hydrophilicity / lipophilicity balance, such as ( As the amphoteric surfactant, for example, egg lecithin or soybean lecithin or a purified derivative thereof can be used.

[0220] Examples of surfactants suitable for preparing the emulsion according to the present invention can be selected from polyvinyl alcohol (PVA), sodium lauryl sulfate (SDS), polyoxyethylene sorbitan monooleate (Tween 80) and bio-based surfactants. SDS is particularly suitable for the present invention.

[0221] Preparation of emulsion

[0222] Emulsions are formed by contacting a continuous phase and a dispersed phase in a microfluidic device (Dolomite microchip or Ehrfeld micromixer). The size and size distribution of the droplets formed (before diffusion) depend on the chosen microfluidic device and the operating conditions applied in terms of the flow rates of the continuous and dispersed phases.

[0223] Diffusion of latent solvent

[0224] The emulsion flows through microchannels (or tubes), typically made of PTFE, allowing the latent solvent of the microdroplets to diffuse towards the aqueous continuous phase.

[0225] After diffusion, the diameter of these post-diffusion droplets is smaller than the diameter of the pre-diffusion droplets. This reduction in droplet diameter depends on several factors, such as the amount of cosolvent used and the diffusion and / or convection dynamics. Depending on the conditions, the diameter reduction can be about 20% or even 50%.

[0226] The emulsion flow within the microchip is visualized by a camera coupled to an integrated Meros HighSpeed Digital Microscope (e.g., described by Dolomite Microfluidics). Visualization of the emulsion flow within the microchip enables the determination of the diameter of the microdroplets before diffusion. The microdroplets exiting the microchannel are then collected on a glass slide and the diameter of the microdroplets after diffusion is characterized by optical microscopy.

[0227] interfacial polymerization

[0228] After passing through a microfluidic device and then through microchannels that enable diffusion of the latent solvent, the emulsion is added to an aqueous solution containing monomer B or prepolymer B. Contact between monomers and / or prepolymers A and B at the interface of the microdroplets after diffusion leads to the formation of a polymer shell by interfacial polycondensation.

[0229] The interfacial polymerization step can be carried out batchwise, in which case the emulsion is mixed with the polymerization solution in a suitable reservoir. The interfacial polymerization step can also be carried out continuously in a microfluidic device (Ehrfeld microreactor or tube).

[0230] Depending on the choice of monomers or prepolymers A and B (Table 1), the polymer shell can be a polyamide obtained by polycondensation of diacids or acid chlorides and diamines, a polyurea obtained by polycondensation of diisocyanates and diamines, a polyurethane obtained by polycondensation of diisocyanates and diols, or a polyester obtained by polycondensation of dicarboxylic acids and diols.

[0231] Advantageously, the shell is a polyurea obtained using an isocyanate monomer or prepolymer A, the isocyanate prepolymer possibly containing from 2 to 4 isocyanate functional groups.

[0232] Isocyanate molecules with low volatility (flash point above 120° C.) are preferred because of their low toxicity.

[0233] According to one aspect, the isocyanate is a diisocyanate selected from the group consisting of toluene 2,4-diisocyanate (TDI), hexamethylene 1,6-diisocyanate (HDI), isophorone diisocyanate (IPDI), polydiphenylmethane diisocyanate (PMDI), hexamethylene diisocyanate biuret, HDT-LV (low viscosity aliphatic polyisocyanate based on hexamethylene diisocyanate trimer), aliphatic isocyanates, pentamethylene diisocyanate (PDI).

[0234] According to one aspect, the isocyanate is a prepolymer, such as HDB-LV (hexamethylene diisocyanate biuret), HDT-LV or pentamethylene diisocyanate (PDI), preferably the isocyanate is HDB-LV.

[0235] According to another aspect, the isocyanate is preferably selected from the group consisting of hexamethylene diisocyanate trimer, isophorone diisocyanate trimer or hexamethylene diisocyanate biuret, wherein even more preferred is hexamethylene diisocyanate biuret, such as HDB-LV.

[0236] Depending on the number of isocyanate functional groups, the shell of the microcapsules can be crosslinked, thereby increasing the strength of the shell of the microcapsules, which has the effect of reducing the permeability of the polymer shell, improving the retention of the active ingredient and modifying its release.

[0237] The monomers and / or prepolymers B used to obtain the polyurea shell are amines, preferably selected from 1,3-propylenediamine, 1,4-butylenediamine, ethylenetriamine, pentaethylenehexamine, hexamethylenediamine, bis(3-aminopropyl)amine, bis(hexamethylene)triamine, tris(2-aminoethyl)amine, triethylenetetramine, N,N'-bis(3-aminopropyl)-1,3-propylenediamine, tetraethylenepentamine, pentaethylenehexamine, branched polyethyleneimine, chitosan, nisin, gelatin, 1,3-diaminoguanidine, 1,1-dimethylbiguanidine, guanidine, arginine, lysine, ornithine, hexamethylenediamine (HMDA), polyethyleneimine (PEI), ethylenediamine (DEA), diethylenetriamine (DETA), triethylenetetramine (DETA), aromatic polyamines (XDA), aliphatic polyamines (TEPA), polyetheramines, guanidine carbonate, and combinations of these amines.

[0238] Preferably, the polyurea shell is obtained by condensation of a diisocyanate (eg HDB-LV) and a diamine (eg guanidine carbonate or ethylenediamine).

[0239] According to one aspect of the present invention, the polymer shell may be a polyamide obtained by polycondensation of an acid dichloride (monomer or prepolymer A) and an amine (monomer or prepolymer B).

