Method for formulating a liquid or semi-liquid composition, compositions obtained by such a method, and corresponding uses.

Abstract

The present invention relates to obtaining a liquid or semi-liquid composition containing at least one active substance or active ingredient. This composition can be used in the formulation of biocidal compositions, plant protection compositions, or cosmetic compositions.

Description

Title of the invention: Method for formulating a liquid or semi-liquid composition, compositions obtained by such a method, and corresponding uses. Scope of the invention

[0001] The invention relates to the field of formulating liquid or semi-liquid compositions containing at least one active substance or active ingredient. The invention is particularly applicable to the formulation of compositions for pest control, such as biocidal products, veterinary products and physical barriers, plant protection products, and cosmetic compositions.

[0002] More specifically, the invention relates to a method for formulating a liquid or semi-liquid composition containing at least one active substance, as well as the compositions obtained by such a method, and corresponding uses. Previous art

[0003] Many formulations of liquid or semi-liquid compositions containing one or more active substances use water. Water has the combined advantages of being economical and having no effect on human or environmental toxicity.

[0004] Such liquid or semi-liquid compositions may include ready-to-use compositions but also compositions concentrated in active substance(s) intended to be diluted extemporaneously with water.

[0005] However, the use of water in formulations can lead to the hydrolysis of the active substances contained therein, resulting in a decrease in their effectiveness.

[0006] In order to protect the active substances from such action by water, formulation processes leading to the encapsulation of the active substances are known. Such processes make it possible to obtain capsules inside which the active substances are protected from water and therefore cannot be hydrolyzed.

[0007] However, in the field of biocides, the compounds used to form such capsules, such as polyurea and formaldehyde, are petrochemical compounds whose use poses problems, particularly with regard to the environment. In particular, the polyurea- or formaldehyde-based encapsulations currently on the market have the disadvantage of generating microplastics and using raw materials classified as hazardous to humans and the environment, such as isocyanates.

[0008] Furthermore, most biocides are dispersed in the environment in liquid form, and after evaporation, leave traces of active substances with which Harmful organisms come into contact with the active substance as they pass through the treated area. However, the active substance degrades in the environment at varying rates due to natural oxidation or the influence of UV radiation, thus reducing its long-term effectiveness.

[0009] Furthermore, in the field of insecticides, certain formulations possess extremely high wetting power in order to improve the penetration of the active substance onto insects. However, the inventors have observed that approximately 30% of the active substance can be absorbed by the carrier and is therefore unavailable to act on insects.

[0010] Compositions containing film-forming compounds, such as silanes, siloxanes, aminosiloxanes, polysiloxanes, or fluorinated compounds, have been developed to limit the absorption of the active substance by the substrates to which the compositions are applied. However, the effectiveness of the compositions is reduced by the presence of these film-forming raw materials. This effect could be explained by the fact that the film-forming raw materials can have a detrimental effect on the active substance by creating a network that traps it.

[0011] Since many active substances are lipophilic and therefore immiscible in water, it is necessary to make emulsions to bind the aqueous phase and the phase containing the lipophilic active substance, and therefore to use surfactant compounds to stabilize such emulsions.

[0012] The interactions between the surfactant and the active substance create intermolecular bonds, which are either steric or electrostatic depending on the nature of the surfactants involved. These interactions modify the three-dimensional mobility of the active substance by forming a new surfactant-active substance system, generally designated by the acronym "TA-SA". The drawback of this new TA-SA system is a loss of specificity of the neurotoxic chemical message. Indeed, the insertion of the substance onto its active site would be made more difficult by the TA-SA system.

[0013] Another drawback of the TA-SA complex is that it interacts with non-target proteins and also with the cell membrane and its phospholipids. These non-specific interactions result in disrupting cell membrane permeability13 J, but also in decreasing the specificity of the neurotoxic chemical message.

[0014] In the presence of surfactants, the active substance no longer focuses on its receptor because the TA-SA complex binds to other sites. In other words, the TA-SA system acts diffusely on the cell and not on the insecticide receptor. The The chemical message is therefore no longer as specific and the active substance loses its effectiveness.

