Method for producing a polymer matrix loaded with an active substance using a gas, products and related uses

Abstract

The present invention relates to the field of polymer matrices loaded with active substances, in particular to a method that makes it possible to obtain said loaded matrices. More particularly, the invention relates to a method for incorporating an active substance into a polymer matrix using a gas, comprising the following successive steps: a) impregnation of the polymer with a gas in a non-supercritical state, b) incorporation of the active substance. The present invention relates to said method, the incorpo-rated matrices resulting from this method, and the uses of said method.

Description

[Technical Field]

[0001] The present invention relates to the field of polymer matrices loaded with active substances, and in particular to the methods making it possible to obtain said matrices.

[0002] More particularly, the present invention relates to a method for producing a polymer matrix loaded with an active substance using a gas, its use and products derived from this method.

[0003] The method according to the invention is aimed at producing matrices loaded with active substances for various applications in humans and also in the veterinary field, where plastic processing methods are often used to produce diffusion devices.

[0004] These diffusion devices often take the form of collars or bracelets for topical application for anti-parasitic or insecticidal purposes, and can also allow for the diffusion of other active substances such as essential oils.

[0005] Among the plastic processing methods used to create these diffusion devices can be found, among others, but not exclusively, extrusion and injection molding.

[0006] Extrusion is a continuous processing method in which the polymer, in granular or powder form, is introduced into a heated sleeve with a worm screw in a single-screw extruder or two counter- or co-rotating screws in a twin-screw extruder. The material is conveyed, homogenized, plasticized, and forced through a die of the desired shape.

[0007] Generally, injection molding is a manufacturing method in which molten material is injected into a pre-prepared mold and then allowed to cool, during which time the material solidifies and takes the shape of the mold before being ejected.

[0008] Generally, polymers can be divided into two categories: a distinction is made between thermoplastics and thermosets.

[0009] Thermoplastics contain linear polymer chains made up of monomers that can induce reversible physical states upon heating or cooling the material.

[0010] Thermoplastics exist in two forms: amorphous and semi-crystalline. The amorphous form has a glass transition temperature (T g ), and in fact, if the temperature of a thermoplastic polymer is lower than this temperature, the polymer is more brittle and is said to be glassy. Conversely, if the temperature of a thermoplastic polymer is higher than T g If it is higher, the polymer chains are more fluid and the material is in a rubbery state.

[0011] With regard to semi-crystalline forms, when such polymers are heated, their structure becomes disordered and the material becomes fluid. This phenomenon is called melting and occurs at a melting temperature (T f ) is associated with this state. For semi-crystalline polymers, crystalline zones coexist with amorphous zones.

[0012] Thermosets, on the other hand, are characterized by three-dimensional networks, where polycondensation, polymerization, and even reticulation of polymer patterns are found, resulting in an irreversible state of the material once it is placed in its final form.

[0013] Advantageous polymers within the meaning of the present invention are chosen from among thermoplastic polymers.

[0014] In the context of the present invention, the term "matrix" is properly understood as an element that can receive or be impregnated with a substance and allow it to diffuse over time. The polymer matrix thus constitutes, in the context of the present invention, an active substance reservoir, allowing for sustained release of this active substance.

[0015] By active agent reservoir is meant a polymer matrix loaded with an active agent in which the active agent is uniformly distributed during the entrapment process. It should therefore be understood that the present invention does not include compartmentalization of the active agent within the matrix.

[0016] The term entrapment in the context of the present invention can be defined as the incorporation or penetration of a liquid or solid active substance into the interior of a polymer matrix as defined above.

[0017] It is also possible to use the terms diffusion, migration, emanations or release interchangeably to refer to the displacement of an active substance from the interior to the exterior of a polymer matrix. In the remainder of this application, the terms matrix, polymeric matrix, polymer matrix, solid matrix, thermoplastic matrix and also polymer will be used interchangeably to define the polymer matrix according to the invention. [Background technology]

[0018] Known in the prior art is French Patent No. 2901172, which describes a method for incorporating an active substance inside a polymer matrix. This method deals with the problem of incorporating a heat-sensitive active substance into a polymer matrix. In this respect, a method is proposed for incorporating a heat-sensitive active substance composition at ambient temperature, which consists in heating the polymer 1°C to 5°C above its glass transition temperature. The polymers disclosed are ethylene vinyl acetate copolymers (EVA) or polyether block amides (PEBA), which have glass transition temperatures (T) between 20°C and 80°C. g) However, this method does not allow to obtain the uptake conditions of the level of the method according to the invention. Test No. 5 of Example 2 (Fig. 1) shows, inter alia, the results for the comparison of the active substance uptake between PEBA and EVA matrices without CO2 impregnation as described in the prior art and with CO2 uptake using the method described according to the invention. These results show the superiority of the method according to the invention. In fact, EVA and PEBA type polymers have very low negative T g However, the prior art method has a high degree of difficulty, making it impossible to effectively incorporate the active substance at the indicated rate by reproducing the steps of the method described in the prior art. Furthermore, this prior art method cannot be easily extended to other matrix-active substance pairs; i.e., the reproducibility of this incorporation method for other polymers or other active substances is not guaranteed. Furthermore, the use of PEBA is not a feasible solution from an industrial point of view; this type of polymer confers excessive flexibility on the resulting device, which is incompatible with most of the applications sought, and its cost is prohibitively high. Other problems inherent in the use of these polymer matrices also exist. In this regard, the issue of product efficacy over time can be cited. Indeed, it would be desirable to obtain a stable, long-lasting product that does not lose its incorporation capacity over time and can release larger amounts of active substance over a longer period of use. Finally, French Patent No. 2901172 does not describe any method involving gases, nor does it suggest the use of gases to aid in the incorporation of active substances.

[0019] Many prior art documents describe the use of fluids to impregnate polymers, but the temperature and pressure conditions are supercritical, resulting in extremely high pressure and / or temperature conditions. U.S. Pat. No. 4,598,006 describes a method for impregnating thermoplastic polymers using a gas as a volatile swelling agent. However, this method involves a first step of dissolving an active substance in the volatile swelling agent under supercritical or near-supercritical conditions. The preferred thermoplastic material is then contacted with the volatile swelling agent containing the active substance to be incorporated at very high pressure (2,500 psi, or 173 bar). The volatile swelling agent serves to simultaneously dissolve the active substance for incorporation and expand the thermoplastic material, which is only performed under supercritical or near-supercritical conditions. This document further describes only a method in which incorporation into the interior of the polymer is carried out simultaneously with its impregnation and under very high pressure conditions, thus requiring special equipment to generate and withstand such pressure, making the implementation complicated. Moreover, as shown in the examples, the entrapment rate of this type of method remains very low, with less than 6.5% of the active substance found in the final product derived from this method using supercritical or near-supercritical CO. This method does not provide a solution that can improve the entrapment of active substances using gases under non-supercritical pressure conditions.