[0240] According to another aspect of the present invention, the polymer shell may be a polyurethane obtained by polycondensation of diisocyanate and polyol.

[0241] Examples of polyols are polyvinyl alcohol, 1,4-butanediol, 1,6-hexanediol, 1,3-propylene glycol, 1,5-pentanediol, 1,8-octanediol and glycols, diols or triols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, neopentyl glycol, 1,4-butanediol, 1,5-pentanediol, 3-methyl-1,5-hexanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, 1,12-octadecanediol, 1,4-cyclohexanedimethanol, dimer fatty acid diols (dimerisyl diol), hydroxypivalate of neopentyl glycol, glycerol and 1,1,1-trimethylolpropane; low molecular weight diols or polyols can be used, such as 1,2-ethanediol, 1,2-propylene glycol, neopentyl glycol, dibromoneopentyl glycol, diethylene glycol, triethylene glycol, isomeric dipropylene glycol and tripropylene glycol, isomeric butanediols, pentanediol, hexanediol, heptanediol, octanediol, nonanediol, decanediol, undecanediol, 1,3-cyclohexanedimethanol and 1,4-cyclohexanedimethanol, hydrogenated bisphenol A, dimeric fatty alcohols, 1,1,1-trimethylolethane, 1,1,1-trimethylolpropane, glycerol, pentaerythritol, sugar alcohols (such as xylitol, sorbitol or mannitol), sugars (such as sucrose), other polyols, low molecular weight alkoxylation products of the above diols and polyols, and mixtures of the above alcohols.

[0242] According to another aspect of the present invention, the polymer shell may be a polyester obtained by polycondensation of a dicarboxylic acid and a polyol. Examples of dicarboxylic acids are sebacic acid, dodecanedioic acid, adipic acid, and methylsuccinic acid. Examples of diols are 1,9-nonanediol and 1,10-decanediol.

[0243] Microfluidic devices

[0244] Microfluidic devices enable the preparation of emulsions.

[0245] The interfacial polymerization step, for its part, can be carried out batchwise or continuously.

[0246] Microfluidic devices suitable for the present invention are cascade or laminated micromixers (Ehrfeld) or microchips (Dolomite).

[0247] Micro mixer (Ehrfeld) is a mixer consisting of multiple channels, and these multiple channels can be parallel or laminated (lamination), and advantageously, multiple channels are parallel. It can achieve output: up to 9L / h. There is an expandable device that can achieve output up to 1000L / h. According to one aspect of the invention, the flow rate of the dispersed phase solution in the micro mixer is between 10mL / min and 100mL / min, advantageously 10mL / min, and the flow rate of the continuous phase is between 20mL / min and 200mL / min, advantageously between 20mL / min and 200mL / min, more advantageously 20mL / min, 30mL / min, 40mL / min, 50mL / min, 60mL / min, 70mL / min, 80mL / min, 90mL / min, 100mL / min, 200mL / min. In the micromixer, the flow rate can be generated using two pressure pumps, such as the HNP Mikrosysteme pressure pumps that deliver flow rates ranging from 1 mL / min to 300 mL / min. In the Ehrfeld micromixer, according to the formula We = ρ c u 2 d / γ, the Weber number of the dispersed phase obtained according to the method of the present invention, is between 1 and 10.

[0248] According to one aspect, the microchip is made of hydrophilic glass and comprises a cross, "T" or "Y" shaped mixer combined with an outlet microchannel. The width of the microchannel at the junction is at least 50 μm or even 105 μm. According to one aspect of the invention, the flow rate of the dispersed phase solution in the microchip is between 0.2 μL / min and 7 μL / min, advantageously 1 μL / min, and the flow rate of the continuous phase solution is between 6 μL / min and 1000 μL / min, advantageously between 40 μL / min and 150 μL / min, more advantageously 40 μL / min, 60 μL / min, 70 μL / min, 80 μL / min, 90 μL / min, 100 μL / min, 120 μL / min, 140 μL / min. According to one aspect, the microfluidic device can comprise a Dolomite 3D flow focusing microchip whose channel is 50 microns at the junction. Within the microchip, the flow rate can be controlled using two pressure pumps equipped with two types of flow rate sensors of the Mitos Flow Rate Sensors type, such as that described by Dolomite Microfluidics, UK.

[0249] The flow rate of the dispersed phase ranges from 0.2 μL / min to 7 μL / min, and the flow rate of the continuous phase ranges from 6 μL / min to 1000 μL / min. c u 2 d / γ, the Weber number of the dispersed phase obtained according to the method of the present invention is between 10 -4 to 10 -3 between.

[0250] The use of microchips is particularly suitable for preparing calibration capsules of small sizes, less than 50 microns.

[0251] The use of an Ehrfeld micromixer as such is more particularly suited for the continuous preparation of capsules of even smaller diameters, typically less than 10 microns, and at flow rates of about 100 mL / min.

[0252] Microchannels for latent solvent diffusion

[0253] The microchannel or tube in which the diffusion of the latent solvent into the aqueous solution occurs is advantageously made of Teflon and has a length of at least 30 cm to 1 meter. In a microfluidic device, a microchip or micromixer is directly connected to a Teflon (PTFE) microchannel at its outlet.

[0254] The emulsion formed using the reactor is fed into a polytetrafluoroethylene (PTFE) microchannel having a length of at least 30 cm or at least 1 meter at a flow rate of 0.1 m / s.

[0255] The diameter of the PTFE tube or microchannel is between 500 μm and 2000 μm.