[0015] By way of example, a widely used surfactant in biocidal formulations is a nonionic surfactant called polysorbate 80. However, it is known to those skilled in the art that polysorbate 80 has the disadvantage of penetrating the intercellular regions of organisms. One of the negative consequences of complex penetration is the separation of membrane phospholipids, which increases the fluidity of cell membranes. A second negative consequence of this penetration of the TA-SA complex is the binding of polysorbate to keratin filaments, which disrupts the integrity of the surrounding corneocytes. Objectives of the invention

[0016] In order to overcome the aforementioned drawbacks, the inventors have developed a method for formulating a liquid or semi-liquid composition containing at least one active substance: - whose specificity is improved compared to compositions obtained by prior art formulation processes, or - whose active substance content can be reduced compared to compositions obtained by prior art formulation processes which have substantially the same effectiveness, particularly for applications in the plant protection and biocidal fields, or - enabling the production of compositions in which toxicity is reduced, compared to compositions obtained by prior art formulation processes, or - enabling increased mobility and availability compared to compositions obtained by prior art formulation processes exhibiting substantially the same effectiveness, or - allowing for improved protection against water molecules and ultraviolet radiation of the active substance compared to compositions obtained by prior art formulation processes and having substantially the same effectiveness.

[0017] In the context of cosmetic use, the term active substance will be understood as an active ingredient (a term generally used in this field). Description of the invention

[0018] The present invention therefore aims to provide a method for formulating a liquid or semi-liquid composition comprising at least one active substance, said method comprising the following steps: - preparation of a non-polar oily phase comprising • at least one active substance (or active ingredient) present at a concentration of 0.01% to 90% by mass relative to the total mass of the nonpolar fatty phase, • at least one wax present at a rate of 5% to 60% by mass relative to the total mass of the non-polar fatty phase, • at least one solvent suitable for solubilizing the wax, preferably an acetal, present at a concentration of 5% to 94.99% by mass relative to the total mass of the nonpolar fatty phase, - preparation of a polar aqueous phase comprising • water present at a concentration of more than 90% by mass relative to the total mass of the polar aqueous phase, • at least one gelling agent present at a concentration of 0.01% to 1% by mass relative to the total mass of the aqueous phase, - heating the non-polar fatty phase to a first temperature T1 and heating the polar aqueous phase to a second temperature T2, said first temperature T1 and the second temperature T2 being higher than the melting temperature of the wax, the first T1 and second temperature T2 having a temperature difference of no more than 5°C and preferably being equal; - mixing of the entire polar aqueous phase heated to the second temperature T2 with 1 to 20% by mass of the non-polar fatty phase heated to the first temperature T1 relative to the total mass of the mixture.

[0019] The inventors have pointed out that such a process makes it possible to obtain a composition containing an aqueous phase and an oily phase that is particularly stable, without having to include a surfactant compound in the composition.

[0020] Unlike compositions comprising surfactants or film-forming agents obtained by prior art formulation processes, compositions obtained by the process according to the invention do not create networks capable of trapping the active substance and hindering its access to its site of action. Indeed, the compositions thus obtained exhibit a film-forming effect that does not negatively immobilize or trap the active substance. Therefore, the active substance in the liquid or semi-liquid compositions obtained with the process according to the invention exhibits improved mobility and can access its active site more easily.The process according to the invention therefore offers the possibility of reducing the quantity of active substance present in the liquid or semi-liquid composition, while maintaining an effectiveness of the active substance contained therein at least equivalent to that obtained with prior art formulation processes using surfactant compounds or . film-forming agents. In addition, the composition obtained with the process according to the invention allows the active substance to interact more specifically at its site of action, i.e. without causing undesired interaction with cell membrane phospholipids.

[0021] Furthermore, the process according to the invention makes it possible to obtain a composition in which the active substance is protected by means of a double encapsulation.

[0022] Thus, in the process according to the invention, the first step of producing a nonpolar oily phase allows for initial liquid-liquid encapsulation of the active substance, leading to the formation of so-called liquid-liquid capsules. This initial encapsulation also protects the active substance, particularly through the use of wax, from reactions with water present in the aqueous phase, and, once the composition is distributed at its application site, from reactions with external elements such as oxygen, ultraviolet radiation, etc.