[0020] Regarding the use of gases in polymers, the prior art contains many references to the foaming or expansion techniques of thermoplastics with the aim of lightening the final material, but these references do not relate to the field of the present invention or to the associated problems of incorporation of active substances.

[0021] In fact, Duarte et al., in two publications ("Subcritical carbon dioxide foaming of polycaprolactone for bone tissue regeneration", The Journal of Supercritical Fluids, Vol. 140, October 2018, pp. 1-10; and "PDLLA enriched with ulvan particles as a novel 3D porous scaffold targeted for bone engineering", The Journal of Supercritical Fluids, Vol. 65, May 2012, pp. 32-38), mention the use of a method using CO2 incorporation, but in a field very distant from the present invention and for very different purposes. In fact, Duarte et al. aim to realize 3D support structures / scaffolds of polycaprolactone or PDLLA / Ulvan in the field of in situ bone regeneration. Their aim is to be able to use a single-step method using carbon dioxide to realize 3D polymeric structures in situ by injecting said polymer in the form of an expanded foam. Their goal is to obtain a highly porous structure capable of incorporating active substances. Their method achieves the desired structure using a gas incorporation temperature of at least 45°C and a pressure of 50 bar. Unlike this prior art and all other techniques that define porous structures obtained by gas impregnation, the method of the present invention does not result in the formation of expanded foams or any other porous structures. Moreover, the method of the present invention achieves gas incorporation into the polymer at temperatures strictly below 40°C, i.e., significantly lower than the temperatures of the prior art, and at pressures below 35 bar. Furthermore, the 50 bar pressure used in the prior art requires sophisticated equipment and even stricter safety conditions than the pressure used in the present invention. The test described in Example 12 shows a scanning microscopy analysis of a polymer matrix impregnated according to the present invention, and no porosity was observed.The prior art documents do not suggest the method according to the invention or describe the matrices obtainable by the method according to the invention.

[0022] In their publication (Chemotherapeutic implants via subcritical CO2 modification, Biomaterials. December 2007; 28(36):5562-9), Powel et al. mention a method for incorporating chemotherapy treatments inside PLA absorbable polymers using compressed CO2 at a temperature of 40°C and a pressure of 45 bar. The CO2 impregnation step inside the polymer requires heating to 40°C, unlike the method of the present invention, which is preferably carried out at 25°C. Furthermore, the active substance loaded into the polymer is rapidly released within 2 days. This document does not describe an improved method for incorporating active substances inside polymers using gas, where the impregnation preferably occurs at 25°C and a pressure of less than 35 bar, and the release continues for as long as possible.

[0023] US 2021 / 0269607 describes a method for incorporating an active substance into a polymer, limited to polybutylene succinate (PBS), which must be provided with a porous or cavity-containing structure to allow for the incorporation. The porous structure is obtained, on the one hand, by the obligatory presence of additives that modify the polymer's structure, and, on the other hand, by a gas impregnation step carried out with CO2 under supercritical conditions (100 bar / 40°C). Therefore, US 2021 / 0269607 does not describe the use of the method at non-supercritical temperatures or pressures, nor does it suggest the possibility of incorporating an active substance without the need for a porous or cavity-containing structure.

[0024] WO 2014 / 146864 describes a method that involves mixing a starch-based product with a phenolic derivative, a solvent, and a buffer solution, and exposing the mixture to a fluid at a temperature and pressure high enough to induce a chemical reaction, but still "subcritical," leading to a modified starch-based product. The fluid used is limited to liquids such as water or any other aqueous ionic liquid. Moreover, the temperature at which the method is carried out is 100°C. WO 2014 / 146864 does not describe at all the incorporation of gases into the polymer to improve the incorporation of active substances. [Prior art documents] [Patent documents]

[0025] [Patent Document 1] French Patent Invention No. 2901172 [Patent Document 2] U.S. Patent No. 4,598,006 [Patent Document 3] US Patent Application Publication No. 2021 / 0269607 [Patent Document 4] International Publication No. 2014 / 146864 [Non-patent literature]

[0026] [Non-Patent Document 1] Duarte et al., "Subcritical carbon dioxide foaming of polycaprolactone for bone tissue regeneration," The Journal of Supercritical Fluids, Volume 140, October 2018, pages 1-10 [Non-patent document 2] Duarte et al., "PDLLA enriched with ulvan particles as a novel 3D porous scaffold targeted for bone engineering," The Journal of Supercritical Fluids, Vol. 65, May 2012, pp. 32-38 [Non-patent document 3] Powel et al., Chemotherapeutic implants via subcritical CO2 modification, Biomaterials. 2007 Dec;28(36):5562~9 Summary of the Invention [Problem to be solved by the invention]

[0027] Therefore, there is a need to provide a method that can be implemented at temperatures and pressures that do not correspond to supercritical conditions, which can overcome the aforementioned drawbacks and increase the amount of active substance that can be stably incorporated into a polymer matrix over a long period of time, regardless of the properties of the matrix or active substance used.In addition, in some cases, there is a need to accelerate the process of incorporating the active substance into the matrix.In addition, in some cases, the properties of the polymer matrix or the properties of the active substance make it impossible to incorporate the active substance.Therefore, there is a need to make the incorporation feasible.

[0028] The terms maximum degree of incorporation, maximum incorporation, maximum incorporation rate, increase in the amount of active substance that can be incorporated into the matrix, increased amount of incorporated active substance can be defined as equivalent to and related to the capacity of the matrix according to the invention to incorporate a certain percentage of active compound, which must include the concept of a maximum that is achievable. [Means for solving the problem]

[0029] Therefore, one object of the present invention is to provide a method for incorporating an active substance into a polymer matrix using a gas that is not in a supercritical fluid state, which can improve the maximum entrapment of the polymer or accelerate or enable the entrapment process. The present invention also relates to the use of the gas to improve the entrapment rate of the resulting product and polymer matrix. Supercritical conditions for a fluid or gas are well known to those skilled in the art and are defined by a precise temperature and pressure pair. These conditions correspond, in particular for carbon dioxide, to a precise temperature / pressure pair of 31°C / 73 bar, i.e., a very high pressure condition. For nitrogen, supercritical conditions correspond to a precise temperature / pressure pair of -147°C / 34 bar, i.e., an extreme temperature. Therefore, a gas in a non-supercritical or "subcritical" state that can be used according to the present invention refers to a gas in which the temperature and pressure value pair used is lower than the threshold value of the value pair known to those skilled in the art that defines its critical point in terms of temperature and / or pressure.

[0030] Furthermore, the use of gases in a non-supercritical state has one notable advantage in terms of ease of implementation of the method. Indeed, industry remains reluctant to use methods at very high pressures, such as those used in technologies that use gases under supercritical conditions. These methods require sophisticated and often expensive equipment. Moreover, these very high pressures remain a sensitive parameter when considering user safety.

[0031] The applicant has been able to develop a method for impregnation of a gas not in a supercritical fluid state that confers improved properties on the impregnated matrix in terms of active substance uptake and maintenance of these capacities over time. More specifically, the applicant proposes a novel method for incorporating an active substance in two consecutive steps: impregnation of a polymer matrix with a gas not in a supercritical fluid state, followed by incorporation of an active substance into the interior of the impregnated polymer matrix.

