Azelaic acid compositions and use thereof

Abstract

Compositions for delivering azelaic acid in a substantially molecularly dispersed, non- crystalline state are provided, comprising acetamide monoethanolamine (Acetamide MEA) as the primary solubilizing agent for azelaic acid and as crystallization inhibitor. The compositions may comprise azelaic acid at concentrations of up to about 25% by weight, exhibiting physical stability and optical clarity. The compositions are structured as submicron emulsions, gel compositions and topical formulations, optionally including structuring systems, and / or rheology modifiers, to further enhance stability and resistance to crystallization. Such compositions are useful for treatment of skin diseases, disorders, or conditions that may benefit from topical application of azelaic acid.

Description

[0001] AZELAIC ACID COMPOSITIONS AND USE THEREOF

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compositions containing azelaic acid and Acetamide MEA (N-acetyl ethanolamine) as a primary solubilizing agent for azelaic acid, and use thereof in the treatment of various dermatological conditions.

[0004] BACKGROUND

[0005] Azelaic acid (HOOC(CH2)7COOH) is a naturally occurring saturated dicarboxylic acid with well-established therapeutic benefits in dermatology. It exhibits anti-inflammatory, antimicrobial, keratolytic, and tyrosinase-inhibiting activities, making it effective in the treatment of conditions such as acne vulgaris, rosacea, and hyperpigmentation disorders. Azelaic acid acts by inhibiting Cutibacterium acnes (formerly Propionibacterium acnes), and inhibiting melanin production, acting as a tyrosinase inhibitor, thereby helping to reduce hyperpigmentation and even skin tone. Azelaic acid gently exfoliates the skin by normalizing keratinization, which helps unclog pores and remove dead skin cells.

[0006] Although azelaic acid is widely used in topical formulations such as creams, gels, and lotions at concentrations typically ranging from about 5% to 20%, its formulation remains challenging due to its poor solubility in water and most conventional cosmetic solvents (approximately 0.24% w / v at 20°C), relatively high melting point (about 106 - 110°C), and strong tendency to recrystallize upon cooling or during storage. Conventional solvents and polyols, including propylene glycol, propylene glycol dicaprylate, ethoxydiglycol and polyethylene glycols (such as PEG-8), and surfactants like polysorbate 80, or microemulsion systems with medium-chain triglycerides, may temporarily solubilize azelaic acid at elevated temperatures but often fail to maintain stable high-load formulations upon cooling or during long-term storage at room temperature, leading to recrystallization, physical instability (sedimentation and phase separation), gritty texture (thereby reduced aesthetic appeal), reduced bioavailability due to inconsistent particle size, potential skin irritation caused by crystalline particles, and decreased consumer acceptability. Existing commercial products, such as Finacea® Gel (15% azelaic acid), Azelex® Cream (20%), and Skinoren®Cream (20%), attempt to address these challenges through complex emulsion or gel systems, yet these approaches often result in opaque formulations or suboptimal aesthetic properties. Accordingly, there remains a need for improved formulations capable of maintaining high concentrations of azelaic acid in a stable, non-crystallizing, and cosmetically elegant form.

[0007] SUMMARY

[0008] The present disclosure addresses challenges in formulating azelaic acid (AzA) into stable aesthetic, efficient and safe-to-use formulations, in which azelaic acid is substantially molecularly dispersed and bioavailable for prolonged periods.

[0009] Disclosed herein are topical compositions and formulations of AzA based on a unique solvent system comprising Acetamide MEA (N-acetyl ethanolamine) as a primary solvent, which has been unexpectedly discovered by the present inventor to function as a potent crystallization inhibitor for azelaic acid. Unlike conventional or state-of-the-art polyol-based solutions of azelaic acid (e.g., propylene glycol or ethoxydiglycol), the Acetamide MEA-based system disclosed herein enables the formation of exceptionally physically stable isotropic, transparent and non-aggregating solutions of azelaic acid even at high active concentrations of up to 20% by weight or more, providing increased bioavailability. Such formulations were successfully applied in the treatment of various skin diseases and conditions that benefit from topical application of azelaic acid.

[0010] In one aspect, the present disclosure relates to solvent systems and compositions comprising Acetamide MEA and, optionally, at least one aliphatic polyol, capable of solubilizing azelaic acid and maintaining the azelaic acid in a substantially molecularly dispersed and noncrystalline state, optionally, for a period of at least 6 months. In some embodiments, azelaic acid remains in a substantially molecularly dispersed and non-crystalline state under ambient storage conditions for up to 24 months. In the solvent systems and compositions, disclosed herein, Acetamide MEA is a primary solubilizing agent for azelaic acid.

[0011] In some embodiments, the weight ratio of Acetamide MEA to azelaic acid in the solvents systems and / or the compositions may be between 1:1 and 5:1, optionally, between 2:1 and 4:1. The concentration of azelaic acid may be from about 1% to about 25% by weight, from about 10%to about 20% by weight, whereas the concentration of Acetamide MEA is from about 15% to about 50% by weight, optionally from about 25% to about 45% by weight.

[0012] In some embodiments, the aliphatic polyol is a C3-C6 aliphatic polyol selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol, and hexylene glycol, optionally at a concentration of from about 5% to about 30% by weight.

[0013] The solvent system and the composition disclosed herein enable the preparation of clear and translucent emulsion, gels and topical formulations based thereon, while inhibiting or preventing nucleation and crystal growth of azelaic acid under ambient storage conditions.

[0014] Thus, in further aspects, the present disclosure relates to submicron emulsions (e.g., microemulsions and nanoemulsions) and gel compositions comprising azelaic acid solubilized in Acetamide MEA and, optionally, at least one aliphatic polyol. The microemulsions and gel compositions may comprise at least one rheology modifying agent and / or at least one particulate structuring agent. Exemplary rheology modifying agents include cellulose-based polymers, present at concentrations from about 0.1% to about 2% by weight, and exemplary particulate structuring agents include silica-derived matrices, optionally, fumed silica, present at concentrations from about 1% to about 9% by weight, optionally from about 2% to about 8% by weight.

[0015] In some embodiments, a disclosed gel compositions comprises a dual-structuring system which includes a cellulose-based polymer, such as hydroxypropyl cellulose (HPC), in combination with an inorganic structuring agent, such as fumed silica, thereby forming a stabilized rheological network that maintains integrity and stability of the products. Such structuring systems are particularly tolerant to elevated electrolyte levels, enabling the incorporation of additional active or functional agents.

[0016] In another aspect, the present disclosure relates topical formulations comprising azelaic acid solubilized in Acetamide MEA as the primary solvent, and a dermatologically acceptable carrier. The topical formulations comprise therapeutic, dermatologic or cosmetic formulations.

[0017] The formulations disclosed herein may be maintained within an optimal acidic pH window of 4.0 to 5.0, optionally, 4.5 to 4.8, ensuring both the chemical stability of the active ingredients and / or the mechanical integrity of their network. In some embodiments, the resulting formulations are optically transparent or translucent with minimal light scattering, substantiallyfree of crystalline particles that could produce a gritty texture, and chemically stable over a broad range of storage temperatures and durations. The formulations may further be compatible with additional active ingredients, thereby enabling the incorporation of secondary actives commonly used in dermatological or cosmetic applications. The disclosed formulations are suitable for routine topical administration, including once-daily or twice-daily use, and may be manufactured using conventional pharmaceutical or cosmetic processing equipment and standard formulation techniques.

[0018] In some embodiments, a disclosed composition, solvent system, submicron emulsion, gel composition and / or topical formulation may further comprise at least one strontium salt and / or dimethyl sulfone (MSM), each independently in a concentration of from about 0.5% to 5% by weight. Exemplary strontium salts include strontium chloride hexahydrate, strontium nitrate and strontium acetate.

[0019] Additional active agents may also be included in a submicron emulsion, gel composition or topical formulation disclosed herein, selected from active agents that provide, for example, exfoliating, keratolytic, depigmenting, antioxidant, skin barrier-supporting, hydrating, anti-aging, and / or penetration-enhancing effects, and / or active agents useful for treating a dermatological disease, disorder, or condition, such as acne, rosacea, hyperpigmentation disorders, and related inflammatory skin conditions.

[0020] In yet another aspect, the present disclosure relates to a method for treating, preventing, ameliorating, mitigating, and / or relieving a skin disease, disorder, or condition that may benefit from topical application of azelaic acid, the method comprising administering to a subject in need thereof a therapeutically or cosmetically effective amount of a composition or formulation comprising azelaic acid solubilized, optionally in a substantially molecularly dispersed state, in Acetamide MEA as a primary solvent. Diseases, disorders or conditions treatable by a disclosed method, include, for example, acne (e.g., acne vulgaris), rosacea, hyperpigmentation disorders, and related inflammatory skin conditions.

[0021] In still a further aspect, the present disclosure relates to a method for providing a solution of azelaic acid wherein azelaic acid is stably maintained in a substantially molecularly dispersedand non-crystalline state, comprising solubilizing azelaic acid in a solvent system comprising Acetamide MEA and, optionally, at least one polyol, as described herein.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Some embodiments of the present disclosure are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments disclosed herein. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments described herein may be practiced.

[0024] Figs. 1A-1E are images of exemplary vials containing preparations of azelaic acid (AzA) (15% (w / w)) dissolved the following solvent systems: Acetamide MEA / AzA (8:2 w / w) (Fig. 1A), propylene glycol / AzA (8:2 w / w) (Fig. IB), ethoxydiglycol / AzA (8:2 w / w) (Fig. 1C), PEG-8 / AzA (8:2 w / w) (Fig. ID) and MEA / propylene glycol (6:2 w / w) / AzA (8:2 w / w) (Fig. IE). Images were captured 24 hours after preparation and storage at 22°C; and

[0025] Figs. 2A-2B are polarized light micrographs (400 x magnification) of a commercially available product comprising 20% azelaic acid dissolved in propylene glycol (Fig. 2A), and 20% azelaic acid solubilized in Acetamide MEA solvent system (Fig. 2B). Images were taken 24 after preparation and storage at 22°C.

[0026] DETAILED DESCRIPTION

[0027] The present disclosure relates to pharmaceutical and cosmetic compositions and formulations comprising azelaic acid as a therapeutic / cosmetic active ingredient and Acetamide MEA as the primary solvent, wherein the azelaic acid is present in a molecularly dispersed, isotropic state that is resistant to crystallization over an extended period of at least 6, typically at least 24 month, under normal storage conditions (15 - 30°C).

[0028] The present disclosure is based on a discovery by the present inventors that Acetamide MEA (N-acetyl ethanolamine) acted as a high-capacity solvent and stabilizer for azelaic acid (AzA) through a previously unrecognized mechanism. Unexpectedly, Acetamide MEA prevented thenucleation of crystals even at high active concentrations (15 - 20% w / w) and maintained perfectly transparent solutions where standard pharmaceutical glycols failed.

