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: Process for formulating a liquid or semi-liquid composition, compositions obtained by such a process, and corresponding uses. Field of invention

[0001] The invention relates to the field of the formulation of liquid or semi-liquid compositions containing at least one active substance or active principle. The invention finds its application in particular in the field of the formulation of compositions for the control of pests such as biocidal, veterinary and physical barrier products, phytosanitary compositions or even cosmetic compositions.

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

[0004] Such liquid or semi-liquid compositions may in particular be 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, leading to a reduction in their effectiveness.

[0006] In order to protect the active substances from such action of 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 formaldehydes11^, are compounds derived from petrochemicals whose use poses problems, particularly with regard to the environment. In particular, the encapsulations present on the market based on polyurea or formaldehyde have the disadvantage of generating microplastics and of using raw materials classified for humans and the environment as isocyanates.

[0008] Furthermore, most biocides are dispersed in the environment in liquid form, and after evaporation, deposit traces of active substances with which Harmful organisms come into contact when passing through the treated area. However, the active substance degrades in the environment at a more or less significant rate under the action of natural oxidation or under the influence of UV radiation, thus reducing its long-term effectiveness.

[0009] Furthermore, in the field of insecticides, certain galenics have an extremely high wetting power so as to improve the penetration of the active substance into insects. However, the inventors have noticed that approximately 30% of the active substance can be absorbed by the support and therefore not be available to act on insects.

[0010] Compositions containing film-forming compounds, such as silanes, siloxanes, aminosiloxanes, polysiloxane or fluorinated compounds, have thus been developed in order to limit the absorption of the active substance by the supports on 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 harmful activity on the active substance by creating a network causing the imprisonment of the active substance.

[0011] Since many active substances are lipophilic and therefore immiscible in water, it is necessary to produce 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. The 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". This new TA-SA system has the disadvantage of a loss of specificity of the neurotoxic chemical message. Indeed, the insertion of the substance on its active site would be made more difficult by the TA-SA system.

[0013] Another disadvantage 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 have the consequence of disrupting the permeability of the cell membranes l3J, but also of reducing 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 sparsely on the cell and not on the insecticide receptor. The chemical message is therefore no longer as specific and the active substance loses its effectiveness.

[0015] For example, a surfactant widely used in biocidal formulations is a non-ionic surfactant called polysorbate 80. However, it is known to those skilled in the art that polysorbate 80l4J has the disadvantage of penetrating into the intercellular regions of organisms. One of the negative consequences of the penetration of the complex is the separation of membrane phospholipids which has the effect of increasing the fluidity of the cell membranes. A second negative consequence of this penetration of the TA-SA complex is the binding of polysorbate with 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 process for formulating a liquid or semi-liquid composition containing at least one active substance: - whose specificity is improved compared to compositions obtained by formulation methods of the prior art, or - whose active substance content can be reduced compared to compositions obtained by prior art formulation processes which have substantially the same effectiveness, in particular for applications in the phytosanitary and biocidal fields, or - allowing the production of compositions in which toxicity is reduced, compared to compositions obtained by formulation processes of the prior art, or - allowing its mobility and availability to be increased compared to compositions obtained by prior art formulation processes having substantially the same effectiveness, or - making it possible to improve the protection against water molecules and ultraviolet radiation of the active substance compared to compositions obtained by formulation methods of the prior art and having substantially the same effectiveness.

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

[0018] The object of the present invention is therefore to provide a method for formulating a liquid or semi-liquid composition comprising at least one active substance, said method comprising the following steps: - production of an apolar fatty phase comprising • at least one active substance (or active principle) present at a rate of 0.01% to 90% by mass relative to the total mass of the apolar fatty phase, • at least one wax present at a rate of 5% to 60% by mass relative to the total mass of the apolar fatty phase, • at least one solvent capable of solubilizing the wax, preferably an acetal, present at a rate of 5% to 94.99% by mass relative to the total mass of the apolar fatty phase, - production of a polar aqueous phase comprising • water present at a rate of more than 90% by mass relative to the total mass of the polar aqueous phase, • at least one gelling agent present at a rate of 0.01% to 1% by mass relative to the total mass of the aqueous phase, - heating the apolar 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 temperature T1 and second temperature T2 having a temperature difference between them of at most 5°C and preferably being equal; - mixing the entire polar aqueous phase heated to the second temperature T2 with 1 to 20% by mass of the apolar fatty phase heated to the first temperature T1 relative to the total mass of the mixture.

