Formulation base comprising eutectic mixtures for liquid compositions intended to be frozen

Abstract

The invention relates to a formulation base for formulating a composition intended to remain stable in liquid, non-crystalline form over a temperature range of between -25°C and 0°C, the formulation base comprising a eutectic mixture of at least two molecules containing a hydrogen bond donor site (HBD) and / or a hydrogen bond acceptor site (HBA). The invention is characterized in that the mixture has an RHB of between 0.50 and 1.50, and a ∆logP of between -0.5 and 1.6, and in that at least one molecule of the eutectic mixture is a polar molecule having a strictly negative IogP. The invention also relates to a composition comprising such a formulation base according to the invention, the composition being stable in liquid, non-crystalline form over a temperature range of between -25°C and 0°C.

Description

[0001] FORMULATION BASE COMPRISING EUTECTIC MIXTURES FOR LIQUID COMPOSITIONS INTENDED TO BE FROZEN

[0002] TECHNICAL FIELD

[0003] The invention relates to a formulation base for a liquid composition intended to be frozen, comprising a eutectic mixture, and to a composition comprising such a formulation base, said composition maintaining a stable state in liquid form within a temperature range of -25°C to 0°C, or even up to +45°C. It has applications in the development of cosmetic, nutraceutical, and pharmaceutical products.

[0004] The cosmetics, nutraceutical, and pharmaceutical industries face several technical challenges when formulating natural products (instability, incompatibility, and limited solubility). Furthermore, these industries must consider expectations regarding sustainability and environmental impact, leading to a growing demand for environmentally friendly solvents in product formulations and a rejection of conventional preservative systems.

[0005] Indeed, the solvents and preservative systems traditionally used in such products often present warnings, or even proven risks to the environment and health due to their toxicity and non-biodegradability.

[0006] The industry now demands products that are not only healthy and environmentally friendly, but also more effective. Effective solvents must improve the solubility and stability of active ingredients, ensure product consistency, and contribute to the sensory properties of finished cosmetic or pharmaceutical products.

[0007] Freezing is a well-established method for preserving and stabilizing products. This requires cosmetic matrices capable of solubilizing active ingredients, remaining stable over a wide temperature range, and remaining easily usable by end consumers. However, freezing products, particularly cosmetics, faces a key challenge: the potential for structural alteration of the formulation, such as phase separation, creaming, coalescence, syneresis, or the formation of ice cubes unsuitable for topical or oral use.

[0008] Deep natural eutectic solvents (NADES), derived from natural and biodegradable components, present a promising alternative that aligns with industry sustainability goals. NADES, with their tunable properties and biocompatibility, have the potential to meet these requirements due to their biodegradability, low toxicity (and therefore environmental friendliness), and low melting points. They are generally composed of natural compounds such as sugars, amino acids, organic acids, and alcohols.

[0009] These solvents have been identified as potential alternatives to conventional organic solvents in various industrial applications, including extraction, catalysis and / or pharmaceutical formulations.

[0010] The synthesis of NADES generally involves the simple mixing of compounds such as polyols and polycarboxylic acids in specific molar ratios. The process is often carried out at elevated temperatures to facilitate the dissolution and interaction of the components.

[0011] Studies have shown that the choice of components and their ratios significantly influence the properties of the resulting NADES.

[0012] For example, Paiva et al. (2014) reported the synthesis of NADES using a combination of glycerol and citric acid. The study highlighted the importance of the molar ratio and temperature for obtaining a homogeneous and stable eutectic mixture.

[0013] Similarly, Dai et al. (2013) explored various combinations of sugars and organic acids, demonstrating that the resulting NADES exhibited improved solubilization capabilities for bioactive compounds.

[0014] Numerous studies have thus demonstrated the versatility of NADES in various fields, highlighting their potential to replace conventional solvents.

[0015] For example, NADES have been used successfully in the extraction of bioactive compounds from plants, the stabilization of enzymes and as a reaction medium in organic synthesis.

[0016] Current research focuses on optimizing component ratios and synthesis conditions to obtain NADES with desired properties.

[0017] However, further exploration of new component combinations and their applications in emerging fields, such as products intended for freezing, remains necessary, as these require careful consideration of their physicochemical properties under low-temperature conditions. Indeed, preserving active ingredients at low temperatures can improve their stability and efficacy, potentially extending product shelf life.

[0018] Conventional solvents used in frozen cosmetics may not offer the desired solubility, stability, and efficacy for active ingredients.

[0019] The growing interest in frozen cosmetic products thus requires the development of suitable solvents capable of maintaining the stability (including without preservative systems) and performance of active ingredients under freezing conditions while maintaining high cosmetic acceptability.

[0020] PREVIOUS TECHNIQUE Several brands have developed and market frozen cosmetic products, capitalizing on the unique advantages they offer.

[0021] Illustrative examples include:

[0022] Mask formulations designed to provide intense hydration and soothing effects, such as the BLITHE® Patting Splash Mask - Rejuvenating Purple Berries, 111SKIN® Sub-Zero Eye Mask, PETER THOMAS ROTH® Extreme De-Tox™ Hydrator Cucumber Gel Mask, and ELEMIS® Peptide Mask 4Thousand Flower, TONYMOLY® I'm Real Aloe Mask Sheet Moisturizing;

[0023] cryogenic serums and creams often formulated with antioxidants, peptides and moisturizing agents, designed to be stored and used in cold conditions to firm and tone the skin, thus enhancing the benefits of the cooling effect such as the COLD CHEMISTRY® Cryo-Active Firming Serum;

[0024] eye gels that target under-eye bags and dark circles by combining a cooling action with ingredients like caffeine and hyaluronic acid, such as SKIN ICELAND® Hydro Cool Firming Eye Gels infused with Icelandic glacial water, peptides and botanicals and designed to firm, tone and depuff the delicate skin around the eyes.

[0025] However, the products currently on the market do not fully exploit the potential of a product designed for cold storage. They often simply utilize cold as a cooling agent or to induce vasoconstriction.

[0026] Furthermore, most contain preservatives and do not claim to increase the stability of the active ingredients or to allow compatibility between several active ingredients within the same formulation.

[0027] Many solvents used often exhibit poor performance at low temperatures, leading to phase separation, crystallization, or loss of solvent power.

[0028] Frozen cosmetic and pharmaceutical products, including dietary supplements and nutraceuticals, also face unique challenges related to the stability and efficacy of active ingredients. Repetitive freezing and thawing cycles can lead to phase separation, crystallization, and degradation of sensitive compounds. Ensuring the homogeneity and bioavailability of active ingredients in frozen formulations is essential for their effectiveness.

