Stabilized retinoid-based eutectics and uses thereof

Abstract

The present invention relates to eutectics wherein one of the components is a retinoid and the other is a hydrogen bond acceptor or a hydrogen bond donor. In such eutectics the retinoid is stabilized against its degradation caused by temperature, pH and / or exposure to light.

Description

[0001] STABILIZED RETINOID-BASED EUTECTICS AND USES THEREOF Claim of Priority This patent application claims the benefit of priority to FR Application Serial No.2411355, filed October 18, 2024, which is incorporated by reference herein in its entirety. Technical field of the invention The present invention is in the field of eutectics wherein one of the components is a retinoid which is able to form hydrogen bonds with a hydrogen bond acceptor or a hydrogen bond donor. In such eutectics the retinoid is stabilized against its degradation caused by temperature, pH and / or exposure to light. Background Retinoids, a broad family of compounds derived from vitamin A, are characterized by a cyclohexene ring, a conjugated tetraene side chain, and a polar functional group. These compounds are classified into three generations based on their molecular structure and receptor selectivity. Retinoids exert their biological effects primarily by binding to nuclear receptors, specifically retinoic acid receptors (RARs) and retinoid X receptors (RXRs). This binding modulates gene expression, influencing processes such as cell proliferation, differentiation, and apoptosis. The metabolism of retinoids involves a series of oxidation steps that convert retinol to retinaldehyde and subsequently to retinoic acid (RA), with further metabolism mediated by cytochrome P450 enzymes. Among the retinoids, retinol is particularly significant due to its pivotal role in various physiological and biological processes, notably in maintaining skin health. Of the retinoids, vitamin A, crucial for a wide range of biological functions, is obtained through diet either as preformed vitamin A from animal sources or as provitamin A carotenoids from plants. Following ingestion, vitamin A undergoes metabolic conversion in the intestine and is predominantly stored in the liver. Retinol, the alcohol form of vitamin A, is essential for vision, cell differentiation, reproduction, and immune function. Its active metabolite, retinoic acid, regulates gene transcription by binding to nuclear receptors. Furthermore, vitamin A is indispensable for mammary gland development, lactation, and skeletal homeostasis. It also plays a critical role in brain function, affecting neuroplasticity and biological rhythms. Specific proteins are involved in the absorption and transport of vitamin A and carotenoids across the enterocyte and to peripheral tissues, including the retina. Recent research has expanded our understanding of retinoids, particularly their potential in addressing metabolic diseases such as obesity and diabetes, due to their role in adipogenesis and pancreatic β-cell function. While vitamin A supplementation may help reduce cancer incidence in deficient populations, its effectiveness in cancer prevention among those with adequate intake remains limited. Vitamin A deficiency can lead to a range of health problems, and treatment typically involves dietary adjustments or supplementation. Natural retinoids, including retinol, retinal, and retinoic acid, are essential for various physiological functions, while synthetic analogs have been developed to enhance their therapeutic applications. These compounds have demonstrated significant potential in several fields, such as cancer treatment, dermatology, neurological disorders like Alzheimer’s disease, and immune regulation. The ability of retinoids to modulate gene expression and influence cellular functions has led to their successful use in treating conditions like acute promyelocytic leukemia and a variety of skin disorders. In the human body, particularly within the skin, retinol is found in notable concentrations in both the dermis and epidermis. Within the epidermis, retinol and its derivatives, such as retinyl propionate and retinyl palmitate, are present in greater concentrations compared to other tissues. These compounds have been shown to improve skin appearance by increasing epidermal thickness, stimulating collagen synthesis, enhancing elastin production, inhibiting collagen degradation, and maintaining water-ion balance. These effects help counteract the natural thinning and wrinkling of the skin associated with aging. Additionally, retinol promotes skin cell renewal by influencing keratinocyte differentiation and proliferation. It also induces elastin gene expression and fiber formation in human dermal fibroblasts, thereby contributing to improved skin integrity and appearance. Beyond its structural benefits, the topical application of retinol has become a cornerstone in dermatology and cosmetology. It is widely used to treat various skin-related conditions, including hyperpigmentation, where it helps regulate pigmentation, and inflammatory skin conditions such as acne, psoriasis, and dyschromia. Retinol is also effective in addressing signs of photoaging, such as wrinkles and age spots, with concentrations of 0.3% and 0.5% showing significant benefits. Furthermore, retinol’s antioxidant properties protect the skin from damage caused by free radicals, contributing to overall skin health and vitality. The global market for cosmetic retinol, valued at USD 22 million in 2021, is projected to expand to USD 36.4 million by 2031, reflecting a compound annual growth rate (CAGR) of 5.5%. Despite this anticipated growth and the widespread use of retinoid-based products, the extensive use of retinol in both cosmetic and clinical settings faces significant limitations. These limitations arise from retinol's instability, which is affected by the formulation medium, pH, as well as its sensitivity to light, heat, and oxidation. Additionally, the risk of skin irritation, known as the “retinoid reaction,” further hinders its use. Researchers have explored various strategies to enhance retinol's chemical stability and reduce skin irritation, including the development of synthetic retinoid derivatives, encapsulation techniques like lipid nanocarriers and cationic polymeric nanoparticles, which also improve skin penetration. Additionally, Jojoba oil (Simmondsia chinensis) has been found to enhance retinol absorption, while microbial production using Yarrowia lipolytica shows promise for bio-based retinol synthesis. Traditionally, retinoids have been stabilized with additives such as antioxidants (e.g., butylated hydroxytoluene and butylated hydroxyanisole) and metal chelators like ethylenediaminetetraacetic acid (EDTA) and its salts to prevent thermal isomerization and degradation. However, concerns over the environmental impact of BHT and EDTA have prompted efforts to develop eco-friendly alternatives that preserve retinoid stability without compromising environmental safety. In this context, deep eutectic solvents (DES) have emerged as eco-friendly alternatives to traditional organic solvents and ionic liquids (ILs) in sustainable chemistry. Composed of hydrogen bond donors and acceptors, DES significantly lower the melting point compared to their individual components. When obtainable from natural sources, they are known as natural deep eutectic solvents (NaDES). These mixtures of compounds possess unique properties— such as low volatility, flammability, and toxicity—along with physicochemical properties that can be tailored by adjusting the type and molar ratio of constituents. Their biodegradability, ease of preparation, and high solubilizing power make NaDES ideal for various applications, including extraction, separation, material synthesis, and organic reactions. Given these advantages, NaDES are increasingly recognized as green alternatives to conventional solvents, particularly in the synthesis of active pharmaceutical ingredients (APIs) and in systems designed for controlled drug release (API-NaDES). Deep eutectic solvents (DES) are a subclass of ionic liquid (IL). A DES is a eutectic mixture of at least two constituent components, generally interacting through hydrogen bonding, that have a lower melting point than that of each component when combined at the proper molar ratio. The components of these clear liquid mixtures are hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs). NaDES and API-NaDES are emerging as innovative solutions in pharmaceutical applications, particularly in enhancing drug delivery and bioavailability. NaDES are effective in stabilizing natural compounds and improving the extraction efficiency of bioactive substances, with properties like viscosity, density, and polarity that can be tailored by adjusting component ratio and water content. In parallel, API-NaDES combine APIs with other compounds to create liquid mixtures at room temperature, significantly enhancing API solubility, permeability, and therapeutic efficiency. However, selecting the optimal counterpart for solubilization of active cosmetic and pharmaceutical agents remains challenging, especially when considering industrial-scale applications that are often constrained by concerns related to toxicity, environmental impact, and cost. While NaDES excel at dissolving polar or