[0032] The method according to the invention makes it possible, on the one hand, to obtain a polymer matrix that retains a better capacity to incorporate an active substance, and, on the other hand, the polymer matrix maintains its capacity even after storage. Thus, thanks to the method according to the invention, there is an effective and time-sustaining increase in the capacity to incorporate. The applicant therefore proposes, by means of the invention, to address the problem of improving the maximum rate of incorporation of an active substance into a polymer matrix for several types of polymers, or to accelerate or enable its incorporation, thanks to a pre-treatment step of the polymer with a gas in a non-supercritical state.

[0033] The method for incorporating an active substance into a polymer matrix using a gas according to the present invention comprises the following successive steps: a) impregnation of the polymer with a gas in a non-supercritical state; b) an active substance incorporation step; Includes.

[0034] Sequential steps according to the present invention mean that the gas impregnation step a) and the active substance incorporation step b) are not carried out simultaneously: the incorporation can take place either immediately after the gas impregnation step, or a few hours, days or even weeks after said impregnation step.

[0035] Thus, the applicant proposes a novel method for incorporating at least one active substance into a polymer matrix in two sequential steps, including a first step of matrix impregnation with a gas that is not in a supercritical fluid state, followed by a second step of incorporating the active substance into the impregnated matrix. The concept of two sequential steps is an important feature of the method according to the present invention, as it has several advantages. In fact, the applicant has surprisingly shown that simultaneous gas impregnation and active substance incorporation do not allow for the incorporation of the active substance into the polymer. Furthermore, the applicant has surprisingly confirmed that when the impregnation is performed upstream of the incorporation step and in the absence of the active substance, this incorporation step allows for a higher matrix incorporation rate than conventional methods. Even more surprisingly, the applicant has also demonstrated that the use of a non-supercritical fluid incorporation step allows for an increase in the incorporation potential of the polymer, and that the polymer maintains its greater incorporation capacity over time. Indeed, a persistent effect of the modifications caused by gas impregnation on the polymer has been observed, which allows the step of incorporation of the active substance to be timed away from the first step of gas impregnation of the matrix without altering the improved incorporation properties. The method therefore advantageously allows the impregnated matrix to be preserved or stored before being subjected to incorporation at a later date, if necessary.

[0036] Thus, the present invention provides: a) impregnation of the polymer with a gas in a non-supercritical state; b) an active substance incorporation step; The present invention relates to a method for incorporating an active substance into a polymer matrix using a gas, comprising the successive steps of: first impregnation; and second impregnation; wherein the first impregnation step confers on the impregnated polymer matrix improved properties of active substance uptake and maintenance of these capabilities over time.

[0037] In this specification, "impregnation" refers to the step of impregnating a polymer with a fluid, preferably a gas, in a non-supercritical state; and incorporation refers to the step of incorporating an active substance inside the polymer matrix. In this specification, the term "polymer" is understood to relate to the advantageous polymers cited above, i.e., any thermoplastic material.

[0038] The polymer constituting the solid matrix is ​​in particular chosen from among the non-biodegradable thermoplastic polymers selected from the group consisting of: - polyolefins and their derivatives selected from polyethylene (PE), polypropylene (PP), ethylene-vinyl acetate copolymer (EVA), ethylene butyl acrylate; - polyamides, copolyamides and their derivatives, - other vinyl polymers, such as polyvinyl chloride (PVC) or styrene-based resins and their derivatives, selected from polystyrene-poly(ethylene-butylene)-polystyrene copolymers (SEBS), polystyrene-polyisoprene-polystyrene copolymers (SIS), polystyrene-polybutadiene-polystyrene copolymers (SBS), - other thermoplastic elastomers, such as thermoplastic polyurethanes (TPU), ether block amides (PEBA), ethylene-propylene-diene (EPDM) or derivatives thereof (PP / EPDM); Polyesters, such as polyethylene terephthalate (PET), polybutylene terephthalate (PBT) or polytrimethylene terephthalate (PTT).

[0039] Alternatively, the polymer that makes up the solid matrix is ​​a bio-based and / or biodegradable thermoplastic polymer that can be: - polyesters or copolyesters selected from polycaprolactone, polylactic acid (PLA), polyesteramides, aliphatic and aromatic copolyesters, agropolymers selected from the group consisting of polysaccharides, starch and its derivatives, cellulose compounds and their derivatives, derivatives of milk proteins or mixtures of all these polymers; - Polymers derived from microbial synthesis, such as polyhydroxyalkanoates (PHAs), poly(β-hydroxybutyrates) (PHBs) or all of their derivatives.

[0040] In a preferred variant, the polymers that can be used as matrices in the present invention are advantageously chosen from ethylene vinyl acetate (EVA), polyamides, polyether block amides (PEBA), polypropylene (PP), polyethylene (PE), thermoplastic polyurethanes (TPU), polyvinyl chloride (PVC), polystyrene, such as polystyrene-b-polybutadiene-b-polystyrene (SEBS) or polystyrene-b-polyisoprene-b-polystyrene (SIS), polyesters, polylactic acid (PLA), and also biodegradable polymers, agropolymers, bioplastics or thermoplastics of biological origin, biopolyesters and their derivatives.

[0041] The active substance used for the present invention is an active substance in powder or liquid form. Preferably, the active substance is lipophilic in nature.

[0042] Lipophilic active substances means that the active substances may be pre-solubilized or dispersed in the oily or fatty phase and further that these active substances have an affinity for the oily or fatty phase.

[0043] The active substances that can be incorporated into the polymer matrix by the method of the present invention can be selected from active substances known to those skilled in the art, such as chemical pharmaceutical active substances or active substances of natural origin, essential oils or mixtures thereof. The active substances that can be used according to the present invention can have various indications, especially in the veterinary field, such as insecticides or repellents, antiparasitic drugs, analgesics, sedatives or antistress agents.

[0044] The pharmaceutical active agent may be selected from among active agents known to those skilled in the art that are available in the veterinary field.

[0045] The insecticidal or repellent pharmaceutical active substance may be selected from among botanical pyrethrum, pyrethroids, pyrethrins and their derivatives, carbamates, formamidines, carboxylic acid esters, N,N-diethyl-3-methylbenzamide (DEET), icaridin, phenylpyrazoles, organophosphorus compounds, organohalogen compounds, neonicotinoids, avermectins and their derivatives, spinosyns, nootkatone and its derivatives, isoxazolines or mixtures thereof.

[0046] The antiparasitic agent may be selected from among anthelmintics, endectocides, isoxazolines or mixtures thereof. Although they have a systemic effect against parasites, some endectocides may also have insecticidal effects.

[0047] The analgesic or sedative may be chosen from among the active substances known to those skilled in the art for their activity, and may in particular be chosen from among derivatives of the cannabinoid type that do not contain tetrahydrocannabinol (THC), such as THC-free cannabidiol (CBD) or THC-free cannabigerol (CBG) or mixtures thereof.