[0023] A second encapsulation then occurs during the mixing of the product preparation by the user. During dilution of the concentrate, some of the gelling agent surrounds the liquid-liquid capsules, forming a plurality of capsules. Each of these capsules thus comprises a liquid matrix including the wax, the solvent, and the active substance, and a solid polymer membrane, enclosing the matrix, made of gelling agent. The capsules are suspended in water, thereby creating an additional layer of protection for the active substance. Nonpolar fatty phase

[0024] The nonpolar fatty phase comprises an active substance present at a concentration of 0.01% to 90% by mass relative to the total mass of the nonpolar fatty phase. Preferably, the active substance may be present at a concentration of 0.01% to 70% by mass relative to the total mass of the nonpolar fatty phase.

[0025] Any lipophilic active substance may be used as an active substance.

[0026] The non-polar fatty phase also comprises at least one wax present at a rate of 5% to 60% by mass relative to the total mass of said non-polar fatty phase.

[0027] Advantageously, a vegetable wax, and preferably rapeseed wax, may be used as the wax.

[0028] The wax content allows for modulation of the residual effect of the active substance, with residual effect increasing with a higher percentage of wax. For the purposes of this invention, residual effect refers to the duration for which the active substance continues to exert its action on a surface. The presence of wax in the composition according to the invention also allows for increased efficacy over time compared to prior art solutions. Thus, it is possible to reduce the amount of active substance in the compositions to obtain an effect at least equivalent to that of prior art compositions.

[0029] The non-polar fatty phase also comprises a solvent suitable for solubilizing said wax, preferably an acetal, present at a rate of 5% to 94.99% by mass relative to the total mass of said non-polar fatty phase.

[0030] Advantageously, the solvent suitable for solubilizing the wax can be present at a rate of 5% to 50% by mass relative to the total mass of the nonpolar fatty phase.

[0031] Advantageously, the non-polar fatty phase may further comprise a synergizer, that is to say a compound enabling the effectiveness of the active substance to be increased. Polar aqueous phase

[0032] The polar aqueous phase comprises, in addition to water, at least one gelling agent present at a concentration of 0.01% to 1% by mass relative to the total mass of said aqueous phase

[0033] Advantageously, the gelling agent can be present at a rate of 0.2% to 0.5% by mass relative to the total mass of the polar aqueous phase.

[0034] As a gelling agent, synthetic or natural gelling agents may be used in the context of the present invention, and for example a crosslinked polyacrylic acid polymer of formula -[CH2CH(COOH)]n- may be used as a gelling agent.

[0035] Advantageously, the polar aqueous phase may further comprise at least one additive selected from a neutralizer, a preservative, and a colorant. Preferably, the composition obtained by the process according to the invention may be free of surfactants.

[0036] For the purposes of this invention, a surfactant-free composition means a composition that does not include any surfactant or includes one or more surfactant(s) in a quantity of less than 0.5% by mass relative to the total mass of the composition.

[0037] The present invention also relates to finished liquid or semi-liquid compositions that can be obtained by the formulation process according to the invention.

[0038] Preferably, such compositions are characterized in that they comprise: - A dispersed phase comprising: • at least one active substance present at a concentration of 0.001% to 10% by mass relative to the total mass of the composition, • at least one wax, present at a concentration of 0.01% to 1% by mass relative to the total mass of the composition, and • at least one solvent suitable for solubilizing wax, preferably an acetal, present at a concentration of 0.01% to 5% by mass relative to the total mass of the composition, - A continuous phase comprising: • water with a content greater than or equal to 85% by mass relative to the total mass of the composition, and • at least one gelling agent present at a rate of 0.01% to 1% by mass relative to the total mass of the composition.

[0039] The active substance (or active ingredient), the solvent, the wax, and the gelling agent are as defined above.

[0040] The present invention also relates to the use of a composition such as described above in a preparation intended for cosmetic use.

[0041] The present invention also relates to the use of a composition such as described above in a preparation intended for phytosanitary use.

[0042] The present invention also relates to the use of a composition as described above in a preparation intended to control pests such as insecticides, veterinary products and physical barriers.