[0256] It is important that the microchannel does not have any hydrophobic properties that would cause the microdroplets to adhere to the walls of the microchannel and then coalesce.

[0257] Example 1: Preparation of microdroplets and microcapsules using Dolomite microchips

[0258] This example describes the preparation of microcapsules consisting of a polyurea shell and a core containing a sunscreen using a Dolomite microchip. The experiments presented demonstrate the feasibility of preparing highly monodisperse polyurea microcapsules (coefficient of variation less than 7%) with a minimum size of about 20 μm by the method according to the invention.

[0259] To investigate the impact, various operating conditions were tested:

[0260] Flow rates of the continuous and dispersed phases;

[0261] the percentage of cosolvent used;

[0262] Choice of co-solvent used.

[0263] In each case, the size of the microdroplets before and after diffusion was compared. The stability of the microdroplets and capsules over time was also analyzed.

[0264] Experimental setup

[0265] The experiment was carried out using a hydrophilic borosilicate glass microchip (Droplet Junction Chip, Dolomite Microfluidics, UK). ) to prepare oil-in-water (O / W) emulsions. The chip geometry is known as flow focusing, with a junction width of 105 μm, a collection channel width of 300 μm, and a height of 100 μm.

[0266] The aqueous and organic phases were separated using two pressure pumps (Mitos P-Pump, response time <4 s, Dolomite Microfluidics, UK). ) are supplied, the pressure pump is equipped with two types of flow rate sensors (Mitos flow rate sensors for dispersed phase 0.2 to 7 μL / min and continuous phase 6 to 1000 μL / min, response time <30 ms, UK, Dolomite Microfluidics The images were taken using a microscope with an integrated microscope (Meros high-speed digital microscope, 4000 fps, Dolomite Microfluidics, UK). ) high-speed camera to visualize the formation and flow of droplets. The experimental setup of microfluidic emulsification is as follows Figure 1 As shown in (a).

[0267] The initially formed organic pre-diffusion droplets then enter a 30 cm Teflon microchannel where the latent solvent is extracted from the droplets by diffusion and / or convection. This results in a reduction in the size of these droplets ( Figure 1 (b) Step 2).

[0268] For the final step ( Figure 1 In step 3) of (b), the interfacial polymerization was continued at ambient temperature (25°C) for four days.

[0269] Chemical system

[0270] The dispersed phase contains a latent solvent, a polyisocyanate prepolymer HDB-LV and an active ingredient octyl salicylate (OS); the aqueous phase contains water and dodecyl sulfate (SDS).

[0271] In this embodiment, relative to the gross weight of organic phase, the ratio of the free isocyanate groups in the molecule of hexamethylene diisocyanate biuret (HDB-LV, Vencorex Chemicals) is 23.5 ± 1.0% by weight. Sodium lauryl sulfate (Across Organics, purity grade), ethylenediamine (Sigma Aldrich, >99%), octyl salicylate (Sigma Aldrich, >99%), butyl acetate (Sigma Aldrich, ACS reagent, >99%) and the need for further purification are required. Distilled water is prepared by GFL single distillation still 2008 (Single Distillation Still 2008, GFL). All liquids are filtered in advance by syringe filter (JVLAB, PTFE with 0.45 μm pores).

[0272] Ethyl acetate and butyl acetate were used as co-solvents.

[0273] The continuous phase consists of 1% by weight of SDS and 99% by weight of water, relative to the total weight of the aqueous phase.

[0274] The aqueous solution in the beaker contained 0.01% by weight of ethylenediamine and 1% by weight of SDS, respectively, relative to the total weight of the aqueous phase.

[0275] Experimental methods

[0276] For each operating condition, the experiment was repeated at least three times to verify reproducibility.

[0277] To investigate the effects of the flow rate of the continuous phase, the concentration of the solvent in the dispersed phase, and the solubility of the solvent in water on the formation of polyurea microcapsules, various chemical systems were tested and are summarized in Table 4. For each chemical system, capsules of four different sizes were prepared using different flow rates of the continuous phase.

[0278] The method comprises the following steps:

[0279] -Preparing a continuous phase solution;

[0280] -Preparing a dispersed phase solution;

[0281] - contacting the dispersed phase with the continuous phase in a microchip connected to a PTFE microchannel;

[0282] - Allowing the emulsion to flow into the PTFE (or Teflon) microchannels to allow the latent solvent of the dispersed phase to diffuse toward the continuous phase;

[0283] - The diffused microdroplets of the emulsion are brought into contact with the polymerizing solution. The microcapsules thus formed can be collected using a pipette and air-dried on a glass slide for analysis.

[0284] Preparation of continuous phase:

[0285] In a beaker, while weighing on a balance, add 1% by mass of SDS and dilute with water.

[0286] - Add a magnetic stirrer and continue stirring for 30 min while heating to below 50°C.

[0287] - Filter the aqueous phase: Use a syringe to draw up the solution. Add a syringe filter and clean the flask with the filtered solution. Use a syringe to draw up the solution and use the filter to transfer the desired solution to a clean flask.

[0288] Preparation of dispersed phase:

[0289] -60% system: In a vial, add 60% by mass of the cosolvent when weighed on a balance

[0290] (butyl acetate or ethyl acetate, depending on the experiment), 12% HDB-LV, and 28% OS.

[0291] -90% system: In a vial, add 90% by mass of the cosolvent when weighed on a balance

[0292] (butyl acetate or ethyl acetate, depending on the experiment), 3% HDB-LV and 7% OS.