[0048] The anti-stress agent may be selected from among the aforementioned derivatives of cannabinoids as well as pheromones or essential oils.

[0049] The essential oils that can be used as active substances according to the present invention can have many indications and properties.

[0050] Essential oils are plant extracts concentrated in volatile aromatic compounds such as, but not limited to, geraniol, limonene, menthol, linalool, citriodiol, citronellal, lactones, etc., without precluding the presence of other essential oil constituents or mixtures thereof.

[0051] The essential oils are preferably selected from lavandin, lavender, orange, margosa, eucalyptus, citronella, lavender, neem, peppermint, spearmint, pennyroyal, field mint, wintergreen, basil, rosemary, cedarwood, citronella, clove, geranium, thyme, or mixtures thereof.

[0052] It is understood that within the context of this application, the active substances mentioned may be subject to mixture within the framework of a particular formulation, and that the applicant is not limited to only one of these categories. It is also understood that the active substance used may also be a mixture of active substances, in particular a mixture of the active substances mentioned above.

[0053] In the context of this application, it is understood that the active substance can also be an additive-type component that a person skilled in the art desires to incorporate into a polymer matrix for its activity in the composition. The applicant has demonstrated that the method of the present invention has the advantage of allowing these components to be easily incorporated or incorporated at a greater rate. Thus, non-limiting examples of additives that can be incorporated as active substances in the present invention include plasticizers, fragrances, fragrance carriers, preservatives, colorants, antioxidants, and UV stabilizers. As a preferred example, the applicant has demonstrated that the incorporation of fragrance carriers in a polymer matrix can be improved by using the method of the present invention. In a specific example of the present invention, the fragrance carrier used is monopropylene glycol.

[0054] In one embodiment, the active agent comprises at least one essential oil.

[0055] In another embodiment, the active substance may also comprise a supplementary oil, which means, for example, a vegetable oil that may be suitably, but not exclusively, selected from almond oil, linseed oil, rapeseed oil, macadamia oil, and also hemp oil, or THC-free CBD oil.

[0056] In one variant embodiment, the active substance is a mixture comprising at least one essential oil, auxiliary oils, optionally together with active substances of botanical or chemical origin and any other supplementary active substances that impart the sought properties to the polymer matrix.

[0057] [Impregnation step] The first step of the method according to the invention is therefore the impregnation of the polymer matrix with a non-supercritical fluid.

[0058] The term impregnation can be defined as subjecting a polymer to the pressure of a fluid under specific pressure and temperature conditions that allow the fluid to penetrate into the interior of the polymer network.

[0059] In one embodiment, the non-supercritical fluid is a gas in a non-supercritical state, such as compressed air, carbon dioxide (CO2), or dinitrogen (N2), preferably carbon dioxide (CO2) or dinitrogen (N2). Indeed, the applicant does not take advantage of the capabilities of these gases in a non-supercritical state, i.e., their solvent properties, since the impregnation step according to the present invention is not responsible for solubilizing the active substance. Furthermore, although the solvent effect of the supercritical fluid on the active substance is believed to be obtainable only in a method in which impregnation is simultaneous with incorporation, the applicant has confirmed that impregnation simultaneous with incorporation of the liquid active substance into the matrix does not solve the problem addressed in the present invention. To improve the incorporation of the active substance into the matrix in the method according to the present invention, it is necessary to carry out the impregnation in a step upstream of incorporation and at gas temperature and pressure values ​​lower than those known in the supercritical state.

[0060] During this impregnation step, the polymer is placed in a pressure-resistant, closed reactor equipped with an open flange, which is itself connected to a gas inlet valve that allows the gas to enter the reactor interior under control, the whole assembly then being connected to a gas supply and containing means for the control of pressure, temperature and for the evaluation of other necessary physicochemical variables known to those skilled in the art.

[0061] The polymer used during the impregnation step in the present invention is in the form of granules, spheres, powder or any other form known to those skilled in the art that is suitable for stirring in an incorporation tank. The impregnation according to the method of the present invention is not carried out on a molded or already formed part. In this regard, any form of blowing of the material with a gas in the impregnation step is also excluded, therefore, there is no volatile blowing agent present and the present invention does not aim to foam the matrix.

[0062] Once the polymer is placed in the reactor, the reactor is then pressurized, and the impregnation step is therefore carried out in the presence of gas under pressure.

[0063] Applicant was able to determine that the improvement in matrix uptake rate and the changes brought about by the non-supercritical fluid resulted from the gas pressure used during the impregnation step being equal to 5 bar.

[0064] This allowed for the evaluation of the pressure range over which the gas could increase the maximum uptake within the matrix. Unexpectedly, Applicant was able to demonstrate that the maximum uptake of the polymer increases with pressure when gas impregnation is performed within the pressure range of 5 to 50 bar, preferably 5 to 35 bar. Applicant determined that above 35 bar, the effect on uptake appears to plateau, and that between 1 bar (atmospheric pressure) and 5 bar, the change in uptake is not significant.

[0065] In one embodiment, the pressure range that can be used during the impregnation step of the process may be between 5 and 35 bar, preferably between 20 and 35 bar, more preferably a pressure of 30 bar.

[0066] Another important factor in the impregnation step, which must be combined with the pressure, is the temperature factor. In fact, the applicant has been able to show that the maximum uptake obtained for the same matrix at the same pressure can vary depending on the temperature under the gas. This temperature under the gas can be defined as the temperature at which the matrix is ​​placed in the presence of the gas in the reactor. Furthermore, it is understood that the temperature under the gas or the temperature under pressure is defined as the temperature applied to the entire system formed by the polymer matrix and the gas in the reactor.

[0067] Within the framework of the polymers and thermoplastics of the present invention, it can be considered that the higher the temperature, the more the polymer network tends to relax, leaving more spaces or cavitations, which may then allow for better entrapment after the impregnation step.

[0068] Surprisingly, however, the Applicant has been able to demonstrate that in the method according to the invention the temperature under pressure must be relatively low for the polymer. In fact, temperatures that can be used during the impregnation step of the method are strictly below 50°C, preferably strictly below 40°C, preferably between 15 and 35°C, more preferably between 20 and 30°C, with the best results being obtained at 25°C. Surprisingly, therefore, the effect of the temperature under pressure on the maximum incorporation rate of the matrix is ​​greater the lower said temperature is.

[0069] Regarding the impregnation duration, regardless of the time required to increase the pressure of the system, this impregnation duration is inversely proportional to the applied pressure: in fact, the stronger the pressure applied to the system, the shorter the impregnation time of the polymer in the non-supercritical fluid, and vice versa.

[0070] For the pressure range of 5 to 35 bar, the impregnation time can be 150 minutes to 5 minutes, respectively.

[0071] [Import Step] The second step of the method is the incorporation of a polymer matrix, where impregnation can be considered as a pretreatment step that precedes the incorporation of the matrix.