hydrophilic solutes, they are generally less effective for non-polar or hydrophobic compounds like retinol. Summary of the invention This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify required or essential features of the claimed subject matter. Nor is this summary intended to be used to limit the scope of the claimed subject matter. The present inventors have surprisingly found that certain retinoids, and retinol in particular, can be stabilized and their solubility in cosmetically suitable bases improved by forming eutectics in association with a counterpart which is a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA). In particular the present inventors have surprisingly found that certain retinoids, and retinol in particular, can be stabilized and their solubility in cosmetically suitable bases improved by forming binary eutectic mixtures with selected counterparts. In one embodiment the counterpart is predominantly hydrophobic, wherein hydrophobicity can be measured by the LogP or alternatively via the Hansen Solubility Parameter. An object of the present invention are therefore stabilized retinoid-based eutectics comprising certain retinoids, and retinol in particular, and a counterpart which is a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA). A further object of the present invention are cosmetic or pharmaceutic compositions comprising a retinoid-based eutectic in a cosmetically or pharmaceutically compatible medium. A further object of the present invention is the use of a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) to stabilize compositions comprising certain retinoids, and retinol in particular, such that at least 31% of the retinoid used to prepare the composition is still present after storage for at least 12 weeks at 25°C. A further object of the present invention is the use of a stabilized retinoid-based eutectic according to the invention to activate expression of genes related to retinoids. Genes related to retinoids include nuclear receptors (RAR-α, RAR-β, RAR-γ, RXR-α, RXR-β, RXR-γ), metabolic enzymes (ALDH, RDH, CYP26A1), binding proteins (CRBP, CRABP), transporters (RBP4, TTR), and downstream target genes such as the Hox genes and genes involved in neurodevelopment, like dopamine and serotonin receptors. A further object of the present invention is the use of a stabilized retinoid-based eutectic according to the invention to improve the aesthetic appearance of the skin. Both the foregoing summary and the following detailed description provide examples and are explanatory only. Accordingly, the foregoing summary and the following detailed description should not be considered to be restrictive. Further, features or variations may be provided in addition to those set forth herein. For example, certain aspects may be directed to various feature combinations and sub-combinations described in the detailed description. Definitions Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls. The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range and includes the exact stated value or range. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that about 0 wt% to about 5 wt% of the composition is the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than or equal to about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “retinoid-based eutectic” means a homogeneous blend of two or more substances, one of which is a retinoid, that, at a specific ratio, melts and solidifies at a single, lower temperature than any of the individual components. When percentages of ingredients in compositions are indicated, the standard error applies. For example, 3.0% is to be interpreted as 2.9% to 3.1% The term “comprises” and variations thereof is to be interpreted as meaning both “includes”, “substantially consists of” and “consists of”, and variations thereof. When an embodiment is herein described which further specifies one or more features of the present invention it is intended that this embodiment can be combined with another embodiment further specifying one or more other features of the present invention into a further embodiment specifying those features combined even when such combined embodiment is not explicitly described herein. When the quantity of an ingredient of a composition is indicated as % or wt% it is intended over the total weight of the composition, unless otherwise indicated. If any given chemical entity is generally known in the art to belong to two or more cosmetic functional classes (is for example known to be both a film former and an emollient) and those functional classes are part of the definition of the claimed subject matter, that chemical entity may be present only once in any embodiment of the claimed invention, i.e. it can belong to only one of those two or more functional classes. Detailed description of the invention The present inventors have surprisingly found that retinoids, and in particular retinol, can be stabilized and its solubility in cosmetically suitable bases improved by forming retinoid-based eutectics in the presence of a counterpart which is a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA). In particular the present inventors have surprisingly found that retinoids, and in particular retinol can be stabilized and their solubility in cosmetically suitable bases improved by forming retinoid-based eutectic with selected counterparts. An object of the present invention are therefore stabilized retinoid-based eutectics comprising a retinoid, and in particular retinol, and a counterpart which is a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA). The retinoid according to the invention is any retinoid that is able to form hydrogen bonds with hydrogen bond donors (HBD) or hydrogen bond acceptors (HBA), such as retinol and retinaldehyde. Because of the high level of conjugation of its OH group, retinoids according to the invention can act as both a hydrogen bond donor and acceptor, interacting with both types of molecules depending on the chemical context. For example, retinol's hydroxyl group can donate a hydrogen bond to an acceptor like an oxygen atom, and it can also accept a hydrogen bond from another donor group. In biological systems, retinol binds to retinol-binding proteins (RBPs) which contain both donor and acceptor sites to stabilize and transport retinol. Correspondingly, retinoid-based eutectics according to the invention can in principle be formed with both hydrogen bond donor (HBD) counterparts and hydrogen bond acceptor (HBA) counterparts. Typical Hydrogen-bond acceptors (HBAs) are Choline / choline chloride (ChCl), Betaine (trimethylglycine), Amino acids with zwitterionic / amide character like proline. Typical Hydrogen-bond donors (HBDs) are sugars and oligosaccharides like glucose, fructose, sucrose, xylose and maltose; polyols / sugar alcohols like glycerol, sorbitol, xylitol and mannitol; organic acids like citric acid, malic acid, tartaric acid, lactic acid and oxalic acid; amino acids & small amides like proline, glycine, alanine and urea; other natural molecules used as HBDs or co-components like phenolic metabolites, terpenoids and fatty acids. Representative NaDES examples (common binary / ternary mixtures) are: - ChCl : Glycerol (1:2) - ChCl : Citric acid (1:1 or 1:2) - Malic acid : Glucose (1:1) or Malic acid : Glucose : Glycerol (ternary) - Proline : Malic acid (1:1) - Betaine : Citric acid (1:1) A key factor in determining the stability of an eutectic is the molar ratios between the components. Common ratios are 1:1, 1:2, 1:3 (HBA:HBD), but optimal ratio depends on the specific pair and targeted melting point / viscosity. Because of this, the optimal ratio between the components of a given binary or ternary eutectic can only be determined experimentally on a case-by-case basis. A number of workflows are available to determine the optimal ratio between the component of a eutectic, depending on whether the goal is “thermodynamic optimum” (true eutectic) or “application optimum” (best viscosity / solvation / extraction, etc.). Examples are: 1. Find the true eutectic by measuring the solid–liquid equilibrium (SLE) 2. Map a binary (or ternary, if water counts as a component) phase diagram by measuring melting / freezing points vs composition—typically with DSC or simple melting-point determinations. The eutectic minimum gives the thermodynamic “optimal” molar ratio. 