[0293] - Add a magnetic stirrer and continue stirring for 30 min while ensuring the vial is sealed with the stopper.

[0294] - Filter the organic phase: Use a syringe to draw up the solution. Add a syringe filter and clean the flask with the filtered solution. Use a syringe to draw up the solution and use the filter to transfer the desired solution to a clean flask.

[0295] Two co-solvents were tested: butyl acetate and ethyl acetate. Table 4 summarizes the experimental titles according to the co-solvents used and their compositions.

[0296] [Table 4]: Composition of the droplet phase of various chemical systems

[0297]

[0298] BA: Butyl acetate

[0299] EA: ethyl acetate

[0300] Preparation of emulsion:

[0301] - Place the aqueous phase flask in the reservoir at the inlet of the pump for the continuous phase;

[0302] - Place the organic phase flask in the reservoir at the inlet of the pump for the dispersed phase;

[0303] - Turn on the pump;

[0304] - Set the flow rate of the dispersed phase (Qd) to: 1 μL / min to 5 μL / min,

[0305] - Set the flow rate of the continuous phase (Qc) to: 40 μL / min to 150 μL / min,

[0306] Interfacial polymerization:

[0307] - Prepare a beaker containing 1 kg of 0.01% ethylenediamine aqueous phase (aqueous polymerization solution);

[0308] - collecting the diffused microdroplets in a beaker at the outlet of the microchannel where the latent solvent diffusion occurs and placing them in the presence of an aqueous polymer solution;

[0309] - Microcapsules were formed in a beaker in the presence of ethylenediamine.

[0310] Interfacial polymerization was continued for four days at ambient temperature.

[0311] The molar amount of amine functional groups in the beaker is at least five times greater than the molar amount of isocyanate functional groups in the collected microdroplets.

[0312] Characterization of microdroplets and microcapsules.

[0313] Measure the size of the microdroplets and microcapsules before and after diffusion. To characterize the thickness of the shell, droplets of the microcapsule suspension are placed on a glass slide and cut using a cover glass with the aid of an optical microscope. Next, the glass slide with the broken microcapsules must be placed on the SEM stage. Finally, the microcapsules placed on the SEM stage are naturally dried for 12 hours. Cut and measure at least three different capsules to measure the average shell (epidermis) thickness.

[0314] The microscope was used with an integrated microscope (Meros high-speed digital microscope, Dolomite Microfluidics, UK). ) high-speed camera to visualize the formation and flow state of microdroplets before diffusion.

[0315] After the diffusion phase in the latent solvent and after polymerization, samples of the diffused microdroplets and microcapsules were collected and subsequently observed by optical microscopy. The droplets were recovered on an optical microscope plate for analysis.

[0316] Characterize microdroplets and microcapsules with diameters between 10 μm and 100 μm by image analysis, either manually or using image processing software. Images provided by the microscope can be recorded on the AM Scope software, where the scale bar represents 3.782 pixels per true μm or 0.946 pixels per true μm, depending on the selected resolution.

[0317] result

[0318] Monodispersity of microdroplets before diffusion, microdroplets after diffusion, and microcapsules

[0319] The coefficient of variation (CV) of the diameter was calculated from the photographs of the microdroplets before diffusion, the microdroplets after diffusion, and the microcapsules. The size distribution of the diameters obtained using the BA-60% system is shown in Figure 2. Figure 2 The flow rates of the continuous phase (Qc) and the dispersed phase (Qd) were 85.0 μL / min and 1.0 μL / min, respectively.

[0320] The calculated average CV values for the microdroplets before and after diffusion were 0.63%, 0.97%, and 6.27%, respectively. Using a microfluidic device, the microdroplets were highly monodisperse, with CV values of approximately 1%, both before and after diffusion.

[0321] Tables 5, 6 and 7 show the reproducibility of the results based on experiments performed three times. [Table 5]: Size distribution of microdroplets before diffusion - BA-60% system

[0322]

[0323] [Table 6] Size distribution of microdroplets after diffusion - BA-60% system

[0324]

[0325]

[0326] [Table 7]: Size distribution of microcapsules - BA-60% system

[0327]

[0328] Effect of flow rates of the continuous and dispersed phases and the percentage of the cosolvent

[0329] The cosolvent used was butyl acetate (BA). Experiments performed at different phase flow rates and cosolvent percentages are presented.

[0330] Results for BA 60% system

[0331] Figure 3The variation of droplet size as a function of the flow rate of the continuous and dispersed phases for a system containing 60% butyl acetate is shown. In these experiments, two different flow regimes had to be used, such as Figure 4 Shown: dripping (a) and spraying (b).

[0332] For a fixed organic phase flow rate, the higher the aqueous phase flow rate, the smaller the size of the microdroplets.

[0333] Figure 5 The size of the droplets after diffusion is shown as a function of the size of the droplets before diffusion. The results are reproducible.

[0334] Independently of the flow rate used, it is possible to estimate an average factor α (ratio between the diameter of the droplets before and after diffusion) equal to 1.37, which is quite close to its theoretical value of 1.41, with a relative difference of 2.8%.

[0335] This theoretical factor (α) can be calculated as follows:

[0336]

[0337] where d pre is the size of the droplet before diffusion, d post is the theoretical size of the microdroplet after diffusion, ρ orga is the density of the organic phase, ρ HDB / OS is the density of a mixture of HDB-LV and octyl salicylate in a mass ratio of 3 / 7, and w HDB / OS is the mass percentage of HDB-LV and octyl salicylate in the organic phase.