[0029] Azelaic acid presents several well-recognized challenges in topical formulation. It is nearly insoluble in water (approximately 2.1 g / L at 20 °C), insoluble in oils, and only sparingly soluble in most conventional cosmetic solvents, making it difficult to prepare formulations containing therapeutically effective concentrations, typically about 15 - 20% by weight. Thus, bioavailability and therapeutic efficacy of AzA is compromised. Although certain organic solvents, such as polyethylene glycol or polypropylene glycol ethers, and particularly ethoxydiglycol or butoxydiglycol, can dissolve azelaic acid to form clear solutions at ambient temperature (e.g., up to about 360 g / L in ethoxydiglycol), their use is limited due to high dermal penetration potential and the tendency of azelaic acid to recrystallize during storage. At elevated concentrations, azelaic acid readily undergoes nucleation and subsequent crystal growth, leading to crystallization or aggregation that can compromise formulation stability, reduce dosing uniformity, and produce an undesirable gritty texture. In addition, some formulations may cause skin irritation or discomfort, partly due to drying effects, the presence of certain salts or derivatives, or the high levels of surfactants sometimes used to improve solubility, which may disrupt the skin barrier or create undesirable residue and tackiness.

[0030] Various approaches have been proposed to address these issues. For example, U.S. Patent No. 6,534,070 describes compositions combining azelaic acid with polyacrylic acid and propylene glycol to enhance stability and penetration, while France Patent No. 2616430 proposes azelaic acid diesters to improve solubility and reduce drying effects. Other formulation strategies, including hydrogels, creams, microemulsions, nanocrystal systems, and liposomal gels, have also been explored. However, many such approaches remain limited by issues of stability, scalability, bioavailability, skin tolerability, or overall therapeutic or cosmetic performance.

[0031] For example, liposomal gel formulations encapsulating azelaic acid within lipid bilayers have been developed to enhance stability and bioavailability by enabling controlled release and improved skin penetration. However, liposomal systems are often sensitive to environmental conditions, which can compromise their stability and complicate large-scale manufacturing. In addition, lipid-based carriers may cause irritation in some individuals, and despite improvedpenetration, the overall therapeutic performance may still be constrained by the skin's barrier function and the formulation's ability to maintain effective concentrations of azelaic acid.

[0032] Nanocrystal formulations have also been proposed, in which azelaic acid is reduced to nanoscale particles to increase surface area and enhance dissolution rate and apparent bioavailability. While such suspensions may improve skin penetration and distribution, they often present manufacturing and stability challenges, as nanocrystal systems require tightly controlled processing conditions and may be difficult to stabilize during long-term storage. Moreover, suboptimal particle size control may increase the risk of skin irritation. Consequently, although nanocrystal formulations can improve bioavailability, their overall therapeutic efficacy and treatment outcomes may remain limited, often requiring frequent application.

[0033] Solvent systems and compositions

[0034] One aspect of the present disclosure relates to a solvent system comprising Acetamide MEA and, optionally, at least one aliphatic polyol, capable of solubilizing azelaic acid and maintaining the azelaic acid in a substantially molecularly dispersed and non-crystalline state.

[0035] In some embodiments, the azelaic acid is maintained in a substantially molecularly dispersed and in a non-crystalline state at room temperature for a period of at least 6 months, for example, for a period of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, months or more.

[0036] In another aspect, the present disclosure relates to a composition in the form of a solution, comprising azelaic acid Acetamide MEA and, optionally, at least one aliphatic polyol, wherein Acetamide MEA functions as a primary solubilizing agent for azelaic acid. The solution is clear and stable at room temperature.

[0037] The term "solubilized", as used herein, refers to the presence of a compound in a composition in a form that is molecularly dispersed or otherwise rendered soluble, including true solutions as well as systems involving micellar, emulsified, or complexed states. Thus, "solubilized" includes dissolved as well as apparently dissolved via surfactants, emulsions, co-solvent systems and complexation.The term "clear and stable", as used herein, means substantially free of detectable crystals and / or aggregates of azelaic acid, at room temperature for a period of at least 6 months.

[0038] The term "substantially", us used herein, refers to a condition that is largely, predominantly, or essentially present, while allowing for minor deviations, trace amounts, or practical measurement limitations that do not materially affect the intended function, property, or performance of the composition. The term acknowledges that absolute conditions are not always achievable due to analytical limits, environmental variability and / or manufacturing tolerances.

[0039] The term "molecularly dispersed", as used herein, refers to a condition in which azelaic acid is dissolved at the molecular level within the solvent system, rather than existing as crystalline aggregates or suspended particles. Such a state may be characterized by optical isotropy (e.g., absence of birefringence under polarized light), lack of detectable particulate matter using appropriate analytical techniques, and single-phase behavior under thermal analysis. Maintaining azelaic acid in this state may contribute to uniformity of the composition and reduced likelihood of crystallization during storage.

[0040] Birefringence refers to the optical phenomenon exhibited by anisotropic materials, such as crystalline solids, in which incident light is divided into two rays that propagate at different velocities and directions due to differences in refractive index within the material, resulting in characteristic light transmission patterns observable under polarized light. This phenomenon, also referred to as double refraction, results in characteristic light transmission patterns that can be observed using polarized light microscopy. In contrast, isotropic systems, such as true solutions in which components are molecularly dispersed, do not exhibit birefringence and appear dark and uniform under polarized light.

[0041] In the context of the compositions and systems described herein, birefringence provides a useful analytical indicator for the presence or absence of crystalline azelaic acid. Crystalline or aggregated forms of azelaic acid exhibit birefringence and may appear as bright, often needle-like structures under polarized light, whereas azelaic acid that is fully solubilized at the molecular level within the solvent system remains optically isotropic and does not produce birefringent signals. Accordingly, the absence of birefringence under polarized light is used to confirm that azelaic acidis present in a substantially molecularly dispersed, non-crystalline state within the composition. This characteristic is associated with improved uniformity, enhanced physical stability, and reduced likelihood of crystallization during storage, and thus serves as an important qualitative indicator of formulation performance in the present invention.

[0042] The term "in a substantially molecularly dispersed and non-crystalline state", as used herein, means that azelaic acid is present predominantly as individual molecules solubilized within the solvent system under the specified storage conditions, rather than as crystalline solids or aggregated particles. The term acknowledges that minor amounts of undissolved or microcrystalline material may be present, provided that such amounts do not materially affect clarity, stability, bioavailability, or therapeutic or cosmetic performance.

[0043] The term "substantially free of detectable crystals and / or aggregates of azelaic acid", as used herein, means that the composition does not contain crystals or aggregates in amounts detectable by standard analytical or visual inspection methods, or in quantities sufficient to affect physical stability, appearance, texture, or performance over the specified storage period. Trace levels of crystalline material below detection limits or below levels that impact performance may still fall within this definition, and the composition may appear clear and uniform to the naked eye.

[0044] Minimal or undetectable crystal and / or aggregate formation may optionally be quantified using acceptable thresholds in the art. For example, crystal / aggregate formation is considered minimal if the concentration of the crystal / aggregate is less than 0.1% of the total solution volume or mass and / or if they are smaller than 1 micron (1 pm) such that they are undetectable to the naked eye. Visual clarity serves as a qualitative test, whereby the solvent system or solution remains visually clear and uniform without visible particles or turbidity.

[0045] Without wishing to be bound by theory, the solvent systems and compositions / solutions described herein may exhibit favorable mixing behavior between azelaic acid and Acetamide MEA, which may contribute to the formation of stable, single-phase systems over a range of concentrations. In contrast to conventional solvent systems that may form metastable or supersaturated solutions prone to crystallization, the solvent systems and compositions described herein may demonstrate reduced tendency toward phase separation or crystal formation under normal storage conditions.As used herein, "Acetamide MEA" includes N-acetyl ethanolamine (an amide derivative of monoethanolamine (MEA)), and commercially available aqueous solutions thereof. Acetamide MEA is typically obtained as a clear, water-miscible liquid and is commonly used in cosmetic and personal care formulations as a humectant and skin- or hair-conditioning agent.

[0046] Without wishing to be bound by theory, the enhanced solubilization and crystallization resistance observed in the disclosed azelaic acid solutions, solvent systems and compositions is believed to arise from specific intermolecular interactions between Acetamide MEA and azelaic acid. In particular, the amide and hydroxyl functionalities of Acetamide MEA are capable of forming hydrogen-bonding interactions with the carboxylic acid groups of azelaic acid, which may enhance solubilization and interfere with intermolecular associations required for nucleation and crystal growth. In addition, the amphiphilic character of Acetamide MEA may promote favorable molecular interactions with both the polar carboxyl groups and the hydrophobic aliphatic chain of azelaic acid, thereby maintaining the active ingredient in a substantially molecularly dispersed state within the formulation matrix. The amide functionality of Acetamide MEA may interact with the polar carboxylic acid groups of azelaic acid, while the ethylamine portion of the molecule may associate with, or accommodate the more hydrophobic regions of the azelaic acid chain, collectively enhancing solubilization.

[0047] These interactions are believed to reduce intermolecular association between azelaic acid molecules and interfere with nucleation and crystal growth, thereby stabilizing azelaic acid in a substantially molecularly dispersed, non-crystalline state during storage. In addition, the Hansen solubility parameters of Acetamide MEA closely approximate those of azelaic acid. Hansen solubility parameters describe the relative contributions of dispersive, polar, and hydrogenbonding interactions that govern molecular compatibility between substances; when the parameters of two materials are similar, thermodynamically favorable mixing is promoted. The close correspondence between the Hansen solubility parameters of Acetamide MEA and azelaic acid is therefore believed to facilitate molecular-level mixing and reduce the thermodynamic driving forces for phase separation or crystallization.

[0048] Furthermore, at sufficiently high concentrations of Acetamide MEA (above 15% w / w), the viscosity of the solvent phase may increase, thereby reducing molecular mobility and diffusionrates of azelaic acid molecules within the formulation. This reduction in molecular mobility can slow diffusion-controlled nucleation and crystal growth processes and hinder the formation of an ordered crystal lattice. Through this combination of hydrogen bonding, solubility parameter compatibility, amphiphilic interactions, and viscosity-related kinetic effects, Acetamide MEA functions not merely as a solvent but rather as an effective crystallization inhibitor capable of maintaining azelaic acid in a substantially molecularly dispersed and non-crystalline state in the solutions, solvent systems, and compositions described herein over extended storage periods.

[0049] In contrast to many glycol-based solvent systems (e.g., propylene glycol and polyethylene glycol, e.g., PEG 400), which frequently allow azelaic acid to recrystallize upon cooling or during storage, the Acetamide MEA-based systems described herein maintain azelaic acid in a substantially molecularly dispersed, non-crystalline state for extended periods. The molecular dispersion achieved by Acetamide MEA represents a true solution rather than a supersaturated state prone to spontaneous precipitation.

[0050] Without wishing to be bound by theory, the enhanced solubility and stability observed in Acetamide MEA compared to known glycol-based solvent systems may arise from Acetamide MEA's better structure compatibility with AzA and its amide functionality that can interact effectively with the carboxylic acid groups of azelaic acid through hydrogen bonding. Solubility is determined by the overall compatibility of the solvent and solute, often described by solubility parameters. Acetamide MEA may have solubility parameters that are closer to that of azelaic acid, making it a better solvent despite its lower polarity compared to, e.g., propylene glycol., thereby promoting stronger solute-solvent interactions than those typically provided by hydroxyl-based solvents.