3. Optimize for a target property (“application optimum”) 4. Choose a response (for example the solubility of a target solute) and screen compositions; the composition giving the best response is taken as the operational “optimum” for that use case. 5. Use quantum-chemical / thermodynamic tools to pre-screen component pairs and likely ratios by predicting activity coefficients and miscibility gaps; these guide which compositions to measure Since small amounts of water are often tolerated and can dramatically lower viscosity and change solvating properties, it can be accounted for as part of the eutectic blend. In one embodiment the counterpart is predominantly hydrophobic, wherein hydrophobicity can be estimated by the LogP or alternatively via the Hansen Solubility Parameter. According to the present invention the hydrophobicity of the counterpart must be in the range 2≤LogP≤8, preferably 2.5≤LogP≤7.7. According to the present invention the retinoid-based eutectics increase in a statistically significant (p <0.05) way the expression of markers indicative of retinoids behavior in skin cells like RAR-a, RAR-β, RAR-g, CRABP-I and CRABP-II. According to a particular embodiment of the invention the increase is between +46% and +5750% versus the non- treated sample (Table 3), including all values therebetween. A further object of the present invention are cosmetic or pharmaceutic compositions comprising a stabilized retinoid-based eutectic in a cosmetically or pharmaceutically compatible medium. The compositions according to the invention comprise typically between 0.05% and 2% based on the total weight of the composition, preferably between 0.1% and 1%. In one embodiment the compositions are used for improving the aesthetic appearance of the skin. The term “improving aesthetic appearance” as used herein means be an improvement of any attribute or characteristic of skin, including without limitation: reducing dermatological signs of chronological aging, photo-aging, hormonal aging, and / or actinic aging; preventing and / or reducing the appearance of lines and / or wrinkles; reducing the noticeability of facial lines and wrinkles, facial wrinkles on the cheeks, forehead, perpendicular wrinkles between the eyes, horizontal wrinkles above the eyes, and around the mouth, marionette lines, and particularly deep wrinkles or creases; preventing, reducing, and / or diminishing the appearance and / or depth of lines and / or wrinkles; improving the appearance of suborbital lines and / or periorbital lines; reducing the appearance of crow's feet; rejuvenating and / or revitalizing skin, particularly aging skin; reducing skin fragility; preventing and / or reversing of loss of glycosaminoglycans and / or collagen; ameliorating the effects of estrogen imbalance; preventing skin atrophy; preventing, reducing, and / or treating hyperpigmentation; minimizing skin discoloration; improving skin tone, radiance, clarity and / or tautness; preventing, reducing, and / or ameliorating skin sagging; improving skin firmness, plumpness, suppleness and / or softness; improving procollagen and / or collagen production; improving skin texture and / or promoting re-texturization; improving skin barrier repair and / or function; improving the appearance of skin contours; restoring skin luster and / or brightness; minimizing dermatological signs of fatigue and / or stress; resisting environmental stress; replenishing ingredients in the skin decreased by aging and / or menopause; improving communication among skin cells; increasing cell proliferation and / or multiplication; increasing skin cell metabolism decreased by aging and / or menopause; retarding cellular aging; improving skin moisturization; enhancing skin thickness; increasing skin elasticity and / or resiliency; enhancing exfoliation; improving microcirculation; decreasing and / or preventing cellulite formation; and any combinations thereof. The cosmetic composition according to the present invention can be in the form of a topical formulation, in particular in the form of an oil-in-water emulsion, a water-in-oil emulsion, a multiple emulsion (Water / Oil / Water or Oil / Water / Oil), a microemulsion, a nanoemulsion, a solution, a suspension, a hydrodispersion, a gel, an ointment, a paste, an aerosol foam, a spray, an aqueous gel, a powder, a foundation, a transdermal patch, a cream or a mask. The composition can also be suitable for enteral or parenteral administration, in particular intradermal or subcutaneous administration. The topical compositions according to the invention may comprise at least one further ingredient commonly found in topical cosmetic and / or medical (e.g. dermatological) compositions chosen from water, oils, which may be chosen in particular from volatile and / or non-volatile, linear or cyclic silicone oils, waxes (such as ozokerite, polyethylene wax, beeswax or carnauba wax), silicone elastomers, nonionic, anionic, cationic and / or amphoteric surfactants, co-surfactant (such as linear fatty alcohols), thickeners, gelling agents, humectants (such as polyols like glycerin), colorants, preservatives, fillers, tensors, sequestrants, perfumes, and mixtures hereof. These compositions can be in particular in the form of oil-in-water emulsions, water-in-oil emulsions, multiple emulsions (Water / Oil / Water or Oil / Water / Oil) which can optionally be microemulsions or nanoemulsions, or in the form of solutions, suspensions, hydrodispersions, gels, ointments, pastes, aerosol foams or sprays, aqueous gels, powders, or foundations or transdermal patches. They can be more or less fluid and have the appearance of creams, emulsions, gels, masks or any other aspect of healthy skin care cosmetics. The person skilled in the art is aware of the procedures, ingredients and forms of common use in the preparation of dermal formulations. A “gel” is a colloid in which the dispersed phase has combined with the continuous phase to produce a semisolid material, such as jelly. An “oil” is a composition containing at least 95% wt of a lipophilic substance. Examples of lipophilic substances include but are not limited to naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof. A “continuous phase” refers to the liquid in which solids are suspended or droplets of another liquid are dispersed and is sometimes called the external phase. This also refers to the fluid phase of a colloid within which solid or fluid particles are distributed. If the continuous phase is water (or another hydrophilic solvent), water-soluble or hydrophilic drugs will dissolve in the continuous phase (as opposed to being dispersed). In a multiphase formulation (e.g., an emulsion), the discreet phase is suspended or dispersed in the continuous phase. Excipients for topical administration may include anti-microbial compounds, e.g. parabens, antioxidants, e.g. sodium ascorbyl acetate and alpha-tocopherol, stabilizers, e.g. sorbitol, and / or emulsifying agents to produce a stable emulsion with both a hydrophilic and a hydrophobic phase. “Diluents” may be included in the formulations to dissolve, disperse or otherwise incorporate the carrier. Examples of diluents include, but are not limited to, water, buffered aqueous solutions, organic hydrophilic diluents, such as monovalent alcohols, and low molecular weight glycols and polyols (e.g. propylene glycol, polypropylene glycol, glycerol, butylene glycol). Appropriate excipients are selected based on the type of formulation. Standard excipients include gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, sugars, and starches. An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. The oil phase may consist at least in part of a propellant, such as an HFA propellant. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers. “Emollients” are an externally applied agent that softens or soothes skin and are generally known in the art and listed in compendia, such as the “Handbook of Pharmaceutical Excipients”, 4th Ed., Pharmaceutical Press, 2003. These include, without limitation, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof. In one embodiment, the emollients are ethylhexylstearate and ethylhexyl palmitate. “Surfactants” are surface-active agents that lower surface tension and thereby increase the emulsifying, foaming, dispersing, spreading and wetting properties of a product. Suitable non- ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof. In one embodiment, the non-ionic surfactant is stearyl alcohol. “Emulsifiers” are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are metallic soaps, certain animal and vegetable oils, and various polar compounds. Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self- emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof. In one embodiment, the emulsifier is glycerol stearate. A “lotion” is a low- to medium-viscosity liquid formulation. A lotion can contain finely powdered substances that are insoluble in the dispersion medium through the use of suspending agents and dispersing agents. Alternatively, lotions can have as the dispersed phase liquid substances that are immiscible with the vehicle and are usually dispersed by means of emulsifying agents or other suitable stabilizers. In one embodiment, the lotion is in the form of an emulsion having a viscosity of between 100 and 1000 centistokes. The fluidity of lotions permits rapid and uniform application over a wide surface area. Lotions are typically intended to dry on the skin leaving a thin coat of their medicinal components on the skin's surface. A “cream” is a viscous liquid or semi-solid emulsion of either the “oil-in-water” or “water-in- oil type”. Creams may contain emulsifying agents and / or other stabilizing agents. In one embodiment, the formulation is in the form of a cream having a viscosity of greater than 1000 centistokes, typically in the range of 20,000-50,000 centistokes. Creams are often preferred over ointments as they are generally easier to spread and easier to remove. An “ointment” is a semisolid preparation containing an ointment base and optionally one or more active agents. Examples of suitable ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointment), and water-soluble bases (e.g., polyethylene glycol ointments). Pastes typically differ from ointments in that they contain a larger percentage of solids. Pastes are typically more absorptive and less greasy than ointments prepared with the same components. A “gel” is a semisolid system containing dispersions of small or large molecules in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid may include a lipophilic component, an aqueous component or both. Some emulsions may be gels or otherwise include a gel component. Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components. Suitable gelling agents include, but are not limited to, modified celluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and combinations thereof. Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alklene glycols, such as propylene glycol; dimethyl isosorbide; alcohols, such as isopropyl alcohol and ethanol. The solvents are typically selected for their ability to dissolve the drug. Other additives, which improve the skin feel and / or emolliency of the formulation, may also be incorporated. Examples of such additives include, but are not limited, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric / caprylic triglycerides, and combinations thereof. “Foams” consist of an emulsion in combination with a gaseous propellant. The gaseous propellant consists primarily of hydrofluoroalkanes (HFAs). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and admixtures of these and other HFAs that are currently approved or may become approved for medical use are suitable. The propellants preferably are not hydrocarbon propellant gases which can produce flammable or explosive vapors during spraying. Furthermore, the compositions preferably contain no volatile alcohols, which can produce flammable or explosive vapors during use. Buffers are used to control pH of a composition. Preferably, the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7. In a preferred embodiment, the buffer is based on triethanolamine, citric acid, sodium hydroxide, disodium phosphate and potassium phosphate. Preservatives can be used to prevent the growth of fungi and microorganisms. Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, potassium sorbate, caprylyl alcohol, 1,2- hexandiol, and thimerosal. Antioxidants can be used in the compositions of the present invention. Examples of antioxidants are tocopherol, hydroxyacetophenone, dimethylmethoxy chromanol and phenethyl alcohol. Viscosity modifiers can additionally be present, such as potassium chloride and natural gums such as xanthan gum, gum arabic, gum tragacanth, carrageenan, chitosan, guar gum, konjac gum, sclerotium gum, dextrins and starch. Chelating agents may additionally be present, such as sodium glucuronate. Fragrances may be added to the compositions of the invention. Penetration enhancers are frequently used to promote transdermal delivery of drugs across the skin, in particular across the stratum corneum. The more commonly used enhancers include urea, (carbonyldiamide), imidurea, N, N-diethylformamide, N-methyl-2-pyrrolidine, 1- dodecal-azacyclopheptane-2-one, calcium thioglycate, 2-pyyrolidine, N,N-diethyl-m- toluamide, oleic acid and its ester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmonooleate, sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate, other fatty acid esters such as isopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleatea and non-ionic detergents such as BRIJ® 76 (stearyl poly(10 oxyethylene ether), BRIJ® 78 (stearyl poly(20)oxyethylene ether), BRIJ® 96 (oleyl poly(10)oxyethylene ether), and BRIJ® 721 (stearyl poly (21) oxyethylene ether) (ICI Americas Inc. Corp.). Emulsion stabilizers, surfactants and emulsifying agents may additionally be present, such as sorbitan isostearate, hydroxyethyl acrylate / sodium acryloxydiethyl taurate copolymer and sorbitan isostearate. Humectants are crucial in skincare by providing essential skin hydration and maintaining the skin's moisture balance. Exemplary humectants are Glycerin, Hyaluronic acid, Aloe vera, Honey, Hydrolyzed proteins, Panthenol, Allantoin, Seaweed & algae, Sodium PCA (sodium pyrrolidone carboxylic acid), Saccharide Isomerate, Sugar Alcohols (e.g. sorbitol), Hydroxy acids (e.g. lactic acid and gluconolactone), agave nectar, betaine, chitosan, trehalose, beta- glucan, topical collagen, galactoarabinan and propanediol. Solvents used in the compositions of the present invention may include water, alcohols such as ethanol and isopropyl alcohol, alkanes such as C15-19 Alkane, silicone oils and mineral oils. Skin conditioning agents may be added to the compositions of the present invention, for example caprylic / capric triglyceride, alpha-glucan triglycerides, palmitoyl tripeptide-5, glycerin, diglucosyl gallic acid, panthenol, pantolactone, sodium stearoyl glutamate, lactic acid, hydrolysed hyaluronic acid, sodium hyaluronate and maltodextrin. Further natural extracts may be present in compositions of the present invention, for example Saccharomyces / Xylinum / Black Tea Ferment, Bellis Perennis (Daisy) Flower Extract, Thermus Thermophillus Ferment and Sphingomonas Ferment Extract. After formulation, the product is filled into an appropriate dispenser and shipped to the end user. Examples of final container may include a pump bottle, squeeze bottle, jar, tube or vial. A further object of the present invention is the use of a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) to stabilize solutions of aretinoid, such that at least 31% of the retinoid used to prepare the solution is still present after storage for at least 12 weeks at 25°C. Examples The invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations to the scope of this invention. Various other aspects, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention or the scope of the appended claims. Chemicals and reagents All-trans Retinol (≥99%) was used for the experiments. Chemical components of NADES, sucrose (SU), xylose (XY), malic acid (MA), lactic acid (LA), menthol (ME), thymol (TH), octanoic acid (OC), decanoic acid (DE), dodecanoic acid (DO), oleic acid (OL), all with purities exceeding 99%, were obtained from Merck. HPLC grade acetonitrile, acetone, ethanol, methanol, and tetrahydrofuran were purchased from Sigma-Aldrich (Steinheim, Germany). Ultra-pure water was obtained through a Milli-Q water purification system A10 Advantage (Millipore Corporation, Bedford, MA, USA). Commercial retinol Two commercial retinol products, DSM Retinol CB 50 (sup-1) and BASF Retinol SU10) (sup-2) with declared retinol content were used as reference. These consists of the active ingredient retinol dissolved in a mixture of natural derived alkanes or soybean oil stabilized by naturally-occurring or added tocopherols. Retinol-Eutectics formation using vacuum evaporation method For the preparation of retinol-eutectics, 11 compounds were used. The different counterparts were selected based on their hydrophobicity, wherein hydrophobicity is estimated based on the LogP or alternatively via the Hansen Solubility Parameter, see Table 1. Table 1. LogP and Hansen Solubility Parameter for selected compounds Hansen Solubility ParametersStability of Log Ra² Compound δD δP δH API-NaDES P (to Retinol) Retinol N.A 6.38 16,74* 2,32* 17,6* 0 Thymol Stable 3.16 19 4,5 10,8 71,4 Menthol Stable 2.68 16 4,7 9 81,8 Octanoic acid Stable 2.92 15,7 3,3 8,2 93,6 Decanoic acid Stable 3.93 16,2 4,2 8,3 91,2 Dodecanoic acid Stable 5.13 16,2 4 7,4 108,0 Oleic acid Stable 7.68 16 2,8 6,2 132,4 - Lactic acid Unstable 17 8,3 28,4 152,7 0.79 - Malic acid Unstable 17,1 12 30,1 250,5 0.87 - Sucrose Unstable 23,4 18,4 20,8 446,2 2.63 - Xylose Unstable - - - - 2.57*Estimate based on β-Carotene Elevated temperatures accelerated retinol degradation, but the extent varied among formulations, indicating that thermal stability depends on the proper hydrogen bond donor at the correct molar ratio. Additionally, the retinol-eutectics were incorporated into an oil-in-water (o / w) emulsion base cream at 0.3 wt% retinol to assess stability in a topical formulation. The retinol-eutectics formulations improved retinol stability in the cream compared to a control without eutectic aggregation. In conclusion, directly liquefying retinol with suitable predominantly hydrophobic counterparts (e.g. having a LogP>0) enhances its stability both as stand-alone mixtures and in topical formulations without the need for additional stabilizers. The preparation method was based on the protocol described by Dai et al., (Dai, Y.; Van Spronsen, J.; Witkamp, G.-J.; Verpoorte, R.; Choi, Y.H. Natural Deep Eutectic Solvents as New Potential Media for Green Technology. Anal. Chim. Acta 2013, 766, 61–68) with slight modifications, where the HBDs and HBA components at the proper molar ratio of 1:1, 1:2, and 2:1 were dissolved in ethanol, mixed in a rotary evaporator under a reduced atmosphere (250 mbar) at 25 °C until a clear liquid was formed (about 30 to 60 min of stirring) and constant weight is reached. With the aforementioned method, API-NADES mixtures of retinol with regard to whole eutectic liquid were prepared. To avoid the effect of UV light and oxygen during the preparation process, the samples were prepared in amber glass vials under nitrogen gas. Proportions of HBDs and HBA species are reported in Table 2. Table 2 - Summary of Retinol-Eutectics Compositions with Corresponding Molar Ratio and Abbreviations.