[0338] Figure 6 The diameter of the microdroplets after diffusion is shown as a function of time. It can be seen that the vast majority of the latent solvent has diffused 5 minutes after it was collected. Other experiments have even shown that after 2 minutes, all the latent solvent has diffused.

[0339] Figure 7 The morphology of the obtained microcapsules is shown. It can be clearly seen that they are spherical. No holes are observable on the surface. The skin is sealed and may contain roughness on the outer surface. Table 8 shows the skin thickness measured during three identical experiments.

[0340] [Table 8]: Skin thickness of 47 μm microcapsules

[0341]

[0342] Results of BA 90% system

[0343] Figure 8The variation of the droplet size as a function of the flow rate of the continuous and dispersed phases is shown. During these experiments, two different flow regimes had to be used, such as Figure 9 Shown: dripping and tip streaming.

[0344] For a fixed organic phase flow rate, the higher the aqueous phase flow rate, the smaller the size of the microdroplets.

[0345] form Figure 9 The conditions for the microdroplets of (b) are: the aqueous phase flow rate is 100 μL / min, and the organic phase flow rate is 5 μL / min. These conditions appear to be very favorable because they can obtain very small monodisperse microdroplets at high flow rates.

[0346] FIG. 10 shows the size of the droplets after diffusion as a function of the size of the droplets before diffusion.

[0347] Independently of the flow rate used, it is possible to estimate an average factor α (ratio between the diameter of the droplets before and after diffusion) equal to 2.10, which is close to its theoretical value of 2.27, with a relative difference of 7.5%.

[0348] Figure 11 shows the morphology of the obtained microcapsules. They are spherical. The skin is sealed and contains roughness on the outer surface. Table 9 gives the skin thickness measured during 3 identical experiments.

[0349] [Table 9]: Skin thickness of 27 μm microcapsules

[0350]

[0351] Effect of cosolvent selection

[0352] The second co-solvent used was ethyl acetate (EA). For reference, Table 10 gives the physicochemical properties of the two co-solvents used.

[0353] [Table 10]: Comparison of the main properties of various solvents used

[0354]

[0355] Results of EA 60% system

[0356] Figure 12 shows the variation of the droplet size as a function of the flow rate of the continuous phase for a system containing 60% butyl acetate.During these experiments, the dripping regime was used.

[0357] For a fixed organic phase flow rate (1 μL / min), the higher the aqueous phase flow rate, the smaller the size of the microdroplets.

[0358] Independently of the flow rate used, it is possible to estimate an average factor α (ratio between the diameter of the droplets before and after diffusion) equal to 1.36, which is quite close to its theoretical value of 1.40, with a relative difference of 2.8%.

[0359] Results of EA 90% System

[0360] The variation of the droplet size as a function of the flow rate of the continuous and dispersed phases is shown in Figure 13. During these experiments, the dripping regime was used.

[0361] For a fixed organic phase flow rate (1 μL / min), the higher the aqueous phase flow rate, the smaller the size of the microdroplets.

[0362] Independently of the flow rate and flow regime used, it is possible to estimate the average factor α (ratio between the diameter of the droplet before and after diffusion) to be equal to 2.15, which is close to its theoretical value of 2.26, with a relative difference of 5.6%.

[0363] These two cosolvents are suitable for reducing the size of the microcapsules and make it possible to obtain similar results.

[0364] in conclusion

[0365] The dispersion of the droplets (coefficient of variation (CV)) is particularly narrow, with the CV ranging from 0.3% to 0.6%. For the microcapsules, they have the same size as the microdroplets after diffusion. The measured CV for the microcapsules is about 6% to 7%.

[0366] The tests made it possible to verify the reduction in the size of the microdroplets between their formation in the microchip and their exit from the microchannels used to diffuse the latent solvent. After diffusion of the latent solvent in the PTFE microchannels, the size of the microdroplets before diffusion decreased by 20% to 50%.

[0367] The various values of the factor α obtained as a function of the operating conditions are summarized in Table 11.

[0368] [Table 11]: Factor α of various chemical systems

[0369]

[0370] The two solvent systems tested gave similar results.The performance of the present invention was verified independent of the co-solvent chosen.

[0371] The thickness of the microcapsule skin ranges from 0.6 to 1.4 mm, depending on the size of the microcapsules.

[0372] Example 2: Preparation of microdroplets and microcapsules by Ehrfeld cascade micromixer

[0373] This example describes the preparation of microcapsules consisting of a polyurea shell and a core comprising a solvent (Cetiol B) using an Ehrfeld micromixer. The presented experiments demonstrate the feasibility of preparing polyurea microcapsules with a minimum size of a few micrometers by the process according to the invention.

[0374] To investigate the impact, various operating conditions were tested:

[0375] Flow rates of the continuous and dispersed phases;

[0376] the percentage of cosolvent used;

[0377] Experimental setup

[0378] The cascade micromixer used is a static micromixer that combines two liquids by repeated transversely offset divisions, thereby combining the two streams according to the "divide and recombine" principle. [Ehrfeld Mikrotechnik BTS, Operating Instructions cascade mixer, OI-0216-3, 2012] Thus, at the beginning of each recombination, the number of fluid layers present doubles, while their diameters halve.

[0379] By repeating this process 11 times, a large number of fluid layers of various compositions were obtained, which represents a method for rapid mass transfer in a mixture. If two immiscible liquids are introduced into the micromixer at relatively high flow rates, the high shear in the mixing channel can produce an emulsion.

[0380] This type of mixer can be used for very viscous fluids or those containing particles. Furthermore, the pressure drop is extremely low, allowing high flow rates to be achieved even when working with highly viscous fluids. The modules used also allow temperature control via heat transfer mechanisms located above and below the mixing structure.