[0043] The features and advantages of the invention will become clearer upon reading the examples described. EXAMPLES Products and raw materials

[0044] - active substances: • cypermethrin, • pyrethrum, • sesame oil, • argan oil, - wax: rapeseed vegetable wax - solvent: acetal - mains water - gelling agent: cross-linked polyacrylic acid polymer marketed under the CARBOPOL® EZ3 brand from the Lubrizol company, - Preservative: Acticide MBS - Other additive: neutralizer

[0045] Example 1 - Preparation of surfactant-free C2 to C4 insecticide compositions

[0046] A first step of the formulation process 1 consists of producing a nonpolar oily phase, which constitutes a first liquid-liquid encapsulation.

[0047] For this purpose, the insecticidal active substance, the wax and the acetal are mixed in the same container.

[0048] A second step consists of preparing a polar aqueous phase. To do this, the gelling agent and water are mixed in a second container.

[0049] The nonpolar oily phase is then heated to a temperature T1 between 60°C and 70°C (depending on the nature of the wax and therefore its melting point), while the polar aqueous phase is heated separately to a temperature T2 between 60°C and 70°C (depending on the nature of the wax and therefore its melting point). The temperatures T1 and T2 are higher than the melting point of the wax, so that the wax can be completely liquefied. Preferably, the temperatures T1 and T2 are identical, but a temperature difference of 5°C is acceptable.

[0050] Subsequently, during a mixing step under agitation with a rotor / stator system, a portion of the non-polar oily phase is taken in order to integrate it into the polar aqueous phase in order to obtain a homogeneous composition comprising less than 10% by mass of active substance relative to the total mass of the composition.

[0051] The process implemented allows obtaining a C2 composition according to the invention, which comprises a dispersed phase including the active substance, the acetal and the wax, and a continuous phase including the gelling agent and water.

[0052] Similarly, compositions C3 and C4 are prepared using the same procedure as C2, but contain wax contents three times and five times greater, respectively, than composition C2. The different compositions C2 to C4 are shown in Table 1 below:

[0053] [Tables] Cl C2 C3 C4 Surfactant (polysorbate 80) 5-10 0 0 0 Water % 90-95 90-95 90-95 90-95 Wax % 0 X 3X 5X Acetal % 0 YYY Cypermethrin % 2.67 2.67 2.67 2.67 Carbopol EZ3 % 0 0.2 0.2 0.2 Neutralizer % 0 0.2 0.2 0.2

[0054] These surfactant-free C2 to C4 compositions are compared to a prior art formulation Cl with surfactant and having the same active substance at the same concentration as the C2 to C4 compositions.

[0055] In Table 1, X can vary between 0.01 and 1% by mass relative to the total mass of the composition, and Y can vary between 0.01 and 5% by mass relative to the total mass of the composition. Efficacy and persistence tests

[0056] Tests evaluating the insecticidal efficacy of compositions C2, C3 and C4 on the one hand and of composition Cl of the prior art containing the same quantity of active substance but containing surfactants were carried out.

[0057] This efficacy was determined by spraying each of the insecticide compositions C1, C2, C3, and C4 onto substrates, on which insects were subsequently placed. The insect mortality rate was then determined by counting the dead insects on these substrates after different periods of time.

[0058] The residual efficacy of the insecticide on the substrates was also studied by depositing new insects on these substrates after a certain time and measuring their mortality rate after different time intervals. The efficacy tests were carried out in accordance with the method described in the English document "Guidance on the Biocidal Products Regulation". More specifically, a group of insects (group 1) was exposed to the different compositions C1, C2, C3, and C4 for a period of 4 hours and 24 hours on the first day of testing (initial T). The dead insects were counted for the first time after the 4-hour period. A further count of the dead insects was carried out after the 24-hour period.

[0059] A new group of insects (group 2) was introduced onto the surfaces treated with the different compositions four weeks after the first application (T=4 weeks) of the compositions to the surfaces. Dead insects were counted after 24 hours of exposure on the treated surface.

[0060] Similarly, a new group of insects (group 3) was introduced onto the surfaces treated with the different compositions eight weeks (T=8 weeks) after the first application of the compositions to the surfaces. Dead insects were counted after 24 hours of exposure on the treated surface.

[0061] The various counts made it possible to determine the effectiveness of the different compositions containing the insecticide. The effectiveness of each composition is expressed as a percentage of dead insects in Table 2.