[0029] Numerous disclosures already exist regarding the use of deep eutectic solvents (DES) and NADES for their solubilization and extraction properties. Illustrative examples include:

[0030] a DES compound of citric acid monohydrate, glycerin and water used for the extraction of polysaccharides (MD YUSOFF MUHAMMAD HASNUN et al., 21-08-2023);

[0031] a DES composed of citric acid monohydrate, glycerin and water used for the extraction of anthocyanin phenols from hibiscus (KURTULBAS EBRU et al., 16-01-2020);

[0032] a NADES composed of 1,3-propandiol, citric acid and water used for the extraction of fatty acids (Wils Laura et al., 15-06-2024);

[0033] a NADES composed of 1,2-propandiol, citric acid and water used for the extraction of plant components (Grozdanova Tsvetinka et al., 01-12- 2020);

[0034] a NADES composed of glycerol, arginine and water used for the solubilization of silymarin (ES2861593A1 , UNIV VALLADOLID, 06-10-2021);

[0035] a NADES composed of fructose, glycerol and water used for the extraction, for example, of plant components contained in flowers (FR3036618A1, GATTEFOSSE SAS, 02-12-2016); and

[0036] a NADES composed of choline chloride, succinic acid, glycerol and water for the extraction of tobacco components (CN115715598A, YUNNAN REASCEND TOBACCO TECH GROUP CO LTD, 28-02-2023).

[0037] In addition to their use as extraction solvents, it should be noted that all of the aforementioned solvents use a significant amount of additional (extrinsic) water.

[0038] Although current NADES offer improved solubilization capabilities and environmental benefits, their performance in frozen formulations has not been thoroughly investigated.

[0039] Challenges such as maintaining homogeneity, preventing crystallization and ensuring the stability of active ingredients in frozen NADES-based cosmetics still need to be addressed.

[0040] Research efforts are needed to develop NADES-based formulations specifically adapted to cosmetic, nutraceutical and / or pharmaceutical applications, particularly those that can withstand freeze-thaw cycles while allowing optimized solubilization of active ingredients.

[0041] Studies are needed to understand the interactions between NADES and active ingredients in frozen products and to optimize formulations for maximum performance.

[0042] There is a real need to find new, simpler product bases, particularly for cosmetics and / or pharmaceuticals, while maintaining the textures appreciated by users, the stability of active ingredients, particularly cosmetics and / or pharmaceuticals taken alone or in combination, without using preservatives, and with acceptable manufacturing costs and where industrial production is not an obstacle.

[0043] TECHNICAL PROBLEM

[0044] Considering the above, one problem that the present invention aims to solve is to develop new products preventing the proliferation of microorganisms within preparations, offering stability over time, both of the vehicle and of the active ingredients, in particular antioxidants, in order to maintain their effectiveness, and advantageously to improve the compatibility of the active ingredients with each other while keeping a galenic suitable for administration on the skin (liquid formula, possibly viscous, at very low temperature).

[0045] BENEFITS PROVIDED

[0046] The combination of compounds used in the formulation base according to the invention gives a eutectic mixture with unique physicochemical properties, allowing the production of a NADES resulting in a solvent with a melting point below -20°C, capable of maintaining the product in a liquid (possibly viscous) state during freezing.

[0047] The formulation base according to the invention allows for improved preservation of the active ingredients taken alone or in combination, at low temperatures helping to preserve the stability and effectiveness of sensitive active ingredients such as vitamins and antioxidants or even cells or cell fragments, namely compounds that are both hydrophilic and lipophilic, which can degrade at room temperature.

[0048] It also helps to improve the stability and effectiveness of cosmetically and pharmaceutically active ingredients by preventing them from crystallizing or degrading when frozen.

[0049] The formulation base according to the invention makes it possible to maintain homogeneity by maintaining a uniform distribution of ingredients throughout the product during freezing and thawing cycles in order to avoid phase separation and to guarantee consistent performance.

[0050] The formulation base according to the invention makes it possible to obtain and maintain the desired texture and sensory properties (with a consistent viscosity over time) despite freezing and thawing cycles during use. To this end, the use of a frozen fluid product provides a cooling effect upon application, delivering an immediate soothing sensation.

[0051] The formulation base according to the invention also allows for a reduction in the concentration of certain active ingredients while maintaining the same efficacy. This also improves the safety profile by limiting degradation products or by offering effective concentrations without reaching, for example, the skin irritation threshold (better benefit / risk ratio).

[0052] This ensures no degradation, which avoids waste due to overdosing of active ingredients to compensate for the rapid degradation of active ingredients.

[0053] For example, the most effective antioxidants are also known to be the most fragile. The formulation basis according to the invention thus avoids the use of chemical forms that are less susceptible to degradation but also less effective in circumventing this problem, or the use of overdoses during manufacturing.

[0054] If we take the more specific example of vitamin C, the most active form is ascorbic acid, which is very sensitive to degradation; therefore, an ester form (ascorbyl palmitate) which is more stable but less effective is often used.

[0055] Finally, the formulation base according to the invention makes it possible to avoid the use of preservative(s), as microbial growth is blocked at low temperature, while also allowing the shelf life of the products to be extended.

[0056] TECHNICAL SOLUTION

[0057] The solution to this problem primarily aims to provide a formulation basis for a composition intended to be stable in liquid and non-crystalline form within a temperature range of -25°C to 0°C, comprising a eutectic mixture of at least two molecules containing a hydrogen bond donor (HBD) site and / or a hydrogen bond acceptor (HBA) site, in which:

[0058] - said donor site is obtained from at least one molecule chosen from a mono-alcohol, a polyol, a monocarboxylic acid, a polycarboxylic acid, a primary or secondary amine, a primary or secondary amide, taken alone or in combination,

[0059] - said acceptor site is obtained from at least one molecule chosen from a mono-alcohol, a polyol, a monocarboxylic acid, a polycarboxylic acid, a mono-ester, a polyester, a mono-ether, a polyether, a primary or secondary amine, a primary or secondary amide, an anhydride, a carbonate, taken alone or in combination,

[0060] and in which the hydrogen bond ratio (HBR) is obtained by dividing the total number of donor sites by the total number of acceptor sites, weighted by the molar ratio of the mixture according to the formula:

[0061]

[0062] with i = a given molecule of the mixture, one or more molecules being able to be considered,

[0063] n = amount of substance (in moles),

[0064] HBD = unit value of the donor site(s) for a molecule of the mixture, and HBA = unit value of the acceptor site(s) for a molecule of the mixture, and in which the LogP of the molecule is measured according to its affinity with water and octanol according to the formula:

[0065] LogP = Log<^^)

[0066]

[0067] '-water

[0068] with C = concentration of the molecule,

[0069] P = partition coefficient,

[0070] and in which the difference in LogP of the molecules in the mixture is calculated according to the formula:

[0071] LogP = \LogP A — LogP B LogP sign A LogP sign B ') with A = a molecule, and

[0072] B = another molecule, different from A,

[0073] characterized in that the RHB is between 0.50 and 1.50,

[0074] AlogP is between -0.5 and 1.6,

[0075] at least one molecule of the eutectic mixture being a polar molecule with a strictly negative logP, and

[0076] The unit values ​​of the donor sites (HBD) and the acceptor sites (HBA) are determined as follows:

[0077] Functional Groups Alcohols Carboxylic Acid Ester OH p. OH s. OH t. CO (OH) (CO)OH CO(OR) (CO)OR Donor 1.5 1 0.5 0 0.5 0 0 Acceptor 1 1.5 0.5 1 0.8 1.3 0.3 Carbonate Groups Anhydride

[0078] functional OfCOlO (O) CO (O ) COfOlCO (CO)O(CO)

[0079] Donor 0 0 0 0

[0080] Acceptor 0.6 1.9 1.6 0.2

[0081] Amide Groups

[0082] functional (CO)NH p. CO(NH) p. (COjNH s. CO(NH) S. (CO)NR t. CO(NR2) t.