[0051] Stable, clear and high concentration solutions or solvent systems of azelaic acid dissolved in Acetamide MEA comprise AzA in an amount from about 10 g / L to about 400 g / L, or approximately from about 5% to 35% (w / w), depending on solvent density. For example, from about 10 g / L to about 25 g / L, from about 20 g / L to about 100 g / L, from about 50 g / L to about 150 g / L, from about 100 g / L to about 250 g / L, from about 150 g / L to about 300 g / L, from about 280 g / L to about 380 g / L, from about 290 g / L to about 370 g / L, from about 300 g / L to about 400 g / L, from about 300 g / L to about 360 g / L, from about 260 g / L to about 350 g / L, from about 290 g / L to about340 g / L, from about 310 g / L to about 350 g / L, from about 320 g / L to about 360 g / L, or from about 280 g / L to about 310 g / L.

[0052] In some embodiments, the solubility of azelaic acid in Acetamide MEA is as high as 350 g / L. In some embodiments, the solubility of azelaic acid in Acetamide MEA is at least 300 g / L. The amount of Acetamide MEA in a disclosed solvent system or composition is from about 10% to about 55% w / w, for example, from about 12% to about 52%, from about 15% to about 50%, from about 18% to about 50%, from about 20% to about 45%, from about 25% to about 50%, from about 25% to about 45%, from about 30% to about 52%, from about 30% to about 48%, from about 35% to about 52%, from about 35% to about 45%, or from about 20% to about 40% by weight.

[0053] In some embodiments, Acetamide MEA is present at concentrations of from about 15% to about 50% or from about 25% to about 45%.

[0054] The weight ratio of Acetamide MEA to azelaic acid in the solvent system or the composition varies between 1:1 and 5:1. In some embodiments the ratio is between 2:1 and 4:1.

[0055] In some embodiments, the compositions and solvent system disclosed herein comprise cosolvents such as, but not limited to, one or more aliphatic polyols. As used herein, the term "aliphatic polyol" refers to a C2-C8, for example, C3-C6, aliphatic compound comprising two or more hydroxyl (— OH ) groups and a saturated or unsaturated, linear or branched carbon backbone, and includes, but is not limited to, glycols, triols, and higher polyols, such as ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, and optionally one or more higher polyols selected from glycerin (glycerol), sorbitol, and xylitol. The aliphatic polyols are present at a concentration of from about 5% to about 30% by weight.

[0056] Submicron emulsion systems

[0057] In a further aspect, the present disclosure relates to submicron emulsions comprising microemulsions and nanoemulsions, comprising azelaic acid dissolved in Acetamide MEA and, optionally, at least one aliphatic polyol.

[0058] As used herein, the term "submicron emulsion" refers to an emulsion system comprising two immiscible liquid phases, typically oil and water, in which the dispersed droplets have anaverage particle size below approximately 1 micrometer. The term is intended to encompass both microemulsions and nanoemulsions, as well as related finely dispersed emulsion systems having droplet sizes in the nanometer to submicron range. Such systems generally comprise at least one oil phase, at least one aqueous phase, and one or more surfactants and, optionally, one or more co-surfactants or co-solvents capable of stabilizing the dispersed droplets. The oil phase is capable of dissolving hydrophobic components; the aqueous phase solubilizes hydrophilic substances. Depending on their structure, these systems may be configured as oil-in-water (0 / W) emulsions, in which oil droplets are dispersed within a continuous aqueous phase, or water-in-oil (W / 0) emulsions, in which water droplets are dispersed within a continuous oil phase. Submicron emulsions may be optically transparent, translucent, or slightly opalescent depending on droplet size and composition. These systems may be thermodynamically stable and / or kinetically stable and may be prepared using spontaneous emulsification or energy-assisted processes such as homogenization, ultrasonication, or microfluidization. Both microemulsions and nanoemulsions can significantly increase the penetration of lipophilic, hydrophilic and amphiphilic substances into and through the skin, compared to conventional vehicles, and are progressively used as drug delivery systems for topical dermatological compositions.

[0059] The present inventor has designed and successfully fabricated novel formulations based on microemulsions and nanoemulsions containing azelaic acid completely dissolved in a solvent system comprising Acetamide MEA and glycols at a concentration range of from 5% to about 20% (w / w). This is the first time that stable microemulsions / nanoemulsions were obtained, containing an effective concentration of azelaic acid, thus enabling increased penetration of AzA into the skin.

[0060] Optimization of microemulsions / nanoemulsions resulted in inclusion of additional solvents besides Acetamide MEA such as, but not limited to, glycols. For example, inclusion of PEG-400 as co-emulgator was beneficial for polysorbates-induced emulsification. As the oily phase, adipate esters or fatty acid esters of glycerin were used.

[0061] The AzA concentration in a contemplated microemulsion or nanoemulsion is from about 3% to 30% (%wt), for example, from about 5% to 30%, from about 5% to 25%, from about 5% to 20%, from about 7% to 25%, from about 8% to 20%, from about 10% to 25%, from about 10% to20%, from about 10% to 15%, from about 13% to 20%, from about 15% to 25%, or from about 18% to 28% of total emulsion weight.

[0062] In some embodiments, the micro- or nanoemulsion systems are stabilized by the inclusion of one or more surfactants, for example glycols. As used herein, the term "glycols" broadly refers to organic compounds containing one or more hydroxyl (—OH) groups, including diols such as ethylene glycol, propylene glycol, and butylene glycol, as well as related derivatives such as glycol ethers and esters, for example ethoxydiglycol and butoxydiglycol, and polymeric glycols including polyethylene glycol (PEG; comprising repeating units of ethylene oxide) and polypropylene glycol and their corresponding esters. Such compounds are typically of low molecular weights, contain multiple functional groups, are linear or branched and typically exhibit properties such as water solubility, hygroscopicity, and low volatility. Due to these characteristics, glycols are widely used in pharmaceutical and cosmetic formulations as solvents, humectants, emulsifying or stabilizing agents, conditioning agents, and penetration enhancers.

[0063] The oily phase of the micro / nanoemulsion can be formulated using different types of lipids and oils such as triglycerides and essential oils to produce emulsions of different physicochemical and biological properties. The aqueous portion may be manipulated by adding different water-soluble components.

[0064] The micro- or nano-emulsified comprising azelaic acid can be molded and formulated as one or more skincare products such as ointments, creams, lotions, oils, liquids, sprays, foams or milks.

[0065] Rheology modifiers

[0066] As used herein, the term "rheology" refers to the flow and deformation behavior of a material under applied stress or shear, including properties such as viscosity, elasticity, yield stress, thixotropy, and shear-dependent flow characteristics. In the context of the compositions described herein, rheology governs the mechanical and flow properties of solvent systems, gels, submicron emulsions, and related compositions comprising azelaic acid dissolved in Acetamide MEA. Rheological behavior influences important formulation attributes, including physical stability,resistance to sedimentation or phase separation, spreadability during topical application, and overall sensory characteristics.

[0067] The term "rheology modifier" refers to a material capable of altering or controlling the rheological properties of a composition. Rheology modifiers may increase viscosity, impart viscoelasticity, generate yield stress, or form a structural network that immobilizes the liquid phase. In some embodiments, rheology modifiers form a three-dimensional network that converts a liquid solvent system into a semi-solid gel composition. Suitable rheology modifiers include, but are not limited to, particulate structuring agents, polymeric thickeners, clays, and other materials capable of modifying the mechanical and flow properties of the composition.

[0068] As used herein, the term "particulate structuring agent" refers to solid particles capable of forming a three-dimensional network within a liquid phase through particle-particle interactions, aggregation, or percolation, thereby immobilizing the liquid and imparting gel-like rheological properties. Non-limiting examples include silica-based materials such as fumed silica and derivatives thereof. Such structuring agents may generate yield stress, defined herein as the minimum applied stress required to initiate flow in a material that behaves as a viscoelastic solid at low stress levels.

[0069] In some embodiments, rheology modifiers are used in the compositions described herein to structure gel compositions, stabilize submicron emulsions, restrict droplet mobility, improve suspension stability, and adjust the viscosity and sensory properties of compositions comprising azelaic acid dissolved in Acetamide MEA.

[0070] Gel compositions

[0071] To enhance the stability and bioavailability of azelaic acid dissolved in Acetamide MEA and improve delivery and efficacy, the present inventors utilized fumed silica and / or its derivatives as nano-structured inorganic matrices for supporting azelaic acid-containing submicron emulsions and solvent systems.

[0072] In a further aspect, the present disclosure relates to a gel composition comprising azelaic acid, Acetamide MEA, at least one rheology modifying agent and at least one particulate structuring agent, wherein the azelaic acid is solubilized in the composition.As used herein, the term "gel" refers to a semi-solid composition in which a liquid phase is immobilized or substantially immobilized by a three-dimensional network, thereby imparting viscoelastic properties and resistance to flow. Such networks may be formed by polymeric structuring agents, particulate networks, supramolecular interactions, or by sufficiently high viscosity of the solvent system itself. Accordingly, gels encompassed by the present disclosure may include structured gels, non-structured gels, anhydrous gels, organogels, or other gel-like compositions.

[0073] The term "anhydrous gel" refers to a gel composition in which the primary liquid phase is substantially free of water and is instead composed predominantly of non-aqueous solvents, such as Acetamide MEA and optional co-solvents or polyols. As used herein, "substantially free of water" means that water is not intentionally added to the composition and, if present, occurs only in trace amounts resulting from residual moisture in raw materials or environmental exposure.

[0074] The term "structured gel" refers to a gel in which the liquid phase is immobilized within a three-dimensional network formed by structuring agents such as silica particles (e.g., fumed silica), polymeric thickeners, or combinations thereof. Such structuring agents may also be referred to herein as rheology modifiers, as they function to modify the rheological properties of the composition, including viscosity, yield stress, and viscoelastic behavior. Accordingly, in certain contexts the terms "structuring agents" and "rheology modifiers" may be used interchangeably to describe materials capable of forming or enhancing the structural network responsible for the gellike properties of the composition. The structural network may be generated by particulate interactions, polymeric networks, supramolecular assemblies, nanostructured fibers, or other mechanisms capable of immobilizing the liquid phase and imparting gel-like rheological properties.

[0075] In some embodiments, the gel composition (and the submicron emulsion) comprises at least one particulate structuring agent at a concentration from about 1% to about 9% by weight, for example, from about 2% to about 8% by weight.

[0076] In contrast, a "non-structured gel" refers to a viscous or semi-solid composition exhibiting gel-like rheological behavior primarily due to the inherent viscosity of the solvent system or dissolved components rather than a discrete particulate or polymeric network.The gel structure may be formed by any material or combination of materials capable of generating a three-dimensional network that immobilizes the liquid phase and produces gel-like rheological behavior.

[0077] In some embodiments, gel compositions comprising azelaic acid dissolved in Acetamide MEA include one or more rheology modifiers to produce structured gel systems. In some embodiments, gel-like behavior may arise primarily from the intrinsic viscosity and intermolecular interactions of the solvent system itself.