[0072] During the incorporation step, the impregnated matrix is ​​placed in a stirred tank equipped with heating means known to those skilled in the art. Surprisingly, the applicant has found that the incorporation rate of the pre-impregnated matrix is ​​always higher than that of the non-impregnated matrix, and this is independent of the incorporation temperature.

[0073] At the end of this incorporation step, the matrix can be defined as an active substance incorpo- rated or active substance loaded matrix that is ready for shaping according to known techniques in plastics molding processing.

[0074] The incorporation temperature depends on the nature of the polymer, more particularly the nature of the active substance-matrix pair, but for the polymers of the present invention, T g It is appropriate to process at an incorporation temperature higher than, but lower than, the melting temperature of the polymer. A person skilled in the art will be able to adapt the incorporation temperature to the properties of the polymer matrix and the active substance(s) selected. Taking these parameters into account, the best results for incorporation of active substances into the polymers tested according to the invention were obtained for incorporation temperatures between 30°C and 100°C, preferably between 35°C and 65°C.

[0075] Thus, we again see a transition state at the molecular level where the amorphous part of the polymer is fluidized, i.e. the chains that make up the polymer network are more fluid at this temperature.

[0076] In these temperature ranges, the use of a pre-impregnation step of the matrix with a gas in a non-supercritical state according to the invention makes it possible to improve the maximum uptake of the matrix, regardless of the uptake temperature. Therefore, using the method of the invention, it is possible to lower the uptake temperature for a given and known uptake rate. On an industrial scale, such a process would then have lower energy costs thanks to the matrix being impregnated according to the method of the invention.

[0077] In addition to the effect of improving the maximum uptake of a given polymer, the Applicant has been able to demonstrate that impregnation also reduces the duration of the uptake step compared to conventionally used loading methods, and that this effect is even more pronounced for EVA. Thus, the method used is faster, therefore less expensive, and more effective in terms of uptake of the active substance.

[0078] On the other hand, for a given polymer, at a similar uptake duration, Applicant's method consistently shows an increase in the maximum uptake rate compared to conventional methods, even in matrices that are described as difficult to uptake or for active substances that are known to be difficult to uptake.

[0079] Although not exhaustive, these difficult matrices may for example belong to the class of polypropylene (PP) or polyethylene (PE).

[0080] The Applicant has thus been able to develop a method for producing a polymer matrix loaded with an active substance, which includes an impregnation step before the step of incorporating the active substance. The loaded matrix obtained at the end of the method thus benefits from a better incorporation rate of the active substance compared to the methods previously used in this field. By better incorporation rate, it is meant that the incorporation rate of the active substance is increased by at least 15% and can reach 100%, depending on the nature of the polymer and the active substance.

[0081] As a result of the method of the present invention, the loaded matrix can be molded by means known to those skilled in the art to form an active substance of the desired shape, ready for use. Thus, the polymer matrix can be obtained in the form of granules, which can then be injected in a press or other injection or extrusion means to give the matrix the desired shape. Devices derived from the loaded matrix obtained by the method of the present invention can be used, without limitation, in the form of collars, bracelets, harnesses, ear tags, or any other form of active substance diffusion device for animals. To realize these diffusion devices, such as collars, it is necessary to obtain a homogeneous polymer matrix to ensure optimal diffusion and good distribution of the active substance within the matrix. The method of the present invention makes it possible to obtain such a matrix incorporating at least one active substance in a homogeneous form.

[0082] The present invention therefore provides a method for producing a polymer matrix loaded with at least one lipophilic liquid active substance using a gas, comprising the steps of: a) a step of impregnation of the polymer with said gas in a non-supercritical state at a temperature strictly below 40°C and at a pressure of between 5 and 35 bar; b) an incorporation step of the active substance at a temperature between 30°C and 100°C; The present invention relates to a method comprising the following successive steps:

[0083] The present invention also relates to a method characterized in that the non-supercritical gas of the impregnation step is selected from carbon dioxide (CO2) or dinitrogen (N2), and that the gas impregnation step is preferably carried out at a temperature between 15°C and 35°C, preferably between 20°C and 30°C, for a duration preferably between 5 minutes and 150 minutes.

[0084] The present invention therefore relates to a method as described above, characterized in that the polymer is preferably a thermoplastic selected from ethylene vinyl acetate (EVA), polyamide, polyether block amide (PEBA), polypropylene (PP), polyethylene (PE), thermoplastic polyurethane (TPU), polyvinyl chloride (PVC), polystyrene, such as polystyrene-b-polybutadiene-b-polystyrene (SEBS) or polystyrene-b-polyisoprene-b-polystyrene (SIS), polyester, polylactic acid (PLA), as well as biodegradable polymers, agropolymers, bioplastics or thermoplastics of biological origin, biopolyesters.

[0085] The method according to the invention is characterized in that the active substances incorporated within the polymer matrix are chosen from among chemical pharmaceutical active substances, naturally occurring active substances, essential oils, vegetable oils or mixtures thereof.

[0086] In another embodiment, the present invention also relates to a polymer matrix loaded with at least one lipophilic liquid active substance obtained according to the method according to the invention, characterized in that the incorporation rate of the active substance is increased by at least 15% compared to the incorporation of the active substance carried out in the matrix according to a method without a gas impregnation step.

[0087] The present invention also relates to the use of a gas in a non-supercritical state for impregnating a polymer matrix, characterized in that the gas is impregnated at a temperature strictly below 40°C and at a pressure of 5 to 35 bar in order to increase the amount of active substance incorporated in the polymer matrix. Preferably, the gas is selected from carbon dioxide (CO2) or dinitrogen (N2).

[0088] The method of the present invention will be better understood through the following non-limiting examples and figures.

[0089] The examples described below make it possible to confirm the advantages of the method according to the invention for a range of different polymers and active substances.

[0090] With regard to polymers, in particular non-biodegradable polymers such as EVA, polyamide, polyethylene, polypropylene, polyester, or biodegradable polymers such as biopolyesters or casein-derived polymers were tested.