[0002] Retinol-Eutectics cream preparation The initial retinol-eutectics (Table 1) were added to a base cream (o / w) emulsion in concentration of 0.3wt% of retinol with regard to whole emulsion and homogenised by 1000W hand blender (Blokker, type BL-11305) for complete mixing. The control emulsion was prepared by addition of the retinol powder to little ethanol to form a premix and then added to the base cream in concentration of 0.3wt% of retinol and the mixture was homogenised using equivalent conditions to the API-NADES base cream emulsions. HPLC-DAD analysis Retinol contents in the formulated eutectics, base cream and tested commercial products at each time point were measured by HPLC-DAD method using an Agilent 1100 / 1200 Series instrument (Agilent Technologies, Santa Clara, California, USA) equipped with a diode array UV / Vis detector and ChemStation data acquisition system. In brief, the chromatographic separation was performed on a reversed-phase column (Luna C18 (2) 150 × 4.6 mm, 3.5 μm particle size) (Phenomenex, Torrance, CA, USA) eluted at ambient temperature, at 325 nm (A325nm) except for API-NADES cream at 350 nm (A350nm). Mobile phase, consisting of water (A), methanol (B) and acetonitrile: isopropanol: acetone (45:45:10, v / v / v) (C) in gradient elution mode was utilized as follows: (time (min); % A; % B): (0; 20; 80), (15; 12; 88), (17; 0; 100), (25; 0; 100), (27; 20; 80), (35; 20; 80) at a flow rate of 1 mL / min, followed by a flush out step and a re-equilibration time. Injection volume was 10 μL in all tested products. Preparation of standard solution All retinol stock standard solutions were prepared by dissolving appropriate amounts of the individual retinol in ethanol. Three calibration standards were prepared from each individual stock standard solution by dilution in ethanol at concentrations 0.78125, 1.5625, 3.125, 6.25, 12.5, 25, 50 and 100 mg / L for retinol, and concentrations 31.25, 62.5, 125, 250, and 500 mg / L for supplier 1 and supplier 2. All solutions were prepared protected from light. All samples were prepared in at least triplicate. Long-term stability tests Long-term stability studies have been carried out at 4 different storage temperatures. Retinol- eutectics cream combinations were transferred into glass vials immediately after preparation and stored at 4, 25 , 37 and 45 ± 0.5 °C without topping up with nitrogen gas. The chemical stability (retinol content) and physical stability (organoleptic visualisation for signs of crystallization, creaming and coalescence) were monitored up to 3 months. At each time point, samples were taken, extracted and diluted with ethanol and analyzed in duplicate with HPLC for residual retinol. Data Processing and multivariate data analysis of HPLC-DAD data The amount of retinol that elutes was determined by the area under the curve (AUC) calculated automatically by the Agilent’s HPLC software (ChemStation) expressed in units. The statistical differences between all the various samples were determined using repeated measure ANOVA test, followed by post hoc Fisher’s LSD test. p values ≤0.05 were considered as significant. Results and discussion Hydrophobic Conformers We explored the direct liquefaction of retinol to form binary eutectic mixtures, aiming to create a stable liquid formulation while minimizing the complexity and potential risks associated with multi-component eutectics decreasing the high E-factor associated with the pharmaceutical industry. This strategy leverages the ability of eutectic mixtures to disrupt the crystalline structure of APIs and produce a liquid phase, without relying on the solubilizing power of pre-formed NADES or the introduction of numerous additional components. The conformers used in this study were carefully selected based on their potential to form hydrophobic eutectics. The selection included menthol (ME), thymol (TH), octanoic acid (OC), decanoic acid (DE), dodecanoic acid (DO), and oleic acid (OL) in 1:1, 1:2, and 2:1 molar ratio. In experimental investigations, all the fatty acids (OC, DE, DO, and OL) and terpenes (ME and TY) demonstrated complete eutectic formation with retinol across the three molar ratio evaluated. The enhanced efficacy of these hydrophobic compounds can be attributed to the principle of "like dissolves like," as retinol, a non-polar molecule, is more effectively liquefied by non-polar agents. To validate and test the concept, other hydrogen bond donors (HBDs), including solid organic acids such as lactic and malic acid, as well as sugars like sucrose, and xylose, were evaluated. The hypothesized interactions between retinol and the tested polar compounds are primarily governed by the potential formation of hydrogen bonds. However, retinol itself, due to its non-polar nature, does not typically engage in hydrogen bonding as readily as the polar compounds under investigation. The experimental attempts to create a eutectic mixture were unsuccessful, as evidenced by visible separation and sedimentation of the polar compounds used. This outcome highlights the limited interaction between retinol and the polar compounds, further emphasizing the challenges in forming a stable eutectic blend when non-polar and polar molecules are involved. The experimental findings suggest that the anticipated hydrogen bonding and other intermolecular forces were insufficient to overcome the inherent differences in polarity between the components, leading to the observed phase separation. Due to the failing attempts and unsuccessful eutectification of retinol with these polar compounds, they were subsequently disqualified and excluded from further stability studies. Chemical stability of retinol as a function of temperature Thymol, menthol, octanoic acid, decanoic acid, dodecanoic acid, and oleic acid at molar ratios of 1:1, 1:2, and 2:1 were used as counterparts for retinol. The resulting retinol-eutectics were tested as stand-alone mixtures over three months at temperatures of 4, 25, 37, and 45^°C. The thymol-retinol eutectics at a 1:1 molar ratio (Thy-re 1:1) exhibited the highest stability, retaining approximately 89% of its initial retinol content after three months at 25^°C and about 88% at 4^°C. This significantly surpassed other formulations and commercial retinol products with added stabilizers. The exceptional stability of Thy-re 1:1 is attributed to strong intermolecular hydrogen bonding between thymol and retinol, resulting in a more stable network. Thymol and menthol retinol-eutectics liquified formulas Retinol stability in various formulations of Thy-re and Me-re at different molar ratio (1:1, 1:2, 2:1) was evaluated over a 3-month period under different storage temperatures (4, 25, 37 and 45 °C). Degradation kinetics can offer more in-depth insights into retinol instability in topical formulations but are only rarely utilized within stability evaluations in cosmetic products. We addressed this issue by initially determining the best model to describe the degradation kinetics of retinol in our retinol-eutectics. Zero, first, and second-order models were tested. The decrease in retinol concentration generally followed second-order kinetics in most eutectic mixtures (∼R²^>^0.90), which differs from previous reports on retinol that have shown first-order kinetics. The Thy-re 1:1 (Ty-1) formulation was the most stable among the tested samples at ambient temperature (25^°C), with approximately 89% of retinol remaining after 3 months. This is more than two-fold higher than the least stable formulations, such as Thy-re 1:2 (Ty-2) and Thy-re 2:1 (Ty-3), which retained about 50% of retinol under the same conditions. At 4^°C, retinol stability was generally higher