[0078] In some embodiments, the gel compositions (for brevity also referred to herein as "gels") described herein comprise a silica-derived matrix capable of structuring the solvent phase and forming a stable gel network. As used herein, the term "silica-derived matrix" refers to a structural network formed from silica-containing materials that are capable of interacting through particleparticle interactions to generate a three-dimensional framework within the liquid phase. Such matrices may immobilize or substantially immobilize the solvent system, thereby converting a liquid composition into a semi-solid gel exhibiting viscoelastic or yield-stress behavior. In the compositions disclosed herein, the silica-derived matrix may structure azelaic acid compositions, solvent systems comprising Acetamide MEA and optional co-solvents, or submicron emulsions thereby forming stable gel compositions in which azelaic acid remains solubilized or substantially molecularly dispersed.

[0079] The silica-derived matrix may comprise fumed silica and / or derivatives of silica capable of acting as particulate structuring agents. As used herein, the term "fumed silica" refers to finely divided amorphous silicon dioxide (SiO2) produced by flame hydrolysis or related high-temperature vapor-phase processes, resulting in primary particles typically in the nanometer size range. These primary particles aggregate into branched, fractal-like structures with very high specific surface area and surfaces rich in silanol groups (Si-OH). The surface silanol groups enable hydrogen bonding and particle-particle interactions that promote the formation of a three-dimensional particulate network within liquid media. When dispersed in suitable solvent systems, such as compositions comprising Acetamide MEA and optional co-solvents, these aggregates can interact to form a silica-derived matrix capable of immobilizing the solvent phase and imparting gel-like rheological behavior.In some embodiments, the fumed silica may be hydrophilic or surface-modified to produce hydrophobic or organophilic grades. Examples include commercially available materials such as hydrophilic fumed silicas (e.g., AEROSIL® 200, AEROSIL® 300) and surface-treated fumed silicas (e.g., AEROSIL® R972, AEROSIL® R805), although other silica materials with comparable structuring properties may also be used. The resulting silica-derived matrix may increase viscosity and generate yield stress within the composition, thereby restricting molecular mobility and contributing to the physical stabilization of the system. In compositions comprising azelaic acid solubilized in Acetamide MEA, such structuring may assist in maintaining the active ingredient in a substantially molecularly dispersed state and reduce the tendency of azelaic acid to crystallize or aggregate during storage.

[0080] As used herein, the term "silica derivatives" refers to silica-based materials whose surfaces have been chemically modified or functionalized to alter surface polarity, solvent compatibility, dispersibility, or structuring performance. Such materials include, for example, hydrophobically treated silicas, organosilane-treated silicas, and surface-silylated silicas.

[0081] In some embodiments, the silica-derived matrix (also interchangeably referred to herein as "silica-based structuring materials") may further include silica in different physical forms, such as fumed silica, silica nanoparticles, or silica aerogels, whether unmodified or surface-modified. Examples of suitable surface modifications include alkyl, polydimethylsiloxane, or other organosilane-derived groups that enhance compatibility with organic or substantially non-aqueous solvent systems. These silica-based structuring materials may be used individually or in combination to contribute to a particulate structuring network capable of immobilizing the solvent phase and producing stable gel compositions suitable for pharmaceutical or cosmetic compositions comprising azelaic acid and Acetamide MEA.

[0082] In certain embodiments, the gel compositions described herein comprise a structured gel matrix in which a submicron emulsion, including a microemulsion or nanoemulsion, is incorporated. In such embodiments, azelaic acid solubilized in Acetamide MEA may be present within the dispersed emulsion phase and immobilized within the gel network. The structured matrix, for example a silica-derived matrix, may enhance physical stability by restricting molecular mobility and reducing the tendency of azelaic acid to crystallize. Accordingly, the resulting gelcompositions may maintain azelaic acid in a substantially molecularly dispersed state while maintaining optical clarity and resistance to crystallization during storage, thereby providing desirable rheological and sensory properties suitable for topical pharmaceutical, dermatological or cosmetic compositions.

[0083] In some embodiments, the silica-derived gel compositions described herein may also contribute to improved physical stability by maintaining a uniform dispersion of the active ingredient within the solvent phase, thereby reducingthe likelihood of precipitation during storage or use. The high specific surface area of the silica-based structuring agents may further promote interactions between the active ingredient and the gel matrix, which can help maintain homogeneous distribution of azelaic acid within the composition.

[0084] In addition, the nanostructured characteristics of the silica-derived matrix may influence the interaction between the composition and the skin surface during topical application. Such gel systems may facilitate uniform spreading and improve the distribution of the active ingredients across the treated area. In some embodiments, the structured gel matrix can further modulate the migration of azelaic acid from the composition to the skin surface, thereby contributing to sustained availability of the active ingredient during topical application.

[0085] Any of the compositions and systems disclosed herein can be adjusted to a mildly acidic pH range, for example about pH 4.0 to about pH 5.0, and in some embodiments about pH 4.5 to about pH 4.8. Maintaining the compositions and systems within this pH range assists in maintaining azelaic acid predominantly in its protonated form (pKal ~ 4.55), thereby supporting its solubility in the solvent system and reducing the likelihood of salt formation or precipitation. Furthermore, azelaic acid exhibits enhanced antimicrobial efficacy in its protonated form, contributing to preservation and therapeutic action thereof. Keeping the pH in the range of 4.5-4.8, i.e., close to the natural acidic mantle of healthy skin (pH 4.5-5.5), promotes barrier function and minimizes irritation potential.

[0086] In some embodiments, maintaining a mildly acidic environment also contributes to the stability of silica-based structuring systems when present, and provides good compatibility with the natural acidity of the skin surface.The pH of the composition can be adjusted using suitable acidifying or alkalizing agents. For example, organic acids such as lactic acid, gluconic acid, or citric acid may be used to lower pH. In certain embodiments, lactic acid or gluconic acid are applied as buffers due to their buffering capacity and compatibility with strontium salts, whereas citric acid is used in formulations without strontium. In embodiments employing strontium salts as anti-irritant agents, maintaining pH <5.0 prevents the formation of insoluble salts such as strontium citrate that would compromise clarity and texture.

[0087] Mild bases such as sodium hydroxide solution (e.g., at (10% w / v), triethanolamine, or tromethamine can be used, if necessary, to increase pH. In some embodiments, buffering agents may be included in amounts sufficient to maintain pH stability during storage, for exdamlke, buffer capacity is maintained at >0.01 M to resist pH drift.

[0088] Topical formulations

[0089] In a further aspect, the present disclosure relates to topical formulations comprising azelaic acid solubilized in the formulation by Acetamide MEA.

[0090] As used herein, the term "topical formulation" refers to a pharmaceutical, dermatological, or cosmetic formulation comprising azelaic acid and Acetamide MEA and intended for application to the skin or mucous membranes. Such formulations may further comprise pharmaceutically or cosmetically acceptable excipients, carriers, or auxiliary ingredients and may be prepared in a variety of dosage forms

[0091] As used herein, the term "formulation" refers to a finished or ready-to-use pharmaceutical, dermatological, or cosmetic product comprising azelaic acid and suitable for topical application to the skin. The term is intended to be interpreted broadly and encompasses shelf-stable products prepared from any of the compositions or systems described herein, including, without limitation, solvent systems comprising Acetamide MEA, compositions or solutions comprising azelaic acid dissolved Acetamide MEA, submicron emulsions (including microemulsions and nanoemulsions), and anhydrous gel systems. Such formulations may optionally be structured or modified using one or more rheology modifiers, but the presence of such modifiers is not required. Accordingly, the term "formulation" includes final products in the form of solutions, gels, emulsions,microemulsions, nanoemulsions, creams, lotions, serums, or other cosmetically or pharmaceutically acceptable dosage forms that may be packaged, stored, distributed, and applied by a user.

[0092] As used herein, the term "pharmaceutical formulation" refers to a formulation comprising azelaic acid and Acetamide MEA, optionally together with pharmaceutically acceptable excipients, that is intended for therapeutic use in the prevention, treatment, or management of a medical condition affecting the skin or mucous membranes. Such pharmaceutical formulations may be designed for topical administration and may take the form of solutions, gels, emulsions, submicron emulsions, creams, lotions, or other pharmaceutically acceptable dosage forms capable of maintaining azelaic acid in a substantially molecularly dispersed state and delivering it to a target site in a pharmaceutically effective amount.

[0093] As used herein, the term "dermatological formulation" refers to a topical formulation comprising azelaic acid and Acetamide MEA that is intended for application to the skin for the treatment, management, or improvement of dermatological conditions. Dermatological formulations may include pharmaceutical or cosmetic preparations designed to address conditions such as acne, rosacea, hyperpigmentation, melasma, or other skin disorders. Such formulations may comprise solvent systems, gel compositions, or submicron emulsionsm, and may take the form of solutions, gels, emulsions, submicron emulsions, creams, lotions, or other dermatologically acceptable dosage forms capable of maintaining azelaic acid in a substantially molecularly dispersed state and delivering it to a target site in a dermatologically effective amount.

[0094] As used herein, the term "cosmetic formulation" refers to a formulation comprising azelaic acid and Acetamide MEA intended for topical application to the skin primarily for cosmetic purposes, including improving the appearance, texture, or condition of the skin. Cosmetic formulations may include, without limitation, serums, creams, gels, lotions, emulsions, or other cosmetically acceptable compositions designed to provide aesthetic benefits such as skin brightening, tone-evening, or skin-conditioning effects. Such formulations are capable of maintaining azelaic acid in a substantially molecularly dispersed state and delivering it to a target site in a cosmetically effective amount.In certain embodiments, the dermatological formulations described herein may be pharmaceutical or cosmetic formulations depending on their intended use and regulatory classification.

[0095] The terms "therapeutically effective amount", "dermatologically effective amount" and "cosmetically effective amount", as used herein, refer to an amount of azelaic acid sufficient to produce a desired therapeutic, dermatological, or cosmetic effect, respectively, when applied to the skin or mucous membranes. The effective amount may vary depending on factors including the formulation, the concentration of azelaic acid in the formulation, mode of administration, frequency of application, the condition being treated or improved, and the characteristics of the individual subject.

[0096] In some embodiments, azelaic acid may be present in the formulation at concentrations ranging from about 5% to about 30% by weight, for example from about 5% to about 20% by weight, although other concentrations may also be used, provided they achieve the intended therapeutic, dermatological, or cosmetic effect.

[0097] A desired effect may include, for example, reduction of inflammation, inhibition of microbial growth, normalization of keratinization, improvement of skin tone or appearance, or treatment or improvement of dermatological conditions such as acne (including acne vulgaris), rosacea, disorders of cutaneous hyperpigmentation, or related dermatological conditions. "Related dermatological conditions" refers to skin disorders sharing similar etiological or pathophysiological mechanisms with the conditions specifically recited herein, including disorders associated with inflammation of the pilosebaceous unit, abnormal keratinization, microbial colonization, or dysregulated melanocyte activity, such as, but not limited to, perioral dermatitis, seborrheic dermatitis, folliculitis, post-inflammatory hyperpigmentation, melasma, lentigines, dyschromia, and related cutaneous disorders.