[0083] Donor 0.8 0 0.4 0 0 0

[0084] Acceptor 0.6 1.5 0.4 1.5 0.1 1.8 Groups Ether Carbonyl Amine

[0085] functional O eth. CO cet. CO aid. NH p. NH s. NR t.

[0086] Donor 0 0 0 1.5 1.2 0

[0087]

[0088] Acceptor 0.5 0.8 0.6 0.5 1 1

[0089] It also relates to a composition comprising, in a physiologically acceptable medium, a formulation base according to the invention, said composition being stable in liquid and non-crystalline form, in a temperature range between -25°C and 0°C.

[0090] Its ultimate purpose is the use of the formulation base according to the invention to maintain a stable and liquid composition, in a temperature range between -25°C and 0°C.

[0091] The invention and its resulting advantages will be better understood upon reading the description and non-limiting embodiments that follow.

[0092] DESCRIPTION OF IMPLEMENTATION METHODS

[0093] The invention relates to a formulation basis for a composition intended to be stable in liquid and non-crystalline form within a temperature range of -25°C to 0°C, comprising a eutectic mixture of at least two molecules containing a hydrogen bond donor (HBD) site and / or a hydrogen bond acceptor (HBA) site, wherein:

[0094] - said donor site is obtained from at least one molecule chosen from a mono-alcohol, a polyol, a monocarboxylic acid, a polycarboxylic acid, a primary or secondary amine, a primary or secondary amide, taken alone or in combination,

[0095] - said acceptor site is obtained from at least one molecule chosen from a mono-alcohol, a polyol, a monocarboxylic acid, a polycarboxylic acid, a mono-ester, a polyester, a mono-ether, a polyether, a primary or secondary amine, a primary or secondary amide, an anhydride, a carbonate, taken alone or in combination,

[0096] and in which the hydrogen bond ratio (HBR) is obtained by dividing the total number of donor sites by the total number of acceptor sites, weighted by the molar ratio of the mixture according to the formula:

[0097]

[0098] RHB X.ni.HBA,

[0099] with i = a given molecule of the mixture, one or more molecules being able to be considered,

[0100] n = amount of substance (in moles),

[0101] HBD = unit value of the donor site(s) for a molecule of the mixture, and HBA = unit value of the acceptor site(s) for a molecule of the mixture, and in which the LogP of the molecule is measured according to its affinity with water and octanol according to the formula:

[0102] LogP = Log ai--)

[0103] '-water

[0104] with C = concentration of the molecule,

[0105] P = partition coefficient,

[0106] and in which the difference in LogP of the molecules in the mixture is calculated according to the formula:

[0107] LogP = \LogP A — LogP B \. sign^LogP^. sign(LogP B ~) with A = a molecule, e

[0108]

[0109] t

[0110] B = another molecule, different from A.

[0111] Essentially, RHB is between 0.50 and 1.50, and AlogP is between -0.5 and 1.6.

[0112] Preferably, the RHB is between 0.80 and 1.2, more preferably 1.

[0113] The hydration of compounds can influence the hydrogen bond ratio (HBR). However, the HBR as defined above is determined for compounds in anhydrous form. Essentially, at least one molecule in the eutectic mixture is a polar molecule with a strictly negative logP.

[0114] In other words, the eutectic mixture is limited to mixtures of strictly polar compounds, or to mixtures of polar / nonpolar compounds. Mixtures of strictly nonpolar compounds are excluded from the invention.

[0115] According to one embodiment of the invention, the eutectic mixture comprises a pair of polar molecules.

[0116] According to another embodiment of the invention, the eutectic mixture comprises a polar / nonpolar molecule pair.

[0117] A "polar molecule" is defined as a molecule with a preferential affinity for aqueous media or hydrophilic solvents, resulting in significantly higher solubility in aqueous media or hydrophilic solvents than in lipophilic or organic solvents. A molecule is considered polar when its solubility in aqueous media or hydrophilic solvents is greater than its solubility in lipophilic or organic solvents, and in particular when its octanol / water partition coefficient (logP) is strictly negative, that is, negative and not equal to 0.

[0118] A "nonpolar molecule" is defined as a molecule with a preferential affinity for lipophilic or organic solvents, resulting in significantly higher solubility in lipophilic or organic solvents than in hydrophilic solvents or aqueous media. A molecule is considered nonpolar when its solubility in lipophilic or organic solvents is greater than its solubility in hydrophilic solvents or aqueous media, and in particular when its octanol / water partition coefficient (logP) is strictly positive, that is, positive and not equal to 0.

[0119] LogP represents the decimal logarithm of the ratio of the concentrations of the compound in two immiscible phases, octanol and water, at equilibrium. The classic "shake-flask" method involves mixing an excess of the compound with a water / octanol mixture, stirring until equilibrium is reached, then separating the phases and quantifying the concentration of the compound in each using appropriate analytical techniques (UV-visible, HPLC, or mass spectrometry). A negative logP indicates that the compound preferentially distributes in the aqueous phase, confirming its water-soluble nature. A positive logP indicates that the compound preferentially distributes in the octanol phase, confirming its lipid-soluble nature.

[0120] The invention is based on a model for formulating a eutectic mixture which takes into account the donor and acceptor sites, as well as the LogP and RHB of the molecules involved.

[0121] A hydrogen bond is known to link a hydrogen atom attached to a heteroatom with another heteroatom (the heteroatoms can be replaced by an aromatic ring). Generally, the more electrons charged the group, the more stable the bond and the more likely it is to form.

[0122] It is known that a water molecule can be defined as "a", "d", "dd", "aa", "da", "dda", "daa" and "ddaa" where "d" and "a" are respectively the donor and acceptor sites (with varying bond strengths).

[0123] From this premise, we can deduce and simplify that an alcohol molecule has both one donor site and one acceptor site. For example, a carboxylic acid has one donor site and two acceptor sites, esters have two acceptor sites, and carbonyls have one acceptor site; ethers also have one acceptor site.