across all formulations. Ty-1 maintained about 88% of its initial retinol content after 3 months, while Ty-2 retained approximately 86%, and Ty-3 retained about 63%. The Me-re formulations also showed similar trends, with Me-re 1:1 (Me-1) retaining around 85%, Me-re 1:2 (Me-2) around 77%, and Me-re 2:1 (Me-3) between 72% and 76% after 3 months at 4^°C. Elevated temperatures significantly accelerated retinol degradation. At 37^°C, Ty-1 retained only about 16% of its initial retinol content after 3 months. Ty-2 and Ty-3 showed slightly better stability at this temperature, retaining approximately 46% and 18%, respectively. The Me-re formulations also exhibited decreased stability at 37^°C, with retinol content ranging from about 32% to 53% after 3 months. At 45^°C, the degradation was even more pronounced. Ty-1 and Ty-3 retained less than 10% of retinol after 3 months, while Ty-2 retained about 15%. Me-re formulations at this temperature retained between 19% and 41% of their initial retinol content. The control samples showed significantly lower stability compared to the Thy-re and Me-re formulations. The Control-Pure sample retained only about 3% of retinol after 3 months at 25^°C. Supplier 1 (sup-1) and supplier 2 (sup-2) samples, which are commercial retinol products already stabilized with high amounts of stabilizers, also exhibited substantial degradation. For instance, sup-2 retained only about 14% of retinol after 3 months at 25^°C and as low as 2% at 45^°C. This observation indicates that the presence of various stabilizers does not necessarily ensure the stability of retinol formulations. This is in stark contrast to the Thy-re and Me-re formulations, which had no added antioxidants or stabilizers, nor nitrogen spiking to remove oxygen, yet demonstrated superior stability. The effect of temperature on retinol stability is evident from these results. On average, increasing the storage temperature from 25^°C to 45^°C reduced the retinol content by an additional 40% to 80% over 3 months, depending on the formulation. The increase in temperature accelerated the degradation rate, but the extent varied among formulations, indicating that thermal stability is dependent on the proper HBD at the correct molar ratio. Despite the lack of chemical stability at high temperatures, all retinol-eutectics (Thy-re and Me-re) exhibited very high physical stability even at elevated temperature (45^°C) with no signs of separation and crystallization upon storage up to 3 months. The exceptional stability observed in the Ty-1 eutectic may be attributed to the formation of a deep eutectic mixture between thymol and retinol, leading to significant negative deviations from ideal mixing behavior. Thymol's molecular structure involves resonance effects where the lone pairs of electrons on the oxygen atom are delocalized across the aromatic ring, imparting sp² character to the oxygen. This delocalization makes the hydroxyl group of thymol more positively charged than usual, causing the oxygen atom to be a weaker hydrogen bond acceptor while its bonded hydrogen becomes a stronger hydrogen bond donor. In contrast, retinol possesses a conventional hydroxyl group in the isoprenoid side chain capable of forming typical hydrogen bonds in its pure state. When thymol and retinol are combined in a 1:1 molar ratio specifically, a favorable interaction occurs: the highly effective hydrogen bond donor of thymol's hydroxyl group forms a strong hydrogen bond with the oxygen atom of retinol. This interaction is stronger than the hydrogen bonds present in the pure components, resulting in a more stable intermolecular network. The formation of these robust intermolecular hydrogen bonds in the Ty-1 mixture likely contributes to the reduced mobility of retinol molecules, effectively shielding them from degradation pathways such as oxidation or isomerization. This enhanced stabilization explains the lower degradation rate observed in the Ty-1 formulation compared to other formulations or pure retinol samples. Fatty acids retinol-eutectics liquified formulas Retinol stability in various formulations of fatty acid-retinol mixtures (Oc-re, De-re, Do-re, and Ol-re) at different molar ratio (1:1, 1:2, 2:1) was evaluated over a 3-month period under different storage temperatures (4, 25, 37, and 45^°C). Zero, first, and second-order models were tested. The decrease in retinol concentration generally followed first and second-order kinetics in most products (∼R²^>^0.90. In addition, we observed a relationship between the alkyl chain length of the fatty acids and the stability of retinol at various temperatures. The Do-re 1:1 (Do-1) formulation was the most stable among the tested samples at ambient temperature (25^°C), with approximately 56% of retinol remaining after 3 months. This is higher than the less stable formulations, such as Oc-re 1:1 (Oc-1) and De-re 1:1 (De-1), which retained about 41% and 33% of retinol under the same conditions, respectively. The Ol-re 1:2 (Ol-2) formulation also showed relatively good stability at 25^°C, retaining approximately 50% of retinol after 3 months. The Ol-re 1:1 (Ol-1) formulation retained about 36% of retinol, indicating that increasing the alkyl chain length beyond C12 (dodecanoic acid) at the same molar ratio (1:1) did not further enhance stability. At 4^°C, retinol stability was generally higher across all formulations. Do-1 maintained about 92% of its initial retinol content after 3 months, while De-re 1:1 (De-1) and Oc-1 retained approximately 86%, and 81%, respectively. The Ol-re formulation showed lower stability at this temperature, retaining about 56% of retinol. This trend suggests that increasing the alkyl chain length up to C12 improves retinol stability at lower temperatures. Elevated temperatures significantly accelerated retinol degradation across all formulations. At 37^°C, Do-re 1:2 (Do-2) retained only about 9% of its initial retinol content after 3 months. De-re 1:2 (De-2) and Ol-re 1:2 (Ol-2) showed slightly better stability at this temperature, retaining approximately 17% and 16%, respectively. The Oc-re formulations also exhibited decreased stability at 37^°C, with retinol content ranging from about 3% to 11% after 3 months. At 45^°C, the degradation was even more pronounced, with all formulations retaining less than 2% of retinol after 3 months. This indicates that at very high temperatures, the chain length of the fatty acid has a minimal impact on retinol stability, as degradation is significant regardless of the formulation. From these results, we can conclude that increasing the alkyl chain length of the fatty acid up to C12 enhances the stability of retinol at various temperatures. The Do-1 formulation consistently showed better stability compared to formulations with shorter (Oc, De) or longer (Ol) fatty acid chains. However, increasing the chain length beyond C12 does not further improve stability and may even decrease it, as observed with the Ol-re formulations. The effect of temperature on retinol stability is evident from these results. On average, increasing the storage temperature from 25^°C to 45^°C reduced the retinol content by an additional 50% to 90% over 3 months, depending on the formulation. The increase in temperature accelerated the degradation rate, but the extent varied among formulations, indicating that thermal stability is dependent on the proper hydrophobic chain length of the fatty acid at the correct molar ratio. Despite the lack of chemical stability at high temperatures, all API-NADES formulations exhibited very high physical stability even at elevated temperature (45^°C) with no signs of separation and crystallization upon storage up