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

[0020] Unlike compositions comprising surfactants or film-forming agents, obtained by the formulation processes of the prior art, the compositions obtained by the process according to the invention do not create networks likely to cause the imprisonment of the active substance and to hinder its access to its site of action. Indeed, the compositions thus obtained have a film-forming effect having no negative action of immobilization or imprisonment of the active substance. Thus, the active substance included in the liquid or semi-liquid compositions obtained with the process according to the invention has improved mobility and can access its active site more easily.The method 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 the formulation methods of the prior art using surfactant compounds or film-forming agents. In addition, the composition obtained with the method according to the invention allows the active substance to interact more specifically on its site of action, that is to say without causing unwanted interaction with the phospholipids of. cell membranes.

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

[0022] Thus, in the method according to the invention, the first step of producing a non-polar fatty phase makes it possible to obtain a first liquid-liquid type encapsulation of the active substance, which leads to the formation of so-called liquid-liquid capsules. This first encapsulation also makes it possible, in particular thanks to the use of wax, to protect the active substance from reactions of water, present in the aqueous phase but also once the composition is distributed on its application site, from reactions with external elements such as oxygen, ultraviolet rays, etc.

[0023] Then a second encapsulation is carried out when the user mixes the product preparation. When diluting the concentrate, part of the gelling agent surrounds the liquid-liquid capsules, so as to form a plurality of capsules. Each of these capsules thus comprises a liquid matrix comprising the wax, the solvent and the active substance, and a membrane of a solid polymer, encompassing the matrix, consisting of gelling agent. The capsules are suspended in the water, thus creating overprotection of the active substance. Non-polar fatty phase

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

[0025] Any lipophilic active substance can be used as the active substance.

[0026] The apolar 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 apolar fatty phase.

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

[0028] The wax content makes it possible to modulate the persistence of the active substance, the persistence increasing with a higher percentage of wax. For the purposes of the present invention, persistence means the duration during which the active substance continues to exert its action on a surface. The presence of wax used in the composition according to the invention also makes it possible to obtain increased effectiveness over time compared to the solutions of the prior art. Thus, it is possible to reduce the quantity of active substance present in the compositions to obtain an effect at least equivalent to the compositions of the prior art.

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

[0030] Advantageously, the solvent capable of solubilizing the wax may be present at a rate of 5% to 50% by mass relative to the total mass of the apolar fatty phase.

[0031] Advantageously, the apolar fatty phase may further comprise a synergist, i.e. a compound making it possible to increase the effectiveness of the active substance. Polar aqueous phase

[0032] The polar aqueous phase comprises, in addition to water, 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.

[0033] Advantageously, the gelling agent may 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 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 gelling agent.

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

[0036] By surfactant-free composition is meant, within the meaning of the present invention, a composition not comprising any surfactant or comprising one or more surfactants in an amount 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 capable of being 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 rate of 0.001% to 10% by mass relative to the total mass of the composition, • at least one wax, present at a rate of 0.01% to 1% by mass relative to the total mass of the composition, and • at least one solvent capable of solubilizing the wax, preferably an acetal, present at a rate of 0.01% to 5% by mass relative to the total mass of the composition, - A continuous phase including: • 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 principle), the solvent, the wax, and the gelling agent are as defined previously.

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

[0041] The present invention also relates to the use of a composition 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 combat pests such as insecticides, veterinary products and physical barriers.