[0098] The formulations disclosed herein (additionally, or alternatively to the compositions and systems disclosed herein), optionally further comprise one or more secondary active agents to modulate skin sensitivity, enhance therapeutic or cosmetic efficacy, and expand the range of dermatological indications. In particular, the formulations may include, for example, anti-irritant agents to mitigate sensory effects such as stinging, burning, or itching that may be associated withhigher concentrations of azelaic acid. For example, strontium salts sch as strontium chloride hexahydrate, strontium nitrate, or strontium acetate, can be present at about 0.5-5.0% by weight. Strontium ions (Sr2+) are known to modulate sensory responses, including interaction with transient receptor potential vanilloid 1 (TRPV1, a type of ion channel protein found primarily on sensory nerve endings, including those in the skin), thereby reducing irritation perception. In some embodiments, dimethyl sulfone (MSM) may be included at about 0.5-5.0% by weight as a penetration enhancer and anti-inflammatory agent. MSM may also contribute to stabilization of emulsion interfaces due to its polarity and can provide additional anti-inflammatory effects. In some embodiments, a combination of strontium salts (e.g., about 2-4% w / w) and MSM (e.g., about 2-3% w / w) is employed to provide a synergistic or optimal effect in reducing irritation and stabilizing the microemulsion interface, while maintaining relatively high concentrations of azelaic acid.

[0099] The presence of Acetamide MEA in the formulations disclosed herein affords broad compatibility with a variety of additional active agents and enables stable co-formulation without inducing crystallization or instability. Such compatible actives (also referred to herein as "secondary actives" or "secondary active ingredients") may include, for example, alpha- and betahydroxy acids, for example glycolic acid (about 2-10% w / w), lactic acid (about 2-10% w / w), salicylic acid (about 0.5-2.5% w / w), and mandelic acid (about 5-10% w / w), which may provide exfoliating, keratolytic, humidity, comedolytic, anti-inflammatory, antimicrobial and / or penetrationenhancing effects, sometime in a synergism with azelaic acid (e.g., glycolic acid) and / or with each other. Depigmenting agents can also be included, such as octadecenedioic acid (about 0.5-2.0% w / w; acting as tyrosine inhibitor), kojic acid (about 1-3% w / w), tranexamic acid (about 2-5% w / w), and niacinamide (about 3-5% w / w), which act through mechanisms including tyrosinase inhibition, plasminogen modulation, or melanosome transfer inhibition.

[0100] In some embodiments, the secondary active ingredient is salicylic acid at a concentration of 0.5% to 2.5% by weight.

[0101] In some embodiments, the formulations (and / or the compositions and systems) comprise retinoids, including retinol (about 0.1-1.0% w / w) which is stabilized by anhydrous environment, retinaldehyde (about 0.05-0.1% w / w), or hydroxypinacolone retinoate (about 0.5-2.0% w / w),which provide synergistic effects in acne treatment, skin renewal, and anti-aging applications, particularly in anhydrous or low-water systems that enhance their stability.

[0102] In some embodiments, the secondary active ingredient is retinol at a concentration of 0.1% to 1.0% by weight.

[0103] Antioxidants and vitamins may also be incorporated, including, but not limited to, tocopherols or tocotrienols (about 0.1-1.0% w / w), ascorbyl tetraisopalmitate (about 1-3% w / w), panthenol (about 1-5% w / w), and ergothioneine (about 0.1-0.5% w / w), which provide protection against oxidative stress, support skin barrier function, and improve overall skin condition.

[0104] Hydrating and barrier-supporting agents can also be included, such as sodium hyaluronate (about 0.1-2.0% w / w) of varying molecular weights (e.g., (10 kDa to 1,500 kDa), ceramides (about 0.5-2.0% w / w), beta-glucan (about 0.5-2.0% w / w), and allantoin (about 0.2-0.5% w / w), which may enhance hydration, promote barrier repair, promote immunomodulation and / or support wound healing and skin recovery.

[0105] In some embodiments, peptide-based actives are incorporated, for example, palmitoyl tetrapeptide-7, palmitoyl tripeptide-1, palmitoyl pentapeptide-4, and acetyl hexapeptide-8, typically at concentrations ranging from about 0.001% to about 0.5% by weight. The peptides provide anti-inflammatory effects, IL-6 modulation, matrix support, promote collagen and / or glycosaminoglycan synthesis, modulate neurotransmitters and / or reduce wrinkles. In some embodiments, the peptide component may be selected as a metal-free signaling peptide, for example palmitoyl tetrapeptide-7, to enhance compatibility with electrolyte-containing systems and to avoid potential interactions with strontium / MSM-based anti-irritant agents.

[0106] In some embodiments, plant-derived extracts or natural compounds are incorporated, such as, but not limited to, Centella asiatica extract (about 0.1-1.0% w / w), green tea extract (e.g., EGCG, about 0.5-2.0% w / w), licorice extract (e.g., glabridin, about 0.5-2.0% w / w), and resveratrol (about 0.1-1.0% w / w), which provide antioxidant, anti-inflammatory, anti-ageingand / or skin-conditioning benefits.

[0107] The ability of the present formulations to accommodate such a broad range of active agents distinguishes them from conventional azelaic acid formulations, which are often limited bysolubility constraints, pH incompatibilities, or instability issues that restrict multi-active formulations.

[0108] Compositions and formulations described herein exhibit high optical transparency, which may be attributed, at least in part, to refractive index matching between the components of the continuous phase and the dispersed or structured phases. For example, solvent systems comprising Acetamide MEA (refractive index n ~ 1.465), propylene glycol (n ~ 1.432), and non-ionic surfactants such as polysorbates (n ~ 1.468) may provide a combined refractive index in the range of approximately 1.455-1.460. This range may closely match that of silica-based structuring agents, such as amorphous fumed silica (n ~ 1.458), thereby reducing light scattering and enabling compositions that appear optically clear or glass-like despite the presence of dispersed structuring particles, for example, suspended silica particles at concentrations up to 6% w / w.

[0109] The formulations disclosed herein exhibit favorable physicochemical, sensory and aesthetic properties, including high optical transparency, smooth texture, absence of grittiness, and good spreadability, which may be evaluated using standard sensory assessment methodologies, as demonstrated in Example 2 herein. Maintaining azelaic acid in a substantially molecularly dispersed state may contribute to improved availability of the active ingredient at the skin surface relative to crystalline suspensions.

[0110] The compositions, systems and formulations disclosed herein are suitable for various regulatory classifications depending on concentration and intended use. Compositions and formulations comprising azelaic acid at lower concentrations (< 1 0% under USA regulations) are suitable for over-the-counter use, while higher concentrations (for example, 15-20% following clinical validation in the USA) can be formulated as prescription pharmaceutical products following appropriate clinical validation. The compositions may be used in cosmetic formulations in accordance with applicable regional regulations.

[0111] The compositions and formulation disclosed herein exhibit compatibility with a variety of packaging materials commonly used in pharmaceutical or cosmetic products. Stability evaluations indicated that the compositions remained stable when stored in containers such as high-density polyethylene (HDPE) tubes, lined aluminum tubes, polyethylene terephthalate (PET) bottles with polypropylene (PP) pumps, airless pump systems, glass containers, or polypropylene jars. In certaincases, airless packaging systems is preferred, particularly for compositions comprising oxygensensitive components, such as retinoids or ascorbic acid derivatives. Overall, the formulations and compositions exhibit minimal interaction with packaging materials, with no significant evidence of leaching, swelling, or degradation under typical storage conditions.

[0112] Methods of treatment

[0113] In another aspect, the present disclosure relates to methods for treating, preventing, ameliorating, or improving dermatological conditions that may benefit from topical administration of azelaic acid. Azelaic acid is known to exhibit multiple biological activities, including antimicrobial, anti-inflammatory, keratolytic, and depigmenting effects, which make it suitable for use in a wide range of skin conditions. These activities may include inhibition of acne-associated microorganisms, modulation of inflammatory pathways, normalization of keratinization within the pilosebaceous unit, and inhibition of tyrosinase activity involved in melanogenesis.

[0114] Accordingly, embodiments disclosed herein provide methods for treating, preventing, ameliorating, mitigating, and / or relieving a skin disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically or cosmetically effective amount of a composition or formulation comprising azelaic acid solubilized, and in some embodiments present in a substantially molecularly dispersed state, in Acetamide MEA as a primary solvent.

[0115] Skin diseases, disorders, or conditions treatable by a disclosed method include, but are not limited to, acne (e.g., acne vulgaris), rosacea, hyperpigmentation disorders, and related inflammatory skin conditions, wherein "related inflammatory skin conditions" includes conditions associated with cutaneous inflammation and / or abnormal keratinization or pigmentation, such as folliculitis, perioral dermatitis, seborrheic dermatitis, and post-inflammatory erythema, as long as such conditions are responsive to the anti-inflammatory, antimicrobial, keratolytic and / or depigmenting effects of azelaic acid.

[0116] In some embodiments, a disclosed method is used forthe treatment of acne, including mild to moderate acne, encompassing both comedonal and inflammatory forms. The treatment reduces microbial proliferation, decreases inflammatory responses, and assists in normalizing follicular keratinization. In some embodiments, the treatment comprisesapplication / administration of a formulation or a composition as described herein, comprising azelaic acid at a concentration of 15% to 20% by weight. In some embodiments, the method is used as monotherapy. In some embodiment, the is applied in combination with additional treatments, including topical or systemic antibiotics, retinoids, or hormonal therapies.

[0117] In some embodiments, a disclosed method is used for the treatment of rosacea, including papulopustular rosacea and erythema-associated conditions. Azelaic acid may reduce inflammation and visible redness associated with rosacea, and the method described herein may provide improved cosmetic acceptability and reduced irritation potential, thereby supporting patient compliance.

[0118] In additional embodiments, the method is used for the treatment of disorders of cutaneous hyperpigmentation, including melasma, post-inflammatory hyperpigmentation, lentigines, and other conditions associated with abnormal melanocyte activity. Azelaic acid may inhibit tyrosinase and modulate melanocyte function, thereby contributing to reduction of hyperpigmented lesions and improvement of overall skin tone. In some embodiments, the method is used as monotherapy. In some embodiment, the method is applied in combination with additional treatments, for example combined therapy with niacinamide, e.g., at a concentration of from about 3% to about 5% by weight.

[0119] The ability to maintain azelaic acid in a substantially molecularly dispersed state promotes uniform application and consistent exposure of the skin to the active ingredient.

[0120] In accordance with the methods disclosed herein, the compositions and formulations can be applied once or multiple times daily over a period sufficient to achieve a desired therapeutic or cosmetic effect. The methods described herein are applicable to human subjects and can be adapted for different skin types and treatment regimens.

[0121] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the present disclosure.

[0122] As used herein the term "about" refers to ± 10 %.The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

[0123] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0124] Throughout this application, various embodiments described may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0125] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other embodiment described herein.

[0126] Various embodiments and aspects of the present disclosure as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

[0127] EXAMPLES

[0128] Reference is now made to the following examples, which together with the above description illustrate some embodiments of the present disclosure in a non-limiting fashion. Generally, the nomenclature used herein, and the laboratory procedures utilized in the present disclosure include molecular, chemical, biochemical and / or microbiological techniques. Such techniques are thoroughly explained in the literature. Other general references are providedthroughout this document. The procedures therein are believed to be well known in the art and are provided for the convenience of the reader.