[0381] The optimum temperature is 25°C, but the temperature can be varied to change the viscosity.

[0382] The cascade micromixer has two inlet channels and one outlet channel, and is combined with a polytetrafluoroethylene (PTFE) microchannel having a length of 53.5 cm. The passage volume of the microfluidic mobile phase is

[0383] L=53.5cm

[0384] d 内部 =2mm

[0385] Therefore, the volume of the microchannel is

[0386] V = 4.24 × 10 -5 ml

[0387] For a flow rate of 100 mL / min: transit time 1.01 s.

[0388] Two pumps were used to supply the micromixer with the dispersed and continuous phases.

[0389] The organic diffusion front droplets then enter a Teflon tube or microchannel where the latent solvent is extracted from the droplets by diffusion and / or convection. This results in a size reduction of these droplets.

[0390] At the outlet of the microchannel, the emulsion was sent to a beaker filled with polymerization solution, where the interfacial polymerization reaction was carried out at ambient temperature for 4 days.

[0391] Chemical system

[0392] The dispersed phase comprises a latent solvent, a polyisocyanate prepolymer HDB-LV and a solvent; and the aqueous phase comprises water and dodecyl sulfate (SDS).

[0393] In this embodiment, the ratio of the free isocyanate groups in the molecule of hexamethylene diisocyanate biuret (HDB-LV, Vencorex Chemicals) is 23.5 ± 1.0% by weight relative to the gross weight of the organic phase. Use ethylenediamine (Sigma Aldrich, >99%), octyl salicylate (Sigma Aldrich, >99%), ethyl acetate (ACS reagent, >99%) and Cetiol B without additional purification. Distilled water is produced by GFL single distillation still 2008 (Single Distillation Still 2008, GFL). All liquids are filtered in advance through a syringe filter (JVLAB, PTFE with 0.45 μm pores).

[0394] Ethyl acetate was used as a co-solvent while Cetiol B was used as a solvent.

[0395] The continuous phase consists of 1% by weight of SDS and 99% by weight of water, relative to the total weight of the aqueous phase.

[0396] The aqueous solution in the beaker contained 0.01% by weight of ethylenediamine and 1% by weight of SDS, respectively, relative to the total weight of the aqueous phase.

[0397] Experimental methods

[0398] The experimental procedures are identical to those described in Example 1 if Cetiol B is used instead of octyl salicylate.

[0399] Table 12 summarizes the experimental names according to the co-solvents used and their compositions. [Table 12]: Composition of the droplet phase of various chemical systems

[0400]

[0401] EA: ethyl acetate

[0402] result

[0403] Monodispersity of microdroplets before diffusion

[0404] Figure 14 shows photographs of microdroplets before diffusion for given dispersed and continuous phase flow rates. As can be clearly seen in Figures 15 and 16, the microdroplet sizes are polydisperse, as indicated by the distribution of microdroplet diameters. For the two flow rate ranges presented, the CVs are 36.5% and 40.7%, respectively.

[0405] The main advantage offered by this mixer is not the ability to control the size of the microdroplets, but rather the ability to use flow rates much higher than those permitted by the microchip. It is possible to operate with flow rates of 200 mL / min for both phases, whereas within the microchip, the flow rate of the dispersed phase is measured in μL / min and is therefore 200,000 times smaller. Ehrfeld also offers a scaled-up device that can achieve flow rates approaching 1000 L / h.

[0406] Effect of flow rates of the continuous and dispersed phases

[0407] Figure 17 shows the effect of the flow rate of the continuous phase on the size of the microdroplets before diffusion. The higher the flow rate, the smaller the microdroplets. For example, when the flow rate is from 50 to 60 mL / min, their average diameters are 19.3 and 16.6 μm, respectively. When the flow rate of the dispersed phase increases, the same effect is observed. An increase in one of the two flow rates causes the size of the microdroplets to decrease before diffusion.

[0408] Effect of the percentage of cosolvent

[0409] The cosolvent used was ethyl acetate. This article presents experiments conducted at varying percentages of cosolvent for fixed continuous and dispersed phase flow rates. As can be seen in Figure 18, the average size of the microdroplets after diffusion is much smaller than before diffusion, and this phenomenon becomes more pronounced with increasing percentages of cosolvent. The results obtained are summarized in Table 13 below, which is illustrated in Figures 19 and 20.

[0410] [Table 13]: Properties of microdroplets before and after diffusion.

[0411]

[0412]

[0413] Regarding the coefficient of variation (CV), the polydispersity of the microdroplets after diffusion is the same as before diffusion. For the systems EA60% and EA90%, the ratio α is 3.2 and 6.0, respectively, which explains the size reduction achieved. The discrepancy between the experimental and theoretical values undoubtedly stems from the polydispersity of the achieved sizes.

[0414] Characteristics of microcapsules

[0415] Figure 21 shows a photograph of microcapsules obtained using the EA 60% system. Figures 22 and 23 give the diameter distribution of capsules formed using the EA 60% and EA 90% systems. These values are collated in Table 14.

[0416] [Table 14]: Characteristics of microcapsules

[0417]

[0418] It can be noted that the characteristics of the capsules are very close to those of the microdroplets after diffusion in terms of mean diameter and coefficient of variation.

[0419] in conclusion

[0420] This test can verify the reduction in the size of the microdroplets between their formation in the micromixer and their exit from the microchannels used to diffuse the latent solvent. After diffusion of the latent solvent in the PTFE microchannels, the size of the microdroplets before diffusion was reduced by up to 6 times.