[0124] We believe that to formulate a NADES reaction, it is necessary to establish a relationship between an acceptor site and a donor site, considering a mole-to-mole equilibrium. A first mathematical equation has therefore been developed to determine whether a mixture can tend to form a NADES reaction. To do this, the total number of donor sites (HBD) is divided by the total number of acceptor sites (HBA), weighted by the molar ratio of the mixture. The result is a value, which for an ideal mixture is 1.

[0125] We observe that the results obtained do not support the formation of a NADES in the mole-to-mole ratio of "1 donor function for 1 acceptor function". Indeed, all the tested results are well below 1, and do not allow us to propose a consistent confidence interval.

[0126] Within the framework of the invention, it is therefore essential to have a proper definition of hydrogen bonds.

[0127] An electron-enriched heteroatom is more likely to generate hydrogen bonds (donor and acceptor).

[0128] The definition according to the invention of acceptor and donor sites is thus based on the ability of a molecule to give or accept a proton to form a hydrogen bond.

[0129] Within the framework of proton-donating sites, we normalize these values ​​around the secondary alcohol (OH s.) which has a value of 1. The primary alcohol, being more sterically decoupled, is assigned a value of 1.5. Conversely, the tertiary alcohol, being very hindered (despite an inductive effect of the carbons), sees its value decrease to 0.5. The carboxylic acid exhibits electron delocalization, which makes the proton of the functional group less available, with a value of 0.5.

[0130] In the present invention, a donor site is necessarily an acceptor site. Conversely, an acceptor site may not be a donor; this is the case, for example, with esters, ethers, etc.

[0131] A given molecule in the mixture may therefore have at least one donor site and one acceptor site, or may have only one acceptor site.

[0132] For acceptor sites, a secondary alcohol (value of 1.5) is more enriched than a primary alcohol (value of 1). However, in the case of a tertiary alcohol, steric hindrance plays too significant a role and reduces its capacity to accept protons (value of 0.5). The delocalization of electrons in the carboxylic acid differs between the oxygens of the functional group. The atom bearing the hydrogen has a less acceptor effect (value of 0.8) than its neighbor (value of 1). However, the proton can be carried by either of the two heteroatoms, regardless of their position. Conversely, esters do not exhibit free distribution of their aliphatic residues over time. The carbonyl function of the ester is therefore more available than that of the carboxylic acid with a value of 1.3, and the second heteroatom is sterically hindered, which lowers its value to 0.3.The same principle applies to ether functions, which are not depleted by a carbonyl group, and therefore have a value of 0.5. For carbonyls, the ketone function is more electron-enriched than the aldehyde function, making it more suitable as an acceptor site.

[0133] Essentially, the unit values ​​of donor sites (HBD) and acceptor sites (HBA) are determined as follows:

[0134] Functional Groups Alcohols Carboxylic Acid Ester OH p. OH S. OH t. CO (OH) (CO)OH CO(OR) (CO)OR Donor 1.5 1 0.5 0 0.5 0 0 Acceptor 1 1.5 0.5 1 0.8 1.3 0.3 Carbonate Groups Antn fdride

[0135] functional O(CO)O fO)CO(O) CO (O) CO (CO)O(CO)

[0136] Donor 0 0 0 0

[0137] Acceptor 0.6 1.9 1.6 0.2

[0138] Amide Groups

[0139] functional (CO)NH p. CO(NH) p. (CO)NH s. CO(NH) s. (CO) HR t. CO1NR2) t.

[0140] Donor 0.8 0 0.4 0 0 0

[0141] Acceptor 0.6 1.5 0.4 1.5 0.1 1.8 Groups Ether Carbonyl Amine

[0142] functional O eth. CO cet. CO aid. NH p. NH S. NRt.

[0143] Donor 0 0 0 1.5 1.2 0

[0144]

[0145] Acceptor 0.5 0.8 0.6 0.5 1 1

[0146] These donor and acceptor sites are counted for each molecule used according to their HBA (Hydrogen Bond Acceptor) and HBD (Hydrogen Bond Donor).

[0147] For the donor site preferentially used in the mixture, the mono-alcohol is isopropanol or ethanol; the polyalcohol is pentanediol, propanediol, 1,2-propylene glycol, erythritol, butylene glycol, sorbitol or glycerol; the mono-carboxylic acid is lactic or pyruvic acid; the polycarboxylic acid is succinic, sebacic, oxalic, azelaic, tartaric or citric acid; the primary or secondary amine is an amino acid chosen from histidine, lysine, arginine, glycine, sarcosine, alanine and their derivatives; the secondary amide is allantoin or panthenol.

[0148] For the preferred acceptor site in the mixture, the mono-alcohol is isopropanol or ethanol; the polyalcohol is pentanediol, propanediol, 1,2-propylene glycol, erythritol, butylene glycol, sorbitol, or glycerol; the mono-carboxylic acid is lactic or pyruvic acid; the polycarboxylic acid is succinic, sebacic, oxalic, azelaic, tartaric, or citric acid; the mono-ester is ethyl lactate, methyl acetate, ethyl acetate, isobutyl acetate, or butyl acetate; the polyester is glycerol diacetate or triethyl citrate; the mono-ether is dicapyl ether; the polyether is dimethyl isosorbic acid; The primary and secondary amine is an amino acid chosen from histidine, lysine, arginine, glycine, sarcosine, alanine and their derivatives; the secondary amide is allantoin or panthenol; the anhydride is maleic anhydride or citraconic anhydride; the carbonate is glycerol carbonate or dicaprylyl carbonate.

[0149] Ionic compounds are not of interest within the scope of the invention.

[0150] Therefore, within the scope of the invention, it is essential to consider the LogP, which provides information on the hydrophilic or lipophilic nature of a molecule by measuring its affinity for water and octanol. The LogP is equal to the logarithm of the ratio of the concentrations of the substance under study in octanol and in water:

[0151] LogP = Log&^

[0152]

[0153] ^water

[0154] The larger and more positive the value, the more lipophilic the substance will be. Conversely, the more negative the value, the more hydrophilic the molecule will be.

[0155] Since RHB does not take into account the solubility of the assets, we must incorporate LogP into our calculations. To do this, we need to estimate, firstly, the difference between the two species involved, and secondly, the respective signs of the LogP values ​​for each species. To achieve this, we will implement ALogP, which is the absolute value of the difference between the LogP values, multiplied by their respective signs. ALogP is calculated using the following formula:

[0156] LogP = \LogP A — LogP B LogP sign A LogP sign B ')

[0157] According to one embodiment of the invention, insofar as more than two molecules are used in the eutectic mixture according to the invention, the LogPs furthest from said used molecules are taken into account for the calculation of the ALogP.