[0129] Materials and Methods

[0130] The compositions, systems and formulations described herein (for brevity, collectively referred to herein as "compositions") provide manufacturing advantages, including the ability to form homogeneous systems without the need for high-shear homogenization, particularly in submicron emulsion embodiments. Compositions are prepared using conventional cosmetic or pharmaceutical processing equipment, including standard mixing vessels and filling systems. In some embodiments, the compositions maintained their clarity upon cooling without requiring extended cooling cycles.

[0131] The molecularly dispersed state of azelaic acid in the compositions prepared in accordance with the present disclosure was supported by a combination of analytical techniques. For example, the absence of birefringence under polarized light microscopy, a technique that detects crystalline or anisotropic materials based on their interaction with polarized light, indicated a lack of crystalline domains. Dynamic light scattering (DLS), which measures fluctuations in scattered light intensity to determine the presence and size of particles in solution, showed no detectable particle size distribution, consistent with the absence of aggregated or particulate species. In addition, differential scanning calorimetry (DSC), a thermal analysis method that measures heat flow associated with phase transitions such as melting or crystallization, exhibited no detectable transitions attributable to azelaic acid, indicating the absence of a crystalline phase. Collectively, these observations were consistent with azelaic acid being present in a substantially molecularly dispersed, non-crystalline state within the compositions. In addition, the optical clarity of the compositions facilitated preliminary quality assessment by visual inspection, as loss of transparency indicated instability or phase separation.

[0132] The manufacturing process is scalable from laboratory (e.g., 100 g) to commercial production (e.g., 400 kg), while maintaining consistent physicochemical properties.(i) color variation measurements

[0133] CIELAB (also termed CIE L*a*b* or L*a*b* color space) is an internationally standardized color measurement system developed by the International Commission on Illumination (CIE) to quantitatively describe and compare colors. CIELAB represents color in a three-dimensional space using three coordinates: L* - lightness, range: 0 (black) to 100 (white); a* - red-green axis, wherein positive values - red and negative values - green; and b* - yellow-blue axis, wherein positive values - yellow and negative values - blue. Together, these three parameters define the exact color position of a sample in color space. The system was designed so that numerical differences correspond closely to human visual perception of color differences.

[0134] Quantitative color variation of the formulations was determined using instrumental colorimetric analysis based on the CIELAB color space. Color measurements were performed using a calibrated spectrophotometer equipped with a D65 standard illuminant and a 10° standard observer. Samples were placed in optically transparent cuvettes with a defined path length of 1 cm. Prior to measurement, the instrument was calibrated using a certified white calibration standard according to the manufacturer's instructions, to ensure measurement accuracy and reproducibility.

[0135] Measurements were taken for each sample prior to testing to establish baseline values and repeated after exposure to the relevant stress conditions, including photostability testing or storage studies. The overall color difference (AE) between the baseline and post-test samples was calculated according to the standard CIELAB color difference equation: AE - [(AL*)2+ (Aa*)2+ (Ab*)2]> . Each measurement was performed in triplicate, and mean values were used for AE calculation. In general, AE values below approximately 1.0 are considered not perceptible to the human eye, whereas higher values indicate increasing levels of visible color change. Accordingly, formulations exhibiting AE values below 1.0 after testing were considered to maintain acceptable color stability.EXAMPLE 1

[0136] Stability data, and comparative tests for Acetamide MEA solvent system The stability of the solvent system and azelaic acid solutions disclosed herein was qualitatively and quantitatively evaluated.

[0137] 5

[0138] (i) Qualitative comparative stability test

[0139] For this purpose, compositions comprising azelaic acid (AzA; 15% (w / w)) dissolved in various solvents at a solvent-to-AzA ratio (solvent / AzA) of 8:2 (w / w) were prepared. The solvent systems tested included: ethoxydiglycol / AzA, propylene glycol / AzA, PEG-8 / AzA, Acetamide io MEA / AzA and MEA / propylene glycol (6:2 w / w) / AzA. The resulting solutions were stored at 22°C ± 2°C and monitored periodically by visual inspection and microscopic examination to assess stability, i.e., crystallization and clarity. The results are shown in Table 1.

[0140] Table 1. Comparative stability results

[0141]

[0142] 15Images of exemplary vials containing the tested compositions are presented in Figs. 1A-1E. As shown in Figs. 1A and IE, the compositions comprising azelaic acid solubilized in Acetamide MEA and Acetamide MEA / propylene glycol (6:2 w / w), respectively, were clear and isotropic with no visible evidence of crystallization. This clarity was maintained even after 30 days of storage. The composition comprising azelaic acid dissolved in propylene glycol and ethoxydiglycol (Figs. IB and 1C, respectively), macro-crystallization and sediment were formed after approximately 24 hours, whereas in the composition comprising AzA dissolved in PEG-8 (Fig. ID), heavy crystallization was observed.

[0143] Microscopic observations of a commercially available product comprising 20% azelaic acid dissolved in propylene glycol, and 20% azelaic acid solubilized in Acetamide MEA solvent system of the present disclosure, are shown in Figs. 2A and 2B, respectively. The polarized light micrograph (400x magnification) of the commercially available product (Fig. 2A) clearly shows crystalline aggregates, birefringent needle-like structures, and non-uniform particle distribution indicative of crystallization, as compared to the almost complete dissolution of AzA obtained in the Acetamide MEA solvent system (Fig. 2B). These results demonstrate the superiority of the Acetamide MEA solvent system, in terms of crystal formation and clarity, over the polyglycol solutions.

[0144] (ii) Quantitative stability assessment

[0145] Quantitative stability studies were conducted under accelerated storage conditions of 40°C and 75% relative humidity to evaluate the physical and chemical stability of a composition comprising the azelaic acid solubilized in the Acetamide MEA solvent system (Acetamide MEA / AzA (8:2 w / w) over time. Exposure to these accelerated conditions increases the rate of physical or chemical changes, thereby enabling estimation of long-term stability. Samples were periodically examined for evidence of crystallization, particle formation, optical clarity, chemical integrity of the active ingredient, and rheological stability.

[0146] Throughout a six-month storage period under these conditions, no visible crystallization of azelaic acid was observed. Particle size analysis performed by laser diffraction confirmed the absence of particles larger than 1 pm, indicating that azelaic acid remained substantially free of detectable crystalline aggregates.Optical clarity measurements showed transmittance values greater than 95% at a wavelength of 600 nm using a 1 cm optical path length, demonstrating that the composition remained highly transparent. Chemical stability was assessed by high-performance liquid chromatography (HPLC), which indicated less than 2% degradation of azelaic acid over the test period. Rheological measurements further showed that the apparent viscosity of the composition remained stable, with less than a 10% change measured at a shear rate of 25 s’1.

[0147] The results disclosed herein, collectively, confirm that the disclosed solvent systems and compositions effectively maintained azelaic acid in a stable, substantially molecularly dispersed and non-crystalline state even under accelerated storage conditions.

[0148] (iii) Freeze-thaw cycling

[0149] The physical robustness of a composition comprising azelaic acid solubilized in the Acetamide MEA solvent system (Acetamide MEA / AzA (8:2 w / w)) was further evaluated through freeze-thaw cycling tests designed to simulate temperature fluctuations that may occur during storage and transportation. Samples were subjected to five consecutive freeze-thaw cycles, each consisting of storage at -10°C followed by equilibration at +25°C over a 24-hour period. Throughout the cycling process, the compositions showed no evidence of azelaic acid crystallization, phase separation, or viscosity breakdown upon visual and rheological examination.

[0150] These results indicate that composition comprising azelaic acid solubilized in the Acetamide MEA maintains physical stability and structural integrity under repeated temperature stress conditions.

[0151] (iv) Photostability

[0152] Photostability of a composition comprising azelaic acid solubilized in the Acetamide MEA solvent system (Acetamide MEA / AzA (8:2 w / w)) was assessed under accelerated ultraviolet exposure to evaluate potential degradation of azelaic acid and changes in product appearance. Samples were exposed to UV-A radiation at 340 nm with an irradiance of 0.89 W / m2for a total duration of 168 hours. Following exposure, the samples retained approximately 98% of the initial azelaic acid content as determined by HPLC analysis, indicating minimal photodegradation. Inaddition, no visible discoloration was observed following UV exposure, with color variation remaining below AE < 1.0 (CIELAB scale), and the composition maintained its optical transparency.

[0153] These results demonstrate that the disclosed compositions and solvent systems exhibit strong resistance to UV-induced degradation and maintain their physical and chemical stability under accelerated photostability conditions.

[0154] EXAMPLE 2

[0155] Comparative sensory evaluation

[0156] In a qualitative comparative evaluation, two exemplary test compositions comprising azelaic acid 15% (w / w) solubilized by Acetamide MEA were assessed against a commercially available azelaic acid formulation ("Commercial AzA") comprising 20% azelaic acid dissolved in propylene glycol, using a trained sensory panel (n= 15) . The test compositions included azelaic acid (AzA; 15% (w / w)) solubilized in 100% Acetamide MEA at a solvent-to-AzA ratio (solvent / AzA) of 8:2 (w / w) (Acetamide MEA / AzA) or in a solvent system comprising Acetamide MEA and propylene glycol at relative amounts 20:17.5 (w / w) and solvents / AzA of 8:2 (w / w) (Acetamide MEA / propylene glycol / AzA).

[0157] The evaluations were performed using a standardized 10-point scale across multiple sensory and aesthetic attributes. The results for Acetamide MEA / AzA are shown in Table 2.

[0158] Both test compositions demonstrated consistently improved performance relative to the comparator across all evaluated parameters. In particular, the compositions exhibited substantially higher visual clarity, improved spreadability, faster apparent absorption, reduced residue or stickiness, and a smoother, non-gritty texture upon application. Panelists further reported a more favorable skin feel following short-term application, characterized as smooth and non-greasy, compared to the tacky or less refined feel associated with the comparative formulation.

[0159] Overall acceptance scores were higher for the test compositions, indicating a clear preference among participants for the sensory profile of the inventive formulations. Without wishing to be bound by theory, these improvements can be associated with the ability of the test compositions to maintain azelaic acid in a substantially molecularly dispersed state, thereby reducing the presence of crystalline particles that can negatively affect texture and appearance.Table 2. Sensory evaluation results

[0160]

[0161] These qualitative observations support the conclusion that the compositions disclosed herein may provide enhanced user experience and improved aesthetic properties compared to conventional azelaic acid formulations.

[0162] EXAMPLE 3

[0163] Preparation of isotropic solutions and anhydrous gel compositions

[0164] Topical compositions were prepared as anhydrous systems comprising azelaic acid at concentrations of about 5-20% by weight, solubilized in Acetamide MEA present at about 15-50% by weight, optionally from about 25% to about 45% w / w as the sole solvent, or as co-solvent combined with one or more C3-C6 aliphatic polyol co-solvents, such as propylene glycol or butylene glycol, present at about 5-30% by weight. The resulting compositions formed clear, isotropic solutions in which azelaic acid was maintained in a substantially molecularly dispersed state.