[0091] Various types of active substances were also tested, in particular: - insecticidal or repellent chemically active substances, such as pyrethroids, pyrethrins and their derivatives, organophosphorus compounds, in particular icaridin, permethrin, fenothrin, diazinon, - insecticidal compounds of plant origin, e.g. plant pyrethrum, - vegetable oils known to be difficult to absorb, such as neem oil and sweet almond oil; - essential oils such as lavandin, peppermint or cedarwood oil, mixtures composed of essential oils, auxiliary oils and / or botanical or chemical active substances, such as, for example, a mixture of linseed oil, vegetable pyrethrum and lavandin essential oil (referred to below as active substance A in the examples), or a mixture of sweet almond oil, peppermint essential oil and cedar essential oil (referred to below as active substance B in the examples), or a mixture of lavandin, geraniol and pyrethrum (referred to below as active substance C in the examples), or a mixture of icaridin, lavandin essential oil, geraniol and coconut oil (referred to below as active substance D in the examples), - Additives such as a fragrance carrier, such as monopropylene glycol (referred to as Active Substance E in the examples below). [Brief explanation of the drawings]

[0092] [Figure 1] 1 shows the results of a comparative study of conventional entrapment methods and the method of the present invention for several active substance-matrix pairs, as described in Example 2. [Figure 2] 1 shows the results of a test of the maximum amount of active substance that can be incorporated as a function of the impregnation pressure, as described in Example 3. [Figure 3] As described in Example 4, a comparative study between the method of the present invention and a conventional method for an active substance that is considered difficult to incorporate is shown. [Figure 4] 1 shows the maintenance of uptake rate over time for matrices after impregnation as described in Example 5. [Figure 5] 1 shows an investigation of the effect of CO 2 on uptake maximum as a function of uptake temperature, as described in Example 6. [Figure 6] 1 shows the uptake maxima obtained using a matrix of biopolyester with various active substances, with or without treatment with CO 2 as described in Example 7. [Figure 7] 1 shows the uptake maxima obtained with different insecticidal active substances in different polymer matrices with or without treatment with CO 2 as described in Example 8. [Figure 8] 1 shows the cumulative quantity of active substance A released over time by EVA matrices obtained by the method with and without treatment with CO 2 as described in Example 9. [Figure 9] 1 shows the cumulative quantity of active substance B released over time by polyamide matrices obtained by the method with or without treatment with CO 2 as described in Example 10. [Figure 10] 1 shows a scanning microscope image of a polymer matrix obtained according to the method of the present invention, as described in Example 12. [Figure 11] 1 shows a scanning microscope image of a polymer matrix without gas impregnation, as described in Example 12. [Figure 12] 1 shows the maximum uptake possible for essential oil alone in an EVA matrix with or without treatment with CO 2 as described in Example 13. DETAILED DESCRIPTION OF THE INVENTION

[0093] Example 1: Progress of the method according to the invention in a polymer matrix made of EVA Matrix impregnation: The EVA granules containing no active substance are placed in an impregnation reactor supplied with a CO2 source. To maintain the gas in a non-supercritical state, the temperature is fixed at 25°C and the pressure applied to the granules is 30 bar. The granules are then maintained at these conditions for a period of 120 minutes before being subjected to the incorporation step.

[0094] Importing a matrix: The impregnated EVA granules are then loaded with an active substance.

[0095] For this purpose, the granules are placed in an incorporation reactor in the presence of the active substance at a fixed temperature of 61° C. The reactor is subjected to stirring for an incorporation duration of 2 hours 30 minutes, at the end of which duration granules loaded with the active substance are obtained, said granules at the end of this step now constituting the loaded or incorporation matrix.

[0096] The granules can then be injection molded in a press or by other means known to those skilled in the art to form the desired shape of the active mass ready for use. Kinetic and assay studies on standardized shapes make it possible to compare the effect of the method of the present invention on the incorporation of the active substance into the matrix.

[0097] The method described herein has been repeated in the various cases tested by the Applicant, who has adapted the temperature to the nature of the polymer and active substance used.

[0098] Example 2: Comparative study of conventional and incorporation methods for multiple active substance-matrix pairs Several tests were carried out to allow the comparison of the incorporation rate of the active substance inside the matrix. The incorporation rate was evaluated gravimetrically and corresponds to the ratio between the mass of the active substance added and the total mass (matrix and active substance), which is determined from the incorporated matrix.

[0099] Several active substance-matrix pairs were studied. Applicant's tests were compared with a conventional incorporation method, which included only the incorporation step and not the impregnation step. In other words, the conventional incorporation test completely replicated the incorporation step of the method of the present invention, but only under the conditions of the incorporation step.

[0100] Of course, these conditions may vary depending on the nature of the active substance-matrix pair, and applicants have been able to adapt these conditions.

[0101] Tests were carried out on various polymers using active substance mixtures A or B, which were mixtures of active substances in various compositions.

[0102] For clarity, Active Substance A contains linseed oil, pyrethrum plant and lavandin essential oil, while Active Substance B contains sweet almond oil, peppermint essential oil and cedar essential oil.

[0103] In the test, the same protocol as in Example 1 is repeated, only the incorporation conditions may vary depending on the nature of the active substance-matrix pair. [Test 1:] Active substance / matrix pair: Active substance A, EVA. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Acquisition parameters: 61°C, 2 hours 30 minutes. [Test 2:] Active substance / matrix pair: active substance B, polyamide. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Acquisition parameters: 70°C, 3 hours. [Test 3:] Active substance / matrix pair: Active substance A, polyethylene. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 90°C, 3 hours. [Test 4:] Active substance / matrix pair: Active substance E, casein-based biodegradable polymer. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 30°C, 5 hours. [Test 5:] Active substance / matrix pair: Active substance A, PEBA. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Acquisition parameters: 61°C, 3 hours 15 minutes. [Test 6:] Active substance / matrix pairs: Active substance A, polypropylene. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 90°C, 3 hours. [Test 7:] Active substance / matrix pair: Active substance A, polyester. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Acquisition parameters: 70°C, 2 hours 30 minutes. [Test 8:] Active substance / matrix pair: Active substance A, polyethylene. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 61°C, 3 hours.

[0104] [result] For each of these tests, the Applicant was able to demonstrate that the use of a gas in a non-supercritical state to impregnate the matrix prior to active substance incorporation makes it possible to obtain consistently better rates of incorporation of active substance in matrices resulting from the method according to the invention compared to matrices resulting from a method carried out without a prior impregnation step with CO, regardless of the active substance-matrix pair chosen.

[0105] The full results are presented in the table in Figure 1.

[0106] Overall the results show that the percentage increase in the uptake of the active substance is at least 15% and can reach 100%, depending on the nature of the polymer.

[0107] Example 3: Analysis of the maximum incorporation pressure Tests were performed to determine the maximum amount of active substance that could be incorporated within the impregnated polymer matrix as a function of the impregnation pressure.

[0108] The impregnation process is as described in Example 1, with gas pressure applied to the granules during the impregnation stage varying from atmospheric pressure (1 bar), i.e. no pressure applied, to a pressure of 35 bar.

[0109] The uptake method applied is that of Example 1.

[0110] Tests were carried out according to the parameters described in Example 2, Test 1, using a mixture of EVA as polymer and Active Substance A.

[0111] Figure 2 shows that from a gas impregnation pressure of 5 bar, the maximum possible uptake already reaches values ​​higher than those obtained in conventional methods without an impregnation step (see the table in Figure 1). Applicant has been able to demonstrate that by carrying out gas impregnation within the pressure range of 5 to 35 bar, the maximum polymer uptake increases with pressure. Applicant has determined that above 35 bar, the effect on uptake appears to plateau, and that between 1 bar (atmospheric pressure) and 5 bar, the change in uptake is not significant. In another embodiment of the method according to the invention, the selected pressure is preferably fixed at 30 bar.