[0158] As an illustrative example, with 3 molecules used (a, b, c), the minimum and maximum LogP values ​​of said molecules are considered for the calculation:

[0159] ALogP=ABS(MAX(LogPa;LogPb;LogPc)- MIN(LogPa;LogPb;LogPc))*sign(MAX(LogPa;LogPb;LogPc))*sign(MIN(LogPa;LogPb;Lo gPc))

[0160]

[0161] In other words:

[0162] Max=MAX(LogPa;LogPb;LogPc) corresponds to the maximum of the 3 values;

[0163] Min=MIN((LogPa;LogPb;LogPc) corresponds to the minimum of the 3 values; and ALogP=ABS(Max-Min)*sign(Max)*sign(Min).

[0164] The prediction model implemented according to the invention thus makes it possible to obtain the formulation of a NADES involving molecules with high melting points, and results in the production of a solvent with a melting point below -25°C, which allows it to be maintained stable in the liquid or viscous state over a wide temperature range between -25°C and 0°C, or even up to +45°C. The characteristics are therefore as follows:

[0165] - the RHB as defined must be between 0.5 and 1.5, preferably between 0.8 and 1.2, and more preferably between 1; and

[0166] - AlogP as defined above is between -0.5 and 1.6.

[0167] Advantageously, the formulation base according to the invention is stable in liquid and non-crystalline form in that it is homogeneous and does not change phase at temperatures between -25°C and 0°C, and also at room temperature and in particular up to +45°C. The formulation base is stable with no crystallization of any of the products in the mixture at temperatures between -25°C and 0°C, and also at room temperature and in particular up to +45°C.

[0168] By "stable" we mean the ability of a composition to retain its physico-chemical, organoleptic and functional characteristics over time, and in particular when exposed to various storage or handling conditions (temperature, light, agitation, thermal cycles, etc.), and especially in a temperature range between -25°C and +45°C.

[0169] The term "liquid" or "viscous" refers to a physical state of matter in which the formulation exhibits the ability to flow under the influence of gravity, without retaining a fixed shape, and adapts to the shape of its container. At a given temperature below 0°C, in its current state down to -25°C, and under standard atmospheric pressure (1 atm), the formulation does not exhibit a rigid, crystalline, or stable amorphous structure characteristic of the solid state. The formulation is considered liquid if its dynamic viscosity, measured according to a standard protocol such as ISO 3104, is below a threshold allowing observable macroscopic flow, generally less than 10 5 mPa.s (milliPascal-second). This property distinguishes the liquid from a solid or semi-solid state at the temperature considered.

[0170] As an illustrative example, the formulation base is liquid (or viscous) and has a viscosity between 1 mPa.s and 8000 mPa.s at temperatures between -25°C and 0°C, and also at room temperature and especially up to +45°C, preferably between 1 and 1100 mPa.s.

[0171] In the context of this invention, the term "crystallization" refers to the transition of a molecule from an amorphous or dissolved state to an ordered crystalline solid state, generally in the form of particles or needles. This phenomenon is characterized by the formation of a three-dimensional crystalline lattice detectable using analytical techniques such as X-ray powder diffraction (XRPD), polarized microscopy, or differential scanning colorimetry (DSC). In the pharmaceutical and cosmetic fields, in particular, crystallization can compromise the bioavailability, stability, or aesthetic appearance of a formulated product, notably by altering its solubility or texture.

[0172] A stable and "non-crystalline" formulation, as defined in the present invention, refers to a composition in which the molecule(s) capable of crystallizing are maintained in an amorphous or molecularly dispersed state, without the formation of a detectable crystalline network, for a specified period (for example, at least 3 to 6 months) under defined storage conditions, namely at temperatures between -25°C and 0°C, and also at room temperature, particularly up to +45°C. This stability of the non-crystalline state is confirmed by the absence of crystalline peaks on the X-ray diffractogram, the absence of melting on the DSC curve, and / or the absence of visual signs of precipitation or recrystallization in the formulated matrix.

[0173] Advantageously, the formulation base according to the invention is also transparent.

[0174] Another object relates to a composition comprising, in a physiologically acceptable medium, a formulation base according to the invention, said composition being stable in liquid and non-crystalline form, in a temperature range between -25°C and 0°C.

[0175] A physiologically acceptable medium is defined as a medium that is compatible and suitable for use in contact with human and animal cells, particularly with skin, mucous membranes and / or hair, without toxicity, irritation, undue allergic response and the like, and proportionate to a reasonable benefit / risk ratio.

[0176] A physiologically acceptable medium according to the invention may include any excipient known and used in the cosmetic and / or pharmaceutical field, compatible with the composition according to the invention.

[0177] Naturally, a person skilled in the art will take care to choose any compound(s) to be added to the composition according to the invention in such a way that the advantageous properties inherent in the present invention are not, or are not substantially, altered by the proposed addition. Their concentration will also be chosen so as not to impair the advantageous properties of the compositions according to the invention.

[0178] For example, compounds such as stabilizers, pH adjusters, emulsifiers, and / or solubilizing agents can be advantageously used to improve the properties of the solvent mixture used in the compositions. The choice of these compounds is based on their durability, effectiveness, and compatibility with the desired formulation.

[0179] The composition according to the invention is liquid (or viscous) and has a viscosity between 1 mPa.s and 8000 mPa.s at temperatures between -25°C and 0°C, and also at room temperature and in particular up to +45°C. Advantageously, the composition according to the invention is stable in liquid and non-crystalline form in that it is homogeneous and does not change phase at temperatures between -25°C and 0°C, and also at room temperature and in particular up to +45°C.

[0180] According to an advantageous embodiment of the invention, the composition further comprises at least one active ingredient, which is cosmetically or pharmaceutically active. The active compound is advantageously a cosmetically active compound for the care of the skin and hair, for improving well-being or personal or oral hygiene; perfumes are an example of a compound that can improve well-being.

[0181] Preferably, it is in a form suitable for topical or oral application.

[0182] Preferably, the composition is presented in a form suitable for topical application as a serum, gel, lotion, mist, or bi-phase product.

[0183] According to one embodiment of the invention, the composition comprises between 0% and 20% intrinsic water by weight of the total weight of said composition, preferably between 0% and 15%, more preferably between 0% and 10%, even more preferably between 0% and 8%, and even more preferably between 0% and 2%.

[0184] According to a particular embodiment of the invention, the composition does not include extrinsic water.

[0185] By "extrinsic water" we mean additional water intentionally added during the formulation of the composition.

[0186] By "intrinsic water" we mean the water present in the composition in an unintentional way, linked in particular to the hygroscopic nature of the composition, that is to say its natural tendency to absorb and retain the humidity of the ambient air.

[0187] A final object concerns the use of the formulation base according to the invention to maintain a stable and liquid composition, in a temperature range between -25°C and 0°C.

[0188] EXAMPLES

[0189] The present invention will now be illustrated by means of the following examples.

[0190] The molecules used in the formulation basis according to the invention and their acronyms are referenced in Table 1 below.