[0421] The microdroplets and microcapsules have polydisperse diameters before and after diffusion.

[0422] The concept of the present invention has been demonstrated in an Ehrfeld cascade mixer, which provides a much higher production flow rate than would be possible using a microchip. The mixer can also achieve capsule sizes approaching micrometers.

[0423] [Table 15] List of abbreviations used:

[0424]

[0425]

[0426] [Table 16]: List of quantities used:

[0427]

[0428] Example 3: Preparation of micron-sized droplets and microcapsules by Ehrfeld cascade micromixer

[0429] This example describes the preparation of microcapsules consisting of a polyurea shell and a core containing a sunscreen agent using an Ehrfeld micromixer. The experiments presented demonstrate the feasibility of preparing polyurea microcapsules with micrometer-sized diameters using the method according to the present invention. To investigate their effects, various concentrations of surfactant were tested:

[0430] Experimental setup

[0431] The cascade micromixer used is a static micromixer that combines two liquids by repeated transversely offset divisions, thereby combining the two streams according to the "divide and recombine" principle. [Ehrfeld Mikrotechnik BTS, Operating Instructions cascade mixer, OI-0216-3, 2012] Thus, at the beginning of each recombination, the number of fluid layers present doubles, while their diameters halve.

[0432] By repeating this process 11 times, a large number of fluid layers of various compositions were obtained, which represents a method for rapid mass transfer in a mixture. If two immiscible liquids are introduced into the micromixer at relatively high flow rates, the high shear in the mixing channel can produce an emulsion.

[0433] This type of mixer can be used for very viscous fluids or those containing particles. Furthermore, the pressure drop is extremely low, allowing high flow rates to be achieved even when working with highly viscous fluids. The modules used also allow temperature control via heat transfer mechanisms located above and below the mixing structure.

[0434] The optimum temperature is 25°C, but the temperature can be varied to change the viscosity.

[0435] The cascade micromixer has two inlet channels and one outlet channel, and is combined with a polytetrafluoroethylene (PTFE) microchannel having a length of 53.5 cm. The passage volume of the microfluidic mobile phase is

[0436] L=53.5cm

[0437] d 内部 =2mm

[0438] Therefore, the volume of the microchannel is

[0439] V = 4.24 × 10 -5 ml

[0440] For a flow rate of 200 mL / min: transit time 0.50 s.

[0441] Two pumps were used to supply the micromixer with the dispersed and continuous phases.

[0442] The organic diffusion front droplets then enter a Teflon tube or microchannel where the latent solvent is extracted from the droplets by diffusion and / or convection. This results in a size reduction of these droplets.

[0443] At the outlet of the microchannel, the emulsion was sent to a beaker filled with polymerization solution, where the interfacial polymerization reaction was carried out at ambient temperature for 4 days.

[0444] Chemical system

[0445] The dispersed phase comprises a latent solvent, a polyisocyanate prepolymer, HDB-LV and a solvent, and the aqueous phase comprises water and dodecyl sulfate (SDS).

[0446] In this embodiment, the ratio of the free isocyanate groups in the molecule of hexamethylene diisocyanate biuret (HDB-LV, Vencorex Chemicals) is 23.5 ± 1.0% by weight relative to the gross weight of the organic phase. Use ethylenediamine (Sigma Aldrich, >99%), octyl salicylate (Sigma Aldrich, >99%) and ethyl acetate (ACS reagent, >99%) without additional purification. Distilled water is produced by GFL single distillation still 2008 (Single Distillation Still 2008, GFL). All liquids are filtered in advance through a syringe filter (JVLAB, PTFE with 0.45 μm pores).

[0447] The dispersed phase contained the latent solvent ethyl acetate, the polyisocyanate prepolymer HDB-LV and the active ingredient octyl salicylate (OS).

[0448] The continuous phase consists of 1 to 2% by weight of SDS and 99 to 98% by weight of water, relative to the total weight of the continuous phase.

[0449] The aqueous solution in the beaker contained 0.1% by weight of ethylenediamine and 1% by weight of SDS, respectively, relative to the total weight of the aqueous phase.

[0450] Experimental methods

[0451] If octyl salicylate is used instead of Cetiol B, the experimental methods are the same as those described in Example 2. The optimal flow rate of the dispersed and continuous phases is set to 200 mL / min.

[0452] Table 16 summarizes the experimental names according to the co-solvents used and their compositions. [Table 16]: Composition of the dispersed phase of various chemical systems

[0453]

[0454] EA: ethyl acetate

[0455] [Table 17]: Continuous phase composition of various chemical systems

[0456]

[0457] SDS: Sodium dodecyl sulfate

[0458] result

[0459] Effect of active ingredients

[0460] Table 18 summarizes the information regarding the droplet size after diffusion in an aqueous phase containing 1% SDS. It can be clearly seen that the droplet size is less polydisperse (CV of 27.5%) than the droplet size prepared in Example 2 (CV of 45.0%). When all other parameters are equal, the final droplet size reaches an average of 3.5 μm, which is comparable to the average size of Example 2 (3.2 μm). Therefore, using octyl salicylate instead of Cetiol B as the active ingredient produces more monodisperse droplets after diffusion in ethyl acetate.

[0461] [Table 18]: Properties of microdroplets before and after diffusion.