[0043] The characteristics and advantages of the invention will appear more clearly on 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: crosslinked polyacrylic acid polymer marketed under the CARBOPOL® EZ3 brand from Lubrizol, - preservative: Acticide MBS - Other additive: neutralizer

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

[0046] A first step of the formulation process 1 consists of producing an apolar fatty 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 producing a polar aqueous phase. To do this, the gelling agent and water are mixed in a second container.

[0049] The apolar fatty phase is then heated to a temperature T1 of 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 of 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 temperature of the wax, so that the wax can be completely liquefied. The temperatures T1 and T2 are preferably the same, but a temperature difference of 5°C is tolerated.

[0050] Subsequently, during a mixing step with stirring using a rotor / stator system, a portion of the apolar fatty phase is removed in order to integrate it into the polar aqueous phase with the aim of obtaining a homogeneous composition comprising less than 10% by mass of active substance relative to the total mass of the composition.

[0051] The method implemented makes it possible to obtain a composition C2 in accordance with the invention, which comprises a dispersed phase comprising the active substance, the acetal and the wax, and a continuous phase comprising the gelling agent and the water.

[0052] In the same way, compositions C3 and C4 are prepared according to the same procedure as C2, but respectively comprise wax contents three times higher and five times higher than composition C2. The different compositions C2 to C4 are presented in Table 1 below:

[0053] [Tableauxl] 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 compositions C2 to C4 are compared to a prior art formulation C1 with surfactant and having the same active substance at the same concentration as compositions C2 to C4.

[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 for evaluating the insecticidal efficacy of compositions C2, C3 and C4 on the one hand and of composition C1 of the prior art containing the same quantity of active substance but containing surfactants were carried out.

[0057] This effectiveness was determined by spray-depositing each of the com- Insecticide positions Cl, C2, C3 and C4 on supports, on which insects are subsequently placed. The insect mortality rate is then determined by counting the dead insects on these supports after different periods of time.

[0058] The persistence of the effectiveness of the insecticide on the supports was also studied by depositing new insects on these supports after a certain time and measuring their mortality rate after different periods of time. The effectiveness tests were carried out in accordance with the method described in the English document "Guidance on the Biocidal Products Regulation". More precisely, 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 new 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 onto 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 to the treated surface.

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

[0062] [Tables2] Initial 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 emerges from the results of this table that the initial efficacies after 4 hours of exposure (initial T) of compositions C2, C3 and C4 are significantly higher than the efficacy of composition Cl according to the prior art, and have respective efficacies of 100%, 100% and 83%, whereas Cl shows an efficacy of 39% after 4 hours.

[0064] It should also be noted that composition C2 has a higher efficiency than compositions C3 and C4. Thus, a high percentage of wax can reduce the efficiency.

[0065] It is clear from the results in this table that composition C2 has a 24-hour efficacy significantly higher than the efficacy of Cl four weeks after the first application 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 has a higher long-term efficacy than a composition according to the prior art. This improved efficacy can in particular be explained by better accessibility of the active site of the active substance, thus making the active substance more available.

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

[0068] A cypermethrin-based composition intended for biocidal use is prepared in accordance with 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 and at temperature. This phase constitutes the apolar fatty phase.

[0071] In the same way, the gelling agent (CARBOPOL EZ3), the tap water, and the 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 apolar fatty phase is taken and added to the tank of the aqueous phase. The mixture is then stirred for 5 minutes, then a neutralizer is added to the mixture. The stirring speed is then increased.

[0073] Finally, the mixture is stirred for at least one hour at a temperature between 60 and 70°C depending on the nature of the wax. Raw materials % by mass relative to the total mass of the apolar fatty phase % by mass relative to the total mass of the mixture Apolar 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 - Production of a pyrethrum-based composition intended for use in a phytosanitary preparation

[0076] A pyrethrum-based composition intended for phytosanitary use is prepared in accordance with 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 apolar fatty phase consists of pyrethrum, acetal, rapeseed wax and a synergist. The polar aqueous phase consists of tap water, the gelling agent Carbopol EZ3 and an Acticide MBS preservative.