[0191] Table 1:

[0192] Molecule Code

[0193] 1,2-Hexanediol Hb

[0194] 1,2-Propanediol MPG

[0195] 1,3-Propanediol P

[0196] 1,5-Pentanediol PE

[0197]

[0198] Azelaic acid (Aa) Citric acid (C)

[0199] Glycerol Diacetate GD

[0200] Ferulic acid (FE)

[0201] Erythritol E

[0202] Lactic acid L

[0203] Levulinic acid LA

[0204] Mandelic acid MA

[0205] Glycerol Carbonate GC

[0206] Oxalic acid O

[0207] Succinic acid S

[0208] Tartaric acid T

[0209] Maltose M

[0210] Maleic anhydride ANM

[0211] Sebacic acid SE

[0212] Cetearyl alcohol GE

[0213] Dimethyl Isosorbic D

[0214] Fructose F

[0215] Glycerol G

[0216] Hexanediol H

[0217] Isopropanol 1

[0218] Isopropyl Myristate IM

[0219] Ethyl lactate LE

[0220] Pentylene Glycol PG

[0221] Propanol PRO

[0222] Pentanol PEG

[0223] Sorbitol SO

[0224]

[0225] Triethyl Citrate TO

[0226] The formulation of the mixtures implemented within the framework of the invention involves one or more acceptor and donor sites. Examples of molecules of interest and their respective HBD and HBA values ​​are given in Table 2 below.

[0227] Table 2:

[0228] Molecule Molecular formula HBD HBA

[0229] 1,3-Propanediol CgHgOz 3 2

[0230] 1,5-Pentanediol C5H12 O2 3 2

[0231] 0

[0232] Succinic acid HO. JL

[0233] C4H6O4 OH

[0234] 0 1 3.6

[0235] HO. / 0

[0236] 0 0

[0237] Citric acid CgHgOy

[0238] 2 5.9

[0239] Triethyl Citrate C12 H2O7

[0240]

[0241] H 3 C 0 0 C H 3 0.5 5.3

[0242] Various formulation bases (some of which are according to the invention) have been prepared and are referenced in Table 3 below. For example, the mixture "FZ-A1-P3C1" corresponds to a mixture of 3 moles of 1,3-propandiol per 1 mole of citric acid.

[0243] The preparation of the mixtures is carried out by bringing into contact chemical compounds capable of forming a deep natural eutectic solvent (NADES).

[0244] To ensure reproducibility of results and scalability, a mixture is considered complete after a synthesis time of three days, excluding nighttime periods. When both initial compounds are liquid at room temperature, the final mixture is a homogeneous liquid. When one of the two compounds is solid at room temperature, the mixture is a liquid that may exhibit characteristic "honey-in-water" streaks.

[0245] Preparations are made in quantities ranging from 10 g to 600 g, depending on experimental needs and the availability of raw materials. The quantity prepared does not affect the preparation method.

[0246] Depending on the circumstances, the preparation is carried out either cold or hot.

[0247] In the case of a cold preparation, the compounds are introduced into a beaker covered with parafilm and held in place by a clamp.

[0248] The mixture is agitated using a motor equipped with a marine propeller.

[0249] Agitation is carried out at room temperature, on average between 20°C and 23°C, during the synthesis time.

[0250] In the case of hot preparation, heating is intended to accelerate the interaction of chemical species in order to promote the formation of hydrogen bonds, while preventing chemical reactions between molecules. For this purpose, the temperature is maintained below 90°C.

[0251] When using low-volatility compounds, they are placed in a beaker containing a magnetic stir bar, positioned on a temperature-controlled stirring plate and held in place by a clamp. When using volatile solvents, the compounds and the magnetic stir bar are placed in a two-necked round-bottom flask. The entire assembly is then placed under reflux.

[0252] The heating is initially set at 50°C for 15 minutes to allow for initial homogenization and to control the temperature rise. The temperature is then increased to 60°C and maintained for a further 10 minutes.

[0253] Following this step, the reaction temperature is adjusted according to the energy required for NADES formation. When the energy requirement is higher, the temperature is increased to 80°C and then maintained at this value under stirring for a total reaction time of approximately 72 hours. When the energy requirement is lower, the mixture is maintained under stirring at 60°C for a similar reaction time. The RHB and ALogP values ​​assigned according to the invention for each test are specifically indicated.

[0254] Table 3:

[0255] RHB ALogP code RHB ALogP code FZ-A1-P3C1 0.924 0.7 FZ-A1-GD1S1 0.321 0.3 FZ-A1-P6C1 1.117 0.7 FZ-A1 -PE2S1 0.921 0.5 FZ-A1-F1S6 0.391 2.2 FZ-A1-PE3S1 1.042 0.5 FZ-A1-P1S1T1 0.574 1.3 FZ-A1-E1S2 0.574 1.7

[0256] 0.704 1.3 FZ-A1 - 0.952 1.2 FZ-A1-P2S1T1 P1G2S1

[0257] FZ-A1- 0.991 1.2 1.218 0.4 P2G1S1 FZ-A1-P6S1

[0258] 0.421 0.4 FZ-A1 - 1.085 1.3 FZ-A1-GC1T1 P12S1T1

[0259] FZ-A1- 0.697 2.8 1.121 0.4 GD1SO1 FZ-A1-P4S1

[0260] FZ-A1-M1S6 0.440 4.1 FZ-A1-P8S1 1.276 0.4

[0261] 0.294 -2 FZ-A1- 0.902 2.1 FZ-A1-T1TC1 P3SO3T1

[0262] FZ-A1-C1G1 0.638 0.1 FZ-A1 -PE3T1 0.952 1.8 FZ-A1-C1G2 0.775 0.1 FZ-A1-PE3O1 1.042 0.2

[0263] 0.854 0.1 FZ-A1- 1.218 0.9 FZ-A1-C1G3 PE3O1 P3

[0264] FZ-A1-GC1S1 0.325 0.9 FZ-A1-P6L1 1.275 0.3

[0265] 0.690 2.5 FZ-A1- 0.723 -7.5 FZ-A1 -SOI SI MPG10IM6

[0266] 0.765 2.5 FZ-A1- 0.953 -7.5 FZ-A1-SO2S1 MPG26IM2

[0267] FZ-A1-P1SE1 0.714 -3.1

[0268] FZ-A1 -P2SE1 0.921 -3.1

[0269] 1.042 -3.1

[0270]

[0271] FZ-A1 -P3SE1

[0272] These same formulation bases (some of which are according to the invention) were tested to demonstrate their stability at different temperatures. The samples were placed at room temperature for at least 30 days, in an oven at +45°C for at least 30 days, and in a freezer at -20°C for at least 24 hours.