[0462]

[0463] Effect of surfactant concentration

[0464] This article presents experiments conducted with a higher SDS concentration (2%) in the aqueous phase, with both the continuous and dispersed phase flow rates fixed at 200 mL / min. Figures 24 and 25 show that the average droplet size before and after diffusion was significantly smaller than that of droplets prepared using 1% SDS in the aqueous phase. This is due to the decrease in interfacial tension between the oil and aqueous phases as the surfactant concentration increases. The results obtained are summarized in Table 19, which is illustrated in Figures 24 and 25.

[0465] [Table 19]: Properties of microdroplets before and after diffusion.

[0466]

[0467] Regarding the coefficient of variation (CV) ( FIG. 26 ), the microdroplets before and after diffusion were more monodisperse than those prepared using 1% SDS in the aqueous phase. The diameters of the microdroplets comprising the largest population ranged from 0.8 to 1.2 μm. The experimental and theoretical ratios were 3.18 and 2.26, respectively, which are very similar values. The discrepancy between the experimental and theoretical values undoubtedly stems from the polydispersity of the sizes obtained. They are lower than those obtained in Example 2 using Cetiol B as the active ingredient.

[0468] in conclusion

[0469] This test demonstrated that the size of the microdroplets decreases between their formation in the micromixer and their exit from the microchannels used to diffuse the latent solvent. After diffusion of the latent solvent within the PTFE microchannels, the size of the microdroplets before diffusion decreased by a factor of 3.18, which is very close to the theoretical factor of 2.26.

[0470] When octyl salicylate was used instead of Cetiol B as the active ingredient, the size distribution of the microdroplets before and after diffusion was more monodisperse.

[0471] The concept of the present invention has been demonstrated in an Ehrfeld cascade mixer, which provides a much higher production flow rate than would be possible using a microchip. The mixer can also achieve capsule sizes approaching micrometers.

[0472] [Table 20] List of abbreviations used:

[0473]

[0474] [Table 21]: List of quantities used:

[0475]

[0476]

Claims

1. A method for preparing polymer microcapsules, comprising the steps of: a. preparing an emulsion in the form of microdroplets comprising an aqueous continuous phase and a dispersed phase by microfluidics, the dispersed phase comprising a monomer or prepolymer A and a latent solvent at least partially miscible in the continuous phase; b. a step of partially or completely diffusing the latent solvent of the dispersed phase toward the continuous phase by diffusion and / or convection; c. a step of interfacial polymerization by polycondensation by contacting the microdroplets of the emulsion with a polymerization solution comprising a second monomer or prepolymer B.

2. The method according to claim 1, characterized in that If monomer A or prepolymer A is an acid chloride or an isocyanate, monomer B or prepolymer B is an amine, or if monomer A or prepolymer A is an isocyanate or a carboxylic acid, monomer B or prepolymer B is an alcohol, advantageously monomer A or prepolymer A is an isocyanate and monomer B or prepolymer B is an amine.

3. The method according to claim 1 or 2, characterized in that The isocyanate is a diisocyanate, advantageously the isocyanate is a diisocyanate selected from the group consisting of toluene 2,4-diisocyanate (TDI), hexamethylene 1,6-diisocyanate (HDI), isophorone diisocyanate (IPDI), polydiphenylmethane diisocyanate (PMDI), hexamethylene diisocyanate biuret (HBD-LV), hexamethylene diisocyanate trimer (HDT-LV (low viscosity aliphatic polyisocyanate based on hexamethylene diisocyanate trimer)), aliphatic pentamethylene diisocyanate (PDI), a combination of these diisocyanates, advantageously the isocyanate is hexamethylene diisocyanate biuret (HBD-LV).

4. The method according to any one of claims 1 to 3, characterized in that The amine is selected from hexamethylenediamine (HMDA), polyethyleneimine (PEI), ethylenediamine (En), diethylenetriamine (DETA), triethylenetetramine (TETA), aromatic polyamines (XDA), aliphatic polyamines (TEPA), polyetheramines, guanidine carbonate, and combinations of these amines. Advantageously, the amine is En or guanidine carbonate.

5. The method according to any one of the preceding claims, characterized in that The solubility of the latent solvent in water at 20° C. is between 1 g / L and 100 g / L.

6. The method according to any one of the preceding claims, characterized in that The latent solvent is selected from butyl acetate, ethyl acetate, amyl acetate, butyl stearate, advantageously the latent solvent is butyl acetate or ethyl acetate.

7. The method according to any one of the preceding claims, characterized in that The dispersed phase comprises at least 60% by weight of the co-solvent relative to the total weight of the dispersed phase.

8. The method according to any one of the preceding claims, characterized in that The dispersed phase comprises at least one excipient and / or active ingredient and / or solvent.

9. The method according to any one of the preceding claims, characterized in that Relative to the total weight of the dispersed phase, the dispersed phase comprises: a. 60% to 90% by weight of a latent solvent; b. 3 to 12% by weight of monomers and / or prepolymers A; 7 to 30% by weight of solvent; c. Active ingredient and monomer or prepolymer A in a ratio of 3:

7.

10. The method according to any one of the preceding claims, characterized in that Relative to the total weight of the continuous phase, the continuous phase comprises: a. 0.1% to 5% of a surfactant, advantageously the surfactant is SDS; b. Appropriate amount of water.

11. The method according to any one of the preceding claims, characterized in that The diffusion step is performed by flowing the emulsion through a microfluidic microchannel.

12. The method according to any one of the preceding claims, characterized in that The polymerization step is performed continuously or batchwise in microfluidic microchannels.

13. A microfluidic device comprising a microchip or a cascade micromixer connected to a microfluidic microchannel made of PTFE and having a diameter between 500 μm and 2000 μm.

Images