to 3 months. The enhanced stability observed in formulations containing medium-chain fatty acids, particularly Do-1, can be attributed to the molecular interactions between retinol and the fatty acid chains. Considering that retinol has a length of approximately 15.5^Å, it is suggested that retinol molecules can integrate both at the planar interface “between” and “within” the hydrophobic alkyl chains, aligning to the fatty acid long axis chains, facilitating optimal hydrophobic interactions. The improved efficacy of these hydrophobic compounds can be explained by the principle of "like dissolves like". Retinol, being a non-polar molecule, is more effectively dissolved by non-polar agents such as fatty acids with suitable chain lengths. The medium-chain fatty acids, like dodecanoic acid in Do-1 provide a hydrophobic environment that mainly stabilizes retinol through van der Waals interactions and minimizes exposure to degradative agents. Chemical stability of retinol-eutectics cream as a function of temperature Retinol stability in cosmetic cream formulations (o / w) containing various retinol-eutectics was evaluated over a period of three months at storage temperatures of 4, 25, 37, and 45^°C. The results obtained showed a significant decline in retinol content across all tested formulations. Despite the lack of chemical stability at high temperatures, all retinol-eutectics cream formulations exhibited very high physical stability with no signs of creaming and coalescence upon storage up to 3 months. Based on the analysis of the retinol-eutectics formulations we observed a relationship between the type of retinol-eutectics and the stability of retinol at various temperatures. At 25^°C, the Control-cream showed a significant decline, retaining approximately 13-19% of retinol after 3 months. the Me-re 1:1 (Me-1) formulation demonstrated higher stability, retaining 34–36% of retinol, nearly double that of the Control-cream. The Do-re 1:1 (Do-1) formulation also outperformed the Control-cream, retaining about 32–35%. The Thy-re 1:1 (Ty-1) formulation retained about 23–24%, which is still higher than the Control-cream. The Oc-re 1:1 (Oc-1) and De-re 1:1 (De-1) formulations retained lower amounts of retinol, approximately 17–21% and 3–4%, respectively. At 4^°C, the Control-cream retained about 20% of retinol after 3 months. In contrast, the Me-1 formulation maintained the highest stability, retaining 62–65% of its initial retinol content. The Oc-1 and Ol-re 1:1 (Ol-1) formulations also showed good stability, retaining approximately 62.6–63.2% and 57.2%, respectively. The Do-1 and Ty-1 formulations exhibited moderate stability, retaining about 54.4–54.8% and 46.6–54.1%, respectively –all substantially higher than the Control-cream. The De-1 formulation displayed lower stability, retaining only about 18.1–18.7% of retinol, comparable to the Control-cream. Elevated temperatures significantly accelerated retinol degradation across all formulations, where the Control-cream exhibited complete degradation by the third month, with retinol levels dropping to 0%. At 37^°C, the Do-1 formulation retained about 15–18% of its initial retinol content after 3 months, which was higher than other formulations. The Me-1 formulation showed significant degradation, retaining only about 0.3–5.8% of retinol. The Ty- 1 formulation retained about 4.2–4.7%, while the Ol-1 formulation showed variable results, with retinol content dropping to negligible amounts or even zero, indicating complete degradation. The Oc-1 and De-1 formulations exhibited the least stability at this temperature, with retinol levels falling to zero after 3 months. At 45^°C, degradation was even more pronounced, with most formulations retaining minimal or undetectable levels of retinol after 3 months. The Ty-1 formulation retained about 7.3–8.6% of retinol, while the Me-1, Oc-1, De-1 formulations showed complete degradation, with no retinol detected similar to the Control- cream. These results indicate that the inclusion of retinol-eutectics formulations can enhance retinol stability compared to the Control-cream, particularly at lower temperatures. The Me-1 and Do-1 formulations demonstrated significantly better stability at 4^°C and 25^°C compared to the Control-cream. For instance, at 25^°C after 3 months, the Me-re 1:1 formulation retained up to 36.3% of retinol, nearly triple the retention in the Control-cream (12.8–19.4%). However, at higher temperatures (37^°C and 45^°C), retinol degradation was significant across all formulations, including those with Retinol-Eutectics and the Control-cream. Retinol is a widely used dermatologic agent effective in treating skin conditions such as acne, photoaging, and other skin disorders. However, it requires proper stabilization within its final cosmetic or pharmaceutical formulations due to its poor solubility and instability. In this study, we evaluated the stability of retinol in various hydrophobic eutectic formulations— specifically using thymol, menthol, and fatty acids like octanoic, decanoic, dodecanoic, and oleic acids. Long-term and accelerated stability testing revealed that our formulations significantly enhanced retinol stability compared to the control cream and even commercial stabilized retinol products, despite the absence of added stabilizers. Based on the obtained results after long-term and accelerated stability studies, it is evident that appropriate selection of hydrophobic counterparts and formulation strategies can significantly enhance retinol stability without the need for additional stabilizers. Gene expression Protocol Normal human fibroblasts were cultivated with culture medium (Dulbecco Modified Eagle Medium+Fetal calf serum) and treated with 0.0001% equivalent dose of all-trans Retinol of Free Retinol or Retinol-NaDES for 6 hours. Non treated cells were incubated under the same conditions. Gene expression of CRABPI, CARBPII, RAR-alpha, RAR-beta, RAR-gamma, was quantified by using Real-Time RT-PCR. Total mRNA were extracted by using NucleoMag RNA kit (Macherey-Nagel) and quantified with a spectrophotometer at 260 nm. First strand cDNA synthesis was performed with the High cDNA reverse transcription kit (Thermo). Real-Time PCR was carried out with the QS7 (Quantstudio 7 Flex Real-Time PCR System) by using the TaqMan specific primers and probes. Relative changes in gene expression were calculated according to the 2−ΔΔCT method. The gene expression was compared with untreated cells. All of the Retinol-Eutectics studied, but Retinol:C121:1 eutectic mixture, displayed a statistically significant (p <0.05) increased gene expression for all studied markers versus the non-treated sample. In the case of Retinol:C121:1 and Retinol:Thymol 1:1 eutectic mixtures, the gene expression related to RAR-β, RAR-g was significantly higher (p < 0.05) than the sample treated with free Retinol by 199-213% and 182-187% respectively. In-between retinol-eutectic samples, Retinol:C121:1 eutectic mixture displayed a significantly higher expression of CARBPII related genes than Retinol:Thymol and Retinol:Menthol by 34% and 25% respectively. Table 3. Gene expression cells treated with retinol-eutectics or free retinol Gene Expression (RQ)Retinol- RAR- EutecticsRatioα CRABPI CRABPIIFree Retinol n / a 1.331ª 30.624ª 1.478ª 5.257ª 2.046ª Ty:re NaDES1:1 2.198ª 57.53ª^ 3.156ª^ 2.382ª 1.752ªC12:re NaDES1:1 1.71 55.977ª^ 2.95ª^ 3.344ª 2.354ªMe:re NaDES2:1 1.46ª 22.111ª 1.439ª 2.268ª 1.869ªª significantly different (p<0.05) vs. non treated (RQ=1) ^ significantly different (p<0.05) vs. Retinol Free Ty:re = Thymol-Retinol NaDES Me:re NaDES = Menthol- Retinol NaDES C12:re NaDES = Lauric acid- Retinol NaDES