[0273] The stability results obtained are listed in Table 4 below. Table 4:

[0274] Stable and Stable and Stable and Stable and Liquid-to-liquid code to Liquid-to-liquid code at TA and +45°C -20°C TA and +45°C -20°C

[0275]

[0276] FZ-A1 -P3C1 YES YES FZ-A1-GD1S1 NO NO

[0277] FZ-A1 -P6C1 YES YES FZ-A1 -PE2S1 YES NO

[0278] FZ-A1-F1S6 NO NO FZ-A1 -PE3S1 YES YES

[0279] FZ-A1 -P1S1T1 YES YES FZ-A1 -E1S2 NO NO

[0280] FZ-A1 -P2S1T1 YES YES FZ-A1 -P1G2S1 YES YES

[0281] FZ-A1 -P2G1S1 YES YES FZ-A1 -P6S1 YES YES

[0282] FZ-A1-GC1T1 NO NO FZ-A1-P12S1T1 YES YES

[0283] FZ-A1- GD1SO1 NO NO FZ-A1 -P4S1 YES YES

[0284] FZ-A1-M1S6 NO NO FZ-A1 -P8S1 YES YES

[0285] FZ-A1-T1TC1 NO NO FZ-A1 -P3SO3T1 NO NO

[0286] FZ-A1 -C1G1 YES YES FZ-A1 -PE3T1 YES NO

[0287] FZ-A1 -C1G2 YES YES FZ-A1 -PE3O1 YES YES

[0288] FZ-A1 - FZ-A1 -C1G3 YES YES PE3O1 P3 YES YES

[0289] FZ-A1-GC1S1 NO NO FZ-A1-P6L1 YES YES

[0290] FZ-A1- FZ-A1 -SELF IF NO NO MPG10IM6 NO NO

[0291] FZ-A1- FZ-A1-SO2S1 NO NO MPG26IM2 NO NO

[0292] FZ-A1-P1SE1 NO NO

[0293] FZ-A1-P2SE1 NO NO

[0294]

[0295] FZ-A1 -P3SE1 NO NO

[0296] These same formulation bases (some of which are according to the invention) have been tested in such a way as to highlight their stability as a function of the polarity of the molecules of the eutectic mixture.

[0297] The stability results obtained are listed in Table 5 below. Table 5:

[0298] Solvent Code 1 LogP 1 Solvent Code 2 LogP 2 Stable and ALogP RHB

[0299] Liquid at -20°C FZ-A1-PE3O1 1.5- -0.1 Acid -0.3 0.2 1.04 YES Pentanediol Oxalic Acid

[0300] FZ-A1-PE3S1 1.5- -0.1 Acid -0.6 0.5 1.04 YES Pentanediol Succinic Acid

[0301] FZ-A1 - 1.5- -0.1 Acid -0.3 0.9 1.08 YES PE3O1P3 Oxalic Pentanediol

[0302] FZ-A1 - MPG -0.3 Anhydride -0.1 0.2 0.82 YES MPG6ANM1 maleic

[0303] FZ-A1-PE6D1 1.5- -0.1 Dimethyl -0.6 0.5 1.29 YES Pentanediol Isosorbic

[0304] FZ-A1-PE6S1 1.5- -0.1 Acid -0.6 0.5 1.22 YES

[0305]

[0306] Pentanediol Succinic FZ-A1 - MPG -0.3 Acid -0.6 1.6 0.89 YES MPG12S1T1 Succinic

[0307] FZ-A1 - MPG -0.3 Acid -0.5 0.2 YES MPG2LA1 levulinic 0.72

[0308] FZ-A1 - MPG -0.3 Acid -0.7 0.4 YES MPG4L1 Lactic 0.86

[0309] FZ-A1 - 1.5- -0.1 Triethyl 0.1 -0.2 YES PE12TC1 Pentanediol Citrate 1.25

[0310] FZ-A1-I6D1 Isopropanol 0.3 Dimethyl -0.6 -0.9 NON Isosorbic 0.55

[0311] FZ-A1 - MPG -0.3 Lactate 0.2 -0.5 YES MPG6LE1 ethyl 0.88

[0312] FZ-A1-PE6LE1 1.5- -0.1 Lactate 0.2 -0.3 YES Ethyl Pentanediol 1.26

[0313] FZ-A1 - Pentylene 0.2 Anhydride -0.1 -0.3 YES PG6ANM1 maleic glycol 0.82

[0314] FZ-A1-PG6S1 Pentylene 0.2 Acid -0.6 -0.8 Non-glycol Succinic Acid 0.86

[0315] FZ-A1- MPG -0.3 Acid 1.6 -1.9 NON MPG6A1 azelaic 0.86

[0316] FZ-A1- Propanol 0.3 Acid -0.6 -0.9 NON PRO6S1 succinique 1.04

[0317] FZ-A1-PE5A1 1.5- -0.1 Acid 1.6 -1.7 NON Pentanediol azélaïque 1.18

[0318] FZ-A1- 1.5- -0.1 Acidic 1.6 -1.9 1.02 NON PE5A1MPG1 Pentanediol azélaïque

[0319] FZ-A1-H1LA1 Hexanediol 1,4 Acide -0,5 NON levulinique -0,80 0,76

[0320] FZ-A1- Pentanol 1.6 Acid -0.6 NON PEO6S1 succinique -2.20 1.04

[0321] FZ-A1- Hexanediol 1.4 Acid 0.6 NON H3MA1 mandélique 0.30 1.13

[0322] FZ-A1-H3FE1 Hexanediol 1.4 Acidic 1.5 NON ferrulic 1.20 1.14

[0323] FZ-A1-H4A1 Hexanediol 1,4 Acid 1,6 NON azélaïque 1,30 1,12

[0324] FZ-A1-H6A1 Hexanediol 1,4 Acid 1,6 NON azélaïque 1,30 1,22

[0325] FZ-A1- Hexanediol 1.4 Acid 0.6 NON H4MA1 mandélique 0.30 1.19

[0326] FZ-A1-H5A1 Hexanediol 1,4 Acid 1,6 NON azélaïque 1,30 1,18

[0327] FZ-A1-H4FE1 Hexanediol 1,4 Acidic 1,5 NON ferrulic 1,20 1,20

[0328] FZ-A1- Hexanediol 1,4 Acid 1,6 1,3 1,25 NON H12A1MA1 azélaïque

[0329] FZ-A1-H3A1 Hexanediol 1,4 Acid 1,6 0,2 NON azélaïque 1,04

[0330] FZ-Al-Hb6Al 1.2- 0.7 Acidic 1.6 0.9 NOT

[0331]

[0332] Hexanediol azélaïque 0,86FZ-A1- 1,2- 0,7 Acid 0,6 0,1 NON Hb4MAl Hexanediol mandélique 0,86

[0333] FZ-A1- 1,2- 0,7 Acid 0,6 0,1 NON Hb6MAl Hexanediol mandélique 0,90

[0334] FZ-A1- 1.2- 0.7 Acid 1.5 0.8 NON Hb4FEl Hexanediol férulique 0.86

[0335] FZ-A1-CE4A2 Cetearyl 11.49 Acid 1.6 8.48 NON alcohol azélaïque 0.71 FZ-A1- Cetearyl 11.49 Isopropyl 7.2 2.88 NON CE2IM1 alcohol Myristate 0.83

[0336] FZ-A1-CE2A1 Cetearyl 11.49 Acid 1.6 8.48 NOT

[0337]

[0338] azelaic alcohol 0.71

[0339] According to the results thus obtained, it appears that only the formulation bases corresponding to the formula according to the invention (compounds in bold in Tables 4 and 5 above) with an RHB between 0.50 and 1.50, and an AlogP between -0.5 and 1.6 are stable and liquid at a temperature of -20°C.