[0062] [Tables2] Initial temperature (T) T=4 weeks T=8 weeks 4 hours 24 hours 24 hours 24 hours Cl 39% 100% 8% 2% C2 100% 100% 100% 100% C3 100% 100% 28% 14% C4 83% 100% 30% 26%

[0063] It appears from the results in this table that the initial efficiencies after 4 hours of exposure (initial T0) of compositions C2, C3 and C4 are significantly higher higher than the efficacy of the Cl composition according to the prior art, and have respective efficiencies of 100%, 100% and 83%, while Cl shows an efficacy of 39% after 4 hours.

[0064] It should also be noted that composition C2 exhibits superior efficacy compared to compositions C3 and C4. Thus, a high percentage of wax may decrease efficacy.

[0065] The results in this table show that composition C2 exhibits significantly greater efficacy at 24 hours than composition Cl four weeks and eight weeks after the first application. However, it should be noted that a high wax content reduces the efficacy of the composition.

[0066] Thus, a composition according to the invention exhibits higher long-term efficacy than a composition according to the prior art. This improved efficacy can be explained, in particular, by better accessibility of the active site of the active substance, thereby making the active substance more available.

[0067] Example 2 - Preparation of a cypermethrin-based composition for use in a biocidal preparation

[0068] A cypermethrin-based composition intended for biocidal use is prepared according to the process according to the invention.

[0069] The quantities of each ingredient are indicated in Table 3 below.

[0070] To do this, the active substance (cypermethrin), the acetal and the wax are weighed and then mixed for approximately 30 minutes in a container until a homogeneous phase is obtained at temperature. This phase constitutes the non-polar oil phase.

[0071] Similarly, the gelling agent (CARBOPOL EZ3), tap water, and preservative (Acticide MBS) are weighed and then mixed for approximately 30 minutes in a container until a homogeneous phase is obtained at temperature. This phase constitutes the polar aqueous phase.

[0072] Once the two phases are homogeneous, a determined quantity of the nonpolar oily phase is taken and added to the aqueous phase tank. The mixture is then stirred for 5 minutes, and a neutralizer is added. The stirring speed is then increased.

[0073] Finally, the mixture is placed under agitation for at least one hour at a temperature between 60 and 70°C depending on the nature of the wax.

[0074] [Tables3] Raw materials % by mass relative to the total mass of the nonpolar fatty phase % by mass relative to the total mass of the mixture Nonpolar fatty phase 4 Cypermethrin 70 Acetal 10 Rapeseed wax 20 Polar aqueous phase Mains water 95.50 Acticide MBS 0.20 Carbopol EZ3 0.20 Neutralizer 0.10

[0075] Example 3 - Preparation of a pyrethrum-based composition for use in a plant protection product

[0076] A pyrethrum-based composition intended for phytosanitary use is prepared according to the process according to the invention, in the same way as in Example 2. The quantities of raw materials to be taken are indicated in Table 4 below.

[0077] In this example, the nonpolar oily phase consists of pyrethrum, acetal, rapeseed wax, and a synergist. The polar aqueous phase consists of mains water, the gelling agent Carbopol EZ3, and the preservative Acticide MBS.

[0078] The addition of synergizer in the non-polar fatty phase was done to improve the efficacy of the product.

[0079] [Tables4] Raw materials % by mass relative to the total mass of the nonpolar oil phase % by mass relative to the total mass of the mixture Nonpolar oil phase 2.5 PYRETHRUM 70 Acetal 9.5 Rapeseed vegetable wax 20 Synergizer 0.5 Polar aqueous phase Tap water 96.7 Carbopol EZ3 0.20 Neutralizer 0.1 Acticide MBS 0.50

[0080] Example 4 - Preparation of a composition based on sesame oil and argan oil intended for use in a cosmetic preparation

[0081] A composition based on sesame oil and argan oil intended for cosmetic use is prepared according to the process according to the invention, in the same way as in Examples 2 and 3. The quantities of the different ingredients are indicated in Table 5 below.

[0082] The advantage of this composition is to avoid the toxicity of surfactants on skin cells.

[0083] [Tables5] Raw materials % by mass relative to the total mass of the non-polar fatty phase % by mass relative to the total mass of the mixture Non-polar fatty phase 2 Sesame oil 22.5 Argan oil 22 Acetal 44.5 Rapeseed vegetable wax 11 Polar aqueous phase Tap water 97.3 Gelling agent 0.20 Preservative 0.50 References

[0084] [1] Lemaire J., (2016). Formaldehyde, a possible environmental pollutant of The atmosphere of work offices: assessment of the knowledge and professional practices of French occupational physicians on this ubiquitous irritant and carcinogen in our indoor air.