Claims

CLAIMS What is claimed is:

1. Retinoid-based eutectic comprising a retinoid and at least a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA).

2. The retinoid-based eutectic according to claim 1, wherein the HBD is predominantly hydrophobic with a LogP>0.

3. The retinoid-based eutectic according to any of the preceding claims, wherein the HBD is chosen in the group consisting of monoterpenoids, C8-C20 fatty acids and combinations thereof.

4. The retinoid-based eutectic according to claim 3, wherein the monoterpenoid is thymol and / or menthol.

5. The retinoid-based eutectic according to claim 4, wherein the C8-C20 fatty acid is caprylic acid, capric acid, lauric acid and / or stearic acid.

6. The retinoid-based eutectic according to any of the preceding claims, wherein the molar ratio of retinoid / HBD is between 1:2 and 2:

1.

7. The retinoid-based eutectic according to claim 6, wherein the molar ratio of retinoid / HBD is 1:

1.

8. Cosmetic or pharmaceutic composition comprising the retinoid-based eutectic of claims 1-7 in a cosmetically or pharmaceutically compatible medium.

9. Cosmetic or pharmaceutic composition according to claim 8 in a form suitable for topical administration.

10. Cosmetic or pharmaceutic composition according to claim 9, wherein the composition is in the form of an oil-in-water emulsion, a water-in-oil emulsion, a multiple emulsion (Water / Oil / Water or Oil / Water / Oil), a microemulsion, a nanoemulsion, a solution, asuspension, a hydrodispersion, a gel, an ointment, a paste, an aerosol foam, a spray, an aqueous gel, a powder, a foundation, a transdermal patch, a cream or a mask.

11. Use of a hydrogen bond donor (HBD), a hydrogen bond acceptor (HBA) or combinations of a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA) to form a retinoid-based eutectic, such that at least 31% of the retinoid used to prepare the eutectic is still present after storage for at least 12 weeks at 25°C.

12. Use of a retinoid-based eutectic according to any of claims 1-7 to increase expression of genes related to retinoids.

13. Use of a retinoid-based eutectic according to any of claims 1-7 to improve the aesthetic appearance of the skin.

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