[0112] Example 4: Comparative test between conventional uptake methods and the method of the present invention using an active substance that is difficult to uptake In these tests, the active substances are selected from neem oil, icaridin or sweet almond oil (HAD). The progress of the method according to Example 1 is followed for their incorporation into an EVA-based matrix. These active substances are incorporated alone, not in a mixed state, and are described as being difficult to incorporate directly into the polymer.

[0113] The temperature, pressure and time parameters used are as follows: - Active substance / polymer pair: neem oil / EVA Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 63°C, 6 hours. - Active substance / polymer pair: Icaridin / EVA: Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 63°C, 6 hours. - Active substance / polymer pair: sweet almond oil / EVA Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 63°C, 6 hours.

[0114] The comparative results [Figure 3] show that the method of the present invention allows for much better incorporation of these active substances than conventional incorporation methods. Thus, the impregnation step of Applicant's method allows for significant success with regard to the difficult incorporation of these active substances.

[0115] In fact, for each of these difficult to incorporate active substances, the amount of active substance incorporated using the method of the present invention is increased by at least 20% compared to the amount of active substance incorporated using a method without the CO2 impregnation step.

[0116] Example 5: Maintenance of matrix uptake rate over time after impregnation according to the method of the present invention In order to know whether the effect of the impregnation step is temporary, the applicant was able to evaluate the persistence of the impregnation of the matrix over time.

[0117] For this purpose, tests to evaluate the maximum uptake according to Examples 1 and 2 were carried out on lots of EVA granules pre-impregnated according to the method of the invention. The same active substances A and B were tested, as was active substance C, which contained lavandin, geraniol and pyrethrum.

[0118] The protocol used was as follows: After the polymer matrix has been selected, an impregnation step with carbon dioxide (CO2) or nitrogen (N2) is carried out at a temperature of 25°C and a pressure of 30 bar.

[0119] Once the matrix is ​​impregnated, a fraction of said matrix is ​​taken to carry out the uptake test, designated t0, and the remainder of the impregnated material is stored in an open container to allow complete desorption of the selected gas.

[0120] Once uptake has occurred at t0, the amount of active substance incorporated is measured. The test is repeated once a week for 4-5 weeks, each time taking a new fraction of matrix from an open container that serves for storage.

[0121] [Figure 4] illustrates these results.

[0122] Thus, Applicant was able to demonstrate that once the matrix is ​​impregnated, the uptake capacity of the matrix remains unchanged and maintains an improvement over conventional methods. Indeed, linearity was observed in various uptake tests for different active substance-matrix pairs. Thus, impregnated matrices can be stored and preserved without uptake of the active substance after the initial impregnation step, and these matrices will retain their improved uptake over time for at least 30 days after the impregnation step.

[0123] Example 6: Study of the effect of the CO2 impregnation step depending on the uptake temperature To study the influence of the non-supercritical CO2 impregnation step on the uptake temperature, the Applicant carried out several comparative tests at different uptake temperatures of the active substance in the matrix, in which the maximum uptake values ​​according to the method of the present invention were evaluated.

[0124] These tests were performed using the active-matrix pair Active A-EVA.

[0125] The maximum amount of active substance incorporated as a function of temperature was evaluated, and four tests were carried out at temperatures of 35°C, 40°C, 50°C and 63°C. These four tests were carried out on matrices impregnated with CO2 and on non-impregnated matrices to study the effect of CO2 on the uptake of the active substance.

[0126] [Figure 5] shows that impregnation of the matrix with CO2 can improve the amount of active substance incorporated, regardless of the uptake temperature.

[0127] Thus, another advantage of the method according to the present invention is demonstrated: if necessary, a defined amount of active substance can be incorporated at a lower temperature. The curves show that, in practice, using a method without CO2 impregnation, a maximum amount of incorporated active substance of 15% active substance A (wt. % of active substance relative to the total weight of the matrix incorporated) is achieved at an incorporation temperature of 50°C. With the method according to the present invention, this value of 15% is achieved at a significantly lower incorporation temperature of 40°C. With the same amount of active substance incorporated, the method according to the present invention allows for the use of lower incorporation temperatures compared to conventional methods, which is a considerable advantage. Therefore, in practice, this method allows for the incorporation of many heat-sensitive and / or volatile active substances without the risk of decomposition or evaporation. Furthermore, heating at a lower temperature allows for time savings in carrying out the entire method, which is an advantage at an industrial level.

[0128] Example 7: Study of the method according to the invention on the maximum uptake of different active substances into biodegradable polymers. Applicants have sought to demonstrate that the method allows for better active agent incorporation into different types of polymers, including biodegradable polymers.

[0129] The impregnation conditions are those of Example 2.

[0130] For all active substances tested, the uptake parameters were a temperature of 70° C. and an uptake time of 6 hours.

[0131] The biopolymer used is a biopolyester and the active substances tested are active substances A, C and D described above.

[0132] The results in FIG. 6 show that the method according to the invention once again makes it possible to improve the amount of active substance incorporated in the case of biopolyester type polymers for the three types of active substance mixtures tested.

[0133] Example 8: Study of the method according to the invention with active substances of the chemopreventive type on different polymer matrices The applicants have attempted to demonstrate the effectiveness of the method using different active substances of chemical pharmaceutical type in different polymer matrices.

[0134] The polymers used are of the non-degradable type, i.e. EVA and polyamide, and of the biodegradable type, i.e. biopolyester.

[0135] The active substances tested are various pyrethroid-type insecticides or repellents or organophosphate molecules.

[0136] The impregnation conditions are those of Example 1. The active substance incorporation conditions are as follows: - Active substance / polymer pair: Permethrin / EVA Uptake parameters: 63°C, 5 hours. - Active substance / polymer pair: fenothrin / EVA Uptake parameters: 63°C, 5 hours. - Active substance / polymer pair: Diazinon / EVA Uptake parameters: 63°C, 5 hours. - Active substance / polymer pair: Diazinon / biopolyester Acquisition parameters: 70°C, 5 hours. - Active substance / polymer pair: diazinon / polyamide Acquisition parameters: 70°C, 5 hours.

[0137] The results in FIG. 7 confirm that the method according to the invention allows for an increased amount of active agent to be incorporated, regardless of the nature of the active agent or the polymer matrix.

[0138] Example 9: Cumulative quantity of active substance A released over time The polymeric matrix obtained according to the method of the present invention is used to treat a subject in need by contacting the subject with the entrapped, impregnated polymeric matrix, allowing the polymeric matrix to release and diffuse the entrapped active agent over time.

[0139] It is therefore important to verify whether the resulting matrix is ​​sufficient to allow the release of the incorporated active substance.

[0140] Measurements of the cumulative quantity of active substance released by the matrices obtained by the method according to the invention are carried out over a period between day 1 (D1) and day 180 (D180) and compared with measurements obtained with loaded polymer matrices achieved by direct loading of the active substance without an impregnation step.

[0141] The polymer used here is EVA and the active substance incorporated is active substance A as defined above.