[0340] Table 5 also shows that only the set of formulation bases comprising at least one polar molecule (taken in combination with another polar molecule or a nonpolar molecule), with an RHB between 0.50 and 1.50 and an AlogP between -0.5 and 1.6, are stable.

[0341] Formulation bases consisting solely of nonpolar molecules (logP>0) do not exhibit the desired stability, including formulation bases with an RHB between 0.50 and 1.50 and an AlogP between -0.5 and 1.6.

[0342] Advantageously, these same formulation bases according to the invention are also stable and liquid at room temperature and in particular up to +45°C.

Claims

DEMANDS 1. Formulation basis for a composition intended to be stable in liquid and non-crystalline form within a temperature range of -25°C to 0°C, comprising a eutectic mixture of at least two molecules containing a hydrogen bond donor (HBD) site and / or a hydrogen bond acceptor (HBA) site, wherein: - said donor site is obtained from at least one molecule chosen from a mono-alcohol, a polyol, a monocarboxylic acid, a polycarboxylic acid, a primary or secondary amine, a primary or secondary amide, taken alone or in combination, - said acceptor site is obtained from at least one molecule chosen from a mono-alcohol, a polyol, a monocarboxylic acid, a polycarboxylic acid, a mono-ester, a polyester, a mono-ether, a polyether, a primary or secondary amine, a primary or secondary amide, an anhydride, a carbonate, taken alone or in combination, and in which the hydrogen bond ratio (HBR) is obtained by dividing the total number of donor sites by the total number of acceptor sites, weighted by the molar ratio of the mixture according to the formula: Ei ni. HB Di RHB ^ni.HBAi with i = a given molecule of the mixture, one or more molecules being able to be considered, n = amount of substance (in moles), HBD = unit value of the donor site(s) for a molecule of the mixture, and HBA = unit value of the acceptor site(s) for a molecule of the mixture, and in which the LogP of the molecule is measured according to its affinity with water and octanol according to the formula: LogP = Logeai--) ^water with C = concentration of the molecule, P = partition coefficient, and in which the difference in LogP of the molecules in the mixture is calculated according to the formula: LogP = \LogPA — LogP B LogP sign A LogP sign B ') with A = a molecule, and B = another molecule, different from A, characterized in that the RHB is between 0.50 and 1.50, the AlogP is between -0.5 and 1.6, at least one molecule of the eutectic mixture being a polar molecule whose logP is strictly negative, and The unit values ​​of the donor sites (HBD) and the acceptor sites (HBA) are determined as follows: Functional Groups Alcohols Carboxylic Acid Ester OH p. OH s. OH t. CO (OH) (CO) OH CO(OR) (CO)OR Donor 1.5 1 0.5 0 0.5 0 0 Acceptor 1 1.5 0.5 1 0.8 1.3 0.3 Carbonate Groups Anhydride functional O(CO)O (O) CO (O) CO (O j CO (CO)O(CO) Donor 0 0 0 0 Acceptor 0.6 1.9 1.6 0.2 Amide Groups functional (CO)NH p. CO(NH) p. (CO)NH s. CO(NH) S. (CO)NR t. CO(NR2) t. Donor 0.8 0 0.4 0 0 0 Acceptor 0.6 1.5 0.4 1.5 0.1 1.8 Groups Ether Carbonyl Amine functional O eth. CO cet. CO aid. NH p. NH S. NR t. Donor 0 0 0 1.5 1.2 0 Acceptor 0.5 0.8 0.6 0.5 1 1 2. Formulation basis according to claim 1, characterized in that the RHB is between 0.80 and 1.2, preferably 1.

3. Formulation base according to any one of the preceding claims, characterized in that for the donor site, the mono-alcohol is isopropanol or ethanol; the polyalcohol is pentanediol, propanediol, 1,2-propylene glycol, erythritol, butylene glycol, sorbitol or glycerol; the mono-carboxylic acid is lactic or pyruvic acid; the polycarboxylic acid is succinic, sebacic, oxalic, azelaic, tartaric or citric acid; the primary or secondary amine is an amino acid selected from histidine, lysine, arginine, glycine, sarcosine, alanine and their derivatives; the secondary amide is allantoin or panthenol.

4. Formulation base according to any one of the preceding claims, characterized in that, for the acceptor site, the mono-alcohol is isopropanol or ethanol; the polyalcohol is pentanediol, propanediol, 1,2-propylene glycol, erythritol, butylene glycol, sorbitol, or glycerol; the mono-carboxylic acid is lactic or pyruvic acid; the polycarboxylic acid is succinic, sebacic, oxalic, azelaic, tartaric, or citric acid; the mono-ester is ethyl lactate, methyl acetate, ethyl acetate, isobutyl acetate, or butyl acetate; the polyester is glycerol diacetate or triethyl citrate; the mono-ether is dicapyl ether; the polyether is dimethyl isosorbic acid; the primary or secondary amine is an amino acid chosen from histidine, lysine, arginine, glycine, sarcosine, alanine and their derivatives; the secondary amide is allantoin or panthenol; the anhydride is maleic anhydride or citraconic anhydride;The carbonate is glycerol carbonate or dicaprylyl carbonate.

5. Composition comprising, in a physiologically acceptable medium, a formulation base according to any one of the preceding claims, said composition being stable in liquid and non-crystalline form, in a temperature range between -25°C and 0°C.

6. Composition according to claim 5, characterized in that it has a viscosity between 1 mPa.s and 8000 mPa.s.

7. Composition according to claim 5 or 6, characterized in that it further comprises at least one active ingredient.

8. Composition according to any one of claims 5 to 7, characterized in that it is in a form suitable for topical or oral application.

9. Composition according to claim 8, characterized in that it is in the form of a serum, gel, lotion, mist, biphasic.

10. Composition according to any one of claims 5 to 9, characterized in that it comprises between 0% and 15% intrinsic water by weight of the total weight of said composition, preferably between 0% and 8%, and more preferably between 0% and 2%.

11. Composition according to any one of claims 5 to 10, characterized in that it does not comprise extrinsic water.

12. Use of the formulation base according to any one of claims 1 to 4 to maintain a stable and liquid composition, in a temperature range between -25°C and 0°C.

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