[0078] The addition of synergist in the apolar fatty phase was made to improve the effectiveness of the product. Raw materials % by mass relative to the total mass of the apolar fatty phase % by mass relative to the total mass of the mixture Apolar fatty phase 2.5 PYRETHRE 70 Acetal 9.5 Rapeseed vegetable wax 20 Synergizer 0.5 Polar aqueous phase Mains water 96.7 Carbopol EZ3 0.20 Neutralizer 0.1 Acticide MBS 0.50

[0080] Example 4 - Production 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 in accordance with the process according to the invention, in the same manner 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. Raw materials % by mass relative to the total mass of the apolar fatty phase % by mass relative to the total mass of the mixture Apolar fatty phase 2 Sesame oil 22.5 Argan oil 22 Acetal 44.5 Rapeseed vegetable wax 11 Polar aqueous phase Mains 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: evaluation 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 linked 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

Claims

1. A method of formulating a liquid or semi-liquid composition comprising at least one active substance, said method comprising the following steps: - production of an apolar fatty phase comprising: • said active substance present at a rate of 0.01% to 90% by mass relative to the total mass of said apolar fatty phase, • at least one wax present at a rate of 5% to 60% by mass relative to the total mass of said apolar fatty phase, and • at least one solvent capable of solubilizing said wax, preferably an acetal, present at a rate of 5% to 94.99% by mass relative to the total mass of said apolar fatty phase; - production of a polar aqueous phase comprising: • water present at a rate 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 said apolar fatty phase to a first temperature T1 and heating 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 temperature T1 and second temperature T2 having between them a temperature difference of at most 5°C and preferably being equal; - mixing all of said polar aqueous phase heated to said second temperature T2 with 1 to 20% by mass of said apolar fatty phase heated to said first temperature T1 relative to the total mass of said mixture.

2. A formulation process according to claim 1, wherein said active substance is present in an amount of 0.01% to 70% by mass per relative to the total mass of said apolar fatty phase.

3. Formulation process according to any one of claims 1 and 2, wherein said solvent capable of solubilizing said wax is present in an amount of 5% to 50% by mass relative to the total mass of said apolar fatty phase.

4. A formulation process according to any one of claims 1 to 3, wherein said gelling agent is present in an amount of 0.2% to 0.5% by mass relative to the total mass of said polar aqueous phase.

5. A formulation process according to any one of claims 1 to 4, wherein said wax is a vegetable wax, preferably a rapeseed wax.

6. A 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-,

7. Formulation process according to any one of claims 1 to 6, according to which said apolar fatty phase further comprises at least one synergist.

8. Formulation process according to any one of claims 1 to 7, according to which said polar aqueous phase further comprises at least one additive chosen from a neutralizer, a preservative, a colorant.

9. A formulation process according to any one of claims 1 to 8, wherein said composition is free of surfactant.

10. Liquid or semi-liquid composition (1) obtainable by a formulation process according to any one of claims 1 to Q

11. Liquid or semi-liquid composition (1) according to claim 10, further comprising: - A dispersed phase comprising: • at least one active substance present in an amount of 0.001% to 10% by mass relative to the total mass of the composition, • at least one wax present in an amount of 0.01% to 1% by mass relative to the total mass of the composition, • at least one solvent for said at least one wax, preferably an acetal, present in an amount of 0.01% to 5% by mass relative to the total mass of the composition, - A continuous phase comprising: • water in 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.

12. Use of a composition as defined according to claim 10 or 11 in a preparation intended for cosmetic use.

13. Use of a composition as defined according to claim 10 or 11 in a preparation intended for phytosanitary use.

14. Use of a composition as defined in claim 10 or 11 in a preparation for controlling pests such as insecticides, veterinary products and physical barriers.