[0085] [2] Afsset, (2009). Health risks related to the presence of formaldehyde. Air and chemical agents.

[0086] [3] Lemery E., (2015). Structure and physicochemistry of surfactants, their impacts on skin toxicity and barrier function.

[0087] [4] Nokhodchi A., Shokri J., Dashbolaghi A., Hassan-Zadeh D., Ghafourian T. and Barzegar-Jalali M., (2003). The enhancement effect of surfactants on the penetration of lorazepam through rat skin. Int. J. Pharm.

Claims

Demands

1. A method for formulating a liquid or semi-liquid composition comprising at least one active substance, said method comprising the following steps: - preparation of a non-polar oily phase comprising: • said active substance present at a rate of 0.01% to 90% by mass relative to the total mass of said nonpolar fatty phase, • at least one wax present at a rate of 5% to 60% by mass relative to the total mass of said nonpolar fatty phase, and • at least one solvent suitable for solubilizing said wax, 1 edit solvent being an acetal, present at a rate of 5% to 94.99% by mass relative to the total mass of said nonpolar fatty phase; - preparation of a polar aqueous phase comprising: • water present at a concentration of more than 90% by mass relative to the total mass of said polar aqueous phase, and • at least one gelling agent present at a rate of 0.01% to 1% by mass relative to the total mass of said aqueous phase; - heating of said non-polar oily phase to a first temperature T1 and heating of said polar aqueous phase to a second temperature T2, said first temperature T1 and said second temperature T2 being higher than the melting temperature of said wax, said first T1 and second temperatures T2 having a temperature difference of at most 5°C between them and preferably being equal - mixing of the entirety of said polar aqueous phase heated to said second temperature T2 with 1 to 20% by mass of said non-polar fatty phase heated to said first temperature T1 in relation to the total mass of said mixture.

2. Formulation method according to claim 1, wherein said active substance is present at a rate of 0.01% to 70% by mass relative to the total mass of said nonpolar fatty phase.

3.

4.

5.

6.

7.

8.

9.

10. Formulation process according to any one of claims 1 and 2, wherein said solvent suitable for solubilizing said wax is present at a rate of 5% to 50% by mass relative to the total mass of said nonpolar fatty phase. A formulation process according to any one of claims 1 to 3, wherein said gelling agent is present at a concentration of 0.2% to 0.5% by mass relative to the total mass of said polar aqueous phase. A formulation process according to any one of claims 1 to 4, wherein said wax is a vegetable wax, preferably rapeseed wax. Formulation process according to any one of claims 1 to 5, wherein said gelling agent is a crosslinked polyacrylic acid polymer of formula -[CH2CH(COOH)]n-. Formulation method according to any one of claims 1 to 6, wherein said nonpolar fatty phase further comprises at least one synergizer. Formulation process according to any one of claims 1 to 7, wherein said polar aqueous phase further comprises at least one additive selected from a neutralizer, a preservative, a colorant. Formulation process according to any one of claims 1 to 8, wherein said composition is free of surfactant. Liquid or semi-liquid composition (1) obtainable by a formulation process according to any one of claims 1 to 9, comprising: - A dispersed phase comprising: • at least one active substance present at a concentration of 0.001% to 10% by mass relative to the total mass of the composition, • at least one wax present at a concentration of 0.01% to 1% by mass relative to the total mass of the composition, • at least one solvent of said at least one wax, - A continuous phase comprising: • water with a content greater than or equal to 85% by mass relative to the total mass of the composition, and at least one gelling agent present at a concentration of 0.01% to 1% by mass relative to the total mass of the composition, characterized in that said solvent is an acetal present at a rate of 0.01% to 5% by mass relative to the total mass of the composition.

11.

12.

13. Use of a composition as defined in claim 10 in a preparation intended for cosmetic use. Use of a composition as defined in claim 10 in a preparation intended for phytosanitary use. Use of a composition as defined in claim 10 in a preparation intended to combat pests such as insecticides, veterinary products and physical barriers.