[0165] The compositions were structured to form gels by the addition of one or more inorganic rheology modifiers, such as fumed silica or silica derivatives (for example silica dimethyl silylate),which were present at about 1-8% by weight. The silica-derived structuring agents formed a three-dimensional particulate network within the solvent system, thereby immobilizing the liquid phase and producing stable anhydrous gel compositions. The refractive indices of Acetamide MEA (approximately n - 1.465) and amorphous silica (approximately n - 1.458) are sufficiently similar such that the resulting structured gel exhibited high optical clarity or glass-like transparency while remaining substantially free of an aqueous phase. The structured gel compositions exhibited viscosities within a range suitable for topical administration, for example, about 15,000 to about 45,000 cP as measured using a Brookfield RVT viscometer (spindle #6, 10 rpm, 25°C).

[0166] The anhydrous nature of the gel compositions provided additional advantages, including improved compatibility with water-sensitive ingredients, reduced reliance on conventional antimicrobial preservatives, enhanced stability during storage under elevated temperature or humidity conditions, and favorable penetration characteristics for lipid-soluble active ingredients when applied topically to the skin.

[0167] EXAMPLE 4

[0168] Preparation of structured microemulsion

[0169] Transparent microemulsions were prepared, comprising azelaic acid at concentrations of 5-20% by weight, solubilized in a solvent system containing Acetamide MEA present at about 15-40% by weight as the sole solvent, or as co-solvent combined with one or more C3-C6 aliphatic polyol co-solvents (e.g., propylene glycol or butylene glycol), present at about 5-30% by weight. The microemulsions were stabilized by one or more non-ionic surfactants, for example polysorbate 80 and / or polysorbate 20, present at about 10-25% by weight, and further stabilized by an organic ester phase present at about 1-8% by weight, for example dimethyl adipate, isopropyl palmitate, or caprylic / capric triglyceride, and an aqueous phase present at about 5-25% by weight that optionally contained dissolved electrolytes or functional salts.

[0170] The microemulsions were structured using a synergistic combination of at least two rheology modifiers, for example, a cellulose-based polymer such as hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC) or hydroxypropyl methylcellulose (HPMC), present at about 0.1-2% by weight in combination with a particulate structuring agent such as fumed silica present at about1-6% by weight. The combined rheology modifiers provided enhanced viscosity and structural stability to the microemulsion (phase separation was prevented), thereby assisting in maintaining a substantially isotropic system in which azelaic acid remained solubilized or substantially molecularly dispersed.

[0171] The resulting structured microemulsions exhibited a mean droplet diameter of less than about 200 nm, as measured by dynamic light scattering, with a polydispersity index of less than about 0.3, indicating a relatively narrow droplet size distribution consistent with thermodynamically stable microemulsions.

[0172] Such systems maintained their dispersed structure even in the presence of dissolved salts or electrolytes, including multivalent cations such as strontium salts that were optionally present in concentrations of up to about 5% by weight. The compositions exhibited viscosities suitable for topical administration, for example about 8,000 to about 25,000 cP as measured using a Brookfield RVT viscometer (spindle #5, 10 rpm, 25°C).

[0173] EXAMPLE 5

[0174] Preparation of macroemulsions comprising azelaic acid solubilized in Acetamide MEA Topical compositions are prepared as conventional oil-in-water (O / W) or water-in-oil (W / O) macroemulsions, both comprising azelaic acid solubilized in a solvent system containing Acetamide MEA. These emulsions are prepared by first dissolving azelaic acid in Acetamide MEA to form substantially clear solutions, followed by incorporating the clear solution into either the aqueous phase or the oil phase of the emulsion during the manufacturing process. The resulting emulsion contain azelaic acid in a substantially molecularly dispersed state, reducing the likelihood of crystal formation and the gritty or sandy texture often associated with known azelaic acid cream formulations.

[0175] The obtained macro-emulsion compositions further accommodate at least one of: emollient oils, fatty esters, triglycerides, silicones, or other cosmetically or pharmaceutically acceptable oil-phase components to provide enhanced skin-conditioning properties. Additional active ingredients may be added, including oil-soluble compounds such as tocopherol, retinyl esters and / or related ingredients commonly used in dermatological or cosmetic formulations. Suchemulsions can be formulated to provide occlusive or high-emollience topical compositions suitable for overnight treatment or for use on dry or sensitive skin, as well as topical cosmetic products that contain pigments or colorants designed to impart color to the skin and provide coverage, similar to facial foundation or tinted skincare products.

[0176] EXAMPLE 6

[0177] Preparation of an anhydrous gel composition

[0178] A basic anhydrous gel formulation was prepared using the ingredients listed in Table 3, as follows.

[0179] Table 3. Formulation Composition

[0180]

[0181] First, a solvent system was prepared by combining Acetamide MEA and propylene glycol in a suitable mixing vessel equipped with an overhead stirrer to form a homogeneous solvent phase. The cellulose-based polymer (hydroxypropyl cellulose (H PC)) was then dispersed into the solvent under moderate agitation, at about 200 - 300 rpm, until a clear solution was obtained. The mixture was subsequently heated to a temperature of about 75 - 85°C, after which azelaic acid wasgradually added while maintaining the temperature and continuous stirring until complete dissolution was achieved and a clear solution was obtained. The lipophilic additive tocopheryl acetate, was then incorporated and mixed until uniform.

[0182] The solvent system in which AzA was completely solubilized was cooled to a temperature of about 35 - 40°C, after which fumed silica, the particulate structuring agent, was slowly added with an increase in mixing speed to about 400 - 500 rpm. Mixing continued for about 15 - 20 minutes to allow formation of a uniform gel structure. The composition was then cooled to room temperature under continued gentle stirring. A fragrance was added and mixed gently to ensure uniform distribution. The resulting composition was subjected to de-aeration under reduced pressure, e.g., about 50 - 100 mbar, for about 10 - 15 minutes, and subsequently filled into appropriate containers.

[0183] The resulting composition was obtained as a crystal clear, transparent gel, having a slight yellow tint. The composition exhibited a pH of about 4.6 - 4.8 without the need for external adjustment, a viscosity of about 22,000 ± 3,000 cP (measured using a Brookfield RVT viscometer spindle #6, 10 rpm, 25°C), and a transmittance of about 96% at 600 nm (1 cm path length). The composition exhibited physical stability, remaining substantially free of crystallization after storage for at least 18 months at 25°C.

[0184] EXAMPLE 7

[0185] Preparation of a microemulsion-based gel composition comprising an anti-irritant complex

[0186] Transparent gel compositions were prepared by combining azelaic acid at about 15 - 20% by weight, Acetamide MEA at about 25 - 35% by weight, propylene glycol at about 10-20% by weight, at least one non-ionic surfactant (e.g., polysorbate 80 and / or polysorbate 20) at about 10 - 20% by weight in total, an organic ester internal phase at about 2 - 8% by weight, a cellulose-based polymer (hydroxypropylcellulose) at about 0.3 - 1.5% by weight, and an inorganic structuring agent (fumed silica or silica dimethyl silylate) at about 2 - 6% by weight. An aqueous electrolyte phase at about 5 -15% by weight was added, containing a strontium salt (strontium chloride hexahydrate) at about 1 - 4% by weight and / or dimethyl sulfone (MSM) at about 1 - 4% by weight.Optional preservatives, fragrances, and other excipients were also included in sufficient amounts to complete the formulation to 100% by weight.

[0187] The organic ester internal phase was selected from dimethyl adipate, isopropyl isostearate, ethylhexyl isostearate, isopropyl palmitate, or caprylic / capric triglyceride, which provided a gradient of polarity within the oil phase that supported solubilization of azelaic acid and optional co-actives while maintaining a light, non-greasy sensory profile.

[0188] A gel composition was prepared by first forming a solvent system comprising Acetamide MEA and the aliphatic polyol, into which the cellulose-based polymer, acting as a first rheology modified, was dispersed under moderate agitation until a substantially clear, structured liquid was obtained. The mixture was then heated to a temperature sufficient to dissolve azelaic acid completely, e.g., to about 70 - 90°C, and azelaic acid was added portion-wise while stirring until it was completely dissolved and a clear isotropic solution was formed.

[0189] In a separate vessel, the non-ionic surfactant system and the selected organic ester internal phase were combined and optionally warmed to facilitate mixing. This surfactant / ester mixture was then incorporated into the azelaic acid / Acetamide MEA solvent system under agitation to form a pre-microemulsion base.

[0190] An aqueous electrolyte phase was prepared by dissolving the strontium salt and / or MSM in purified water at a temperature sufficient to ensure complete dissolution. The aqueous phase was then gradually introduced into the pre-microemulsion base under continuous stirring while maintaining optical clarity and an isotropic appearance of the system. After formation of microemulsion, the structuring agent fumed silica was slowly added under increased shear until a homogeneous gel structure exhibiting the desired yield value was obtained. The resulting composition was then allowed to cool to approximately ambient temperature under gentle mixing.

[0191] The pH of the resulting gel was adjusted, if needed, to about 4.5-4.8 using a suitable acid, for example, lactic acid or gluconic acid. Optional preservatives, fragrances, or additional active ingredients were incorporated at this stage. The finished composition was de-aerated under reduced pressure and filled into suitable containers.The resulting gel formulations were optically clear or substantially transparent, exhibited a viscosity of about 8,000-25,000 cP at 25°C under low shear, and remained substantially free of visible azelaic acid crystals following storage under ambient or accelerated stability conditions.

[0192] EXAMPLE 8

[0193] Preparation of depigmentation formulation with octadecenedioic acid Octadecenedioic acid modulates melanogenesis through complementary pathways. Depigmenting formulations comprising octadecenedioic acid and azelaic acid were prepared by solubilizing azelaic acid at about 12-18% by weight and octadecenedioic acid at about 0.5-2.0% by weight in a solvent system comprising Acetamide MEA at about 28-38% by weight and propylene glycol, at about 15-25% by weight. The composition further comprised a non-ionic surfactant (polysorbate 80), at about 8-15% by weight, an organic ester internal phase (dimethyl adipate), at about 2-6% by weight, a cellulose-based polymer at about 0.5-1.5% by weight, and an inorganic structuring agent (fumed silica) at about 2-5% by weight. An aqueous phase was present at about 5-12% by weight, optionally comprising water-soluble components. Optional additives included, for example, hydrating agents (e.g., sodium hyaluronate at about 0.1-1.0% by weight), antioxidants (e.g., tocopheryl acetate at about 0.3-0.8% by weight), a preservative system and other excipients in amounts sufficient to complete the composition to 100% by weight.

[0194] A composition was prepared by first forming an anhydrous solvent system comprising Acetamide MEA and the selected polyol, into which the cellulose-based polymer was dispersed under agitation until a clear solution was obtained. The solvent base was then heated to a temperature that provided complete solubilization of azelaic acid and octadecenedioic acid, e.g., about 70-90°C, and azelaic acid together with octadecenedioic acid were added portion-wise under continued stirring until both active components were completely dissolved, forming a clear and substantially molecularly dispersed solution. The surfactant and the organic ester phase were then incorporated under mixing to form a pre-microemulsion base. An aqueous phase, optionally containing water-soluble active ingredients, was then added gradually under continuous agitation while maintaining optical clarity of the system.The inorganic structuring agent fumed silica was subsequently introduced under increased shear to form a homogeneous gel structure having the desired consistency. The composition was then cooled to approximately ambient temperature, and the pH was adjusted to about 4.5-4.8 using lactic acid or gluconic acid. Optional hydrating agents, antioxidants, and preservatives were incorporated at this stage. The composition was de-aerated under reduced pressure and filled into suitable containers.