[0142] The matrices achieved by direct incorporation without an impregnation step allowed the incorporation of up to 19% of active substance A (as reported in the table in Figure 1).

[0143] The method according to the invention allowed the obtained matrices to advantageously incorporate up to 31% of active substance A inside the EVA matrix (as shown in the table in Figure 1).

[0144] Figure 8 shows the cumulative quantity of active substance released as a function of time according to the two matrices achieved. The following can be observed: On the one hand, the matrices obtained by the method according to the invention make it possible to release larger amounts from the first day than matrices obtained by conventional methods without a prior impregnation step with gas. On the other hand, the cumulative amount of released active substance remains greater over time for the matrices obtained according to the invention. Indeed, it has been observed that on the 20th day, the matrices obtained by the method according to the invention released approximately 3700 mg of active substance, compared to 2000 mg for the conventional method. On the 153rd day, the matrices obtained by the method according to the invention released an additional 6793 mg, compared to approximately 4000 mg for the conventional method.

[0145] Therefore, the matrix obtained according to the method of the present invention not only allows for improved incorporation of the active substance, but also allows for the release of the active substance in larger amounts over a period that can reach several months. No retention of the active substance in the matrix is ​​observed, and the active substance is fully released. Therefore, it can be concluded that the polymer matrix impregnated and incorporated according to the method of the present invention allows for long-term treatment with a larger amount of released active substance. Therefore, the matrix obtained according to the method of the present invention allows for a more effective diffusion device.

[0146] Example 10: Cumulative quantity of active substance B released over time The polymeric matrix obtained according to the method of the present invention is used to treat a subject in need by contacting the subject with the entrapped, impregnated polymeric matrix, allowing the polymeric matrix to release and diffuse the entrapped active agent over time.

[0147] It is therefore important to verify whether the resulting matrix is ​​sufficient to release the incorporated active substance. Measurements of the cumulative amount of active substance released by the matrix obtained by the method according to the invention are carried out over a period of time between day 1 (D1) and day 196 (D196) and are compared with measurements obtained with a conventionally incorporated polymer matrix, achieved by direct incorporation of the active substance without an impregnation step. The polymer used here is a polyamide, and the incorporated active substance is active substance B as defined above.

[0148] The matrices achieved by direct incorporation without an impregnation step allowed the incorporation of up to 16% of active substance B (as reported in the table of Figure 1).

[0149] The method according to the invention allowed the obtained matrices to advantageously incorporate up to 22% of active substance B inside the polyamide matrix (as shown in the table of FIG. 1).

[0150] Figure 9 shows the cumulative quantity of active substance released as a function of time according to the two matrices achieved. The following can be observed: On the one hand, the matrices obtained by the method according to the invention make it possible to release larger amounts from the first day than matrices obtained by conventional methods without a prior impregnation step with gas. On the other hand, the amount of active substance released remains higher over time: in fact, it has been observed that at 30 days the matrix obtained by the method according to the invention releases an additional 1450 mg / day compared to about 680 mg for the conventional method.

[0151] Therefore, the matrix obtained according to the method of the present invention not only allows for improved incorporation of the active substance, but also allows for the release of said active substance in larger amounts over a period that can reach several months. No retention of the active substance in the matrix is ​​observed, and said active substance is fully released. From this, it can therefore be concluded that the polymer matrix impregnated and incorporated according to the method of the present invention leads to long-term treatment with a larger amount of released active substance. Therefore, the matrix obtained according to the method of the present invention thus makes it possible to obtain a more effective diffusion device.

[0152] Example 11: Comparison of the one-step method and the two-step method according to the present invention The applicant has attempted to simultaneously impregnate the matrix with a non-supercritical fluid and incorporate the active substance in the same step. It has been found that this does not allow for the incorporation of the active substance. Therefore, simultaneous impregnation with the incorporation of the active substance does not allow for the incorporation of the active substance. Surprisingly, only the sequential two-step method according to the present invention exhibits improved properties for the incorporation of the active substance.

[0153] Example 12: Scanning microscope analysis of the polymer matrix obtained according to the method Scanning microscope analysis was carried out on polymer matrices according to the invention that had not been impregnated and that had subsequently been impregnated with CO gas. Surprisingly, the images obtained in Figures 10 and 11 did not show any porosity in the matrix before or after treatment with CO. Surprisingly, therefore, impregnation of a matrix with gas according to the method of the invention does not give the matrix a porous structure, which would explain the improved quantity of active substance incorporated, contrary to what is known in the state of the art.

[0154] Example 13: Comparative study of conventional and incorporation methods with EVA-type polymers and essential oils. The impregnation and incorporation parameters for the method according to the invention applied to this matrix are as follows: Active substance / matrix pair: lavandin essential oil, EVA. Impregnation parameters: CO2, 25°C, 30 bar, 120 min. Uptake parameters: 63°C, 5 hours.

[0155] The results in Figure 12 confirm that the method according to the invention allows for increased uptake of essential oil alone inside the polymer matrix compared to that obtained using conventional uptake methods without the CO2 impregnation step.

Claims

1. 1. A method for producing a thermoplastic polymer matrix filled with at least one lipophilic liquid active substance using a gas, comprising: a) Carbon dioxide (CO) at a temperature strictly below 40°C and a pressure of 5 to 35 bar. ２ ) or dinitrogen (N ２ impregnation of the polymer with said gas in a non-supercritical state selected from the group consisting of b) an incorporation step of the active substance at a temperature between 30°C and 100°C; A method comprising the successive steps of:

2. 2. The method of claim 1, wherein the gas impregnation step is carried out at a temperature between 15°C and 35°C.

3. 3. The method of claim 2, wherein the gas impregnation step is carried out at a temperature between 20°C and 30°C.

4. 3. The method according to claim 2, characterized in that the duration of the impregnation step is between 5 minutes and 150 minutes.

5. 5. The method according to claim 1, wherein the polymer is a thermoplastic selected from ethylene vinyl acetate (EVA), polyamide, polyether block amide (PEBA), polypropylene (PP), polyethylene (PE), thermoplastic polyurethane (TPU), polyvinyl chloride (PVC), polystyrene, such as polystyrene-b-polybutadiene-b-polystyrene (SEBS) or polystyrene-b-polyisoprene-b-polystyrene (SIS), polyester, polylactic acid (PLA), as well as biodegradable polymers, agropolymers, bioplastics or bio-based thermoplastics, biopolyesters.

6. 6. The method according to any one of claims 1 to 5, characterized in that the incorporated active substances are selected from among chemical pharmaceutical active substances, naturally occurring active substances, essential oils, vegetable oils or mixtures thereof.

7. Carbon dioxide (CO) for impregnation into the thermoplastic polymer matrix ２ ) or dinitrogen (N ２ ) in a non-supercritical state, characterized in that the gas is impregnated at a temperature strictly below 40°C and at a pressure of 5 to 35 bar, in order to increase the amount of lipophilic liquid active substance incorporated inside the thermoplastic polymer matrix.

Images