[0195] The resulting formulations were obtained as a transparent to slightly translucent gel having a pH of about 4.5-4.7 and a viscosity of about 12,000-20,000 cP at 25 °C. Both azelaic acid and octadecenedioic acid remained stable within the composition, exhibiting greater than about 95% retention after storage for about 12 months at 25°C, with no observable precipitation or phase separation.

[0196] Such compositions provide a stable, standalone vehicle for the combined delivery of multiple depigmenting agents, including dicarboxylic acids, having complementary mechanisms of action relevant to the modulation of skin pigmentation.

[0197] EXAM PE 9

[0198] Preparation of anhydrous compositions comprising azelaic acid and retinoid actives Anhydrous gel compositions suitable for anti-aging and anti-acne applications were prepared, comprising azelaic acid at about 10-15% by weight, hydroxypinacolone retinoate at about 0.5-2.0% by weight, salicylic acid at about 1.0-2.5% by weight, Acetamide MEA at about 35-45% by weight, and a C3-C6 aliphatic polyol, e.g., propylene glycol, at about 18-28% by weight. The composition further comprised a cellulose-based polymer at about 0.8-1.5% by weight and an inorganic structuring agent such as fumed silica at about 3-6% by weight to form a structured anhydrous gel. Additional components were optionally included such as a soothing agent, for example, bisabolol at about 0.2-0.5% by weight, one or more lipophilic antioxidants (e.g., tocopherol and / or butylated hydroxytoluene) at about 0.5-1.2% by weight in total, and optional fragrance at about 0.05-0.2% by weight.

[0199] A composition was prepared by combining Acetamide MEA with the selected polyol in a suitable anhydrous mixing vessel, followed by dispersion of the cellulose-based polymer underagitation until a clear, structured liquid was obtained. The Acetamide MEA solvent system was then heated to about 70-85°C and azelaic acid together with salicylic acid were added portionwise under continuous stirring until complete dissolution was achieved and a substantially molecularly dispersed solution was formed. The mixture was subsequently cooled to below about 40-45°C in order to preserve the stability of temperature-sensitive components, after which hydroxypinacolone retinoate, bisabolol, and the lipophilic antioxidants were incorporated with gentle mixing until uniformly distributed.

[0200] Fumed silica was then gradually introduced under increased agitation to form a homogeneous anhydrous gel having the desired consistency. The composition was further cooled to ambient temperature under continued gentle mixing. The pH of the composition was in the range of 4.3-4.6 due to the presence of acidic active ingredients and did not require further adjustment. Optional fragrances were optionally incorporated at this stage. The composition was de-aerated under reduced pressure and filled into suitable packaging, for example airless or opaque containers, to limit exposure of the retinoid component to light and oxygen.

[0201] Resulting formulations were obtained as a crystal clear to pale yellow gel exhibiting a viscosity of about 20,000-30,000 cP at 25°C and a water content of less than about 1% by weight, as determined by Karl Fischer titration. Hydroxypinacolone retinoate remained stable within the anhydrous matrix, exhibiting greater than about 90% retention after storage for up to about 24 months, consistent with reduced hydrolytic degradation in the absence of water. Incorporation of the retinoid at temperatures below about 40-45°C, together with maintenance of a mildly acidic environment of about pH 4.5, supported the retinoid chemical stability within the formulation. The anhydrous nature of the formulation reduces hydrolytic degradation therefore reducing or eliminating the need for preservatives.

[0202] EXAMPL 10

[0203] Compatibility with Packaging Materials

[0204] The stability of the compositions and formulation prepared in accordance with the present disclosure was tested in various containers and packaging configurations, commonly used inpharmaceutical and cosmetic applications. The compositions / formulations were kept in the tested packages for at least 12 months at 25°C. The results are summarized in Table 4.

[0205] High-density polyethylene (HDPE) tubes are flexible, chemically resistant plastic containers that provide good barrier properties against moisture and are widely used for semi-solid formulations such as gels and creams.

[0206] Lined aluminum tubes comprise a collapsible metal body with a protective lining (e.g., epoxy or polymer coating) that prevents direct contact between the formulation and the metal, thereby offering excellent barrier protection against light, oxygen, and moisture.

[0207] Polyethylene terephthalate (PET) bottles with polypropylene (PP) pumps are rigid containers equipped with dispensing mechanisms that allow controlled delivery of liquid or semiliquid formulations while minimizing contamination during use.

[0208] Airless pump systems (typically constructed from PP and / or polyethylene (PE)) are designed to limit exposure of the formulation to air by using a vacuum or piston mechanism, thereby reducing oxidation and improving stability, particularly for oxygen-sensitive ingredients.

[0209] Glass jars with metal lids provide an inert and impermeable containers that offer high chemical resistance and premium aesthetic appeal, although they may allow some interaction at the closure interface (e.g., gasket materials).

[0210] Polypropylene jars are lightweight, durable containers with good chemical resistance and compatibility with a wide range of formulations, commonly used for creams and gels requiring wide-mouth access.

[0211] Table 4. Packaging stability assessment results

[0212]

[0213]

[0214] Almost all containers provided excellent stability in terms of interaction with the packaging material, viscosity, discoloration and / or oxidation. No leaching, swelling, or compatibility issues were observed with these standard cosmetic packaging materials. Airless pump systems are recommended for formulations containing oxygen-sensitive ingredients (retinoids, ascorbic acid derivatives).

Claims

WHAT IS CLAIMED IS:

1. A solvent system comprising Acetamide MEA and, optionally, at least one aliphatic polyol, capable of solubilizing azelaic acid.

2. The solvent system of claim 1, capable of maintaining the azelaic acid in a substantially molecularly dispersed and non-crystalline state.

3. A composition comprising azelaic acid, Acetamide MEA and, optionally, one aliphatic polyol, wherein Acetamide MEA is a primary solubilizing agent for azelaic acid.

4. The solvent system of claim 1 or 2, or the composition of claim 3, wherein azelaic acid is substantially solubilized and / or molecularly dispersed and in non-crystalline state, for a period of at least 6 months at room temperature.

5. The solvent system or the composition of claim 4, wherein the weight ratio of Acetamide MEA to azelaic acid is between 1:1 and 5:1, optionally, between 2:1 and 4:1.

6. The solvent system or the composition of any one of claims 1 to 5, wherein the concentration of azelaic acid is from about 1% to about 25% by weight.

7. The solvent system or the composition of any one of claims 1 to 6, wherein the concentration of Acetamide MEA is from about 15% to about 50% by weight.

8. The solvent system or the composition of any one of claims 1 to 7, wherein the aliphatic polyol is a C3-C6 aliphatic polyol selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol, and hexylene glycol, optionally at a concentration of from about 5% to about 30% by weight.

9. A submicron emulsion comprising azelaic acid solubilized in Acetamide MEA and, optionally, at least one aliphatic polyol.

10. The submicron emulsion of claim 9, comprising a microemulsion or a nanoemulsion, optionally comprising at least one rheology modifying agent and / or at least one particulate structuring agent.

11. A gel composition comprising azelaic acid, Acetamide MEA, at least one rheology modifying agent and / or at least one particulate structuring agent, wherein the azelaic acid is solubilized in the composition.

12. The submicron emulsion or gel composition of any one of claims 9 to 11, wherein: (i) the at least rheology modifying agent is a cellulose-based polymer, optionally selected from hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC) or hydroxypropyl methylcellulose (HPMC), optionally at a concentration from about 0.1% to about 2% by weight; and(ii) the at least one particulate structuring agent comprises a silica-derived matrix, optionally, fumed silica, optionally at a concentration from about 1% to about 9% by weight, optionally from about 2% to about 8% by weight.

13. A topical formulation comprising azelaic acid solubilized in Acetamide MEA as the primary solvent, and a dermatologically acceptable carrier.

14. The submicron emulsion, the gel composition or topical formulation of any one of claims 9 to 13, characterized by at least one of:(i) the azelaic acid is in a substantially molecularly dispersed and non-crystalline state; (ii) the azelaic acid is substantially solubilized and / or molecularly dispersed and in noncrystalline state, for a period of at least 6 months at room temperature;(iii) the Acetamide MEA is a primary solubilizing agent for azelaic acid;(iv) the weight ratio of Acetamide MEA to azelaic acid is between 1:1 and 5:1, optionally, between 2:1 and 4:1;(v) the concentration of azelaic acid is from about 1% to about 25% by weight, optionally from about 10% to about 20% by weight;(vi) the concentration of Acetamide MEA is from about 15% to about 50% by weight, optionally from about 25% to about 45% by weight;(vii) the aliphatic polyol is a C3-C6 aliphatic polyol selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol, and hexylene glycol, optionally at a concentration of from about 5% to about 30% by weight;(viii) being transparent; and(ix) having a pH of 4.0 to 5.5, optionally, 4.5 to 4.8.

15. The composition, solvent system, submicron emulsion, gel composition or topical formulation of any one of claims 1 to 14, further comprising at least one strontium salt and / or dimethyl sulfone (MSM), optionally, wherein the strontium salt is selected from the group consisting of strontium chloride hexahydrate, strontium nitrate and strontium acetate.

16. The composition, solvent system, submicron emulsion, gel composition or topical formulation of claim 15, wherein the concentration of the strontium salt and / or MSM, each independently, is from about 0.5% to 5% by weight.

17. The submicron emulsion, gel composition or topical formulation of any one of claims 9 to 16, comprising one or more active agents that provide exfoliating, keratolytic, depigmenting, antioxidant, skin barrier-supporting, hydrating, anti-aging and / or penetration-enhancing effects, and / or one or more active agents for treating a dermatological disease, disorder, or condition, optionally selected from acne, rosacea, hyperpigmentation disorders, and related inflammatory skin conditions.

18. The submicron emulsion, gel composition or topical formulation of claim 17, wherein the one or more active agents are selected from alpha-hydroxy acids, beta-hydroxy acids, antioxidants, retinoids, peptide-based active agents, plant-derived extracts, natural compounds, or vitamins.

19. A method for treating, preventing, ameliorating, mitigating, and / or relieving a skin disease, disorder, or condition that may benefit from topical application of azelaic acid, comprising administering to a subject in need thereof a therapeutically or cosmetically effective amount of a composition or formulation comprising azelaic acid solubilized, optionally in a substantially molecularly dispersed state, in Acetamide MEA as a primary solvent.

20. The method of claim 19, wherein the composition or formulation are selected from the composition, solvent system, submicron emulsion, gel composition or topical formulation according to any one of claims 1 to 18.

21. The method of claim 19 or 20, wherein the disease, disorder or condition is selected from acne, rosacea, hyperpigmentation disorders, and related inflammatory skin conditions.

22. A method for providing a solution of azelaic acid wherein azelaic acid is stably maintained in a substantially molecularly dispersed and non-crystalline state, comprising solubilizing azelaic acid in a solvent system comprising Acetamide MEA and, optionally, at least one polyol.

23. The method of claim 22, wherein azelaic acid is maintained in a substantially molecularly dispersed and non-crystalline state for a period of at least 6 months at room temperature.

24. The method of claim 22 or 23, wherein azelaic acid and / or the solvent system is as defined in any one of claims 5 to 8.

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